Carbonic anhydrase inhibitors modify intracellular pH transients and contractions of rat middle cerebral arteries during CO2/HCO3- fluctuations.
The CO2/HCO3- buffer minimizes pH changes in response to acid-base loads, HCO3- provides substrate for Na+,HCO3--cotransporters and Cl-/HCO3--exchangers, and H+ and HCO3- modify vasomotor responses during acid-base disturbances. We show here that rat middle cerebral arteries express cytosolic, mitochondrial, extracellular, and secreted carbonic anhydrase isoforms that catalyze equilibration of the CO2/HCO3- buffer. Switching from CO2/HCO3--free to CO2/HCO3--containing extracellular solution results in initial intracellular acidification due to hydration of CO2 followed by gradual alkalinization due to cellular HCO3- uptake. Carbonic anhydrase inhibition decelerates the initial acidification and attenuates the associated transient vasoconstriction without affecting intracellular pH or artery tone at steady-state. Na+,HCO3--cotransport and Na+/H+-exchange activity after NH4+-prepulse-induced intracellular acidification are unaffected by carbonic anhydrase inhibition. Extracellular surface pH transients induced by transmembrane NH3 flux are evident under CO2/HCO3--free conditions but absent when the buffer capacity and apparent H+ mobility increase in the presence of CO2/HCO3- even after the inhibition of carbonic anhydrases. We conclude that (a) intracellular carbonic anhydrase activity accentuates pH transients and vasoconstriction in response to acute elevations of pCO2, (b) CO2/HCO3- minimizes extracellular surface pH transients without requiring carbonic anhydrase activity, and (c) carbonic anhydrases are not rate limiting for acid–base transport across cell membranes during recovery from intracellular acidification.


An improved method for separation of leucocytes from peripheral blood of the little skate (Leucoraja erinacea).
Cartilaginous fish, especially sharks, rays and skates (elasmobranchs), hold interest as comparative models in immunology because they are thought to be among the organisms most closely related to the ancestor animal that first developed acquired immunity. The aim of this study was to improve methods used for the purification of viable leucocytes from peripheral blood of elasmobranchs. Here we describe modifications of density gradient centrifugation and medium formulation that improve isolation and analysis of highly purified leucocytes from peripheral blood of a model elasmobranch, Leucoraja erinacea, the little skate. These techniques contribute to the preparation of elasmobranch immune cells that can be reliably analyzed by a variety of means, including the study of immune function.


Glycine receptor α2 subunit activation promotes cortical interneuron migration.
Glycine receptors (GlyRs) are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis.


PragmaTic, prospEctive, randomized, controlled, double-blind, mulTi-centre, multinational study on the safety and efficacy of a 6% HydroxYethyl Starch (HES) solution versus an electrolyte solution in trauma patients: study protocol for the TETHYS study.
Trauma may be associated with significant to life-threatening blood loss, which in turn may increase the risk of complications and death, particularly in the absence of adequate treatment. Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss to maintain or re-establish hemodynamic stability with the ultimate goal to avoid organ hypoperfusion and cardiovascular collapse. The current study compares a 6% HES 130 solution (Volulyte 6%) versus an electrolyte solution (Ionolyte) for volume replacement therapy in adult patients with traumatic injuries, as requested by the European Medicines Agency to gain more insights into the safety and efficacy of HES in the setting of trauma care. TETHYS is a pragmatic, prospective, randomized, controlled, double-blind, multicenter, multinational trial performed in two parallel groups. Eligible consenting adults ≥ 18 years, with an estimated blood loss of ≥ 500 ml, and in whom initial surgery is deemed necessary within 24 h after blunt or penetrating trauma, will be randomized to receive intravenous treatment at an individualized dose with either a 6% HES 130, or an electrolyte solution, for a maximum of 24 h or until reaching the maximum daily dose of 30 ml/kg body weight, whatever occurs first. Sample size is estimated as 175 patients per group, 350 patients total (α = 0.025 one-tailed, power 1-β = 0.8). Composite primary endpoint evaluated in an exploratory manner will be 90-day mortality and 90-day renal failure, defined as AKIN stage ≥ 2, RIFLE injury/failure stage, or use of renal replacement therapy (RRT) during the first 3 months. Secondary efficacy and safety endpoints are fluid administration and balance, changes in vital signs and hemodynamic status, changes in laboratory parameters including renal function, coagulation, and inflammation biomarkers, incidence of adverse events during treatment period, hospital, and intensive care unit (ICU) length of stay, fitness for ICU or hospital discharge, and duration of mechanical ventilation and/or RRT. This pragmatic study will increase the evidence on safety and efficacy of 6% HES 130 for treatment of hypovolemia secondary to acute blood loss in trauma patients. Registered in EudraCT, No.: 2016-002176-27 (21 April 2017) and ClinicalTrials.gov, ID: NCT03338218 (09 November 2017).


Effect of systemic corticosteroid therapy for acute heart failure patients with elevated C-reactive protein.
The current study explores whether degree of inflammation, reflected by C-reactive protein (CRP) level, modifies the effect of intravenous (IV) corticosteroid administered in the emergency department (ED) on clinical outcomes in patients with acute heart failure (AHF). We selected patients diagnosed with AHF in the ED, with confirmed N-terminal pro-B-type natriuretic peptide > 300 pg/mL and CRP > 5 mg/L in the ED from the Epidemiology of Acute Heart Failure in the Emergency Departments (EAHFE) registry. In these 1109 patients, 121 were treated by corticosteroid. The corticosteroid therapy hazard ratio (HR) for 30 day all-cause mortality was 1.26 [95% confidence interval (CI) 0.75-2.09, P = 0.38]. Although not statistically significant, HRs tended to decrease with increasing CRP level, with point estimates favouring corticosteroid at CRP levels above 20. In patients with CRP > 40 mg/L, with adjusted HRs of 0.56 (95% CI 0.20-1.55, P = 0.27) for 30 day all-cause mortality, 0.92 (95% CI 0.52-1.62, P = 0.78) for 30 day post-discharge ED revisit, hospitalization, or death, and adjusted odds ratio of 0.61 (95% CI 0.17-2.14, P = 0.44) for in-hospital all-cause mortality. The present analysis suggests that corticosteroids might have the potential to improve outcomes in AHF patients with inflammatory activation. Larger, prospective studies of anti-inflammatory therapy should be considered to assess potential benefit in patients with the highest degree of inflammation.


Inferior vena cava anomalies and variations: imaging and rare clinical findings.
The aim of this paper is to summarize imaging findings of some frequent and infrequent inferior vena cava (IVC) anomalies and variations. IVC anomalies should be suspected in patients presenting with pulmonary emboli, chronic pain, and deep vein thrombosis. To correctly characterize and classify IVC anomalies and variations is of crucial importance for proper planning of surgical interventions and thus for avoiding serious complications. • IVC anomalies should be suspected in patients with pulmonary emboli, pain, and venous thrombosis. • Awareness of IVC anomalies and variations is crucial for clinical and surgical procedures. • Unawareness of these anomalies may lead to severe and deadly complications.


Efficacy and Safety of Non-Steroidal Anti-Androgens in Patients with Metastatic Prostate Cancer: Meta-Analysis of Randomized Controlled Trials.
Prostate cancer (PCa) is the sixth primary cause of cancer death. However, conflicts are present about the efficacy and safety of Non-steroidal anti-androgens (NSAA) for its treatment. The aim of this study was to assess the efficacy and safety of NSAAs versus any comparator for the treatment of advanced or metastatic PCa (mPCa). MEDLINE and the Cochrane Library were searched. References of included studies and clinicaltrials.gov were also searched for relevant studies. Only English language studies after 1990 were considered for review. Randomized controlled trials (RCTs) examining the efficacy and safety of NSAAs as compared with any other comparator including surgery or chemotherapy in mPCa patients were included. The outcomes include efficacy, safety and the tolerability of the treatment. The Cochrane Risk of Bias Assessment Tool was used for quality assessment. Two authors were independently involved in the selection, extraction and quality assessment of included studies and disagreements were resolved by discussion or by consulting a third reviewer. Fifty-eight out of 1307 non-duplicate RCTs with 29154 patients were considered for the review. NSAA showed significantly better progression-free survival [PFS] (Hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.78; P=0.0001), time to distant metastasis or death [TTD] (HR, 0.80; 95% CI 0.73-0.91; P<0.0001), objective response (Odds ratio [OR], 1.64; 95% CI 1.06-2.54; P=0.03) and clinical benefits (OR, 1.33; 95% CI 1.08-1.63; P=0.006) as compared to the control group. There was no significant difference observed between the groups in terms of overall survival (HR, 0.95; 95%CI, 0.87-1.03; P=0.18) and time to progression (HR, 0.93; 95% CI 0.77-1.11; P=0.43). Treatment-related adverse events were more with the NSAA group, but the discontinuation due to lack of efficacy reason was 43% significantly lesser than the control group in patients with mPCa. Rest of the outcomes were appeared to be non-significant. Treatment with NSAA was appeared to be better efficacious with respect to PFS, TTD, and response rate with considerable adverse events when compared to the control group in patients with metastatic PCa.


[Effects of craniocerebral hypothermia on the course of climacteric syndrome].
Craniocerebral hypothermia was used in the treatment of 43 women aged 48 to 55, suffering from the climacteric syndrome of varying severity. The treatment efficacy was confirmed by EEG data and changes in blood levels of ACTH, LH, prolactin, and hydrocortisone.


Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance.
Chemical intolerance (CI) is a widespread occupational and public health problem characterized by symptoms that reportedly result from low-levels of chemical exposure. The mechanisms behind CI are unknown, however modifications of the chemical senses (rather than toxic processes) have been suggested as key components. The aim of this study was to investigate whether individuals with self-reported CI report more sensory irritation during masked acrolein exposure compared to controls without CI. Individuals with CI (n=18) and controls without CI (n=19) were exposed in an exposure chamber. Each participant took part in two exposure conditions - one with heptane (the masking compound), and one with heptane and acrolein at a dose below previously reported sensory irritation thresholds. The exposures lasted for 60min. Symptoms and confidence ratings were measured continuously throughout the exposure as were measurements of electrodermal activity and self-reported tear-film break-up time. Participants were blind to exposure condition. Individuals with CI, compared with controls reported greater sensory irritation in the eyes, nose and throat when exposed to acrolein masked with heptane. There was no difference during exposure to heptane. Masked exposure to acrolein at a concentration below the previously reported detection threshold is perceived as more irritating by individuals with CI compared with controls. The results indicate that there is altered trigeminal reactivity in those with CI compared to controls.


[Clinical and genetic analysis of a patient with 17-hydroxylase/17,20-lyase deficiency].
To explore the clinical and genetic characteristics of a patient with 17-hydroxylase/17,20-lyase deficiency. The patient was infertile without contraception. Laboratory examination showed her chromosomal karyotype to be 46, XX. DNA sequencing was performed to detect variants of CYP17A1 gene in the patient and her family members. Sanger sequencing revealed that the patient has carried homozygous variant c.1486C>T in the exon 8 of the CYP17A1 gene, which resulted in substitution of arginine by cysteine (p.Arg496Cys). Her family members were all heterozygotes for the same variant. Homozygous variant of the CYP17A1 gene c.1486C>T probably underlay the 17-hydroxylase deficiency in this patient. Above finding has enabled accurate genetic counseling and prenatal diagnosis for her family.


Fructooligosaccharides (FOS) significantly increased the relative abundance of intestinal B. pseudolongum in mice with different genotypes.
Fructooligosaccharides (FOS) promote the proliferation of Bifidobacterium, especially Bifidobacterium pseudolongum in C57BL/6J mice. However, the response of intestinal microbes to FOS is influenced by host genotypes. Therefore, we compared the intestinal microbiota of four commonly used mice before and after FOS intervention, including C57BL/6J, BALB/c, Institute Cancer Research (ICR), and Kunming (KM) mice. The intestinal microbiota of the four genotypes exhibited similarities in composition but differences in relative abundance. Bifidobacterium was significantly increased to different degrees in the four genotypes of mice after FOS intervention, and Akkermansia and Bacteroides were also significantly increased in BALB/c and KM mice. Lactobacillus and Alistipes levels were unchanged or decreased. Within the genus Bifidobacterium, B. pseudolongum was the dominant species in the four genotypes of mice and proliferated significantly after FOS intervention, with dramatic proliferation in C57BL/6J mice (9.49%). Furthermore, eight strains of B. pseudolongum were screened from the feces of mice with four genotypes, and there was a great difference in the ability and manner of utilizing FOS among the strains. The strains from C57BL/6J mice exhibited the strongest utilization of 1-kestose (GF2), whereas other strains could utilize both GF2 and nistose (GF3) weakly. The gut microbial analysis of mice with different genotypes complemented our previous studies. The results provided the background strains of the different mouse genotypes and suggested a correlation between the utilization ability and the response of the strains to FOS. Further studies on the utilization ability of strains and competition in the intestine will contribute to the understanding of the mechanisms of the intestinal microbial response to diet.


Predictive value of sperm morphology and progressively motile sperm count for pregnancy outcomes in intrauterine insemination.
To investigate the value of sperm parameters to predict an ongoing pregnancy outcome in couples treated with intrauterine insemination (IUI), during a methodologically stable period of time. Retrospective, observational study with logistic regression analyses. University hospital. A total of 1,166 couples visiting the fertility laboratory for their first IUI episode, including 4,251 IUI cycles. None. Sperm morphology, total progressively motile sperm count (TPMSC), and number of inseminated progressively motile spermatozoa (NIPMS); odds ratios (ORs) of the sperm parameters after the first IUI cycle and the first finished IUI episode; discriminatory accuracy of the multivariable model. None of the sperm parameters was of predictive value for pregnancy after the first IUI cycle. In the first finished IUI episode, a positive relationship was found for ≤4% of morphologically normal spermatozoa (OR 1.39) and a moderate NIPMS (5-10 million; OR 1.73). Low NIPMS showed a negative relation (≤1 million; OR 0.42). The TPMSC had no predictive value. The multivariable model (i.e., sperm morphology, NIPMS, female age, male age, and the number of cycles in the episode) had a moderate discriminatory accuracy (area under the curve 0.73). Intrauterine insemination is especially relevant for couples with moderate male factor infertility (sperm morphology ≤4%, NIPMS 5-10 million). In the multivariable model, however, the predictive power of these sperm parameters is rather low.


Association of F2-isoprostane levels with Alzheimer's disease in observational studies: A systematic review and meta-analysis.
The association between F2-isoprostanes and Alzheimer's disease (AD) has been controversially discussed in the literature since the 1990s. However, no systematic review has been performed so far. A systematic review of observational studies on the associations of F2-isoprostanes and the specific biomarker 8-iso-prostaglandin F2α with AD were conducted. Random-effects model meta-analyses were performed. 29 studies were included in the systematic review, including four longitudinal studies. In an overall meta-analysis of the 25 cross-sectional studies, F2-isoprostane levels were statistically significantly associated with AD (Hedge's g [95% confidence interval]: 1.00 [0.69-1.32]). When studies were grouped by biomarker and sample specimen, F2-isoprostane and 8-iso-prostaglandin F2α levels were statistically significantly elevated in tissue samples of the frontal lobe of AD patients. Moreover, F2-isoprostane levels in cerebrospinal fluid and 8-iso-prostaglandin F2α levels in blood samples of AD patients were significantly increased. Meta-analyses of the few longitudinal studies did not reach statistical significance. Increased concentrations of F2-isoprostanes were found in AD patients. However, due to the lack of adjustment in most cross-sectional case-control studies, results must be interpreted carefully. In addition, the causality of the association is uncertain because evidence from well-conducted longitudinal studies was conflicting, and further longitudinal studies are required to reinforce the results.


The impact of anticipated action effects on action planning.
Three experiments with a total of 72 participants investigated the assumption that motor actions are planned in terms of their sensorial effects. Participants had to prepare a certain action A that consistently led to a sensorial effect (a tone of certain pitch). Instead of (in Experiment 1) or before (in Experiments 2 and 3) the execution of the prepared action, another response B had to be carried out, which either resulted in the same or in a different auditory effect (a tone of same or different pitch). It was found that a to-be-executed response B was in general initiated more quickly when it resulted in the same effect as a concurrently prepared response A. The results are considered as evidence for the basic notion that the preparation and initiation even of very simple actions is mediated by an anticipation of their reafferences.


Proximal Humerus Fractures in the Pediatric Population.
The purpose of this review is to review recent literature focusing on proximal humerus anatomy, epidemiology of these fractures, diagnosis and treatment options, and clinical outcomes. Non- or minimally displaced proximal humerus fractures treated nonoperatively do not lead to short- or long-term complication and do not cross over to operative treatment. There is a higher rate of operative management with older age, increased injury severity score, treatment at an adult hospital, and private insurance. Operative management is preferred with closed or open reduction and percutaneous pinning, but elastic nailing and plate fixation are other options with good postoperative outcomes. Pediatric proximal humerus fractures occur after fall onto the affected shoulder or arm. Diagnosis is usually made with radiographs. Understanding the proximal humerus anatomy is critical to the proper management of these injuries to aid reduction and predict remodeling potential. There is considerable debate around the management of proximal humerus fractures in the pediatric population. Treatment is based on patient age, fracture displacement, and remodeling capacity. Nonoperative management is successful in younger patients or less displaced fractures, and operative management is usually considered in older patients with more displaced fractures.


Unraveling pleiotropic effects of rifampicin by using physiologically based pharmacokinetic modeling: Assessing the induction magnitude of P-glycoprotein-cytochrome P450 3A4 dual substrates.
Rifampicin induces both P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) through regulating common nuclear receptors (e.g., pregnane X receptor). The interplay of P-gp and CYP3A4 has emerged to be an important factor in clinical drug-drug interactions (DDIs) with P-gp-CYP3A4 dual substrates and requires qualitative and quantitative understanding. Although physiologically based pharmacokinetic (PBPK) modeling has become a widely accepted approach to assess DDIs and is able to reasonably predict DDIs caused by CYP3A4 induction and P-gp induction individually, the predictability of PBPK models for the effect of simultaneous P-gp and CYP3A4 induction on P-gp-CYP3A4 dual substrates remains to be systematically evaluated. In this study, we used a PBPK modeling approach for the assessment of DDIs between rifampicin and 12 drugs: three sensitive P-gp substrates, seven P-gp-CYP3A4 dual substrates, and two P-gp-CYP3A4 dual substrates and inhibitors. A 3.5-fold increase of intestinal P-gp abundance was incorporated in the PBPK models to account for rifampicin-mediated P-gp induction at steady state. The simulation results showed that accounting for P-gp induction in addition to CYP3A4 induction improved the prediction accuracy of the area under the concentration-time curve and maximum (peak) plasma drug concentration ratios compared with considering CYP3A4 induction alone. Furthermore, the interplay of relevant drug-specific parameters and its impact on the magnitude of DDIs were evaluated using sensitivity analysis. The PBPK approach described herein, in conjunction with robust in vitro and clinical data, can help in the prospective assessment of DDIs involving other P-gp and CYP3A4 dual substrates. The database reported in the present study provides a valuable aid in understanding the combined effect of P-gp and CYP3A4 induction during drug development.


Attractive benzothiazole-based fluorescence probe for the highly efficient detection of hydrogen peroxide.
In current work, one novel benzothiazole-based fluorescent chemosensor (TZ-BO) with ESIPT luminescence mechanism was designed for the detection of hydrogen peroxide (H2O2) as typical reactive oxygen species (ROS). The boronate catenary in our designed probe molecule TZ-BO is both the blocking group of ESIPT and the reactive group of H2O2. The synthesized probe TZ-BO has the advantages of large Stokes shift, high sensitivity, good selectivity, and fast reaction speed to H2O2. The ability of the probe to detect H2O2 in aqueous media and exogenous H2O2 in cells by fluorescence signal was investigated. The experimental results manifested that probe TZ-BO is able to sensitively detect H2O2 using a fluorescence method in an excellent linear range of H2O2 concentration from 0 to 60 μM (R2 = 0.994). The detection limit was determined as 1.0 × 10-6 M. Most importantly, the probe TZ-BO with highly low cytotoxicity can effectively detect exogenous H2O2 in HeLa cells. This probe provides a promising tool for monitoring the real concentration level of H2O2 in related physiological and pathological researches.


Delta sleep-inducing peptide crosses the blood-brain-barrier in dogs: some correlations with protein binding.
To determine if the nonapeptide delta sleep-inducing peptide (DSIP) and some of its analogs can enter the cerebrospinal fluid (CSF) from the peripheral circulation, dogs anesthetized with sodium pentobarbital were injected with a 100 micrograms/kg bolus of DSIP, desTrp1-DSIP, or D-Ala3-DSIP. Using an antibody that is highly specific for these nonapeptides, we found significant increases in CSF after IV injection of each. Column chromatography of CSF withdrawn after an IV bolus of DSIP showed the increase in immunoreactivity to be due to DSIP and desTrp1-DSIP. Chromatography of radioactivity appearing in the CSF after an IV bolus of 125I-N-Tyr-DSIP showed co-elution with the intact labeled peptide. The CSF/plasma ratios for DSIP and 125I-N-Tyr-DSIP were higher than that for tritiated insulin injected IV. It was also shown that DSIP is reversibly bound to a large molecule in dog plasma and CSF, and that the binding is greater in blood than in CSF. The binding protein demonstrates some specificity for DSIP, binding a smaller percentage of D-Ala3-DSIP, and it appears that it is probably free DSIP that crosses the blood-brain-barrier. Although non-specific crossing cannot be ruled out, the results presented here are also consistent with a specific saturable process for DSIP.


The location and the regulation of the type I-iodothyronine 5'-monodeiodinase (type I-MD) in the rat thyroid: studies using a specific anti-type I-MD antibody.
Type I-iodothyronine monodeiodinase (type I-MD) is abundant in thyroid tissue and contributes to the generation of T3 secreted by the gland. The availability of a specific antibody against rat type I-MD (type I-MD Ab) allowed us to directly identify this enzyme in rat thyroid glands, and in a differentiated strain of rat thyroid cells maintained in continuous culture (FRTL-5 cells). FRTL-5 cells maintain many differentiated functions of thyroid cells, including the expression of TSH receptor and thyroid peroxidase. Using an immunohistochemical technique on rat thyroid sections, a clear staining for type I-MD was demonstrated in follicular cells. The degree of immunoreactivity was greater in small follicles containing little amounts of colloid compared to large follicles lined by functionally inactive cells. Using immunofluorescence (IFL), a strong staining for type I-MD was observed in FRTL-5 cells grown in medium containing TSH. Both in vivo and in culture the staining for type I-MD was localised in the cytoplasm of thyroid cells, while nuclei were negative. Interestingly, no surface staining was shown when viable FRTL-5 cells were submitted to the same IFL procedure. TSH deprivation for 7 days was followed by the disappearance of type I-MD. Immunoreactivity for type I-MD was recovered by addition of TSH, forskolin or thyroid stimulating antibody (TSAb) to TSH-deprived FRTL-5 cells. The effect of TSH was prevented by cycloheximide. There was no induction of type I-MD when IGF-I was added to FRTL-5 cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Cross-border reproductive care for law evasion: should physicians be allowed to help infertility patients evade the law of their own country?
There are fundamental differences between countries with regard to legislation on assisted reproduction. Many infertility patients are looking to evade the law of their own country and make use of reproductive services abroad. The role of the local physician in cross-border reproductive care for law evasion has been characterized as "channeling local patients to foreign medical establishments" and "against the spirit and essence of the law". The logical view is that by supporting CBRC for law evasion, physicians are essentially supporting immoral behavior. We will tackle this position on two levels. First, we will argue that governments should generally be tolerant toward people with different positions on assisted reproduction. Second, we will show that contributing to cross-border reproductive care for law evasion is not necessarily immoral, because the prima facie wrongness of complicity in law evasion can be outweighed by the fact that physicians should act in the best interest of the patient. Several countries have tried to prevent local physicians from helping patients to make use of reproductive services abroad, but they should rather leave it up to the individual physicians to decide whether or not to support a particular patient.


Reoperation for a patient with Starr-Edwards aortic valve malfunction due to pannus formation twenty-nine years after implantation.
We report a re-do case of severe aortic valve stenosis due to pannus formation 29 years after an aortic Starr-Edwards caged-ball valve implantation. A huge shelf of calcified and thick pannus tissue below the valve had reduced the already small orifice by at least a third in surface area. The explanted Starr-Edwards valve revealed no mechanical or structural failure. Early detection and treatment of pannus outgrowth is essential in order to prevent life-threatening prosthetic valve malfunctions.


Assignment of the human gene for peptidase E to the chromosomal region 17q23----17qter.
Peptidase E has been studied in 16 independent human-Syrian hamster hybrids and 16 subclones. Evidence is presented indicating that the human gene for Peptidase E is on chromosome 17 in the region 17q23----17qter.


Injuries and deaths caused by non-human primate attacks: Paediatric vulnerability.
A six-month-old girl was taken from her mother's lap by a macaque monkey (Macaca) that had entered the room through an open door. The monkey escaped with the infant but subsequently dropped her from a rooftop terrace. Death occurred soon after impact with the ground, and was found at autopsy to be due to blunt cranio-cerebral trauma with skull fractures and intracranial haemorrhage. Monkeys and apes may cause a variety of serious and potentially life-threatening injuries and may manifest quite unpredictable and aggressive behaviour around humans. The very young are particularly vulnerable to primate attacks, and 'baby theft' by apes and monkeys is an event that has now been reported, albeit rarely, in a number of different countries around the world. The fatally injured infants have died from bites, falls and drowning. Chimpanzees in the wild may also specifically hunt human infants for food.


Induction of male-typical aggression by androgens but not by estrogens in adult female mice.
Ovariectomized adult CF-1 female mice were implanted with silastic capsules containing either testosterone (T), dihydrotestosterone (DHT), methyltrienolone (R1881), estradiol (E2), diethylstilbestrol (DES), or oil vehicle and were tested for aggressive behavior. The androgenic treatments (T, DHT, R1881) were highly effective in promoting male-like aggression while the estrogens (DES, E2) were completely ineffective. Subsequent receptor-binding studies confirmed assumptions about the specificity of DES, DHT, and R1881 binding to estrogen and androgen receptors in mouse hypothalamus.


Universality and context-specificity in early executive function development.
A renewed interest in early executive function (i.e., EF or the conscious control of thought and behavior) development has led several research groups to suggest that EF may be emerging and is less coordinated (e.g., showing few relations between tasks) in the first few years (Devine et al., 2019; Gago Galvagno et al., 2021; Johansson et al., 2016; Miller & Marcovitch, 2015; Ribner et al., 2022). This potentially universal development in EF does not exclude the possibility that EF may also differ across context (e.g., Gago Galvagno et al., 2021; Lohndorf et al., 2019; Tran et al., 2015) reflecting unique strengths and development built within one's sociocultural environment. The present paper explores potential universal and context-specific early EF developments by focusing on three aims: (1) reviewing work on EF within the first two years of life that may speak to potential universality in the measurement, structure, growth, stability, and conceptualization of early EF (2) reviewing research that may speak to how the sociocultural context may play a role in context-specific development within early EF and (3) examining potential developmental EF frameworks for understanding universal and context-specific developments of early EF within context.


Distinct polymer-dependent sorption of persistent pollutants associated with Atlantic salmon farming to microplastics.
Interactions of microplastics and persistent organic pollutants (POPs) associated with Atlantic salmon farming were studied to assess the potential role of microplastics in relation to the environmental impact of aquaculture. HDPE, PP, PET and PVC microplastics placed for 3 months near fish farms sorbed POPs from aquafeeds. PET and PVC sorbed significantly higher levels of dioxins and PCBs compared to HDPE, while the levels sorbed to PP were intermediate and did not differ statistically from PET, PVC or HDPE. In addition, the composition of dioxins accumulated in caged blue mussels did not reflect the patterns observed on the microplastics, probably due to polymer-specific affinity of POPs. In conclusion, the results of this study show that microplastics occurring near fish farms can sorb aquafeed-associated POPs and, therefore, microplastics could potentially be vectors of such chemicals in the marine environment and increase the environmental impact of fish farming.


Randomness in retrospect: exploring the interactions between memory and randomness cognition.
People tend to believe that sequences of random events produce fewer and shorter streaks than is actually the case. Although this error has been demonstrated repeatedly and in many forms, nearly all studies of randomness cognition have focused on how people think about random events occurring in the present or future. This article examines how our biased beliefs about randomness interact with properties of memory to influence our judgments about and memory for past random events. We explore this interaction by examining how beliefs about randomness affect our memory for random events and how certain properties of memory alter our tendency to categorize events as random. Across three experiments, we demonstrate an interaction between randomness cognition and three well-established but distinct properties of memory: (1) the reconstructive nature of memory, (2) primacy and recency effects, and (3) duration neglect. Theoretical and practical implications are discussed.


Effects of the supplementation with a multispecies probiotic on clinical and laboratory recovery of children with newly diagnosed celiac disease: A randomized, placebo-controlled trial.
To evaluate the efficacy of a multispecies probiotic on clinical and laboratory recovery of children with celiac disease (CeD) at diagnosis. Children with newly diagnosed CeD entered a randomized double-blind placebo-controlled trial. A gluten-free diet (GFD) plus a multispecies probiotic or placebo were administered for 12 weeks. Growth, laboratory, and clinical parameters were recorded at enrollment, after 3 and 6 months of follow-up. Overall, 96 children completed the study: 49 in group A (placebo) and 47 in group B (probiotic). A significant increase of BMI-Z score was found in both groups after 3 and 6 months of treatment (p < 0.001), however the increase of BMI-Z score was significantly higher and faster in Group B than in Group A. Other clinical and laboratory parameters improved in both groups after 3 and 6 months (p<0.001), but no difference was found between the groups and a comparable time trend was observed in both groups. Treatment with a multispecies probiotic induced a higher and faster increase of BMI in children with newly diagnosed CeD. The mechanism of this positive effect remains to be elucidated.


The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus.
Since their approval, thiazolidinediones (TZDs) have been used extensively as insulin-sensitizers for the management of type 2 diabetes mellitus (T2DM). Activation of peroxisomal proliferator-activated receptor gamma (PPARγ) nuclear receptors by TZDs leads to a vast spectrum of metabolic and antiinflammatory effects. In the past decade, clinicians and scientists across the fields of metabolism, diabetes, liver disease (NAFLD), atherosclerosis, inflammation, infertility, and even cancer have had high hopes about the potential for TZDs to treat many of these diseases. However, an increasing awareness about undesirable "off-target" effects of TZDs have made us rethink their role and be more cautious about the long-term benefits and risks related to their use. This review examines the most relevant work on the benefits and risks associated with TZD treatment, with a focus on the only PPARγ agonist currently available (pioglitazone), aiming to offer the reader a balanced overview about the current and future role of TZDs in the management of insulin-resistant states and T2DM.


HER2 overexpression is associated with worse outcomes in patients with upper tract urothelial carcinoma (UTUC).
The aim of our study was to evaluate the expression pattern of HER2 overexpression in patients with upper tract urothelial carcinoma (UTUC) and to evaluate its association with clinical outcomes. This multicenter retrospective study included 732 patients treated with radical nephroureterectomy for UTUC. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest: Scores of 0 or 1 were considered negative and 2 or 3 as positive. To qualify for 2 scoring, complete membrane staining of more than 10 % of tumor cells at a moderate intensity had to be observed. HER2 was overexpressed in 262 (35.8 %) patients. It was associated with pathologic characteristics such as more advanced T stage (p < 0.001), presence of lymph node metastasis (p = 0.006), high-grade tumor (p < 0.001), tumor necrosis (p = 0.01) and lymphovascular invasion (p = 0.02). Patients with HER2 overexpression had a 1.66-fold increased risk of experiencing disease recurrence (95 % CI 1.24-2.24, p = 0.001), 1.55-fold increased risk of death (95 % CI 1.21-1.99, p = 0.001) and 1.81-fold increased risk of cancer-specific death (95 % CI 1.33-2.48, p < 0.001). On multivariable analysis that adjusted for the effects of standard clinicopathologic variables, HER2 overexpression remained associated with disease recurrence (p = 0.04), overall (p = 0.02) and cancer-specific mortality (p = 0.02). Approximately, one-third of UTUC patients overexpressed HER2. HER2 overexpression was associated with features of clinically and biologically aggressive disease as well as prognosis. HER2 may represent a good marker for therapeutic risk stratification and potentially a target for therapy in some UTUC tumors.


DRGs and the "negative" trauma workup.
We conducted a study to assess the financial impact of the diagnostic workup and care of 136 trauma patients admitted to our institution during a six-month period who were subsequently found to have only minor injuries (Injury Severity Score less than or equal to 9, Abbreviated Injury Score less than 3). The New Jersey DRG reimbursement system, an all-payer system, failed to provide adequate financial compensation overall, as the average loss per patient (operating cost minus reimbursement) was $508. Lost potential revenue (hospital charges minus reimbursement) was even greater, averaging $1,834 per patient. We conclude that the New Jersey DRG reimbursement system, in its current form, provides inadequate reimbursement for the system, in its current form, provides inadequate reimbursement for the proper workup and treatment of trauma patients with minor injuries. Because these patients are those most likely to help "subsidize" the care of sicker patients, changes in the system are necessary to allow hospitals to continue to provide state-of-the-art trauma care and to continue to minimize the number of preventable deaths due to trauma.


Uncovering novel 3-hydroxy-4-pyridinone metal ion complexes with potential anti-inflammatory properties.
Ligands of the 3-hydroxy-4-pyridinone (3,4-HPO) type, with one (Hmpp) or two methyl groups (Hdmpp), have been reported to possess biomedical, chemical and analytical applications. In this first screening study aiming to uncover new promising agents to mitigate the oxidative damage highly present in several metabolic disorders, such as diabetes mellitus, we assessed the potential of twelve 3,4-HPO metal ion complexes to modulate oxidative burst in human neutrophils. Metal ion 3,4-HPO complexes of Ni, Fe, V, Co, Cu and Zn were synthesized and tested up to 15μM. Among all the compounds, [Cu(mpp)2] and [Cu(dmpp)2] exhibited the highest scavenging capacity against superoxide radical (O2(-)) (IC50=0.36±0.07 and 0.30±0.06μM, respectively) and against hypochlorous acid (HOCl) (IC50=0.6±0.3 and 0.4±0.1μM, respectively). In the particular case of O2(-), [Fe(mpp)3] and [Fe(dmpp)3] (both at 15μM) presented 35% and 22% of inhibition, respectively, while all the other compounds were neither able to scavenge O2(-) nor stimulate its production. Regarding the scavenging capacity against hydrogen peroxide (H2O2), all the compounds showed low efficiency (from 6-39%). Finally, with exception of [VO(mpp)2] and [VO(dmpp)2], all compounds exhibited scavenging activity against HOCl (39-81%) and the most efficient compounds were Cu(II) and Zn(II) complexes. Thus, these preliminary results uncover promising new metal ion complexes, inhibitors of neutrophil's oxidative burst, with potential anti-inflammatory properties, which may be seen as an useful strategy for further studies in the treatment of a number of diseases where oxidative damage is a serious issue.


Stable isotope tracing internal recycling and evaporation losses in saline lakes on the Qinghai-Tibet Plateau.
Direct measuring of internal lake recycling and evaporation losses remains challenging for lakes on the Qinghai-Tibet Plateau (QTP). Stable isotope techniques provide an effective approach for estimating water vapor cycling ratios and evaporation losses of lakes on the QTP. In this study, the stable isotope values of saline lakes on the QTP were modeled using the stable isotope values of the sampled lake water and their influencing factors. The water vapor recycling ratio and evaporation loss (E/I) of 135 saline lakes on the QTP were evaluated and their influencing factors were revealed. The results showed that stable isotopes in saline lakes on the QTP showed significant spatial variability. Their stable isotopes were affected by the source of water vapor, recharge patterns, and local evaporation conditions. It's worth noting that the average water vapor recycling ratio of saline lakes on the QTP was 20.16 %, one-fifth of the saline lakes had a water vapor recycling ratio beyond 30 %. Saline lakes lose 26 % of their water through evaporation. 26 % of the saline lakes experienced high evaporation losses of >40 % of the total inflow. We found that the main factors controlling the water vapor recycling ratio and evaporation loss in saline lakes on the QTP were precipitation and altitude, respectively. Interestingly, the control factors of water vapor recycling ratio and evaporation loss in saline lakes with elevation above 4500 m showed significant differences compared to saline lakes with elevation below 4500 m. Therefore, the strengthening of lake system monitoring can provide reliable data support for security assessment and effective management of water resources on the QTP.


Effects of different growth patterns of Tamarix chinensis on saline-alkali soil: implications for coastal restoration and management.
To better understand the wetland restoration, the physicochemical property and microbial community in rhizosphere and bulk soil of the living and death Tamarix chinensis covered soil zones were studied. There were differences between growth conditions in the levels of soil pH, salinity, SOM, and nutrient. The living status of T. chinensis exhibited higher capacity of decreasing saline-alkali soil than the death condition of plants, and the living T. chinensis showed higher uptake of N, P, and K as compared with the death samples. Proteobacteria, Bacteroidota, and Chloroflexi were the predominant bacterial communities as revealed via high-throughput sequencing. It is great potential for using halophytes such as T. chinensis to ecological restore the coastal saline-alkali soil. This study could contribute to a better understanding of halophyte growth during the coastal phytoremediation process, and guide theoretically for management of T. chinensis population.


Down-regulated lysosomal processing improved pegylated lipopolyplex-mediated gene transfection.
Nonviral lipid-based gene delivery vectors have been shown to possess better stability and a longer circulation time after surface poly(ethylene glycol) PEG modification. However, surface PEGylation may decrease the transfection efficiency dramatically. In the present study, we addressed the hypothesis that down-regulating lysosomal processing with a clinical available proton pump inhibitor omeprazole might decrease the sequestration of PEGylated Lipid-Mu-DNA (LMD) in intracellular organelles, thereby increasing their transfection efficiencies. LMD nanoparticles were prepared by the self-assembling of cationic liposomes, peptide Mu and plasmid DNA. The characteristics of LMD lipopolyplexes were detected by scanning electron microscopy, photon correlation spectroscopy and DNA gel electrophoresis. They were added to cultured cells with or without omeprazole pretreatment. The detailed cellular uptake and subcellular distribution were followed by flow cytometry and confocal microscopy. Gene transfection efficiencies were evaluated in four cell lines, as well as in xenograft tumor models. Lysosome staining revealed that 0.1 mg/ml (290 μM) omeprazole raised the pH value of intracellular acidic organelles and induced alterations in the lysosomal compartments. Confocal microscopy showed that more gene materials distributed from intracellular organelles to cytoplasms with omeprazole treatment. A luciferase gene transfection assay showed that omeprazole (probably at a nontoxic concentration) increased PEGylated LMD transfection efficiency significantly in human (NCI-H1299, HT-1080 and A375) and mouse (4T1) cell lines, as well as in tumors of H1299 xenograft tumor models (p < 0.05). Omeprazole might be used as a helper to improve gene transfection efficiencies of some PEGylated gene delivery vectors both in vitro and in vivo.


Inhibition of tumor angiogenesis by roxithromycin, a 14-membered ring macrolide antibiotic.
We examined the effects of roxithromycin, a 14-membered ring macrolide antibiotic, on tumor angiogenesis using a mouse dorsal air sac model. The inhibitory effect of roxithromycin was dose-dependent and 100 mg/kg of roxithromycin administered intraperitoneally twice a day reduced the dense capillary network area to about 20% of the control. However, at concentrations of up to 50 microM, roxithromycin had no effect on lung cancer cells and human vascular endothelial cell growth and lung cancer cell production of the angiogenesis-inducing factors interleukin-8 and vascular endothelial growth factor. Roxithromycin at concentrations greater than 20 microM inhibited endothelial cell migration and tube formation.


Patient-machine interactions of intravenous patient-controlled analgesia in bilateral versus unilateral total knee arthroplasty: a retrospective study.
Continuous passive motion after a major knee surgery optimizes functional prognosis, but causes severe pain. In this study, we assessed the effect of intravenous patient-controlled analgesia (IVPCA) on postoperative pain management in unilateral and bilateral total knee arthroplasty (TKA). Data were collected retrospectively from a single medical center from March 2003 to October 2007. All patients who had undergone TKA were given general anesthesia, and the type of surgery that each patient received was planned according to individual needs. A total of 223 patients qualified for this study, with 174 patients in the unilateral TKA group. Data on patient demography, pain scores, and side effect scores were collected. Total dose consumption, demand, delivery doses, demand-to-delivery ratio, and infusion rate were collected from PCA machines and analyzed. The patient pain score and patient satisfaction showed no significant difference between the unilateral and bilateral TKA groups. The incidence of sedation (p < 0.001), nausea (p = 0.013), and vomiting (p = 0.044) during the postoperative 24-48-hour period was higher in the bilateral TKA group. Compared with the patients in the unilateral group, those in the bilateral group showed significantly greater dose consumption during the postoperative 6-12-, 12-18-, and 18-24-hour periods. They also showed more demand for medication during the postoperative 12-18- and 18-24-hour periods and received more bolus doses during the postoperative 12-18-, 18-24-, and 30-36-hour periods. In addition, there was also a significantly higher demand-to-delivery ratio for patients in the bilateral group during the postoperative 6-12-, 12-18-hour periods. In this study, we successfully demonstrated that our IVPCA protocol can provide adequate analgesia for patients after both bilateral and unilateral TKA. However, sedation, nausea, and vomiting occurred more frequently during the postoperative 24-48-hour period in patients who underwent bilateral than unilateral TKA. This may due of the increased number of bolus doses administered to the patients in the bilateral TKA group during the postoperative 12-18, 18-24, and 30-36-hour periods. Therefore, the initial infusion rates for patients undergoing bilateral TKA could be set at a lower threshold in order to reduce the incidence of these side effects.


Thermal Dynamic Self-Healing Supramolecular Dopant Towards Efficient and Stable Flexible Perovskite Solar Cells.
Flexible perovskite solar cells (FPSCs) have attracted great attention due to their advantageous traits such as low cost, portability, light-weight, etc. However, mechanical stability is still the weak point in their practical application. Herein, we prepared efficient FPSCs with remarkable mechanical stability by a dynamic thermal self-healing effect, which can be realized by the usage of a supramolecular adhesive. The supramolecular adhesive, which was obtained by random copolymerization of acrylamide and n-butyl acrylate, is amphiphilic, has a proper glass transition temperature and a high density of hydrogen-bond donors and receptors, providing the possibility of thermal dynamic repair of mechanical damage in FPSCs. The adhesive also greatly improves the leveling property of the precursor solution on the hydrophobic poly[bis(4-phenyl)(2,4,6-trimethylphenyl)]amine (PTAA) surface. PSCs containing this adhesive achieve more than a 20 % power conversion efficiency (PCE) on flexible substrates and a 21.99 % PCE on rigid substrates (certified PCE of 21.27 %), with improved electron mobility and reduced defect concentration.


Acupuncture and moxibustion for malignant tumor patients with psychological symptoms of insomnia, anxiety and depression: a systematic review and Meta-analysis.
To evaluate the efficacy and safety of acupuncture and moxibustion therapy (AMT) for cancer-related psychological symptoms (CRPS) of insomnia, depression and anxiety. Seven databases were searched for randomized controlled trials (RCT) comparing AMT to routine care or conventional drug for alleviating CRPS of insomnia, depression, and anxiety before April 2020. Two independent reviewers performed the data extraction and assessed the risk of bias. A total of 30 RCTs involving 2483 cancer patients were enrolled. The pooled analysis indicated that the treatment group was significantly better than the control group in improving the depression effective rate [= 1.29, 95% (1.12, 1.49), 0.0004], the quality of life (QOL) [1.11, 95% (0.80, 1.42), 0.000 01], and reducing Self-rating Anxiety Scale (SAS) [﹣7.75, 95% (﹣10.44, ﹣5.05), 0.000 01]. But there was no statistically significant difference between two groups in improving the insomnia effective rate [= 1.18, 95% (0.93, 1.51), 0.18]. The subgroup analysis showed the effectiveness of different intervention on CRPS. Compared with routine care, AMT helps relieve CRPS better evaluated by Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Scale (HAMD), and Self-rating Depression Scale (SDS), and depression effective rate. Compared with conventional drug, AMT performs better evaluated by SDS, depression effective rate and QOL. Moreover, the conventional drug showed higher treatment efficacy on improving insomnia effective rate compared with AMT. Compared to conventional drug, AMT plus conventional drug resulted in a significant reduction on CRPS such as PSQI, HAMD, SDS, and SAS, and also had a meaningful improvement on insomnia effective rate, depression effective rate and QOL. Fewer published reports were found on the adverse events of AMT than the conventional drug. The results suggested that AMT might be effective in improving CPRI; however, a definite conclusion could not be drawn because the quality of trials are low. Further large-scale and high-quality RCTs to verify the efficacy and safety of AMT on CRPS are still warranted.


Metabolically active tumour volume segmentation from dynamic [(18)F]FLT PET studies in non-small cell lung cancer.
Positron emission tomography (PET) with (18)F-3'-deoxy-3'-fluorothymidine ([(18)F]FLT) can be used to assess tumour proliferation. A kinetic-filtering (KF) classification algorithm has been suggested for segmentation of tumours in dynamic [(18)F]FLT PET data. The aim of the present study was to evaluate KF segmentation and its test-retest performance in [(18)F]FLT PET in non-small cell lung cancer (NSCLC) patients. Nine NSCLC patients underwent two 60-min dynamic [(18)F]FLT PET scans within 7 days prior to treatment. Dynamic scans were reconstructed with filtered back projection (FBP) as well as with ordered subsets expectation maximisation (OSEM). Twenty-eight lesions were identified by an experienced physician. Segmentation was performed using KF applied to the dynamic data set and a source-to-background corrected 50% threshold (A50%) was applied to the sum image of the last three frames (45- to 60-min p.i.). Furthermore, several adaptations of KF were tested. Both for KF and A50% test-retest (TRT) variability of metabolically active tumour volume and standard uptake value (SUV) were evaluated. KF performed better on OSEM- than on FBP-reconstructed PET images. The original KF implementation segmented 15 out of 28 lesions, whereas A50% segmented each lesion. Adapted KF versions, however, were able to segment 26 out of 28 lesions. In the best performing adapted versions, metabolically active tumour volume and SUV TRT variability was similar to those of A50%. KF misclassified certain tumour areas as vertebrae or liver tissue, which was shown to be related to heterogeneous [(18)F]FLT uptake areas within the tumour. For [(18)F]FLT PET studies in NSCLC patients, KF and A50% show comparable tumour volume segmentation performance. The KF method needs, however, a site-specific optimisation. The A50% is therefore a good alternative for tumour segmentation in NSCLC [(18)F]FLT PET studies in multicentre studies. Yet, it was observed that KF has the potential to subsegment lesions in high and low proliferative areas.


Multicentre trial to introduce the Ottawa ankle rules for use of radiography in acute ankle injuries. Multicentre Ankle Rule Study Group.
To assess the feasibility and impact of introducing the Ottawa ankle rules to a large number of physicians in a wide variety of hospital and community settings over a prolonged period of time. Multicentre before and after controlled clinical trial. Emergency departments of eight teaching and community hospitals in Canadian communities (population 10,000 to 3,000,000). All 12,777 adults (6288 control, 6489 intervention) seen with acute ankle injuries during two 12 month periods before and after the intervention. More than 200 physicians of varying experience were taught to order radiography according to the Ottawa ankle rules. Referral for ankle and foot radiography. There were significant reductions in use of ankle radiography at all eight hospitals and within a priori subgroups: for all hospitals combined 82.8% control v 60.9% intervention(P < 0.001); for community hospitals 86.7% v 61.7%; (P < 0.001); for teaching hospitals 77.9% v 59.9%; (P < 0.001); for emergency physicians 82.1% v 61.6%; (P < 0.001); for family physicians 84.3% v 60.1%; (P < 0.001); and for housestaff 82.3% v 60.1%; (P < 0.001). Compared with patients without fracture who had radiography during the intervention period those who had no radiography spent less time in the emergency department (54.0 v 86.9 minutes; P < 0.001) and had lower medical charges ($70.20 v $161.60; P < 0.001). There was no difference in the rate of fractures diagnosed after discharge from the emergency department (0.5 v 0.4%). Introduction of the Ottawa ankle rules proved to be feasible in a large variety of hospital and community settings. Use of the rules over a prolonged period of time by many physicians of varying experience led to a decrease in ankle radiography, waiting times, and costs without an increased rate of missed fractures. The multiphase methodological approach used to develop and implement these rules may be applied to other clinical problems.


Critical Care of the Vascular Surgery Patient.
Patients that require major vascular surgery suffer from widespread atherosclerosis and have multiple comorbidities that place them at increased risk for postoperative complications and require admission to the intensive care unit (ICU). Postoperative critical care of these patients is focused on hemodynamic optimization, and early identification and management of complications to improve outcomes.


Impact of low-energy CT imaging on selection of positive oral contrast media concentration.
To determine to what extent low-energy CT imaging affects attenuation of gastrointestinal tract (GIT) opacified with positive oral contrast media (OCM). Second, to establish optimal OCM concentrations for low-energy diagnostic CT exams. One hundred patients (38 men and 62 women; age 62 ± 11 years; BMI 26 ± 5) with positive OCM-enhanced 120-kVp single-energy CT (SECT), and follow-up 100-kVp acquisitions (group A; n = 50), or 40-70-keV reconstructions from rapid kV switching-single-source dual-energy CT (ssDECT) (group B; n = 50) were included. Luminal attenuation from different GIT segments was compared between exams. Standard dose of three OCM and diluted solutions (75%, 50%, and 25% concentrations) were introduced serially in a gastrointestinal phantom and scanned using SECT (120, 100, and 80 kVp) and DECT (80/140 kVp) acquisitions on a ssDECT scanner. Luminal attenuation was obtained on SECT and DECT images (40-70 keV), and compared to 120-kVp scans with standard OCM concentrations. Luminal attenuation was higher on 100-kVp (328 HU) and on 40-60-keV images (410-924 HU) in comparison to 120-kVp scans (298 HU) in groups A and B (p < 0.05). Phantom: There was an inverse correlation between luminal attenuation and X-ray energy, increasing up to 527 HU on low-kVp and 999 HU on low-keV images (p < 0.05). 25% and 50% diluted OCM solutions provided similar or higher attenuation than 120 kVp, at low kVp and keV, respectively. Low-energy CT imaging increases the attenuation of GIT opacified with positive OCM, permitting reduction of 25%-75% OCM concentration.


Novel phlebovirus-like-AYUT and Stenotrophomonas maltophilia bacterial co-infection in a Rhipicephalus sanguineus s.l. tick.
Tick-borne viruses and bacteria that can cause diseases of animals and humans have high impact and are of concern as significant threats to human health worldwide. In this research, we screened microorganisms related to those pathogens in ticks from dogs, a cat, and a cow. The techniques used were PCR, DNA sequencing and phylogenetic analysis to detect and classify the microorganisms [Flavivirus, severe fever with thrombocytopenia syndrome virus (SFTSV), Phlebovirus, Coronavirus, Canine Parvovirus, eubacteria, Coxiella and Rickettsia]. A novel virus named Phlebovirus-like-AYUT and Stenotrophomonas maltophilia bacteria were found in one individual tick (Rhipicephalus sanguineus s.l.) from a dog. All tick samples were negative for Rickettsia, while 9/21 (42.9 %) were positive for Coxiella bacteria. The novel virus "Phlebovirus-like-AYUT" (the name derives from Phra Nakhon Si Ayutthaya Province in Thailand) was resolved by phylogenetic analysis of the partial L segment by maximum likelihood (ML) method using MEGA X. The phylogenetic tree also indicated that the virus was related to Phlebovirus in brown dog ticks reported in Trinidad and Tobago. In contrast, Phlebovirus-like-AYUT was in a distinct clade from Lihan tick Phlebovirus-Thailand (LTPV), which was previously found in cow ticks, Rhipicephalus microplus, in Nan Province, Thailand. This study reports the Stenotrophomonas maltophilia bacterium with a novel Phlebovirus-like-AYUT in a brown dog tick. The roles of this bacterium in a virus-positive tick or in viral transmission from animal host requires further investigation.


Risk factors for neonatal encephalopathy in late preterm and term singleton births in a large California birth cohort.
The objective was to investigate maternal and pregnancy characteristics associated with neonatal encephalopathy (NE). We queried an administrative birth cohort from California between 2011 and 2017 to determine the association between each factor and NE with and without hypothermia treatment. From 3 million infants born at 35 or more weeks of gestation, 6,857 cases of NE were identified (2.3 per 1000 births), 888 (13%) received therapeutic hypothermia. Risk factors for NE were stronger among cases receiving hypothermia therapy. Substance-related diagnosis, preexisting diabetes, preeclampsia, and any maternal infection were associated with a two-fold increase in risk. Maternal overweight/obesity, nulliparity, advanced maternal age, depression, gestational diabetes or hypertension, and short or long gestations also predicted NE. Young maternal age, Asian race and Hispanic ethnicity, and cannabis-related diagnosis lowered risk of NE. By disseminating these results, we encourage further interrogation of these perinatal factors.


Assessment of the convulsant liability of antidepressants using zebrafish and mouse seizure models.
In the past, antidepressants have been thought to possess proconvulsant properties. This assumption remains controversial, however, because anticonvulsant effects have been attributed to certain antidepressants. To date, it remains unclear which antidepressants can be used for the treatment of patients with epilepsy with depression. The present study was designed to determine the anticonvulsant and/or proconvulsant effects of three antidepressants (citalopram, reboxetine, bupropion) against pilocarpine- and pentylenetetrazole-induced acute seizures in larval zebrafish and mice. In zebrafish, all antidepressants were anticonvulsant in the pentylenetetrazole model. In addition, citalopram was anticonvulsant in the zebrafish pilocarpine model, whereas reboxetine and bupropion were without significant effect. In mice all three antidepressants increased some thresholds for pentylenetetrazole-induced convulsive-like behaviors at varying doses, whereas thresholds for pilocarpine-induced convulsive-like behaviors were generally lowered, particularly at the highest doses tested. In general we conclude that the convulsant liability of antidepressants is model and concentration dependent.


[Evidence syntheses in public health: An overview].
Since the beginning of the COVID-19 pandemic, there has been a high demand for rapid evidence syntheses to answer urgent public health questions. This article provides an overview of different types of reviews for public health questions and a synthesis of existing recommendations for the preparation of reviews. The aim is to support the planning of one's own review and the critical evaluation of published reviews. The basis of this summary is an extensive search for guidelines and recommendations for different review types. Furthermore, internal journal clubs were held to determine knowledge needs and to critically discuss the various review types. Relating to the dissemination of results, fact sheets were developed for the individual review types including the most important information, prerequisites and work steps, as well as a decision tree for identifying the appropriate review type for the respective question. Of the review types identified, Systematic, Rapid, Scoping, Umbrella, and Narrative Reviews were considered in more detail because they are particularly relevant to public health issues. Together with scoping and umbrella reviews, systematic reviews have the highest resource requirements due to the demands for extensive, systematic evidence synthesis and reproducibility. Rapid methods can accelerate the review process, for example by a very narrowly formulated question, a limited literature search, or the execution of certain steps by one instead of two persons. Systematic Reviews may be considered as the gold standard, but they were developed primarily for clinical questions relating to interventions. This article, however, focusses on review types that consider the diversity of questions as well as the predominant use of quantitative methods in the field of public health. The fact sheets developed and the decision tree should enable low-threshold access to reviews while linking the perspectives of research and resource planning. They complement existing guidelines and recommendations. To answer the diverse spectrum of public health questions, various types of reviews with various requirements and approaches are available. Given this diversity, a systematic introduction can be helpful for researchers planning or assessing a review.


Colorimetric isolation of a novel electrochemically active Pseudomonas strain using tungsten nanorods for bioelectrochemical applications.
Pseudomonas strains are a promising host cell in metabolic engineering for bioconversion, environmental remediation, and most recently for bioelectrochemical applications. This study isolated an electrochemically active Pseudomonas sp. from an anaerobic sludge using a colorimetric and electrochromic WO3 nanorod (WO3-NR) probe. A strategy was developed to determine the presence of electroactive species from enriched cultures. A mixed consortium was enriched using Pseudomonas isolation media containing betaine and triclosan as the carbon source and antibacterial reagent, respectively. A single blue colony was isolated using WO3-NR sandwiched agar plates. The isolate was sequenced by 16 s rRNA and designated Pseudomonas aeruginosa PBH03, producing phenazines and pyocyanin aerobically. The isolate exhibited clear electrochemical characteristics from cyclic voltammetry and linear sweep voltammetry and produced a current density of 9.01 µA cm-2 in a microbial fuel cell.


Who is That? Brain Networks and Mechanisms for Identifying Individuals.
Social animals can identify conspecifics by many forms of sensory input. However, whether the neuronal computations that support this ability to identify individuals rely on modality-independent convergence or involve ongoing synergistic interactions along the multiple sensory streams remains controversial. Direct neuronal measurements at relevant brain sites could address such questions, but this requires better bridging the work in humans and animal models. Here, we overview recent studies in nonhuman primates on voice and face identity-sensitive pathways and evaluate the correspondences to relevant findings in humans. This synthesis provides insights into converging sensory streams in the primate anterior temporal lobe (ATL) for identity processing. Furthermore, we advance a model and suggest how alternative neuronal mechanisms could be tested.


Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats.
This experiment examined both the short-term and the long-term effects of ovariectomy on brown adipose tissue growth and function in rats to determine if reduced brown adipose tissue thermogenesis might contribute to the weight gain and adiposity. Brown adipose tissue function was assessed by measuring sympathetic nervous system activity (estimated by the rate of norepinephrine turnover) and mitochondrial proton conductance (estimated by specific GDP binding) in interscapular brown adipose tissue. Rats (n = 12 per group) were killed 0 (sham), 1, 2, 4, and 12 weeks after ovariectomy. During the first five weeks after ovariectomy rats overrate and rapidly gained weight. The weight gain was due to increases in all carcass components. Five weeks after ovariectomy food intake returned to control levels, and body weights stabilized 12-16% above sham-operated control weights for the duration of the experiment. Between week 4 and week 12 after surgery there was a redistribution of carcass composition, with decreases in carcass water and fat-free dry weights offset by a further increase in total carcass lipid. Brown adipose tissue pads were heavier in the 1-, 2-, and 4-week ovariectomy groups, but only in the 4-week group was the increase statistically significant. Brown adipose tissue protein, DNA, and norepinephrine content was unchanged 1-, 2-, 4-, or 12-weeks after ovariectomy. There was no difference in either the rate of norepinephrine turnover or specific mitochondrial GDP binding between sham-operated and 1-, 2-, 4-, or 12-week ovariectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Sacral osteomyelitis following restorative rectal cancer resection: a delayed presentation of dormant pelvic sepsis.
Sacral osteomyelitis is a rare but potentially fatal complication of pelvic surgery. It is often diagnosed late due to the presence of vague, non-specific symptoms and a low index of suspicion. Previous literature has been limited to a number of case series of patients who have undergone ileoanal pouch formation following proctocolectomy and patients who have undergone pelvic floor reconstruction with mesh sacral colpopexy. Here, we present a patient presenting with sacral osteomyelitis 12 years following anterior resection for colorectal malignancy. We then review the previous literature and discuss the salient management points that may assist in the diagnosis and management of this uncommon complication.


Sub-cell scale features govern the placement of new cells by honeybees during comb construction.
Honeybee comb architecture and the manner of its construction have long been the subject of scientific curiosity. Comb is characterised by an even hexagonal layout and the sharing of cell bases and side walls, which provides maximised storage volume while requiring minimal wax. The efficiency of this structure relies on a regular layout and the correct positioning of cells relative to each other, with each new cell placed at the junction of two previously constructed cells. This task is complicated by the incomplete nature of cells at the edge of comb, where new cells are to be built. We presented bees with wax stimuli comprising shallow depressions and protuberances in simulation of features found within partially formed comb, and demonstrated that construction work by honeybee builders was influenced by these stimuli. The building of new cells was aligned to concave stimuli that simulated the clefts that naturally appear between two partially formed cells, revealing how new cells may be aligned to ensure proper tessellation within comb. We also found that bees built cell walls in response to edges formed by our stimuli, suggesting that cell and wall construction was specifically directed towards the locations necessary for continuation of hexagonal comb.


A novel NSDHL variant in CHILD syndrome with gastrointestinal manifestations and localized skin involvement.
CHILD syndrome is an X-linked dominant disorder associated with pathogenic mutations in the NSDHL gene. The condition is predominantly found in females as it is lethal in males. Most cases present at birth with extensive unilateral ichthyosiform erythroderma involving the trunk and limbs. Milder and less extensive presentations have been reported, leading to misdiagnosis especially during early childhood. We report an adult female of Malay ancestry who presented with minimal skin and limb involvement. She was only diagnosed in adulthood when she presented with gastrointestinal symptoms and worsening of skin manifestations. The clinical diagnosis was suspected after a combination of clinical, pathological and immunohistochemistry correlation, and molecularly confirmed with the discovery of a frameshift variant in NSDHL. The novel variant was inherited from her mother who had some linear hypopigmented patches over the medial aspects of both her arms and right forearm. We uncovered a novel frameshift variant associated with presentations that cast a new light on the clinical features of CHILD syndrome.


NASA scales back its next flagship climate mission.
As two landmark satellites go dark, cuts loom for new bid to probe clouds, aerosols, and warming.


Protection of chickens against H9N2 avian influenza virus challenge with recombinant Lactobacillus plantarum expressing conserved antigens.
Avian influenza virus (AIV) is spreading worldwide and is a serious threat to the health of poultry and humans. In many countries, low pathogenic AIVs, such as H9N2, have become an enormous economic burden on the commercial poultry industry because they cause mild respiratory disease and decrease egg production. A recombinant Lactobacillus plantarum NC8 strain expressing NP-M1-DCpep from H9N2 AIV has been studied in a mouse model. However, it remains unknown whether this L. plantarum strain can induce an immune response and provide protection against H9N2 AIV in chickens. In this study, chickens that were orally vaccinated with NC8-pSIP409-NP-M1-DCpep exhibited significantly increased T cell-mediated immune responses and mucosal sIgA and IgG levels, which provided protection against H9N2 AIV challenge. More importantly, compared with oral administration of NC8-pSIP409-NP-M1-DCpep, intranasal administration induced stronger immune responses and provided effective protection against challenge with the H9N2 virus by reducing body weight loss, lung virus titers, and throat pathology. Taken together, these findings suggest that L. plantarum expressing NP-M1-DCpep has potential as a vaccine to combat H9N2 AIV infection.


A New Polyclad Flatworm, Idiostylochus tortuosus gen. nov., sp. nov. (Platyhelminthes, Polycladida) from France. Can this Foreign Flatworm be Responsible for the Deterioration of Oyster and Mussel Farms?
A new species of polyclad flatworm, Idiostylochus tortuosus gen. nov., sp. nov. (Polycladida, Idioplanidae), from Arcachon Bay (France) is described. This description is based on a morphological analysis and a molecular analysis using partial sequences of the 28S and cytochrome Oxidase I (COI) genes. After the molecular analysis Idiostylochus gen. nov. appears to be the second genus of the Family Idioplanidae and closely related to the family Latocestidae as well as the genera Leptostylochus and Mirostylochus. The molecular data revealed that the new species may belong to an Indonesian or Indo-Pacific family, closely related to genera with origins in South Pacific Ocean waters. This species was found feeding on the oysters and mussels of the Arcachon farms.


Evaluation of the barriers and facilitators of iron supplementation program among adolescent females.
Iron deficiency anemia is a major health problem in female adolescents; so, the iron supplementation program has been implemented in Iranian female high school students for nearly two decades. This study aimed to assess the barriers and facilitators of the program. This cross-sectional study was conducted by cluster random sampling with a sample size of 399 high school girls from the northern, southern, eastern, western and central regions of Iran. To collect data, we applied valid and reliable researcher-made questionnaires. Data were analyzed by SPSS version 22 software using the chi-squared test. From the students' point of view, the most important reasons for not taking iron supplements were the bad taste of iron supplements, nausea after consumption, and not prescription of the iron supplement by physicians. Most the students believed that inviting health care professionals and movies or clips had the greatest impact on encouraging students to take supplements. About 45% of students reported that educational programs were not held for them, and only 28% of students received educational content/educational media about iron supplement. Also, 71% of students reported that there are not enough glasses for the consumption of supplement iron. There were significant relationships between iron supplements distributors (deputy assistant: 22.6% vs. 14.1%, P = 0.045), allocated enough time to intake iron supplements (72.0% vs. 37.1%, P < 0.001), implemented the educational program in schools (61.8% vs. 33%, P < 0.001), and the educator person of the program (health teachers: 42.7% vs. 35.7%, P = 0.039) with consumption of iron supplement by the students. To achieve the goals of the program, it is necessary paying attention to various aspects of the program such as providing better quality iron supplements, providing more appropriate environmental conditions, designing more attractive training programs, strengthening general announcement, and employing more experienced executive staff.


Pesticides, nonylphenols and polybrominated diphenyl ethers in marine bivalves from France: A pilot study.
The present pilot study aimed to provide an overview of organic contaminant concentration levels in the littoral ecosystems of the Pertuis seas. The study determined the concentrations of twenty-nine pesticides, six nonylphenols and seven polybrominated diphenyl ethers (PBDEs) in sediments, seawater, Pacific oysters and blue mussels. Oysters accumulated a higher number of pesticides than blue mussels. Indeed, alpha BHC (0.60-0.72 ng/g, ww), chlorfenvinphos (1.65-2.12 ng/g, ww), chlorpyrifos (0.79-0.93 ng/g, ww), chlortoluron (2.50-4.31 ng/g, ww), metolachlor (up to 0.38 ng/g, ww) and parathion (0.56-0.69 ng/g, ww) were quantified in oysters whereas only alpha BHC (0.24-0.31 ng/g, ww), was quantified in mussels. The present results also revealed that the POPs detected in water or sediments were not ultimately found accumulated in bivalves. Other molecules such as methylparathion and BDE47 were quantified in sediments. These molecules, BDE99 and one nonylphenol (OP2OE) were quantified in seawater. Finally, the comparison with the available environmental guidelines showed that the values measured were at concentrations not considered to cause adverse effects at the populations' level except for chlortoluron in seawater (15-50 ng/L).


Patterns of maternal behavior in the spontaneously hypertensive rat.
Maternal behavior of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats was assessed over the preweanling period (days 1-21). Ten litters of each strain were observed during the dark phase of the light:dark cycle using a scan sampling technique. Cages were observed periodically throughout the day and the momentary behavior of the dam was recorded on a checklist of 9 different behaviors. These behaviors included: nursing entire litter, nursing part of litter, contact with entire litter, contact with part of litter, pup carrying/retrieval, licking pups, sniffing pups, nest building, and away from litter. A second set of ten litters per strain was observed in the same manner during the light phase of the light:dark cycle thus providing around the clock data throughout the entire preweanling period. For purposes of data analysis, the 21-day preweanling period was divided into 7 3-day blocks. The mean relative frequency with which each behavior was observed from SHR and WKY mothers was determined for each block and for each phase of the light:dark cycle separately. SHR mothers were with their pups and nursing them more frequently than WKY mothers during the light phase of the circadian cycle. Complimentary to this finding, WKY mothers were observed away from their pups more frequently than SHR mothers during both light and dark phases. Finally, SHR mothers were observed to lick their pups more often than WKY mothers during both phases of the light:dark cycle. These findings were consistent across the entire preweanling period.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification of impurities in nafamostat mesylate using HPLC-IT-TOF/MS: A series of double-charged ions.
Nafamostat mesylate is a serine protease inhibitor used in the treatment of acute pancreatitis. The impurities in nafamostat mesylate, the active pharmaceutical ingredient (API), were profiled via high performance liquid chromatography tandem ion trap coupled with time-of-flight mass spectrometer (HPLC-IT-TOF/MS). The chromatography was performed on an ACE-3 C18 column (200 mm × 4.6 mm, 3 μm) using methanol and 0.1% formic acid in purified water as mobile phase at a flow rate of 1.0 mL/min. The ions were detected by IT-TOF/MS with a full-scan mass analysis from m/z 100 to 800. In total, eleven impurities were detected in nafamostat mesylate API. The impurity profile was estimated based on the HPLC-IT-TOF/MS data, including accurate masses, MSn fingerprints of fragmentation pathways and a series of double-charged ions. Finally, seven impurities were identified and reported for the first time. The results will provide technical support for the quality control and clinical safety of nafamostat mesylate.


Evaluating the governance and preparedness of the Lebanese health system for the COVID-19 pandemic: a qualitative study.
This study aimed to assess the capacities and governance of Lebanon's health system throughout the response to the COVID-19 pandemic until August 2020. A qualitative study based on semi-structured interviews. Lebanon, February-August 2020. Selected participants were directly or indirectly involved in the national or organisational response to the COVID-19 pandemic in Lebanon. A total of 41 participants were included in the study. 'Hardware' capacities of the system were found to be responsive yet deeply influenced by the challenging national context. The health workforce showed high levels of resilience, despite the shortage of medical staff and gaps in training at the early stages of the pandemic. The system infrastructure, medical supplies and testing capacities were sufficient, but the reluctance of the private sector in care provision and gaps in reimbursement of COVID-19 care by many health funding schemes were the main concerns. Moreover, the public health surveillance system was overwhelmed a few months after the start of the pandemic. As for the system 'software', there were attempts for a participatory governance mechanism, but the actual decision-making process was challenging with limited cooperation and strategic vision, resulting in decreased trust and increased confusion among communities. Moreover, the power imbalance between health actors and other stakeholders affected decision-making dynamics and the uptake of scientific evidence in policy-making. Interventions adopting a centralised and reactive approach were prominent in Lebanon's response to the COVID-19 pandemic. Better public governance and different reforms are needed to strengthen the health system preparedness and capacities to face future health security threats.


Effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats.
This study investigated the effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into control (C, n=10), diabetic (D, n=13) and diabetic treated with rosiglitazone (DT, n=13). Type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). Eleven rats in diabetic untreated group and twelve rats in diabetic treated group were successfully induced to be diabetes. After induction of diabetes, rosiglitazone (3mg/kg/day) was administrated to diabetic treated rats by gavage for 12 weeks. Twelve weeks later, the heart function was detected. Plasma and myocardial adiponectin levels were detected by enzyme linked immunosorbent assay (ELISA). The cardiac mRNA expression of adiponectin receptors 1 and 2, and monocyte chemoattractant protein-1 (MCP-1) was assayed by reverse transcript-polymerase chain reaction (RT-PCR). The cardiac mRNA expression of p22phox and NOX4 was assayed by real-time fluorescence quantitative PCR. The cardiac protein expression of phosphor-AMPK-α (Thr172) and glucose transporter 4 (GLUT4) was determined by Western blotting. The protein expression of adiponectin receptors 1 and 2, and connective tissue growth factor (CTGF)were determined by immunohistochemistrial staining. The ratio of heart weight to body weight was significantly increased in diabetic rats compared to control. Heart function, plasma and myocardial adiponectin levels, the protein and mRNA expression of myocardial adiponectin receptors 1 and 2, myocardial phosphorylation of AMPK-α (Thr172) and the protein expression of myocardial GLUT4 were significantly decreased in diabetic rats compared to control (P<0.05). The expression of myocardial p22phox, Nox4, MCP-1 and CTGF was significantly increased in diabetic rats compared to control (P<0.05). Rosiglitazone treatment significantly attenuated the increased ratio of heart weight to body weight, and the increased expression of myocardial p22phox, Nox4, MCP-1 and CTGF in diabetic rats (P<0.05). Heart function, plasma and myocardial adiponectin levels, the expression of myocardial adiponectin receptors 1 and 2 and GLUT4, and myocardial phosphorylation of AMPK-α (Thr172) were significantly decreased in diabetic treated with rosiglitazone compared to diabetic untreated (P<0.05). These results suggest that the protective effects of rosiglitazone on diabetic rat hearts may be attributable to the increased myocardial adiponectin and its receptors and the decreased myocardial NADPH oxidase.


The projection to the mesencephalon from the dorsal column nuclei. An anatomical study in the cat.
The terminal areas and cells of origin of the projection from the dorsal column nuclei to the mesencephalon were investigated by the intra-axonal transport method. Following injection of wheat germ agglutinin-horseradish peroxidase conjugate into the dorsal column nuclei, anterograde labeling was observed in several regions of the midbrain. The main terminal area was situated at the level of transition between the superior and inferior colliculus on the side contralateral to the injection site and comprised the intercollicular nucleus and part of the external and pericentral nuclei of the inferior colliculus and of the nucleus of the brachium of the inferior colliculus, but there were also projections to the caudal half of the deep and intermediate gray layers of the superior colliculus, the anterior and posterior pretectal nuclei, the nucleus of Darkschewitsch and nucleus ruber. Injections restricted to either the gracile nucleus or the cuneate nucleus revealed a somatotopic termination pattern in the intercollicular nucleus, superior colliculus and pretectal nuclei. The retrograde labeling seen after injection of tracer into the midbrain terminal areas showed that the cells of origin were located mainly in the rostral and caudal parts of the dorsal column nuclei, whereas the middle cell nest neurons were unlabeled, thus supporting previous observations that the neurons projecting to the midbrain constitute a population separate from that projecting to the thalamus. Cell counts revealed that the midbrain projection is of a considerable magnitude, involving between 10,000 and 15,000 neurons; its functional significance is, however, largely unknown.


A common variant in the hepatobiliary phospholipid transporter ABCB4 modulates liver injury in PBC but not in PSC: prospective analysis in 867 patients.
The ATP-binding cassette subfamily B member 4 (ABCB4) gene encodes the hepatic phospholipid transporter. Variants in the ABCB4 gene are associated with various cholestatic phenotypes, some of which progress to liver fibrosis and cirrhosis. The aim of our study was to investigate the role of the cholestasis-associated variant ABCB4 c.711A > T (p.I237I, rs2109505) in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Two cohorts of Polish patients took part in this study. The Szczecin cohort comprised 196 patients with PBC (174 females, 38% with cirrhosis) and 135 patients with PSC (39 females, 39% with cirrhosis). The Warsaw cohort consisted of 260 patients with PBC (241 females, 44% with cirrhosis) and 276 patients with PSC (97 females, 33% with cirrhosis). Two control cohorts-150 healthy blood donors and 318 patients without liver disease, were recruited in Szczecin and in Warsaw, respectively. The ABCB4 c.711A > T polymorphism was genotyped using TaqMan assay. In both PBC cohorts, carriers of the risk variant presented more frequently with cirrhosis (Szczecin: OR = 1.841, P = 0.025; Warsaw: OR = 1.528, P = 0.039). The risk allele was associated with increased serum AST, GGT and ALP (all P < 0.05) at inclusion. During the follow-up, patients in both cohorts significantly improved their laboratory results, independently of their ABCB4 c.711A > T genotype (P > 0.05). During 8 ± 4 years follow-up, a total of 22 patients in the Szczecin PBC group developed cirrhosis, and this risk was higher among carriers of the risk variant (OR = 5.65, P = 0.04). In contrast to PBC, we did not detect any association of ABCB4 c.711A > T with a liver phenotype in PSC cohorts. The frequent pro-cholestatic variant ABCB4 c.711A > T modulates liver injury in PBC, but not in PSC. In particular, carriers of the major allele are at increased risk of progressive liver scarring.


The effect of oxaloacetic acid on tyrosinase activity and structure: Integration of inhibition kinetics with docking simulation.
Oxaloacetic acid (OA) is naturally found in organisms and well known as an intermediate of citric acid cycle producing ATP. We evaluated the effects of OA on tyrosinase activity and structure via integrating methods of enzyme kinetics and computational simulations. OA was found to be a reversible inhibitor of tyrosinase and its induced mechanism was the parabolic non-competitive inhibition type (IC50=17.5±0.5mM and Ki=6.03±1.36mM). Kinetic measurements by real-time interval assay showed that OA induced multi-phasic inactivation process composing with fast (k1) and slow (k2) phases. Spectrofluorimetry studies showed that OA mainly induced regional changes in the active site of tyrosinase accompanying with hydrophobic disruption at high dose. The computational docking simulations further revealed that OA could interact with several residues near the tyrosinase active site pocket such as HIS61, HIS259, HIS263, and VAL283. Our study provides insight into the mechanism by which energy producing intermediate such as OA inhibit tyrosinase and OA is a potential natural anti-pigmentation agent.


Simultaneous Sigmoid Colectomy, Bilobar Liver Resection and Lung Metastasectomy via a Transdiaphragmatic Approach for Stage IV Colonic Adenocarcinoma.
Current evidence supports the curative resection of colorectal cancer and synchronous liver and lung metastases in selected patients.1,2 This video shows simultaneous left colectomy, bilobar liver resection, and lung metastasectomy via a transdiaphragmatic approach for stage IV colorectal cancer.3 PATIENT: A 57-year-old man with a stage IV colonic adenocarcinoma was considered for simultaneous resection of primary, liver, and lung metastases without thoracic incision. The tumor mutational status was KRAS, NRAS, and BRAF wild-type, and the patient underwent preoperative chemotherapy. After performing a midline laparotomy, atypical liver resection of segments 8/4a was performed under the guidance of intraoperative ultrasonography and intermittent Pringle maneuver using the two-surgeon's technique. A small capsular lesion in segment 3 also was intraoperatively detected and resected. Lung metastasectomy of the right lower lobe was performed via a transdiaphragmatic approach using an endoscopic stapler. Sigmoid colectomy with transanal circular-stapled anastomosis was performed. Duration of surgery and blood loss were 358 min and 400 ml, respectively. Histopathological examination showed metastatic colonic adenocarcinoma with negative surgical margins and final stage was T3N2aM1b. The patient was discharged on postoperative day 6 without complication. He was alive and free of disease at 90-day follow-up. Simultaneous colon, liver, and lung resection via a transdiaphragmatic approach is a feasible and safe surgical strategy in selected patients with peripheral lung metastases and favorable tumor biology.4 This surgical strategy avoids thoracic incision, multiple operations, and may reduce the healthcare costs and the recovery time to early implement postoperative therapy.


Prognostic value of CXCL12 and CXCR4 in inoperable head and neck squamous cell carcinoma.
The chemokine CXCL12 and its receptor CXCR4 can affect tumor growth, recurrence, and metastasis. We tested the hypothesis that the CXCL12 and CXCR4 expression influences the prognosis of patients with inoperable head and neck cancer treated with definite radiotherapy or chemoradiotherapy. Formalin-fixed paraffin-embedded pretreatment tumor tissue from 233 patients with known HPV/p16(INK4A) status was analyzed. CXCL12 and CXCR4 expressions were correlated with pretreatment parameters and survival data by univariate and multivariate Cox regression. CXCL12 was expressed in 43.3 % and CXCR4 in 66.1 % of the samples and both were correlated with HPV/p16(INK4A) positivity. A high CXCL12 expression was associated with increased overall survival (p = 0.036), while a high CXCR4 expression was associated with decreased metastasis-free survival (p = 0.034). A high CXCR4 expression could be regarded as a negative prognostic factor in head and neck cancer because it may foster metastatic spread. This may recommend CXCR4 as therapeutic target for combating head and neck cancer metastasis.


Sensitive detection of copper(II) by a commercial glucometer using click chemistry.
The commercially available glucometer has been the most successful point-of-care (POC) sensor up to date. However, the glucometer only responds to glucose rather than other species. Extending the use of the glucometer for monitoring different types of targets would potentially revolutionize the applicability of the glucometer. Here we report a new sensing strategy for sensitive and selective detection of Cu(2+) based on multi-invertase conjugated magnetic bead signal amplification labels and a glucometer transducer. The Cu(2+) is in situ reduced to Cu(+) by sodium ascorbate, which catalyzes the click linking between the alkynyl-DNA immobilized on a disposable screen printed carbon electrode and the azido-DNA attached to the invertase/magnetic bead conjugates. The numerous invertase on the magnetic bead labels through Cu(+)-catalyzed click chemistry reaction convert sucrose to glucose, which is monitored by the glucometer and offers amplified digital readings for Cu(2+) detection. By employing the multi-invertase signal amplification, as low as 10nM Cu(2+) can be detected. Our method also shows high selectivity for Cu(2+) against other metal ions owing to the highly specific Cu(+)-catalyzed click chemistry reaction, and is applicable for monitoring Cu(2+) in real river samples. Our strategy can be easily expanded for the monitoring of a wide range of targets when coupled with various recognition events.


New antiarrhythmic drugs for establishing sinus rhythm in atrial fibrillation: what are our therapies likely to be by 2010 and beyond?
The management of atrial fibrillation (AF) is plagued by, among other things, limitations in the efficacy, tolerance, and safety of currently available agents for the conversion of AF to sinus rhythm and for the maintenance of sinus rhythm. This review describes some of the most promising approaches to new therapies that may overcome some of the limitations of our current therapies. The agents we have chosen to review are representative of these new approaches and have completed their phase III trials and have submitted an application for approval for release by regulatory agencies or have almost completed their phase III trials and appear likely to submit for approval in the not to distant future.