Electrochemical oxidation of berberine and mass spectrometric identification of its oxidation products.
Electrochemical oxidation of the isoquinoline alkaloid berberine in aqueous medium was studied by cyclic and differential pulse voltammetry at a glassy carbon electrode (GCE). Two anodic peaks of the quaternary form of berberine were observed at +1.2V and +1.4V (vs. SCE) in acidic and neutral solutions. When the anodic polarization exceeded the value of +1.1 V, the redox active film is formed on the GCE surface. The formation of adsorbed film was well-documented by quasireversible redox couple at +0.25 V which was studied in redox cycling experiments. In alkaline medium, a new anodic peak at +0.5 V appeared due to oxidation of berberine pseudobase to 8-oxoberberine. Solutions of berberine at different pH were subjected to controlled potential electrolysis on platinum gauze electrode and analyzed using liquid chromatography (HPLC) equipped with electrospray ionization/quadrupole time-of-flight mass spectrometry. The main water soluble monomeric product of berberine oxidation under physiological-near experimental conditions, OP1, was identified as demethyleneberberine cation (2,3-dihydroxy-9,10-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium).


Inhibition of Plasmodium falciparum proliferation in vitro by double-stranded RNA nanoparticle against malaria topoisomerase II.
The need to develop new effective antimalarial agents is urgent due to the rapid emergence of drug resistance to all current drugs by the most virulent human malaria parasite, Plasmodium falciparum. A promising avenue is in the development of antimalarials based on RNA interference targeting expression of malaria parasite vital genes, viz. DNA topoisomerase II gene (PfTOP2). Biodegradable chitosan nanoparticle system has proven to be effective in delivering DNA and small double-stranded interfering RNA to target cells. We have employed a long double-stranded (dsRNA) targeting the coding region of PfTOP2 that is complexed with chitosan nanoparticles in order to interfere with the cognate mRNA expression and examined its effect on P. falciparum growth in culture. Exposure of ring stage-infected erythrocytes to 10 μg/ml PfTOP2 chitosan/dsRNA nanoparticles for 48 h resulted in 71% growth inhibition as determined by [(3)H] hypoxanthine incorporation and microscopic assays, compared with 41% inhibition using an equivalent amount of free PfTOP2 dsRNA or 12% with unrelated chitosan/dsRNA nanoparticles. This inhibition was shown to occur during maturation of trophozoite to schizont stages. RT-PCR analysis indicated 56% and 38% decrease in PfTOP2 transcript levels in P. falciparum trophozoites treated with PfTOP2 dsRNA nanoparticles and free PfTOP2 dsRNA respectively. These results suggest that chitosan-based nanoparticles might be a useful tool for delivering dsRNA into malaria parasites.


Cell-free translation of adenovirus 2 E1a- and E1b-specific mRNAs and evidence that E1a-related polypeptides are produced from E1a-E1b overlapping mRNA.
We have characterized the polypeptides translated in vitro by mRNAs of early region 1 (E1) of human adenovirus (Ad) type 2. Poly (A+) polyribosomal RNA was isolated from early Ad2-infected cells, the viral specific mRNAs were selected by hybridization to Ad2 E1a and E1b DNA, and the mRNAs were translated in vitro using [35S]methionine as a labeled precursor with a rabbit reticulocyte lysate. E1a-selected mRNA was translated to the 45-58-kDa cluster of polypeptides. We show here that E1b-selected mRNA can also be translated to the 45-58-kDa cluster of polypeptides in addition to the major 19-kDa polypeptide. The E1b 58-kDa polypeptide was produced only at a low level unless E1b mRNA is fractionated before translation to enrich for the 58-kDa mRNA. Translation of E1b region-selected mRNAs that have been fractionated by size shows that the 22 S mRNA fraction is translated to at least the 53-58-kDa E1a-related polypeptides as well as to E1b 58- and 19-kDa polypeptides. Our experiments suggest that the 22 S mRNA fraction includes E1a-E1b overlapping mRNA which was translated to E1a-related polypeptides as well as E1b 22 S mRNA. When compared by two-dimensional gel electrophoresis and by tryptic peptide mapping, the cluster of polypeptides translated from E1a-selected mRNA and the cluster translated from E1b-selected mRNA were distinguishable. A possible explanation for this is discussed, based upon splicing sites of the E1a-E1b overlapping mRNA which would result in an amino acid sequence with a COOH-terminal end slightly different from that of E1a polypeptides.


Absence of change of signal-averaged electrocardiogram identifies patients with ventricular arrhythmias who are non-responders to amiodarone.
The aim of this study was to assess the ability of a non-invasive study, the signal-averaged ECG (SAECG), to predict the effect of amiodarone at ventricular level. Amiodarone is the main drug drug used in the treatment of ventricular arrhythmias. Standard ECG does not detect any change in QRS complex resulting from amiodarone therapy. SAECG is more sensitive than ECG for detecting changes in QRS complex. The study examined the effects of amiodarone on SAECG in relation to the results of programmed ventricular stimulation in 68 patients with old myocardial infarction, spontaneous and inducible sustained ventricular tachycardia (VT). Amiodarone prolonged the total QRS duration (dur) (129+/-28 vs. 140+/-30 ms, P<0.05) and low amplitude signal (LAS) dur (45+/-20 vs. 51+/-20 ms, P<0.1), whereas the root-mean-square voltage of the last 40 ms of QRS complex (RMS 40) was significantly reduced (20+/-16 vs. 14+/-9 microV, P<0.05). Changes in SAECG parameters did not differ significantly in patients in whom amiodarone prevented the inducibility of VT (n=15) and those in whom VT remained inducible with amiodarone (n=53), but in baseline QRS duration was significantly shorter in patients in whom amiodarone prevented the VT induction (118+/-26 vs. 133+/-28 ms, P<0.05). In patients in whom amiodarone did not prolong the cycle length of VT (n=15), SAECG did not change significantly (QRS dur 131+/-29 vs. 132+/-27 ms, LAS 42+/-20 vs. 42+/-19 ms, RMS 40 22+/-14 vs. 19+/-11 microV). Comparison of the SAECG data in patients with no inducible VT and those with slowed VT differed significantly (P<0.05) between the control state and the recording with amiodarone. The effects of amiodarone on VT inducibility are predicted by a shorter baseline QRS duration and the degree of drug-induced prolongation of filtered QRS duration. Amiodarone prolonged the QRS duration, LAS duration and decreased RMS 40; this effect was more important in patients with no inducible VT and in those with only slowed VT, than in patients with unchanged or accelerated VT. The absence of changes of QRS duration predicted the induction of a more rapid or not slowed VT with amiodarone with a sensitivity of 87% and a specificity of 83%. Therefore, SAECG appears as an useful and simple means to predict the effects of amiodarone in patients with myocardial infarction and VT.


In Practice CPD 2017 programme.
Zoe Davies describes what the BVA In Practice CPD programme has in store for the coming year.


Phonemic mismatch negativity mediates the association between phoneme awareness and character reading ability in young Chinese children.
Poor phonological awareness is associated with greater risk for reading disability. The underlying neural mechanism of such association may lie in the brain processing of phonological information. Lower amplitude of auditory mismatch negativity (MMN) has been associated with poor phonological awareness and with the presence of reading disability. The current study recorded auditory MMN to phoneme and lexical tone contrast with odd-ball paradigm and examined whether auditory MMN mediated the associations between phonological awareness and character reading ability through a three-year longitudinal study in 78 native Mandarin-speaking kindergarten children. Hierarchical linear regression and mediation analyses showed that the effect of phoneme awareness on the character reading ability was mediated by the phonemic MMN in young Chinese children. Findings underscore the key role of phonemic MMN as the underlying neurodevelopmental mechanism linking phoneme awareness and reading ability.


Mitochondrial malic enzyme in human leukocytes.
Leukocyte samples from 316 unrelated blood donors were screened for malic enzyme (MEM). The frequency of the common allele in this investigation was MEM1 = 0.63. There is evidence for the existence of a rare fourth allele MEM4.


Effect of Food on the Multiple-Peak Behavior After a Single Oral Dose of Diclofenac Sodium Slow-Release Tablet in Humans.
This study evaluated the effect of a standard meal on the multiple-peak behavior of diclofenac sodium following oral administration of a 100-mg slow-release (SR) wax-matrix tablet. The study was a randomized, 3 × 3 Latin-square trial balanced for residual effects, in which 18 subjects were randomly assigned to treatment sequences consisting of three treatments: (A) one 100-mg SR tablet, fasted; (B) one 100-mg SR tablet, fed; and (C) 100-mg diclofenac sodium buffered aqueous solution, fasted. Blood samples were obtained over a 24-h period for Treatments A and B, and over an 8-h period for Treatment C. Food did not significantly affect the extent of absorption but generally delayed the onset of absorption from the SR tablet. The plasma concentration-time profile for the SR tablet under fasted conditions was characterized by multiple-peak behavior. Under fed conditions, the SR tablet showed a more consistent absorption pattern, with a single peak occurring usually between 5 and 6 h. The concentration-time profile of the buffered aqueous solution showed a very rapid absorption phase followed by a rapid decline and a terminal elimination half-life of approximately 1.8 h. A single peak was observed following the buffered aqueous solution. This observation, in conjunction with evidence from other studies, leads to the conclusion that gastrointestinal pH may be responsible for the multiple-peak behavior observed following diclofenac sodium dosing. As compared to the solution, the was-matrix tablet under both fasted and fed conditions showed slow-release, characteristics.


Comparative thermometric coagulation studies of plasmas from normal outbred Swiss Webster mice and persons.
The functional capabilities of a thermometric clot-timer have been demonstrated in a comparative study of human and mouse plasma coagulation. The influence of some variables on coagulation times of mouse and human plasmas were examined in activated partial thromboplastin time, one-stage prothrombin time, and Russell's viper venom time assays. Mouse plasma coagulation times were generally shorter and more reproducible than those of human plasma. Optimal assay conditions are also described.


A new truncating MPZ mutation associated with a very mild CMT1 B phenotype.
We have investigated a 34-year-old female who had mild clinical and electrophysiological features of demyelinating peripheral neuropathy. She presented a novel frameshift mutation (V160fsX3) in the exon 4 of the Myelin Protein Zero (MPZ) gene. Clinical and genetic studies performed on her family revealed the same mutation in her oligosymptomatic mother and sister. Our report expands the number of MPZ mutations and indicates that mutations in exon 4 may cause a mild Charcot-Marie-Tooth type 1B phenotype.


Modeling mortality fluctuations in Los Angeles as functions of pollution and weather effects.
Linear and nonlinear models are used to investigate possible associations between mortality and pollution and weather effects in Los Angeles County. State-space modeling and time and frequency domain regressions are used to modify the data base and to isolate significant weather factors and pollutants associated with increased daily mortality. Nonparametric and parametric regression methods are used to develop nonlinear dose-response profiles relating mortality to temperature and to the statistically significant pollutants. A parametric nonlinear time series model involving linear and squared terms in temperature and the logarithm of pollution provides a reasonable predictive model.


Estrogens protect myocardium against ischemia/reperfusion insult by up-regulation of CRH receptor type 2 in female rats.
The mechanism underlying estrogen cardioprotection remains largely unknown. Urocortin (UCN), a member of corticotropin-releasing hormone (CRH) family, is one of endogenous cardioprotective factors. The goal of present study is to investigate whether estrogens regulate UCN and its receptor CRH receptor type 2 (CRHR2) in female rat heart. 17β-estradiol (E2) was subcutaneously administrated to ovariectomized (OVX) rats for eight weeks. UCN was administrated before simulated myocardial ischemia/reperfusion (I/R). Cell damage was assessed by measurement of infarct size, activity of serum creatine kinase (CK) and lactate dehydrogenase (LDH) and percentage of TUNEL staining in myocardium. The mRNA and protein levels of UCN and CRHR2 were determined in sham operated and OVX rats with or without E2 replacement. DNA methylation frequency of CRHR2 gene promoter was determined by bisulfite-sequencing. UCN administration reduced infarct size, LDH and CK level and percentage of TUNEL staining upon I/R injury. The cardioprotective effects of UCN were abrogated in OVX rats and E2 replacement restored UCN-induced cardioprotection.CRHR2 mRNA and protein expression were down-regulated more than 40% in OVX rats, both of which were restored by E2 replacement. UCN mRNA and protein levels were not affected by ovariectomy and E2 replacement. Hypermethylation in CRHR2 promoter was found in OVX rats, and two of the methylated CpG sites were seated at cis-acting elements. Hypermethylation induced by OVX could also be ameliorated by E2 replacement. Estrogens maintain CRHR2 expression in myocardium, which may through an epigenetic mechanism, and enhance UCN-induced cardioprotective effects against I/R injury.


Real-world treatment patterns and clinical outcomes in advanced cutaneous melanoma patients in France.
Since 2011, the management of advanced melanoma has radically changed with the availability of new therapies (immunotherapy and BRAF-targeted therapy) and with BRAF testing. Following the introduction of these new therapies, the objectives of this AMEL study were to describe treatment patterns and evaluate overall survival (OS) among unresectable stage III/IV melanoma patients, in a real-life setting in France. The AMEL study is a multicentre retrospective record review study. Thirty-three physicians working in 33 unique treatment centres participated in the study. Two hundred and sixty-four patients diagnosed between 1 January 2012 and 31 October 2012 with unresectable stage III/IV melanoma were included in the study. 94.7% of the patients received a first-line antitumour drug treatment, 62.5% a second-line treatment while 26.9% received a third-line treatment with no significant differences between patients with a BRAF mutation (50.4%) and BRAF wild type (47.0%). First-line treatment differs according to the BRAF status: 74.8% of patients with a BRAF mutation received a BRAF inhibitor while 79.3% of the BRAF wild-type patients were treated with conventional chemotherapy. In second line and over, the treatment patterns were more heterogeneous, depending on the BRAF mutation, the treatment received previously, the speed of progression of the disease and the availability of immunotherapy at the time the treatment was initiated. Regardless of the BRAF mutation status, the median OS of patients was 16 months (95% CI = 14-18). Compared to a similar study conducted in 2007 (MELODY), a gain of 4 months is observed. The gain seems to be higher for patients with a BRAF mutation (18 months) than for those without a BRAF mutation (14 months). The OS of patients who sequentially received both a BRAF inhibitor and ipilimumab (28 months) highlights the benefit of this treatment sequence.


[Does recommending the dosing frequency in the electronic prescription improve its adequacy? Before and after study].
To assess whether reporting the dosing frequency into the prescription module of the Institut Català de la Salut (ICS) primary care electronic clinical workstation improves the dosing frequency's adequacy of the prescriptions. Before and after study with non-equivalent control of prescriptions without any change in the dosing frequency. The study periods includes from September 1st, 2019 to February 29th, 2020. Primary care setting. Prescriptions issued by ICS General Practitioner, during the study period of those medicines which indications have a single appropriate dosing frequency or mostly appropriate, are included. Recommendation of the appropriate dosing frequency in the prescription module. Adequacy defined as the coincidence between the prescribed dosing frequency and the appropriate dosing frequency. After the intervention there was a 22.75% increase in prescriptions with adequate dosing frequency. The largest increase occurred in the medicines for the genitourinary system and sex hormones. In absolute terms, the group of anti infective for systemic use is the one that obtained more prescriptions with an adequate dosing frequency between the two periods. The intervention increased the dosing frequency's adequacy leading to improvements in the safety and effectiveness of the treatments. It is evident that the design and implementation of improvements in electronic prescription systems contributes to increasing the quality of the prescription.


A steady state redox zone approach for modeling the transport and degradation of xenobiotic organic compounds from a landfill site.
A redox zonation approach is used as a framework for obtaining biodegradation rate constants of xenobiotic compounds in a landfill plume (Grindsted, Denmark). The aquifer is physically heterogeneous in terms of a complex zonation of different geological units close to the landfill and biogeochemically heterogeneous in terms of a specified redox zonation. First-order degradation rates of six organic compounds (benzene, toluene, ethylbenzene, o-xylene, m/p-xylene, and naphthalene) were calculated in the methanogenic/sulfate- and Fe-reducing zones. The numerical simulations show that all compounds are anaerobically biodegraded, but at very different rates. High rates of biodegradation of most of the compounds (except benzene) were found in the Fe-reducing zone. These rates generally agree with previously published rates. Only o-xylene and toluene were significantly biodegraded in the methanogenic/sulfate-reducing environment. All rates in this redox zone are generally much lower than previously published rates.


Smoothened antagonist sonidegib affects the development of D. melanogaster larvae via suppression of epidermis formation.
Hedgehog (Hh) signaling is essential for the regulation of embryonic growth and development, the maintenance of stem cell autostasis, and tissue formation, whether in vertebrates or invertebrates. However, exploration into the Hh pathway antagonists in Drosophila or other pests of agricultural importance has been scant. In order to gain a better understanding of the potential utility of the antagonists in insect investigations, a conventional Hh antagonist, sonidegib, was used to evaluate the effects on the development of Drosophila larvae. The results showed that early instar larvae exposed to sonidegib exhibited new epidermal abnormalities and decreased motility after molting. Transcriptome analysis revealed that Sonidegib had a profound effect on chitin-based cuticle development throughout all stages of larvae. Physiological experiments revealed that sonidegib suppressed the epidermis formation and decreased the chitin content. The results of this study shed new light on the potential use of Hh antagonists in agricultural pest management.


A polycarbonate ophthalmic-prescription lens series.
Improvements in polycarbonate material, production techniques, and scratch-resistant coatings, combined with a process-oriented design, have resulted in a precision lens series. Surface quality is comparable to that of untreated glass ophthalmic lenses. The repeatability of the process results in closely controlled axial power and off-axis performance. For most lens prescriptions, the ANSI Z80.1 optical-center specifications for prescription accuracy are maintained through a total field of view of 40 deg for an 8-mm range of center-of-rotation distances. Off-axis astigmatism is controlled for near-point seeing. The lenses are both lighter and thinner than those of crown glass. A scratch-resistant coating reduces the reflections normally associated with high-index (1.586) materials. Impact resistance exceeds that required by ANSI Z80.7 and is many times that required by ANSI Z80.1.


Systematic source estimation of spikes by a combination of independent component analysis and RAP-MUSIC. I: Principles and simulation study.
We propose a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) as a new approach to dipole source estimation of epileptiform discharges. The method is minimally dependent on subjective decisions. Ten electroencephalographic (EEG) data matrices were generated by computer, each matrix including real background activity from a normal subject and an array of added simulated spikes. Each spike was a summation of two transients originating from slightly different 'original dipole sources'. The unaveraged EEG matrices were decomposed by ICA, and source estimation was performed by applying RAP-MUSIC to the spatial information defined by the ICA components showing epileptiform activity in their waveform. For comparison, dipoles were also estimated from the same matrices using two existing methods: RAP-MUSIC based on eigen-decomposition of the covariance matrices of averaged spikes and common spatial pattern decomposition. In every simulated EEG data matrix, two dipoles close to the original sources were estimated by the present method. Their unaveraged activities were also similar to those of the original sources. The two existing methods gave less precise results than the proposed method. RAP-MUSIC based on ICA thus proved promising for source estimation of unaveraged epileptiform discharges.


Effect of high-frequency positive-pressure ventilation on halothane ablation of hypoxic pulmonary vasoconstriction.
High-frequency positive-pressure ventilation (HFPPV) was compared to intermittent positive-pressure ventilation (IPPV) during unilateral atelectasis with and without halothane anesthesia. Dogs with electromagnetic flow probes chronically implanted on their main (Qt) and left (Ql) pulmonary arteries were ventilated via Carlen's dual-lumen endotracheal tubes. In eight closed-chest dogs, about 43% of the cardiac output perfused the left lung during bilateral ventilation by either a Harvard animal respirator (IPPV) or a Health-dyne model 300 high-frequency ventilator (HFPPV). Unilateral atelectasis decreased blood flow (Ql/Qt) to that lung. Ql/Qt was 19 +/- 1% with HFPPV during left-lung atelectasis and right-lung ventilation, compared to 32 +/- 1% with unilateral IPPV. This suggests that HFPPV permits stronger hypoxic pulmonary vasoconstriction. Addition of 1% halothane increased blood flow to the atelectatic left lung during unilateral ventilation with IPPV but not with HFPPV. This suggests that halothane decreases the effects of hypoxic pulmonary vasoconstriction during conventional ventilation but not during HFPPV.


Toxicity profile of chemotherapy agents used in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies.
Morbidity associated with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is due to the synergistic effect of cytoreduction, effect hyperthermia and the cytotoxic agents used for HIPEC. This study was done to analyse the postoperative morbidity in relation to the chemotherapy agent used in patients undergoing CRS-HIPEC for peritoneal surface malignancy (PSM) in Indian set up. Patient with PSM, underwent CRS-HIPEC as per the institutional protocol. Patients were stratified as per the chemotherapy drug used during HIPEC & perioperative outcome were documented. 163 patients underwent CRS-HIPEC for PSM: 67.4% were of ovarian primary. Others were colorectal, appendicular, gastric primary and rare tumors.Cisplatin was the most common drug used: as alone (57.05%) or in combination with Adriamycin (12.88%). Mitomycin-C (MMC) was used in 20% and oxaliplatin in 10%.Grade 3-5 morbidity in the whole cohort was 44.8% and grade 1-2 was 74%.Grade 1-2 electrolyte abnormality was the most common morbidity overall and grade 3-4 hematological toxicity was the most common severe morbidity. Frequency of grade 3-5 morbidity were 38.7%, 48.5%,50% and 61.9% for Cisplatin alone, MMC, oxaliplatin and Adriamycin + cisplatin respectively. None of the patients had grade 3-4 nephrotoxicity as sole complication. All major complications were highest in the group who received Adriamycin. Cisplatin was associated with higher rate of electrolyte imbalance, oxaliplatin with post-operative bleeding. Rates of other complications did not differ significantly. Cisplatin followed by MMC were the well tolerated drugs during HIPEC and tolerance to Adriamycin combination regimen in Indian patients was poor.


Incidence of and risk factors for sexual orientation-related physical assault among young men who have sex with men.
We sought to determine incidence of, prevalence of, and risk factors for sexual orientation-related physical assault in young men who have sex with men (MSM). We completed a prospective open cohort study of young MSM in Vancouver, British Columbia, surveyed annually between 1995 and 2004. Correlates of sexual orientation-related physical assault before enrollment were identified with logistic regression. Risk factors for incident assaults were determined with Cox regression. At enrollment, 84 (16%) of 521 MSM reported ever experiencing assault related to actual or perceived sexual orientation. Incidence was 2.3 per 100 person-years; cumulative incidence at 6-year follow-up was 10.8 per 100 person-years. Increased risk of incident sexual orientation-related physical assault was observed among MSM 23 years or younger (relative hazard=3.1; 95% confidence interval [CI] = 1.6, 5.8), Canadian Aboriginal people (relative hazard = 3.0; 95% CI=1.4, 6.2), and those who previously experienced such assault (relative hazard=2.5; 95% CI=1.3, 4.8). These data underscore the need for increased public awareness, surveillance, and support to reduce assault against young MSM. Such efforts should be coordinated at the community level to ensure that social norms dictate that such acts are unacceptable.


The Internet--a new information medium for nurses--Part 1.
Part one of this series examined some Internet basics. Computer requirements and Internet connection options were covered, and Web addresses and search engines were reviewed. With this information in hand, you can determine if your current computer equipment is adequate or what type of computer and modern to purchase, and the type of Internet connection that will be right for you. Once online, remember to type web addresses exactly as they appear and to read the help sections of various search engines to learn how to perfect your search techniques. Part two of this series will cover practical issues of Internet use. Suggestions will be offered for dealing with e-mail file attachments, and how to avoid unsolicited e-mail and computer viruses. Techniques for reviewing and evaluating online health information will be discussed as well.


Cardiovascular safety of lumiracoxib: a meta-analysis of all randomized controlled trials > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis.
The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate. The objective of this study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of > or =1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published. For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46-1.51; versus naproxen: RR 1.49, 95% CI, 0.94-2.36; versus placebo: RR 1.08, 95% CI, 0.41-2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28-2.25; versus naproxen: RR 1.69, 95% CI, 0.82-3.48; versus placebo: RR 1.27, 95% CI, 0.25-6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35-2.35; versus naproxen: RR 1.42, 95% CI, 0.70-2.91; versus placebo: RR 0.59, 95% CI, 0.13-2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone. This meta-analysis of 34,668 patients receiving > or =1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).


Clinical Guidance for Managing Statin and Antimicrobial Drug-Drug Interactions.
This review discusses potential drug-drug interactions between statins and antimicrobials and provides clinician's guidance on how to manage these interactions. In addition to statin utilization increasing in recent years, there is greater emphasis on using moderate to high-intensity statin doses. Statin-related adverse effects are often dose-dependent; therefore, patients may be at increased risk. Antimicrobial use has also increased in recent years, and various efforts have been implemented to ensure appropriate use of antimicrobials. Commonly used antimicrobials, such as macrolide antibiotics and azole antifungals, interact significantly with the CYP3A4 enzyme pathway similarly to lovastatin, simvastatin, and atorvastatin. Consequently, the potential for significant drug-drug interactions is increasing. In 2012, the US Food and Drug Administration strengthened warning labels for statins and dose adjustments related to drug-drug interactions. As such, it is imperative that clinicians are comfortable identifying drug-drug interactions between statins and antimicrobials and making appropriate therapy modifications as clinically warranted. Statins and antimicrobials are frequently coprescribed, and the available pharmacokinetic data supports the potential for clinically significant drug-drug interactions. Macrolides and selected antifungals can significantly increase drug levels of select statins, particularly those metabolized by the CYP3A4 pathway. Contrarily, rifampin can significantly reduce drug levels of statins, limiting their efficacy. Future research efforts should identify interventions to improve clinician recognition of these drug-drug interactions and the prevention of unwarranted statin-related adverse effects.


Evidence for functional differences between the two sites of rabbit transferrin: effects of serum and carbon dioxide.
A recently developed technique combining urea gel electrophoresis with Western immunoblotting has been modified for assessing the relative ability of each iron binding site of rabbit transferrin in delivering iron to rabbit reticulocytes. The two sites can be made to release iron at the same or differing rates, depending on the experimental conditions. In Hanks' balanced salts solution in an atmosphere of room air or 5% CO2, the acid-labile site in the N-terminal lobe of the protein was found to be 1.4- and 2.9-times more effective than its acid-stable counterpart in providing iron to reticulocytes after 90 min incubation. Both sequential and simultaneous release of iron from the two sites was observed, but sequential release was initiated only from the N-terminal site. The same site also proved to be a better iron donor by a factor of 2 when incubations were conducted in Hanks' medium enriched with 20% serum in 5% CO2. Only in 20% serum in air were the two sites found to be equivalent iron suppliers to reticulocytes. In the cases studied, an atmosphere of 5% CO2 increased 2-fold the effectiveness of iron donation by the acid-labile site to reticulocytes, while the presence of 20% serum enhanced the iron-donating ability of the acid-stable C-terminal site. Thus, the transferrin-reticulocyte interaction is sensitive to environmental variables, and such sensitivity may help account for apparent discrepancies in previous studies of the relative iron-donating abilities of the two sites of transferrin.


Resistance to superinfection of Vero cells persistently infected with Junin virus.
Two non-virogenic Vero cell lines persistently infected with the arenavirus Junin (JUNV), named V3 and V7, were characterized with respect to their resistance to superinfection with homologous and antigenically related viruses. Both lines were refractory to JUNV multiplication and partially resistant to other arenaviruses. JUNV was able to adsorb and penetrate persistently infected cells and, although V3 and V7 were able to support synthesis of antigenomic sense viral RNA, protein production of superinfecting virus was totally blocked. This resistance was not mediated by defective interfering particles but rather by a "cell-associated factor" that could be cell to cell transmitted. Prolonged thermal treatment of V3 and V7 abrogated expression of the viral nucleoprotein (N) and turned persistently infected cells permissive to JUNV multiplication. Thermal treated cells cultured at 37 degrees C resumed the expression of N in association to the recovery of resistance. Results strongly suggest a correlation between the presence of the viral nucleoprotein and superinfection exclusion.


Liposome as an adjuvant for the production of estradiol antibodies.
Mice immunized with liposome associated estradiol-bovine serum albumin conjugate (E2-BSA) showed a significantly higher estradiol-specific immune response than did mice injected with the free conjugate. The conjugation of estradiol with BSA is imperative, since injection of liposomes with estradiol in the lipid bilayer was found to be ineffective in inducing an immune response. Entrapment of E2-BSA in neutral and positively charged liposomes was found to be a potent mode of immunostimulation, even better than emulsification in complete Freund's adjuvant (CFA). Covalent liposome surface association of E2-BSA induced a good immunopotentiation. However, the response was lower than that observed with the entrapped conjugate. The affinity and the specificity of antisera, raised in different ways, were determined.


An Internet survey of demographic and health factors associated with risk of sexual dysfunction in women who have sex with women.
There has been scant attention to predictors of sexual dysfunction in women who have sex with women (WSW). To investigate the associations of high risk for sexual dysfunction in an Internet cohort of WSW. A modified version of the Female Sexual Function Index (FSFI) was used to quantify each subject's sexual function. Women who have sex with women were invited to participate in an Internet-based survey by invitations posted on e-mail listservs and on social media sites catering to WSW. Ethnodemographic, health status, and sexual/relationship data were collected. The study was completed by 2,433 adult women. Of these, 1,566 participants had complete data on the FSFI and comprised the study cohort; 388 (24.8%) met the FSFI criteria for high risk of female sexual dysfunction (HRFSD). On multivariable analysis, the following variables were found to be independently associated with the HRFSD; moderate or severe subjective bother regarding sexual function (OR 4.8, 95% CI 3.0-7.9 and 13.7, 95% CI 7.5-25.1, respectively), overactive bladder (OAB) (OR 2.1, 95% CI 1.0-4.5), having a nonfemale or no partner (OR 2.3, 95% CI 1.1-4.7 and 3.2, 95% CI 2.0-5.2, respectively). A history of pregnancy was associated with lower odds of HRFSD (OR 0.567, 95% CI 0.37-0.87). Mean FSFI domain scores for all domains except desire were negatively impacted by partner factors and OAB. A single-item question on sexual bother is strongly predictive of potentially distressing sexual problems in the WSW. A number of health and social factors are associated with risk of sexual problems in the WSW. Assessment of sexual well-being in the WSW is a priority for practicing healthcare providers.


Liver glutathione S-transferase polymorphism in Japanese and its pharmacogenetic importance.
A total of 168 autopsy liver extracts from Japanese individuals were examined for the glutathione S-transferase (GST) isozymes by means of starch gel electrophoresis. The gene frequencies of GST1*1, GST1*2, and GST1*0 in Japanese were 0.252, 0.057, and 0.691, respectively. GST1*3 was detected as a rare variant allele. The incidence of GST1 0 in 41 liver biopsy samples from patients suffering from various liver diseases was investigated using polyacrylamide gel isoelectric focusing. The GST1 0 phenotype was found more frequently in livers with hepatitis and carcinoma than in control livers. The isozymes coded by different GST loci were partially purified and characterized to study their biochemical properties. The apparent Km values with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate for the isozymes at the GST1, GST2, GST3, and GST4 loci were 604, 1345, 776, and 591 microM, respectively.


Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration.
The regulation of tolerance to self-proteins and the suppression of T-cell responses have in part been attributed to the activity of CD25+CD4+ T regulatory (Treg) cells. Further, Treg cells can inhibit the antitumor effectiveness of adoptive immunotherapy and active immunization approaches in preclinical models. In an effort to selectively eliminate Treg cells from human peripheral blood mononuclear cell to potentially bolster antitumor responses, we have evaluated the Treg-cell depleting capacity of the CD25-directed immunotoxin, RFT5-SMPT-dgA. In preclinical studies, incubation of human peripheral blood mononuclear cell with RFT5-SMPT-dgA mediated a partial reduction in the levels of CD25+, Foxp3-expressing CD4+ T cells in vitro. Administration of RFT5-SMPT-dgA to 6 patients with metastatic melanoma induced a transient but robust reduction in the number of CD25high CD4 T cells in vivo (a 97.5% mean reduction at nadir; from 69.4 +/- 12.4 cells/miroL to 1.7 +/- 0.3 cells/microL). The reduction in FOXP3+ CD4 T-cell number was less comprehensive (a 71.3% mean reduction at nadir; from 66.6 +/- 16.5 cells/microL to 14.2 +/- 3.9 cells/tL). This resulted in the selective persistence of a stable number of CD25(low/neg) FOXP3+ CD4+ T cells in vivo. No objective antitumor responses were seen in any patient. Our results indicate that the CD25-directed, RFT5-SMPT-dgA immunotoxin can mediate a transient, partial reduction in Treg-cell frequency and number in vitro and in vivo and suggest that comprehensive eradication of human Treg cells in vivo may require the ability to target and eliminate FOXP3+ CD4+ T cells expressing both high and low levels of CD25.


Kidney and spleen twin grafts in rats: unidirectional graft acceptance in unsuppressed ACI recipients.
In previous studies, we have shown that vascularized spleen grafts can facilitate the acceptance of simultaneously implanted hearts, especially if host splenectomy is done 3 days later. The present study shows that the same protocol works not only for hearts but also for kidneys. A total of 59 renal allografts were carried out in various combinations between LEW and ACI rats. The recipients were submitted to bilateral nephrectomy at the time of graft implantation and host splenectomy 3 days later. Graft function was assessed by survival time of the animals. In addition, BUN, creatinine, and hematocrit were measured in selected individuals. The following observations were made: 1) LEW kidneys were rejected at 92 +/- 65 days while ACI kidneys failed at 17 +/- 1.4 days (p less than 0.025). 2) Control animals without simultaneous syngenic functioning spleen implant rejected their LEW kidneys at 30.6 +/- 24.3 days (p less than 0.005). 3) Eleven rats never rejected their LEW kidneys (four single, seven twin grafts). 4) BUN, creatinine, and hematocrit differed significantly in rats with functioning kidneys compared to those in end stage renal failure (p less than 0.0005, p less than 0.0025, and p less than 10(-7) respectively). It is concluded that the presence of the donor spleen can facilitate the acceptance of a simultaneous kidney graft to various degrees, depending on the strain combination.


[Chemotherapy in basal cell carcinoma. Complete remission of locally advanced basal cell carcinoma following treatment with chemotherapy containing cis-platinum].
A case of locally advanced basal cell carcinoma of the head treated with systemic chemotherapy consisting of cis-platinum, fluorouracil and bleomycin is reported. The treatment resulted in complete remission lasting for 13 months.


Characterization of a newly established, TA-4-producing squamous carcinoma cell line derived from metastatic tongue carcinoma.
A human squamous carcinoma cell line was established from the pleural effusion of a patient with recurrent squamous carcinoma of the tongue. The cell line, designated HST-I, has been passaged 82 times over a period of 4 years. The cells have been shown by light and electron microscopy to be of the squamous epithelial type. Immuno-histochemical staining was positive for keratin. When these cells were transplanted into athymic nude mice, tumors developed at the site of inoculation, which on histological examination were shown to be well-differentiated squamous carcinomas. Karyotypic analysis of cells from the cell line demonstrated an aneuploid human type with a modal chromosome number of 71, with both numerical and structural aberrations. HST-1 cells produce and secrete TA-4, a squamous-cell carcinoma-related antigen, in vitro in culture and in vivo in nude mice bearing the tumors produced by inoculation of cultured cells. Thus, the HST-1 cell line represents a new human tongue squamous carcinoma producing TA-4. This cell line appears useful for facilitating therapeutic investigations as well as biological studies on the association between cancerous growth and circulating TA-4 levels.


Comparison between the results of a recently-developed biological weighting function (V79-RBE10BWF) and thein vitroclonogenic survival RBE10of other repair-competent asynchronized normoxic mammalian cell lines and ions not used for the development of the model.
728 simulated microdosimetric lineal energy spectra (26 different ions between1H and238U, 28 energy points from 1 to 1000 MeV/n) were used in combination with a recently-developed biological weighting function (Parisiet al2020Phys. Med. Biol.1361-6560) and 571 publishedin vitroclonogenic survival curves in order to: (1) assess prediction intervals for thein silicoresults by deriving an empirical indication of the experimental uncertainty from the dispersion in thein vitrohamster lung fibroblast (V79) data used for the development of the biophysical model; (2) explore the possibility of modeling the relative biological effectiveness (RBE) of the 10% clonogenic survival of asynchronized normoxic repair-competent mammalian cell lines other than the one used for the development of the model (V79); (3) investigate the predictive power of the model through a comparison betweenin silicoresults andin vitrodata for 10 ions not used for the development of the model. At first, different strategies for the assessment of thein silicoprediction intervals were compared. The possible sources of uncertainty responsible for the dispersion in thein vitrodata were also shortly reviewed. Secondly, also because of the relevant scatter in thein vitrodata, no statistically-relevant differences were found between the RBE10of the investigated different asynchronized normoxic repair-competent mammalian cell lines. The only exception (Chinese Hamster peritoneal fibroblasts, B14FAF28), is likely due to the limited dataset (allin vitroion data were extracted from a single publication), systematic differences in the linear energy transfer calculations for the employed very-heavy ions, and the use of reference photon survival curves extracted from a different publication. Finally, thein silicopredictions for the 10 ions not used for the model development were in good agreement with the correspondingin vitrodata.


Genomic analyses of Burkholderia cenocepacia reveal multiple species with differential host-adaptation to plants and humans.
Burkholderia cenocepacia is a human opportunistic pathogen causing devastating symptoms in patients suffering from immunodeficiency and cystic fibrosis. Out of the 303 B. cenocepacia strains with available genomes, the large majority were isolated from a clinical context. However, several isolates originate from other environmental sources ranging from aerosols to plant endosphere. Plants can represent reservoirs for human infections as some pathogens can survive and sometimes proliferate in the rhizosphere. We therefore investigated if B. cenocepacia had the same potential. We selected genome sequences from 31 different strains, representative of the diversity of ecological niches of B. cenocepacia, and conducted comparative genomic analyses in the aim of finding specific niche or host-related genetic determinants. Phylogenetic analyses and whole genome average nucleotide identity suggest that strains, registered as B. cenocepacia, belong to at least two different species. Core-genome analyses show that the clade enriched in environmental isolates lacks multiple key virulence factors, which are conserved in the sister clade where most clinical isolates fall, including the highly virulent ET12 lineage. Similarly, several plant associated genes display an opposite distribution between the two clades. Finally, we suggest that B. cenocepacia underwent a host jump from plants/environment to animals, as supported by the phylogenetic analysis. We eventually propose a name for the new species that lacks several genetic traits involved in human virulence. Regardless of the method used, our studies resulted in a disunited perspective of the B. cenocepacia species. Strains currently affiliated to this taxon belong to at least two distinct species, one having lost several determining animal virulence factors.


Bromsulphthalein and indocyanine green elimination from plasma, and urinary bromsulphthalein excretion, in normal cats.
The elimination of bromsulphthalein (BSP) and indocyanine green (ICG) from plasma and urinary excretion of BSP were investigated in healthy cats. At 5 mg kg-1, BSP elimination fitted a two-compartment open model, with mean t1/2 beta of 7.1 (SD 2.5) minutes. A tendency for slower elimination of BSP at 10 mg kg-1 suggested saturation of excretory mechanisms, while at 2 mg kg-1 accurate dosing and assay of low BSP concentrations were difficult. Urinary recovery of BSP at 5 mg kg-1 was 0.01 to 0.13 per cent of the total dose. Plasma ICG (0.5 mg kg-1) data fitted a one-compartment open model, with mean t1/2 2.7 (SD 1.0) minutes. In cats, retention tests are more attractive than clearance tests because fewer blood collections are necessary. Proposed reference values are under 3.6 per cent retention of BSP (5 mg kg-1) at 30 minutes and under 17.5 per cent retention of ICG (0.5 mg kg-1) at 15 minutes. At present economic and technical factors favour BSP over ICG.


Cytokine-mediated up-regulation of CD55 and CD59 protects human hepatoma cells from complement attack.
Hepatic parenchymal cells respond in many different ways to acute-phase cytokines. Some responses may protect against damage by liver-derived inflammatory mediators. Previous investigations have shown that cytokines cause increased secretion by hepatoma cells of soluble complement regulatory proteins, perhaps providing protection from complement attack. More important to cell protection are the membrane complement regulators. Here we examine, using flow cytometry and Northern blotting, the effects of different cytokines, singly or in combination, on expression of membrane-bound complement regulators by a hepatoma cell line. The combination of tumour necrosis factor-alpha, IL-1beta, and IL-6 caused increased expression of CD55 (three-fold) and CD59 (two-fold) and decreased expression of CD46 at day 3 post-exposure. Interferon-gamma reduced expression of CD59 and strongly antagonized the up-regulatory effects on CD59 mediated by the other cytokines. Complement attack on antibody-sensitized hepatoma cells following a 3-day incubation with the optimum combination of acute-phase cytokines revealed increased resistance to complement-mediated lysis and decreased C3b deposition. During the acute-phase response there is an increased hepatic synthesis of the majority of complement effector proteins. Simultaneous up-regulation of expression of CD55 and CD59 may serve to protect hepatocytes from high local concentrations of complement generated during the acute-phase response.


Recent advances in biomedical applications of 2D nanomaterials with peroxidase-like properties.
Significant progress has been made in developing two-dimensional (2D) nanomaterials owing to their ultra-thin structure, high specific surface area, and many other advantages. Recently, 2D nanomaterials with enzyme-like properties, especially peroxidase (POD)-like activity, are highly desirable for many biomedical applications. In this review, we first classify the types of 2D POD-like nanomaterials and then summarize various strategies for endowing 2D nanomaterials with POD-like properties. Representative examples of biomedical applications are reviewed, emphasizing in antibacterial, biosensing, and cancer therapy. Last, the future challenges and prospects of 2D POD-like nanomaterials are discussed. This review is expected to provide an in-depth understanding of 2D POD-like materials for biomedical applications.


An explainable predictive model for suicide attempt risk using an ensemble learning and Shapley Additive Explanations (SHAP) approach.
Machine learning approaches have been used to develop suicide attempt predictive models recently and have been shown to have a good performance. However, those proposed models have difficulty interpreting and understanding why an individual has suicidal attempts. To overcome this issue, the identification of features such as risk factors in predicting suicide attempts is important for clinicians to make decisions. Therefore, the aim of this study is to propose an explainable predictive model to predict and analyse the importance of features for suicide attempts. This model can also provide explanations to improve the clinical understanding of suicide attempts. Two complex ensemble learning models, namely Random Forest and Gradient Boosting with an explanatory model (SHapley Additive exPlanations (SHAP)) have been constructed. The models are used for predictive interpretation and understanding of the importance of the features. The experiment shows that both models with SHAP are able to interpret and understand the nature of an individual's predictions with suicide attempts. However, compared with Random Forest, the results show that Gradient Boosting with SHAP achieves higher accuracy and the analyses found that history of suicide attempts, suicidal ideation, and ethnicity as the main predictors for suicide attempts.


Outcomes after Transgastric Drainage of Pancreatic Duct Leaks.
To determine the outcomes of transgastric drainage (TGD) of pancreatic duct leaks (PDLs), including fluid collections and pancreaticocutaneous fistulae (PCFs). Fifty-four patients who underwent attempted TGD of a PDL from 1992 to 2020 were identified. Data regarding patient comorbidities, fluid collection characteristics, technical success, drain exchanges and removals, recurrent collections, and complications were analyzed. Forty-one patients (41/54, 76%) had a history of pancreatitis. Sixteen patients (16/54, 30%) had a history of recent abdominal surgery. Peripancreatic fluid collections were 11.2 cm ± 4.6 in greatest dimension prior to drainage. Twenty-one collections (21/54, 39%) demonstrated biochemical and/or imaging evidence of an active communication to the pancreatic duct, and 16 (16/54, 30%) of these patients had a PCF due to a direct percutaneous drain prior to TGD. TGD was technically successful in 53 patients (53/54, 98%). During the follow-up period, 46 patients (46/53, 87%) were able to undergo drain removal after resolution of the fluid collection, with a mean catheter indwelling time of 3 months and a median of 1 catheter exchange. There were 2 severe (2/53, 4%) and 4 moderate (4/53, 8%) complications, the most common of which was drain dislodgement requiring repeat transgastric puncture. Recurrent fluid collections were observed in 8 patients (8/53, 15%) after a mean of 5 months following drain removal. There were no recurrent PCFs. TGD of PDLs is technically feasible and efficacious in the vast majority of patients with a relatively low complication rate. This technique is effective in preventing or treating the long-term debilitating complication of PCF.


Appropriate density of PCL nano-fiber sheath promoted muscular remodeling of PGS/PCL grafts in arterial circulation.
Cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering. Porous elastomeric grafts made of poly(glycerol sebacate) (PGS) enforced with polycaprolactone (PCL) nano-fibers degrade rapidly and yield neoarteries nearly free of foreign materials in rat abdominal aorta. However, considering the larger variation of blood pressure and slower host remodeling in human body than in rat, it is important to investigate the in vivo performance of PGS-PCL graft with enhanced mechanical properties, so that optimized arterial grafts could be developed for clinical translation. We acquired increasingly compacted sheath by prolonging the electrospinning period of PCL appropriately, which significantly enforced whole grafts. The rational design of sheath density significantly decreased the risk of dilation, rupture as well as enabling the long-term muscular remodeling. Since 3-12 months after implantation, the PGS grafts with rationally strengthened sheath were remodeled into neoarteries resembled native arteries in the following aspects: high patency rate and even vessel wall thickness; a confluent endothelium and contractile smooth muscle layers; expression of elastin, collagen and glycosaminoglycan; tough and compliant mechanical properties. Although loose sheath may result in rupture of vessel wall, adequate porosity was proved to be essential for sheath structure and directly determined muscular remodeling through M2 macrophage involved constructive remodeling. Therefore, this study confirmed that adequate density of PCL sheath in PGS grafts could initiate stable and high-quality muscular remodeling, which contributes to long-term success in arterial circulation before clinical translation.


Cryosectional observations of functional anatomy of the temporomandibular joint.
The anatomy and function of the temporomandibular joint are complex, and our understanding about how the retrocondylar tissues change when the condyle translates anteriorly has been incomplete. We therefore examined the sectional anatomy of 24 fresh human temporomandibular joints at different gradations of jaw opening, protrusion, and laterotrusion. We found that the tissues of the posterior disk attachment expanded in volume and occupied the space behind the condyle when the mouth was opened, protruded, or laterotruded to the contralateral side. Volumetric expansion of the tissue seemed to be due mainly to distension of the venous structures in the retrodiskal area. In the lateral region of the joint, tissue from the superior aspect of the parotid gland also seemed to contribute to the filling of the space posterior to the condyle. Thus, the retrodiskal tissue appears to have a substantial capacity to expand and fill the mandibular fossa when the condyle translates anteriorly. The possibility of a dynamic vascular physiology is suggested.


Anesthetic considerations for inadvertent severe hypertension in a patient with osteogenesis imperfecta during the perioperative period.
Osteogenesis imperfecta is a rare genetic syndrome caused by mutations of bone matrix protein type I collagen coding genes, which is characterized by increased bone fragility and recurrent fractures. We report a patient undergoing general anesthesia with additional nerve block for wrist and hip fracture repair. Preoperatively, we were confronted with an inadvertent severe hypertension without significant triggers and history, which prompted us to be vigilant for hypertensive emergencies due to the fragile vessel regulation capacity in osteogenesis imperfecta patients.


Detection of HLA antibodies by platelet crossmatching techniques.
Thirty-seven monospecific HLA antibodies directed against all common HLA-A and -B loci and reactive by the microlymphocytotoxicity assay (LCT) were tested against platelets carrying the corresponding antigen by three platelet crossmatch methods, the platelet immunofluorescence test (PIFT), platelet enzyme-linked immunosorbent assay (P-ELISA), and platelet radioimmunoassay (P-RIA). Positive reactions were obtained with the PIFT in 67 percent, the P-ELISA in 41 percent, and the P-RIA in 49 percent of 85 cell-serum pairs. The same cell-serum combinations gave 49 percent positive reactions in the lymphocyte immunofluorescence test. Three multispecific HLA antisera were positive in nine of nine cell-serum combinations by all four methods. Thirteen transfusions were given to eight patients with known HLA antibodies. All donor-recipient pairs were LCT positive, six were PIFT positive, and seven were PIFT negative. Three of seven PIFT-negative and none of six PIFT-positive transfusions were successful. Thus, platelet crossmatching is less sensitive than the LCT for the detection of complement-binding monospecific HLA antibodies. The platelet crossmatch, however, is able to identify some potentially successful HLA-incompatible donors for patients with multispecific HLA antibodies and limited access to HLA-identical donors.


Feasibility of Elder-Friendly Food Applications of Sacha Inchi According to Cooking Method: Focusing on Analysis of Antioxidative Activity and Brain Neuron Cell Viability.
One of the objectives of this study was to determine the effect of the cooking method on the antioxidant activity of Sacha inchi (Plukenetia volubilis). This work was focused on the importance of performing proper cooking for studying Sacha inchi. The result of this study sheds light on preventing nutritional loss with appropriate cooking methods. Three types of cooking processes were selected: uncooked, roasted at 160 °C for 6 min, boiled at 100 °C for 13 min. The results of the present study indicated that roasted Sacha inchi is distinguishable for its high content of antioxidants (total polyphenol content 485.50 μM, total flavonoid content 0.02 μg/mL, DPPH free radical scavenging activity 33.05%, ferric reducing ability 0.19 μM). The results of the present study also indicated that Sacha inchi uniquely promotes HT22 cell viability. With roasted Sacha inchi treatment, HT22 hippocampal neuronal cell showed a significantly increased number of growth (p < 0.001). Results also suggest that the development of tenderized Sacha inchi could help the elderly consumers achieve their target antioxidant provision in smaller portion sizes, thus curtailing the peril of sarcopenia. The mousse type of elderly food may also change the taste of many other nut consumers as they may opt to start selling and consuming Sacha inchi. It could be in the Sacha inchi industry's best interest to make certain all of the population's textural favors are catered.


Algebraic approach for subspace decomposition and clustering of neural activity.
We developed an approach to decompose neuronal signals into disjoint components, corresponding to task- or event-based epochs. This protocol describes how to project behavioral templates onto a low-dimensional subspace of neuronal responses to derive neuronal templates, then how to decompose and cluster neuronal responses using these derived templates. We outline these steps on complementary datasets of calcium imaging and spiking activity. Our approach relies on fundamental, linear algebraic principles and is adaptive to the temporal structure of the neural data. For complete details on the use and execution of this protocol, please refer to Adam et al. (2022).1.


Skeletal stability after correction of maxillary hypoplasia by the Glasgow extra-oral distraction (GED) device.
Maxillary distraction osteogenesis delivers excellent results, particularly in patients with clefts. In the past, devices such as the conventional facemask and the rigid external distraction device have been used to correct maxillary hypoplasia after a Le Fort I osteotomy. We describe a new device, the Glasgow extra-oral distraction device. The extent of skeletal and dental stability of corrections achieved in 10 patients with maxillary hypoplasia associated with clefts was satisfactory. This device costs little, can be produced in developing countries, and provides effective treatment for severe secondary deformity associated with clefts.


Enteric duplication in children: Experience from a tertiary center in South India.
Enteric duplications (EDs) are rare aberrations of the embryonic gut. This study was undertaken to define the clinical characteristics and management challenges of this unusual entity in the Indian population. Hospital records of 35 children with 38 ED operated between 2003 and 2014 were analyzed and followed up. The median age at presentation was 285 days (range 1-day to 16 years) with male preponderance (71%). Small bowel duplications were the most common (44%), and thoracoabdominal duplications were seen in 8% children compared to 2% in the literature. The median duration of symptoms was 18 days (interquartile range [IQR] 3-210 days). Associated anomalies were seen in 49% children with vertebral and spinal anomalies being the most common. Ultrasonogram (US) was done in 83% children and had a sensitivity of 55%. In the presence of a gastrointestinal bleed, Technetium(99m) pertechnetate scintigraphy scan had a positive predictive value of 80%. Thirty-five lesions were completely removed. Mucosectomy was done in two children, and one total colonic duplication was left in situ after providing adequate internal drainage. There was no postoperative mortality. The follow-up was possible in 66% children. EDs are uncommon and have varied, nonspecific symptoms. Thoracoabdominal duplications are more common in the Indian population. The US is a good screening tool but requires a high index of suspicion where complete excision is not possible; the provision of adequate internal drainage is an acceptable alternative. The long-term prognosis of children with ED depends on the extent of physiological disturbance due to associated anomalies.


Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design.
Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years). A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation. The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.


Tbit/s line-rate satellite feeder links enabled by coherent modulation and full-adaptive optics.
Free-space optical (FSO) communication technologies constitute a solution to cope with the bandwidth demand of future satellite-ground networks. They may overcome the RF bottleneck and attain data rates in the order of Tbit/s with only a handful of ground stations. Here, we demonstrate single-carrier Tbit/s line-rate transmission over a free-space channel of 53.42 km between the Jungfraujoch mountain top (3700 m) in the Swiss Alps and the Zimmerwald Observatory (895 m) near the city of Bern, achieving net-rates of up to 0.94 Tbit/s. With this scenario a satellite-ground feeder link is mimicked under turbulent conditions. Despite adverse conditions high throughput was achieved by employing a full adaptive optics system to correct the distorted wavefront of the channel and by using polarization-multiplexed high-order complex modulation formats. It was found that adaptive optics does not distort the reception of coherent modulation formats. Also, we introduce constellation modulation - a new four-dimensional BPSK (4D-BPSK) modulation format as a technique to transmit high data rates under lowest SNR. This way we show 53 km FSO transmission of 13.3 Gbit/s and 210 Gbit/s with as little as 4.3 and 7.8 photons per bit, respectively, at a bit-error ratio of 1 ∙ 10-3. The experiments show that advanced coherent modulation coding in combination with full adaptive optical filtering are proper means to make next-generation Tbit/s satellite communications practical.


Accurate diagnosis of prostate cancer with CRISPR-based nucleic acid test strip by simultaneously identifying PCA3 and KLK3 genes.
Although serum prostate specific antigen (PSA) testing could decrease the morality of prostate cancer (PCa), its low specificity usually led to misdiagnosis due to prostatitis or benign prostatic hyperplasia (BPH). Prostate cancer antigen 3 (PCA3) as an alternative prostate tumor-specificity biomarker could be used to increase the specificity of PCa diagnosis, however, it usually required sophisticated operation and expensive equipment for routine detection. Herein, we constructed an early detection platform for prostate cancer with reverse transcriptase-recombinase aided amplification (RT-RAA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 based nucleic acid test strip. The amplicons of PCA3 and kallikrein related peptidase 3 (KLK3) gene, which amplified simultaneously by single-amplification unit of RT-RAA were specifically recognized by Cas9-sgRNA and visual on the nucleic acid test strip by naked eyes without instruments. Simultaneously detection of PCA3 and KLK3 gene could improve specificity and accuracy of the diagnosis but avoid mutual interference. In addition, the platform presented a detection limit of 500 fg/μL and 50 fg/μL in PCA3 and KLK3 gene, respectively. Furthermore, the analysis result of signal ratio of PCA3 to KLK3 gene of urine and peripheral blood specimens from 32 men with suspected prostate cancer on test strips illustrated that the area under the curve values of urine and peripheral blood specimens were 0.998 and 1.0 respectively. In summary, our study highlighted a facile strategy to design an accurate prostate cancer gene detection platform which had the potential to conduct prostate cancer early detection in the resource-limited or other point-of-care testing (POCT) environments.


Self-selected meal composition alters the relationship between same-day caloric intake and appetite scores in humans during a long-term ad-libitum feeding study.
To determine the effect of an off-protocol meal during a long-term ad libitum feeding study on changes in total caloric consumption and ratings of hunger and satiety. During the ad libitum portion of a 16 weeks research high-protein feeding study, 19 participants were allowed to eat up to one self-selected meal (SSM) a week instead of an intervention diet meal. The SSM was assessed for total caloric and macronutrient composition and compared to the intervention diet for 3 days before and after the SSM day. Visual analog scores rating daily hunger and fullness were collected and compared as well. On the SSM day, the mean ± SD daily caloric intake increased by 262 ± 332 kcal compared to the previous study days (P < 0.001), with no changes in subjective appetite scores. The following day there was a slight but significant reduction in intake (- 58 ± 85 kcal, P = 0.008) compared to the average pre-SSM day with no change in appetite scores. On the SSM day, percent protein intake was inversely associated mean daily caloric intake (r2 = 0.22, P = 0.03). During a long-term, ad-libitum high-protein feeding study, one SSM lower in protein increased daily total caloric consumption with no impact on appetite ratings and incomplete caloric consumption during subsequent days. These data suggest that during ad-libitum feeding, a single meal change in protein content impacts the relationships between daily level of hunger, satiety and calorie intake. NCT05002491 (retrospectively registered 07/20/2021).


Breast cancer education for the Deaf community in American Sign Language.
To create and evaluate an educational video designed to increase breast cancer-related knowledge and screening behaviors among women who are deaf and use American Sign Language (ASL) as their preferred communication method. A test-retest survey was used to determine retained knowledge following an intervention with an ASL breast cancer education video. Deaf-friendly community settings in southern California. 122 women who were deaf with a preference for communicating via ASL. Participants completed a knowledge survey to determine their breast cancer screening practices and baseline breast cancer awareness. Participants then viewed a 30-minute video in ASL. Immediately after viewing the video, participants completed an identical knowledge survey. The survey was administered again two months after the initial intervention to determine long-term breast cancer knowledge retention. Age, breast cancer knowledge and screening practices, education, and health insurance. At baseline, breast cancer knowledge varied widely and respondents' answered an average of 3 out of 10 questions correctly. Postintervention, respondents answered an average of 8 out of 10 questions correctly, a significant increase from the baseline scores. At the two-month follow-up, respondents answered an average of 6 out of 10 questions correctly, still a significant increase from the baseline scores. Breast cancer knowledge of women who are deaf increased significantly by viewing an educational video in ASL and most of the new knowledge remained at the two-month follow-up. Nurses can help improve the Deaf community's (DC's) access to breast cancer-related information by disseminating awareness of this online program. With this online resource, nurses can more easily initiate discussions to help improve knowledge and screening behaviors in a linguistically and culturally appropriate manner. Improving the DC's access to breast cancer information is of paramount importance to reducing breast cancer morbidity and mortality in the DC.


Magnetic resonance imaging of spinal dysraphism.
MR imaging has become the definitive diagnostic procedure for the evaluation of suspected spinal dysrhaphic processes. Techniques for spinal MR imaging are discussed and MR findings in patients with surgically verified dysrhaphic spinal lesions are reviewed.


Response properties of neurons in area 17 projecting to the striate-recipient zone of the cat's lateralis posterior-pulvinar complex: comparison with cortico-tectal cells.
The main input of the lateral part of the cat's lateralis posterior-pulvinar complex (LP-P) comes from the primary visual cortex. We investigated the response properties of cells in area 17 projecting to the striate-recipient zone (LP1) of the cat's LP-P complex. The cells' receptive fields were stimulated with drifting sine-wave gratings. Cells whose fibres terminate in the superior colliculus were also recorded, to determine how their properties compare with those of cortico-LP1 cells and to investigate the possibility that LP1 is innervated by collaterals of cortico-tectal units. A total of 26 cells in the striate cortex were identified by antidromic activation from the LP1 (mean latency 2.2 ms) and 22 from the colliculus (mean latency 2.5 ms). Only six cortical cells could be activated from the LP1 and the colliculus. All cortico-LP1 cells except for two responded to drifting sinusoidal gratings with unmodulated discharges (AC/DC ratios < 1). On the basis of their modulation index, these units were classified as complex cells. All cortico-LP1 cells were selective for the orientation of gratings (mean bandwidth of 28 degrees). There was a tendency for cortico-LP1 cells to prefer vertical and horizontal orientations. More than half of these cells (57%) were direction selective. Strong orientation anisotropies were also found in the receptive fields of cortico-tectal cells, since almost all units responded preferentially to horizontally oriented gratings.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis.
Predisposition to primary biliary cirrhosis (PBC) has been classically linked to HLA-DRB1 locus. However, the presence of the HLA-DRB1*08 antigen has been reported in less than one-third of PBC patients from Northern Europe and Japan. Recently, polymorphisms in the tumor necrosis factor alpha (TNFA) gene promoter at position -308 and in exon 1 of the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene at position 49 have been associated with susceptibility to PBC in Caucasians. In addition, the presence of HLA-DRB1*08 and the TNFA*1 allele was also linked to progression to end-stage liver disease. The aims of the present study were to investigate the frequencies of HLA-DR and DQ antigens and TNFA and CTLA-4 alleles in PBC patients from a different genetic background, as well as to assess the role of TNFA alleles and HLA-DR antigens in disease progression. Determination of HLA-DRB1, DQB1, TNFA and CTLA-4 alleles was performed in patients with PBC and healthy controls using polymerase chain reaction-based techniques. Frequencies of HLA-DR and DQ antigens were similar in PBC patients and healthy controls. Accordingly, no association between TNFA and CTLA-4 alleles was observed in PBC patients. The histological stage at admission of patients with PBC also showed no correlation with HLA antigens and TNFA and CTLA-4 alleles. Susceptibility to PBC in Brazil is not associated with HLA-DR and DQ antigens and CTLA-4 genotypes. TNFA alleles were not shown to influence disease progression.


COVID-induced sentiment and the intraday volatility spillovers between energy and other ETFs.
Did Covid19 induce market turmoil impact the intraday volatility spillovers between energy and other ETFs?. To examine this, we first estimate the realized volatility of ETFs using the 5-min high-frequency data. Next, we employ time-varying parameter vector autoregressions (TVP-VAR). Finally, we utilize the wavelet coherence measure to test the time-frequency impact of COVID-induced sentiment on the spillovers by employing investors' psychological and behavioural factors. We find that oil and stock markets are net transmitters while currency, bonds, and silver markets are net receivers. The wavelet analysis embarked significant impact of media coverage and fake news index towards shaping investors' pessimism for their investments. We proposed useful implications for policymakers, governments, investors, and portfolio managers.


Kenaf (Hibiscus cannabinus L.) core and rice hulls as components of container media for growing Pinus halepensis M. seedlings.
The feasibility of replacing peat or perlite with rice hulls and ground kenaf core to grow a Mediterranean species (Pinus halepensis M.), was investigated. Treatments involved the following growing media: 70 peat:30 perlite as a control, 70 peat:30 rice hulls, 50 peat:50 rice hulls, kenaf (100%) and 60 kenaf:20 peat:20 rice hulls. The seedlings' quality and the physical and chemical properties of the substrates were evaluated. After this, the seedlings were planted in the field and their field performance was recorded. The results showed that the growth medium 70 peat:30 rice hulls can successfully be used for the production of P. halepensis, since the seedlings' nursery and field performance were similar to, or even better than those obtained with the control medium. The seedlings produced in the growth media containing kenaf did not attain a suitable planting size and showed poorer field performance than control seedlings.


Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus-specific CD8+ T cells after direct-acting antiviral therapies.
Chronic hepatitis C virus (HCV) infection impairs HCV CD8+ T-cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus-specific CD8+ T cells occurs after direct-acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow-up [FU] 12 and FU48) of virus-specific CD8+ T cells by multicolour flow cytometry in HCV-cirrhotic patients undergoing DAA therapy (n = 26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA-A*02. HCV noncirrhotic patients (n = 9) and healthy individuals (n = 10) served as controls. We found that the proliferative capacity of HCV-specific CD8+ T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down-regulation of inhibitory co-regulatory receptors in HCV-cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV-specific CD8+ T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the 'exhausted' phenotype in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients did not associate with their functions. Larger studier with longer follow-up may elucidate whether this complex interplay influences the outcome of cirrhotic patients.


Seasonal variation in the acute effect of particulate air pollution on mortality in the China Air Pollution and Health Effects Study (CAPES).
Epidemiological findings concerning the seasonal variation in the acute effect of particulate matter (PM) are inconsistent. We investigated the seasonality in the association between PM with an aerodynamic diameter of less than 10 μm (PM10) and daily mortality in 17 Chinese cities. We fitted the "main" time-series model after adjustment for time-varying confounders using smooth functions with natural splines. We established a "seasonal" model to obtain the season-specific effect estimates of PM10, and a "harmonic" model to show the seasonal pattern that allows PM10 effects to vary smoothly with the day in a year. At the national level, a 10 μg/m(3) increase in the two-day moving average concentrations (lag 01) of PM10 was associated with 0.45% [95% posterior interval (PI), 0.15% to 0.76%], 0.17% (95% PI, -0.09% to 0.43%), 0.55% (95% PI, 0.15% to 0.96%) and 0.25% (95%PI, -0.05% to 0.56%) increases in total mortality for winter, spring, summer and fall, respectively. For the smoothly-varying plots of seasonality, we identified a two-peak pattern in winter and summer. The observed seasonal pattern was generally insensitive to model specifications. Our analyses suggest that the acute effect of particulate air pollution could vary by seasons with the largest effect in winter and summer in China. To our knowledge, this is the first multicity study in developing countries to analyze the seasonal variations of PM-related health effects.


FeMn and FeMnAg biodegradable alloys: An in vitro and in vivo investigation.
Iron-based biodegradable metal bone graft substitutes are in their infancy but promise to fill bone defects that arise after incidents such as trauma and revision arthroplasty surgery. Before clinical use however, a better understanding of their in vivo biodegradability, potential cytotoxicity and biocompatibility is required. In addition, these implants must ideally be able to resist infection, a complication of any implant surgery. In this study there was significant in vitro cytotoxicity caused by pure Fe, FeMn, FeMn1Ag and FeMn5Ag on both human foetal osteoblast (hFOB) and mouse pre-osteoblast (MC3T3-E1) cell lines. In vivo experiments on the other hand showed no signs of ill-effect on GAERS rats with the implanted FeMn, FeMn1Ag and FeMn5Ag pins being removed largely uncorroded. All Fe-alloys showed anti-bacterial performance but most markedly so in the Ag-containing alloys, there is significant bacterial resistance in vitro.


First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors.
PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.


Ancient DNA extraction from plants.
A variety of protocols for DNA extraction from archaeological and paleobotanical plant specimens have been proposed. This is not surprising given the range of taxa and tissue types that may be preserved and the variety of conditions in which that preservation may take place. Commercially available DNA extraction kits can be used to recover ancient plant DNA, but modifications to standard approaches are often necessary to improve yield. In this chapter, I describe two protocols for extracting DNA from small amounts of ancient plant tissue. The CTAB protocol, which I recommend for use with single seeds, utilizes an incubation period in extraction buffer and subsequent chloroform extraction followed by DNA purification and suspension. The PTB protocol, which I recommend for use with gourd rind and similar tissues, utilizes an overnight incubation of pulverized tissue in extraction buffer, removal of the tissue by centrifugation, and DNA extraction from the buffer using commercial plant DNA extraction kits.


All that glitters is not gold: X-ray fluorescence analysis of a fixed dental prosthesis from Colecção de Esqueletos Identificados Século XXI, Portugal (CEI/XXI).
Access to better health care anticipates that more medical devices can be found alongside skeletal remains. Those employed in oral rehabilitation, with available brands or batch/series, can prove useful in the identification process. A previous study in the Colecção de Esqueletos Identificados Século XXI described macroscopically the dental prostheses. An unusual case of a dental device with chromatic alterations demonstrated to require a more detailed analysis. The individual, a 53-year-old male, exhibited, at both arches, a fixed tooth-supported rehabilitation, with gold colouring classified initially as a gold-palladium alloy. Simultaneously, a green pigmentation deposit was observable in bone and prosthesis. This investigation aimed to verify the elemental composition of the dental prosthesis alloy. Elemental analysis was performed by X-ray fluorescence in two regions (labial surface of the prosthetic crown and the root surface of the lower right lateral incisor). Both the spectra and the qualitative results found higher levels of copper and aluminium, followed by nickel, iron, zinc, and manganese. No gold or palladium was detected. The most probable assumption is that a copper-aluminium alloy was used, as its elemental concentration corresponds to those measured in similar devices. Dental prostheses of copper-aluminium alloys have been made popular since the 1980s, particularly in the USA, Japan, and Eastern Europe. Apart from the biographical information, it was also known that the individual's place of birth was an Eastern European country, which highlighted the usefulness of this type of information when dealing with missing people cases.


Enhanced cellulolytic enzyme biosynthesis of Fusarium sp. strain by mutation and optimization of culture conditions.
Mutation and most favorable culture conditions resulted in 1.8 to 3.3-fold increase in beta-1, 4-endoglucanase and filter paper activity by Fusarium sp. 25/2. Culture fluid obtained after 3 days of growth of Fusarium sp. mutant on modified Saunders medium supplemented with 1% filter paper and 0.1% malt seedlings showed beta-1, 4-endoglucanase activity of 42.6 u/ml and FPA of 2.4 mg/0.5 ml x h.


Improvement of arginine hydrochloride based antibody lyophilisates.
Arginine hydrochloride (ArgHCl) can be used as stabiliser of protein drugs in both liquid and freeze dried formulations reducing aggregation. But ArgHCl exhibits a low Tg' value which can lead to cake collapse during lyophilisation. We analysed arginine (Arg) citrate hydrochloride and lactobionate based lyophilisates aiming for elegant cake appearance in combination with minimal protein aggregation using 2 mg/ml monoclonal antibody (mAb) without additional excipients and in combination with sucrose (Suc) as amorphous stabiliser as well as mannitol (Man) and phenylalanine (Phe) as crystalline bulking agents. Furthermore 50 mg/ml mAb was also used. Based on a process which resulted in poor cake appearance for the ArgHCl based cake with 2 mg/ml mAb the combination with sucrose mannitol (Man:Arg 4:1) and phenylalanine (Phe:Arg1:4 1.5:3.5 and 2:3) as well as a high mAb concentration were able to improve cake appearance. Overall the crystalline bulking agent Phe in combination with ArgHCl renders elegant cakes with minimal protein aggregation. The alternative Arg salts did not require cake quality enhancement but mAb stability was inferior to ArgHCl. The combination with mannitol showed reduced stability due to a substantially lower amount of amorphous matrix. Thus the combination of ArgHCl with phenylalanine was superior to any other formulation tested including the sucrose based and may allow for substantial process time reduction due to the crystalline scaffold delivering pharmaceutically elegant cakes.


Hidden Markov model-derived structural alphabet for proteins: the learning of protein local shapes captures sequence specificity.
Understanding and predicting protein structures depend on the complexity and the accuracy of the models used to represent them. We have recently set up a Hidden Markov Model to optimally compress protein three-dimensional conformations into a one-dimensional series of letters of a structural alphabet. Such a model learns simultaneously the shape of representative structural letters describing the local conformation and the logic of their connections, i.e. the transition matrix between the letters. Here, we move one step further and report some evidence that such a model of protein local architecture also captures some accurate amino acid features. All the letters have specific and distinct amino acid distributions. Moreover, we show that words of amino acids can have significant propensities for some letters. Perspectives point towards the prediction of the series of letters describing the structure of a protein from its amino acid sequence.


Between a Rock and a Hard Place: Anticoagulating an Adolescent with Post-Tonsillectomy Massive PE: A Case Report.
To report a case of a morbidly obese 17-year-old boy who presented 4 days post-tonsillectomy with acute deep venous thromboses and a massive pulmonary embolism. To describe a protocol and decision-making tree for providing anticoagulation in the immediate post-tonsillectomy period. A chart review and review of the literature. The patient ultimately did well and had no bleeding from the tonsil beds or further thromboembolic complications. A review of the literature revealed no available data regarding the safety of anticoagulation in the immediate post-tonsillectomy period. We propose that if anticoagulation is needed within 14 days of tonsillectomy, submaximal anticoagulation with a reversible and titratable anticoagulant may be optimal. A multidisciplinary team approach is needed for these complex cases. Future reporting and investigation of anticoagulation post-tonsillectomy is needed.


Genetic discoveries in AD using CSF amyloid and tau.
The use of cerebrospinal fluid levels of Aβ42 and pTau181 as endophenotypes for genetic studies of Alzheimer's disease (AD) has led to successful identification of both rare and common AD risk variants. In addition, this approach has provided meaningful hypotheses for the biological mechanisms by which known AD risk variants modulate the disease process. In this article we discuss these successes and outline challenges to effective and continued applications of this approach. We contrast the statistical power of this approach with traditional case-control designs and discuss solutions to address challenges in quality control and data analysis for these phenotypes. Finally, we discuss the potential for the use of this approach with larger samples as well as the incorporation of next generation sequencing and for future work with other endophenotypes for AD.


Facial photo rejuvenation using two different intense pulsed light (IPL) wavelength bands.
Intense pulsed light (IPL) systems are increasingly used for treatment of photo damaged skin. In the present study, we investigated the clinical efficacy and safety of two different wavelength bands generated by the same IPL device. An IPL device was equipped with either a 555-950 nm filter (VL), or a 530-750 nm filter (PR). Fair, good or excellent clearance of visible telangiectasias was obtained in 81.8% of the patients (PR) and in 58.8% (VL). In the treatment of diffuse erythema, fair, good or excellent clearance was obtained in 72.7% (PR) and in 35.0% (VL). The PR filter was more efficient (P = 0.025) in reduction of diffuse erythema. The average number of treatments was 1.75 (PR) and 1.82 (VL). For the treatment of irregular pigmentation, fair, good or excellent clearance was obtained in 54.5% (PR) and in 61.9% (VL). Multiple treatments of irregular pigmentation were also evaluated. Using the VL filter more than two treatments did not induce further clinical improvement. The patients also scored their over-all satisfaction. Either fair, good or excellent results were reported by 66.7% (PR) and by 76.2% (VL). No skin atrophy, scarring or pigment disturbances were noted after the treatments. Swelling and erythema were registered by 2/3 (PR) and 1/3 (VL) of the patients. The two IPL wavelength bands were both found to be effective in the treatment of photo damaged facial skin. The clinical efficacy and safety of the two different treatment procedures were comparable to those reported in earlier studies, and finally treatment with these filter combinations required less than half the fluence, no active cooling and fewer treatments.


"I felt like I was going to cause conflict. So, I kept quiet …" (Female child rape victim, 15 years).
There is limited research in South Africa that has analysed the experiences of child and youth victims of crime and sexual victimisation who accessed formal response services through the victim empowerment programme. The primary aim of this article is to explore children and youth's experiences of accessing the Victim Empowerment Programmatic services, through the criminal justice system in South Africa. The focus of the article is on childrens' disclosure, reporting and social support. The participants in the study are male and female victim/survivor of crime between the ages of 12-17 years who has been through a Victim Empowerment Programme (VEP) for at least 12 months. The Victim Empowerment Programme is a governmental programme located within the National Department of Social Development in South Africa. The full study is a mixed method study but the children's(youth) participation in the study is limited to qualitative methods. The data analysis utilised a thematic approach and ATLAS.ti software. The findings revealed four themes, namely, (1) children's (as youth) perceptions of the presence and frequency of rape in communities, (2) disclosure and reporting rape; (3) interlinkage of disclosure and reporting of child rape and child sexual victimisation; and (4) seeking social and professional support to deal with the trauma of child (youth) rape and child sexual victimisation. The findings showed that children (youth) perceive their community environments as unsafe spaces where they are exposed to crimes such as rape and burglary; that there are delays in disclosure of sexual victimisation and victims/survivors are still dealing with the trauma of rape as they report the crime and navigate the pathways of the criminal justice system. In conclusion, this study confirms the delay in disclosure of childhood (youth) sexual victimisation and identifies the complex tension for children (youth) who disclose, that they are often pressured to report the crime, and journey through an adversarial criminal justice system, and so 'breaking the silence' is often unpredictable and emotionally and psychologically costly for children and youth.