Global Mortality Burden of Cirrhosis and Liver Cancer Attributable to Injection Drug Use, 1990-2016: An Age-Period-Cohort and Spatial Autocorrelation Analysis.
We analyzed the temporal and spatial variations in mortality burden of cirrhosis and liver cancer attributable to injection drug use (IDU) from 1990 to 2016. Mortality data of IDU-attributable cirrhosis and IDU-attributable liver cancer on the global and national scales from 1990 to 2016 were collected from the Global Burden of Disease (GBD) studies. Age-period-cohort (APC) model analysis was used to analyze the global mortality trends of target disease, and spatial autocorrelation analysis based on Geographic Information System was applied to illustrate the clusters of the most epidemic countries. Globally, from 1990 to 2015, mortality rates (age-standardized, per 100,000) of IDU-attributable cirrhosis increased continually from 1.5 to 1.9, while from 0.4 to 0.9 for IDU-attributable liver cancer. The APC model analysis indicated that the increases of mortality were mainly driven by period effects, with the mortality risk increasing by 6.82-fold for IDU-attributable cirrhosis and 3.08-fold for IDU-attributable liver cancer. The spatial analysis suggested that IDU-attributable cirrhosis mortality were geographically clustered from 1990 to 2016, and hot spots were mainly located in less well developed countries of Latin America, East and Central Europe and Central Asia. Our study provides epidemiological evidence for global interventions against advanced liver disease among injection drug users (IDUs).


Modulation of early functional recovery of Achilles tendon to bone unit after transection by BPC 157 and methylprednisolone.
In the presented study we compared the effect of stable peptide BPC 157 and methylprednisolone on early functional recovery after Achilles tendon to bone transection in a rat model before collagen healing started. Surgical transection of the right Achilles tendon to bone area was performed in seventy two Wistar Albino male rats. Healing Achilles tendon edges were harvested at days 1-4 following the transection. Using Achilles functional index (AFI), myeloperoxidase activity, histological inflammatory cell influx and vascular index early functional recovery was evaluated. Agents (stable peptide BPC 157 10 microg methylprednisolone 5 mg, normal saline 5 ml) were given alone (/kg b.w., intraperitoneally, once daily, first 30 min after surgery, last 24 h before analysis). Control group received normal saline 5 ml/kg. BPC 157 improved functional recovery (AFI values increased at all time points, p <0.05) by anti-inflammatory (decreased myeloperoxidase (MPO) activity and histological inflammatory cell influx, p <0.05) and increased new blood vessel formation (increased vascular index, p <0.05). Methyprednisolone decreased MPO activity and histological inflammatory cell influx, (p <0.05) but also decreased new blood vessel formation and did not affect early functional recovery. Stable peptide BPC 157 with combined anti-inflammatory action and induction of early new blood vessel formation facilitates early functional recovery in Achilles tendon to bone healing.


Effect of depression on phase coherence between respiratory sinus arrhythmia and respiration during sleep in patients with obstructive sleep apnea.
Introduction: A high prevalence of major depressive disorder (MDD) among Obstructive Sleep Apnea (OSA) patients has been observed in both community and clinical populations. Due to the overlapping symptoms between both disorders, depression is usually misdiagnosed when correlated with OSA. Phase coherence between respiratory sinus arrhythmia (RSA) and respiration (λ RSA-RESP) has been proposed as an alternative measure for assessing vagal activity. Therefore, this study aims to investigate if there is any difference in λ RSA-RESP in OSA patients with and without MDD. Methods: Electrocardiograms (ECG) and breathing signals using overnight polysomnography were collected from 40 OSA subjects with MDD (OSAD+), 40 OSA subjects without MDD (OSAD-), and 38 control subjects (Controls) without MDD and OSA. The interbeat intervals (RRI) and respiratory movement were extracted from 5-min segments of ECG signals with a single apneic event during non-rapid eye movement (NREM) [353 segments] and rapid eye movement (REM) sleep stages [298 segments]. RR intervals (RRI) and respiration were resampled at 10 Hz, and the band passed filtered (0.10-0.4 Hz) before the Hilbert transform was used to extract instantaneous phases of the RSA and respiration. Subsequently, the λ RSA-RESP between RSA and Respiration and Heart Rate Variability (HRV) features were computed. Results: Our results showed that λ RSA-RESP was significantly increased in the OSAD+ group compared to OSAD- group during NREM and REM sleep. This increase was accompanied by a decrease in the low frequency (LF) component of HRV. Discussion: We report that the phase synchronization index between RSA and respiratory movement could provide a useful measure for evaluating depression in OSA patients. Our findings suggest that depression has lowered sympathetic activity when accompanied by OSA, allowing for stronger synchronization between RSA and respiration.


Novel regulator of vasopressin secretion: phoenixin.
The newly described hypothalamic peptide, phoenixin, is produced in the hypothalamus and adenohypophysis, where it acts to control reproductive hormone secretion. Both phoenixin and its receptor GPR173 are expressed in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, suggesting additional, nonreproductive effects of the peptide to control vasopressin (AVP) or oxytocin (OT) secretion. Hypothalamo-neurohypophysial explants released AVP but not OT in response to phoenixin. Intracerebroventricular administration of phoenixin into conscious, unrestrained male and female rats significantly increased circulating AVP, but not OT, levels in plasma, and it increased immediate early gene expression in the supraoptic nuclei of male rats. Bath application of phoenixin in hypothalamic slice preparations resulted in depolarization of PVN neurons, indicating a direct, neural action of phoenixin in the hypothalamus. Our results suggest that the newly described, hypothalamic peptide phoenixin, in addition to its effects on hypothalamic and pituitary mechanisms controlling reproduction, may contribute to the physiological mechanisms regulating fluid and electrolyte homeostasis.


Exogenous stem cell factor improves interstitial cells of Cajal restoration after blockade of c-kit signaling pathway.
Interstitial cells of Cajal (ICC) have been endowed with considerable intrinsic plasticity. Blockade of the c-kit signaling pathway results in the shift of ICC towards a smooth muscle-like phenotype. Little is known about stem cell factor (SCF), the ligand of c-kit, and the role it plays in the process of restoration. The aim of this study was to determine whether exogenous SCF can promote ICC replenishment following the blockade of c-kit signaling. Neutralizing anti-c-kit monoclonal antibody (ACK2) was administered to mice for 8 days after birth. Jejunal muscle strips were cultured up to 7 days. Electrical rhythmic changes were monitored and ICC were examined by immunohistochemistry. Expression of c-kit mRNA was detected by reverse transcriptase-polymerase chain reaction, and expression of Kit protein was detected by Western blot. When c-kit receptors were blocked, ICC nearly disappeared from the jejunum accompanied by the loss of electrical slow waves. By day 7, after in vitro culture with SCF (100 ng/ml), the amplitude of muscle strip slow waves was restored to 0.19 +/- 0.07 mV (p < 0.05), whereas the frequency recovered to 13.7 +/- 3.32/min (p < 0.01). Furthermore, labeling for c-kit(+) cells in the myenteric plexus increased and c-kit mRNA and protein expression were up-regulated compared to that of non-treatment with SCF. The c-kit signaling pathway, activated by SCF, is the critical pathway associated with the control of ICC survival and proliferation. The restoration of ICC number and jejunal electrical rhythm, resulting from blockade of the c-kit signaling pathway, could be facilitated by local SCF administration.


Rapid culture-independent quantitative detection of enterotoxigenic Escherichia coli in surface waters by real-time PCR with molecular beacon.
Rapid and reliable detection of enterotoxigenic Escherichia coli (ETEC) is critical for the management of the waterborne diseases threatening human lives worldwide. In this study, a culture-independent real-time PCR assay, in molecular beacon format was designed and validated for detection and quantitative enumeration of ETEC harboring LT1 gene (encoding heat labile toxin) in surface waters contaminated by fecal pollutants of human and animal origin. It was observed that the assay was able to detect 2 CFU/mL of ETEC (r = 0.997; PCR efficiency = 99.8%) from water samples spiked by a reference organism (E. coli MTCC 723). In the presence of 10(6) CFU/mL of nonpathogenic E. coli(E. coli DH5alpha), the lowest detection limit from spiked water samples was 4 CFU/mL. The assay was 500 times more sensitive than conventional PCR using the same oligomers (Student's t test p < 0.05). The assay could specifically detect and quantify ETEC (1.2 x 10(3) to 1.4 x 10(6) CFU/100 mL) in polluted surface waters of river Gomti. The rapid culture-independent assay developed in this study for detection and quantitative enumeration of ETEC can be used for preliminary monitoring of surface waters to prevent waterborne outbreaks.


Neurodevelopmental outcomes after biventricular repair of congenital heart defects.
This study was undertaken to assess neurodevelopment of children after biventricular repair of congenital heart defects. Full-scale, performance, and verbal IQs of 69 patients who had undergone biventricular repair were assessed at 5 years of age with the Wechsler Preschool and Primary Scales of Intelligence-Revised. The Wide Range Assessment of Visual-Motor Abilities was used to measure visual-motor skills. Regression analyses adjusting for parental IQ and socioeconomic status were used to evaluate outcome predictors. Median age at repair was 91 days (range 1-1558 days). Hypothermic circulatory arrest was used in 35 cases (mean duration of hypothermic circulatory arrest 33 +/- 17 minutes). Mean full-scale, performance, and verbal IQs for the entire study population were within the reference range (full-scale 96.9 +/- 15.9, performance 96.6 +/- 16.8, verbal 97.7 +/- 15.2). Anatomic diagnosis, age at operation, and use of hypothermic circulatory arrest did not influence full-scale IQ (P =.66, P =.14, and P =.46, respectively), performance IQ (P =.64, P =.36, and P =.73, respectively), or verbal IQ (P =.74, P =.08, and P =.39, respectively). Among patients subjected to hypothermic circulatory arrest, duration of arrest was evaluated as a predictor of outcome. After adjustment for parental IQ, full-scale (P =.12), performance (P =.07), and verbal (P =.22) IQ scores of patients with more than 39 minutes of hypothermic circulatory arrest were not different from those of patients who had arrest periods of 39 minutes or less. After adjustment for socioeconomic status, however, full-scale (P =.05) and performance (P =.03) IQ scores were lower among patients who had more than 39 minutes of hypothermic circulatory arrest. After adjustment for either parental IQ or socioeconomic status, patients with more than 39 minutes of arrest had lower scores on Wide Range Assessment of Visual-Motor Abilities subtests of visual-motor and fine motor abilities and on several performance IQ subtests. IQs of patients who had undergone biventricular repair of congenital heart defects were within the reference range. However, hypothermic circulatory arrest for longer than 39 minutes was associated with deficits in visual-motor and fine motor skills and possibly in full-scale IQ.


Direct oral anticoagulants in patients with hematologic malignancies.
The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation-therapy was maintained until the platelet count was ≥50 × 109 /L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs.


Considerations and approaches in determining the protein and energy composition of preterm infant formulas.
Optimal early nutritional support is considered a crucial issue in the care of the preterm infant, particularly of those with very low- or extremely low-brithweight. Unfortunately, this goal is seldom satisfactorily attained. Several conditions such as hypoxia, acidosis, patent ductus arteriosus, drug therapy, reduced intestinal motility may interfere with an adequate nutritional delivery in the early neonatal period. Moreover, there is still concern about metabolic and intestinal tolerance of the currently suggested intakes and a lack of uniformity in the nutritional program among different NICUs. Finally, the vast majority of the available preterm formulas are not fully adequate to the real nutritional needs of these infants. Inadequate protein content and inappropriate protein energy ratio of most preterm formulas represent a matter of major concern, since there is a strict relationship between formula composition and the quantity and quality of weight gain. As a consequence there is a need of at least two milk formulas for different preterm infants: one for LBW and VLBW infants, the other for preterm infants weighing >1500 g.


Factors related to successful collaboration in community-campus partnerships.
Collaboration and community partnership have become buzzwords in academic settings, which have received little direction regarding how to make these efforts successful and sustainable. This study attempted to discern the factors involved in setting up one successful community-campus partnership. Four years after opening an all-volunteer free health clinic in Laramie, Wyoming, we interviewed community members and university faculty who were involved in the initial partnership. Analysis of these interviews identified several dynamic tensions that kept the group together Communitand moving toward its goal.


Electromigration behavior of a mixture of chitosan oligomers at different concentrations.
In this study, the effect of the concentration of a chitosan oligomer mixture on its electrophoretic behavior was studied as a function of pH and ionic strength added. It was shown that the concentration has a significant effect on the average electrophoretic mobility of the chitosan oligomer mixture and on isoelectric point. At a concentration of 3%, the ionic strength added did not show any effect on the electromigration behavior of the chitosan oligomer mixture. By decreasing the concentration of the chitosan oligomer mixture, ionic strength showed a significant effect on the average electrophoretic mobility but not on the isoelectric point. The highest shift of the isoelectric point was recorded in water at 0.003% concentration of the oligomer mixture. Under these conditions, the isoelectric point was at pH 5 whereas it was at pH 8 at 3% concentration of chitosan oligomer mixture. Electrophoretic measurements were also taken in water/ethanol aqueous medium. By adding ethanol to the medium, the average electrophoretic mobility decreased. This would have been caused by the increase in viscosity of the medium. Increasing ethanol ratio in the running medium, the isoelectric point moved from pH 5 in water up to pH 6-8 dependently on chitosan oligomer mixture concentration and ethanol content of the medium.


Cytologic findings in tenosynovial giant cell tumors investigated by fine-needle aspiration cytology.
Tenosynovial giant cell tumor is a relatively common benign proliferation affecting the articular and periarticular soft tissues. Cytologic findings on smears obtained by fine-needle aspiration are rather characteristic and include a mixture of oval or polygonal mononuclear cells showing vacuolation and/or pigment deposition along with a population of multinucleated giant cells. Separation from other giant cell lesions including true giant cell tumor of bone, chondroblastoma, aneurysmal bone cyst, and granulomatous inflammation must be made. Careful attention to the cytologic findings and correlation with clinical and radiographic data should result in the appropriate diagnosis of tenosynovial giant cell tumor in most cases.


Electrocardiography in pre-participation screening and current guidelines for participation in competitive sports.
Electrocardiography (ECG) is especially significant in pre-participation screening due to its ability to discover or to rise a suspicion for certain cardiovascular diseases and conditions that represent a serious health risk in athletes. Common, conditionally benign and training related ECG changes are sinus bradycardia and sinus arrhythmia, first degree atrioventricular block, incomplete right bundle branch block, benign early repolarization, and isolated QRS voltage criteria for left ventricular enlargement. Uncommon ECG changes, unrelated to training, and some specific syndromes are ST segment depression and/or ≥ 2 mm T wave inversion in two or more adjacent leads, intraventricular conduction disorder, Wolf-Parkinson-White syndrome, long QT interval syndrome, short QT interval syndrome, catecholaminergic polymorphic ventricular tachycardia, monomorphic ventricular extrasystole and benign ventricular tachycardia. Keywords: examination; athletes; recommendations


Emergent biological properties of arrestin pathway-selective biased agonism.
Our growing appreciation of the pluridimensionality of G protein-coupled receptor (GPCR) signaling, combined with the phenomenon of orthosteric ligand "bias", has created the possibility of drugs that selectively modulate different aspects of GPCR function for therapeutic benefit. When viewed from the short-term perspective, e.g. changes in receptor conformation, effector coupling or second messenger generation, biased ligands appear to activate a subset of the response profile produced by a conventional agonist. Yet when examined in vivo, the limited data available suggest that biased ligand effects can diverge from their conventional counterparts in ways that cannot be predicted from their in vitro efficacy profile. What is currently missing, at least with respect to G protein and arrestin pathway-selective ligands, is a rational framework for relating the in vitro efficacy of a "biased" agonist to its in vivo actions that will enable drug screening programs to identify ligands with the desired biological effects.


[Experience in the treatment of eye tumors using a narrow medical proton beam].
This paper presents the effects of proton beam therapy of 175 patients with tumors of the eye. Irradiation was performed with a narrow medical proton beam (Institute of Theoretical and Experimental Physics) with the energy of 70 MeV (Bragg's peak). The total dose was 6000-7000 rad, irradiation frequency was 5-6 sessions every other day. Irradiation was used to treat intraocular and orbital melanomas, melanomas an cancer lesions of the eyelid and conjunctiva. According to the WHO classification, tumors fell under the T2-T3N0M0 stage. The follow-up periods varied from 1 to 10 years (an average of 3.4 years). Complete tumor regression was observed in 45% of the cases, partial regression in 39%, and the absence of the effect in 16%. Twenty-two patients (12%) underwent enucleation due to progressive tumor growth (16 patients) or postradiation complications (6 patients). Hematogenous metastases within a period of 2-5 years following irradiation were noted in 4% of the cases. The results obtained indicated a high efficacy of proton beam therapy for large ocular tumors. The mortality rate from metastases following irradiation was lower than that following enucleation.


Esophageal hiatal hernia; some aspects of surgical treatment.
Patients with esophageal hiatal hernia often have an array of distressing complaints and physical signs that are difficult to interpret. Physiologic and anatomic studies of the gastroesophageal area in the region of the esophageal hiatus of the diaphragm indicate the existence of a three-in-line sphincter group, consisting of the inferior esophageal constrictor, diaphragmatic pinchcock and cardioesophageal junction. These mechanisms, acting in unison, prevent regurgitation in normal persons.It also can be deduced from clinical, radiologic and experimental data that anatomic disturbances at the esophageal hiatus account for physiologic alterations. A reasonable explanation for the symptoms and signs of esophageal hiatal hernia can be made on the basis of the functional competence of the three-in-line sphincter mechanisms.


Some new aspects of the Boyer reaction.
[reaction: see text] The reaction outcome of 2-azidoethanol and aliphatic aldehyde is found to be dependent on the catalyst and the structure of the azido alcohol. Under the catalysis of Cu(II) triflate, the corresponding acetal is obtained. A similar reaction between 2-aryl-2-azidoethanol and aldehyde catalyzed by BF3 yields a mixture of 3-oxazoline and 2-oxazoline. The latter reaction has been used for the preparation of 3-oxazolines in good enantioselectivity.


Hippocampal atrophy in persons with age-associated memory impairment: volumetry within a common space.
The objective of this study is to demonstrate the assessment of hippocampal atrophy within a standard brain atlas for persons with age-associated memory impairment (AAMI) compared with cognitively intact elderly. High-resolution three-dimensional (3D) brain magnetic resonance imaging (MRI) was performed on 20 nondemented persons: 10 had AAMI and 10 were normal elderly. Scans were aligned to a common atlas template to control for errors due to variable brain size and orientation as well as facilitating communication of results across centers. Manual outlining every 1 mm with volumes determined for both the hippocampal head and body was accomplished after coronal resampling perpendicular to the long axis of the hippocampus. Subject groups were similar in age, sex ratios, and educational achievement. The AAMI group had significantly lower volumes for the right hippocampus and hippocampal head (p =.02) compared with controls. A growing body of work suggests the right hippocampal head as an early site of atrophy in early memory impairment. Subtle atrophic changes are detectable within a common atlas template allowing imaging assessment across centers.


Efficient DNA packaging of bacteriophage PRD1 requires the unique vertex protein P6.
The assembly of bacteriophage PRD1 proceeds via formation of empty procapsids containing an internal lipid membrane, into which the linear double-stranded DNA genome is subsequently packaged. The packaging ATPase P9 and other putative packaging proteins have been shown to be located at a unique vertex of the PRD1 capsid. Here, we describe the isolation and characterization of a suppressor-sensitive PRD1 mutant deficient in the unique vertex protein P6. Protein P6 was found to be an essential part of the PRD1 packaging machinery; its absence leads to greatly reduced packaging efficiency. Lack of P6 was not found to affect particle assembly, because in the P6-deficient mutant infection, wild-type (wt) amounts of particles were produced, although most were empty. P6 was determined not to be a specificity factor, as the few filled particles seen in the P6-deficient infection contained only PRD1-specific DNA. The presence of P6 was not necessary for retention of DNA in the capsid once packaging had occurred, and P6-deficient DNA-containing particles were found to be stable and infectious, albeit not as infectious as wt PRD1 virions. A packaging model for bacteriophage PRD1, based on previous results and those obtained in this study, is presented.


New regression formula to estimate the prenatal crown formation time of human deciduous central incisors derived from a Roman Imperial sample (Velia, Salerno, Italy, I-II cent. CE).
The characterization and quantification of human dental enamel microstructure, in both permanent and deciduous teeth, allows us to document crucial growth parameters and to identify stressful events, thus contributing to the reconstruction of the past life history of an individual. Most studies to date have focused on the more accessible post-natal portion of the deciduous dental enamel, even though the analysis of prenatal enamel is pivotal in understanding fetal growth, and reveals information about the mother's health status during pregnancy. This contribution reports new data describing the prenatal enamel development of 18 central deciduous incisors from the Imperial Roman necropolis of Velia (I-II century CE, Salerno, Italy). Histomorphometrical analysis was performed to collect data on prenatal crown formation times, daily secretion rates and enamel extension rates. Results for the Velia sample allowed us to derive a new regression formula, using a robust statistical approach, that describes the average rates of deciduous enamel formation. This can now be used as a reference for pre-industrial populations. The same regression formula, even when daily incremental markings are difficult to visualize, may provide a clue to predicting the proportion of infants born full term and pre-term in an archaeological series.


Bilateral and multicystic major salivary gland disease: a rare presentation of primary Sjögren's syndrome.
We present a case of a 15-year-old girl with bilateral parotid and sub-mandibular salivary gland enlargement as the sole presentation of primary Sjögren's syndrome. The clinical, radiological, immunological and pathological features have been discussed. The relevant literature has been reviewed. To our knowledge this is the only reported case of Sjögren's syndrome presenting as multicystic disease with bilateral major salivary gland involvement.


[Clinical Guidelines for Cancer Chemotherapy under COVID-19 in the World].
A risk of COVID-19 infection for cancer patients is reported slightly high compared with general citizens. Among patients with cancer and COVID-19, severe illness and mortality is slightly high and associated with general risk factors and risk factors unique to patients with cancer. Cancer therapy should not be stopped or postponed under COVID-19 because cancer will be fatal disease if delaying or stopping cancer treatment. Clinical guidelines for cancer chemotherapy is discussed under COVID-19 in this article.


Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson's Disease Mouse Model.
The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major feature in the pathology of Parkinson's disease (PD). Using neural stem or progenitor cells (NSC/NPCs), the prospect of replacing the missing or damaged DA neurons is very attractive for PD therapy. However, little is known about the endogenous mechanisms and molecular pathways regulating the NSC/NPC proliferation and differentiation in the development of PD. Herein, using Kir6.2 knockout (Kir6.2-/-) mice, we observed that genetic deficiency of Kir6.2 exacerbated the loss of SN DA neurons relatively early in a chronic MPTP/probenecid (MPTP/p) injection course, but rescued the damage of neurons 7 days after the last MPTP/p injection. Meanwhile, we found that Kir6.2 knockout predominantly increased the differentiation of nuclear receptor-related 1 (Nurr1+) precursors to DA neurons, indicating that Kir6.2 deficiency could activate an endogenous self-repair process. Furthermore, we demonstrated in vivo and in vitro that lack of Kir6.2 promoted neuronal differentiation via inhibiting the downregulation of glia cell line-derived neurotrophic factor (GDNF), which negatively related to the level of microRNA-133b. Notably, we revealed that Gdnf is a target gene of miR-133b and transfection of miR-133b could attenuate the enhancement of neural precursor differentiation induced by Kir6.2 deficiency. Collectively, we clarify for the first time that Kir6.2/K-ATP channel functions as a novel endogenous negative regulator of NPC differentiation, and provide a promising neuroprotective target for PD therapeutics.


Comparison of PEG chain length and density on amphiphilic macromolecular nanocarriers: self-assembled and unimolecular micelles.
Two classes of amphiphilic macromolecules were evaluated for drug delivery applications: those that exist as unimolecular micelles and those that self-assemble in aqueous solution to form micelles. This study compares the poly(ethylene glycol) (PEG) chain length and density that constitute the corona of both classes. In particular, the effect of PEG branching on micellar size, water-solubility, resolubilization rate, drug loading efficiency and drug release rate were analyzed. Pluronic P85 and Cremophor EL, commonly used in pharmaceutical applications, were used as controls. Indomethacin (IMC) was used as the drug for encapsulation, release and resolubilization experiments. Results indicated that smaller micellar sizes, higher water solubilities and faster resolubilization rates were achieved from higher PEG densities compared to linear PEG analog of similar mass. Further, micellar sizes of both higher density PEG and linear PEG macromolecules were constant over a wide temperature range (2-70 degrees C). In contrast, Cremophor EL formed aggregates at 15 degrees C and Pluronic P85 underwent a size transition at 45 degrees C. IMC loading efficiencies for all amphiphilic macromolecules were comparable to controls. However, faster resolubilization and slower drug release were observed for higher density PEG macromolecules compared to linear PEG analogs and controls.


Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2.
The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 (Tlr2)-deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF Tlr2-/- and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in Tlr2-/- mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, Tlr2-/- , and heterozygous Vwf+/- mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in Tlr2-/- mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus growth.


Prevalence of antibody to hepatitis C virus in pregnant Taiwanese.
To assess the prevalence of an antibody to hepatitis C virus (anti-HCV) in pregnant women in Taiwan, and elucidate whether or not there is superinfection of the hepatitis B virus (HBV) in such cases, we investigated two independent groups of pregnant women. Group A included 294 without serum alanine aminotranferase (ALT) screening, and group B included 171 pregnant women with an abnormal ALT level (greater than 45 IU/L) who were recruited from 9,523 pregnant women screened for ALT. Blood samplings were taken at early gestation and each serum sample was tested with an HCV EIA kit for anti-HCV. The results showed that 1 woman in group A (0.34%) and 4 women in group B (2.3%) were anti-HCV-positive. However, all 5 cases showed positive antibodies to both the hepatitis B surface and core antigens, but were negative for the hepatitis B surface antigen. Therefore, the prevalence of anti-HCV in pregnant women by current assay in Taiwan is 0.34% without ALT screening, but increases to 2.3% among abnormal ALT cases. The prevalence rate is less than the rates reported in other countries. If confirmed by subsequent study, the results suggest that infection with HCV is low among healthy young females in Taiwan today.


On the role of recognition in decision making.
In 2 experiments, the authors sought to distinguish between the claim that recognition of an object is treated simply as a cue among others for the purposes of decision making in a cue-learning task from the claim that recognition is attributed a special status with fundamental, noncompensatory properties. Results of both experiments supported the former interpretation. When recognition had a high predictive validity, it was relied on (solely) by the majority of participants; however, when other cues in the environment had higher validity, recognition was ignored, and these other cues were used. The results provide insight into when, where, and why recognition is used in decision making and also question the elevated status assigned to recognition in some frameworks (e.g., D. G. Goldstein & G. Gigerenzer, 2002).


Effects of a trauma center on early mortality after trauma in a regional city in Japan: a population-based study.
Although the effects of the trauma center(TC) were researched in several studies, there have been few studies on changes in the regional mortality due to the implementation of a TC. An emergency medical center (EMC) and TC were implemented at Nagasaki University Hospital (NUH) for the first time in the Nagasaki medical region of Japan in April 2010 and October 2011, respectively, and they have cooperated with each other in treating trauma patients. The purpose of this study was to investigate the effects on the early mortality at population level of a TC working in cooperation with an EMC. This is a retrospective study using standardized regional data (ambulance service record) in Nagasaki medical region from April 2007 through March 2017. We included 19,045 trauma patients directly transported from the scene. The outcome measures were prognosis for one week. To examine the association between the implementation of the EMC and TC and mortality at a region, we fit adjusted logistic regression models. The number of patients of each fiscal year increased from 1492 in 2007 to 2101 in 2016. The number of all patients transported to NUH decreased until 2009 to 70, but increased after implementation of the EMC and TC. Overall mortality of all patients in the region improved from 2.3% in 2007 to 1.0% in 2016. In multivariate logistic regression model, odds ratio of death was significantly smaller at 2013 and thereafter if the data from 2007 to 2011 was taken as reference. Implementation of the EMC and TC was associated with early mortality in trauma patients directly transported from the scene by ambulance. Our analysis suggested that the implementation of EMC and TC contributed to the improvement of the early mortality at a regional city with 500000 populations. Level III.


Assembling a xylanase-lichenase chimera through all-atom molecular dynamics simulations.
Multifunctional enzyme engineering can improve enzyme cocktails for emerging biofuel technology. Molecular dynamics through structure-based models (SB) is an effective tool for assessing the tridimensional arrangement of chimeric enzymes as well as for inferring the functional practicability before experimental validation. This study describes the computational design of a bifunctional xylanase-lichenase chimera (XylLich) using the xynA and bglS genes from Bacillus subtilis. In silico analysis of the average solvent accessible surface area (SAS) and the root mean square fluctuation (RMSF) predicted a fully functional chimera, with minor fluctuations and variations along the polypeptide chains. Afterwards, the chimeric enzyme was built by fusing the xynA and bglS genes. XylLich was evaluated through small-angle X-ray scattering (SAXS) experiments, resulting in scattering curves with a very accurate fit to the theoretical protein model. The chimera preserved the biochemical characteristics of the parental enzymes, with the exception of a slight variation in the temperature of operation and the catalytic efficiency (kcat/Km). The absence of substantial shifts in the catalytic mode of operation was also verified. Furthermore, the production of chimeric enzymes could be more profitable than producing a single enzyme separately, based on comparing the recombinant protein production yield and the hydrolytic activity achieved for XylLich with that of the parental enzymes.


Isomerization of 11-cis-retinol to all-trans-retinol in bovine rod outer segments.
It is known that exogenous 11-cis-retinol inhibits the recovery of photosensitivity of bleached rod outer segments (ROS) and 11-cis-retinol exists in the interphotorecepter matrix. We examined the conversion of 11-cis-retinol with bovine ROS. ROS was incubated with 11-cis-retinol under dim red light. Retinoids were extracted from the reaction mixture with hexane and analyzed by HPLC coupled with a fluorescence spectrophotometer. Isomerization of 11-cis-retinol to all-trans-retinol was observed in the presence of ROS. This isomerization was not suppressed by heat treatment and did not have stereospecificity. In addition, we incubated purified rhodopsin and phospholipids extracted from ROS with 11-cis-retinol. Rhodopsin was found to isomerize 11-cis-retinol to all-trans-retinol as well as ROS, but phospholipids did not. In contrast, the phospholipids inhibited the isomerization of 11-cis-retinol to all-trans-retinol by the purified rhodopsin. Commercially available phospholipids, especially phosphatidylserine, also inhibited the isomerization. Our results suggest that rhodopsin has activity for the isomerization of 11-cis-retinol to all-trans-retinol and may play an important role in the detoxification of 11-cis-retinol in the ROS.


[Changes and significance of TNF, sIL-2R, IL-6, IL-4 and IFN-gamma levels in plasma from the patients with hemorrhagic fever with renal syndrome].
To explore the changes of TNF, sIL-2R, IL-6, IL-4 and IFN-gamma levels in plasma from patients with hemorrhagic fever with renal syndrome(HFRS) and analyze the correlation between these cytokine levels and alanine aminotransferase(ALT) level in sera from the patients. The cytokine levels were measured by double mAb sandwich ELISA. An automatic biochemical detector(RA-1000) was employed to determine the ALT level. Levels of TNF, IL-6, IL-4, IFN-gamma and sIL-2R in plasma from the patients were(95.82+/-12.04), (362.46+/-141.26), (17.76+/-3.52), (116.18+/-19.80) ng/L and (898 820+/-127 200) U/L, respectively. These cytokines in plasma from healthy donors were (17.89+/-1.68), (43.81+/-18.08), (4.86+/-1.14), (7.57+/-2.41) ng/L and (66 730+/-29 690) U/L, respectively. The cytokine levels of the patients were notably higher than those of the healthy donors.(P<0.01). At the same time, the average ALT level in sera from the patients was 4.4 fold of that from the healthy donors. Statistical analysis showed that levels of TNF, sIL-2R, IL-6 and IFN-gamma were positively correlated with ALT level, respectively. The HFRS patients have a significant increase in both cytokines (TNF, sIL-2R, IL-6 and IFN-gamma) and ALT levels. And there is a positive correlation between those cytokine and ALT levels, suggesting that the liver injury during HTNV infection may be related to the elevation of above cytokine levels.


Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant.
Autoantibodies to phospholipids (APA) occur frequently in systemic lupus erythematosus (SLE) and other autoimmune disorders and predispose to intravascular thromboses. Major histocompatibility complex (MHC) class II alleles (HLA-DR and DQ) were determined by restriction fragment length polymorphisms (RFLP) in 20 patients with APA (lupus anticoagulant). HLA-DQw7 (DQB1*0301), linked to HLA-DR5 and -DR4 haplotypes, occurred in 70% and was significantly increased compared to 139 race-matched normal controls (P = 0.002, P corrected [pc] = 0.05, odds ratio [OR] = 5.1). Moreover, the frequency of HLA-DQw7 was significantly higher in SLE patients with APA as compared with patients without APA but with other autoantibodies, including anti-Ro and La (P = 0.0001, pc = 0.002, OR = 10.7), anti-Ro alone (P = 0.001, pc = 0.02, OR = 11.2), anti-dsDNA (P = 0.001, pc = 0.02, OR = 7.1), and possibly anti-Sm (P = 0.04, pc = NS, OR = 6.8) and anti-nRNP (U1-RNP) (P = 0.01, pc = NS, OR = 7.8). The DQB1*0301 allele of DQw7 showed the strongest association, while the frequencies of the DQA1*0301 (45%) and DQA1*0501 (50%) alleles did not differ from the controls. Among the HLA-DQB1*0301 (DQw7) negative patients, all possessed HLA-DQw8 (DQB1*0302) and/or HLA-DQw6 (DQB1*0602 or DQB1*0603) alleles. The HLA-DQB1*0301 chain shares an identical seven amino acid sequence with DQB1*0302, *0602, and *0603 chains in the third hypervariable region of the HLA-DQ molecule. This candidate "epitope" may play a role in mediating an autoimmune response to APA.


Repetition priming in adults with Williams syndrome: age-related dissociation between implicit and explicit memory.
We examined implicit and explicit memory in adults with Williams syndrome. An age-related dissociation was found; repetition priming (reflecting implicit memory) did not show change with age, but free recall (reflecting explicit memory) was markedly reduced. We also compared the performance of adults with Williams syndrome to adults with Down syndrome and those with unspecified mental retardation. A similar dissociation was observed in adults with Down syndrome but not in adults with unspecified mental retardation. An IQ-related dissociation was also found. Implicit and explicit memory, therefore, show different degrees of association with age and IQ, supporting theories of these memory processes. Results also suggest that Williams syndrome, similar to Down syndrome, may be associated with precocious aging, resulting in the loss of some cognitive abilities.


Effects of anatomy and diet on gastrointestinal pH in rodents.
The pH of the gastrointestinal tract can have profound influences on digestive processes. Rodents exhibit wide variation in both stomach morphology and dietary strategies, both of which may influence gut pH. Various rodent species have evolved bilocular (or semi-segmented) stomachs that may allow for more microbial growth compared to unilocular (single-chambered) stomachs. Additionally, herbivory has evolved multiple times in rodents. The high dietary fiber typical of an herbivorous diet is known to induce secretion of bicarbonate in the gut. We predicted that stomach segmentation might facilitate the separation of contents in the proximal chamber from that of the gastric stomach, facilitating a chemical environment suitable to microbial growth. To investigate the effect of stomach anatomy and diet on gut pH, several species of rodent with varying stomach morphology were fed either a high or low-fiber diet for 7 days, and pH of the proximal stomach, gastric stomach, small intestine, and cecum were measured. We discovered that rodents with bilocular stomach anatomy maintained a larger pH gradient between the proximal and gastric stomach compartments, and were able to achieve a lower absolute gastric pH compared to those with unilocular stomachs. Dietary fiber increased the pH of the small intestine, but not in any other gut regions. The stomach pH data supports the century old hypothesis that bilocular stomach anatomy creates an environment in the proximal stomach that is suitable for microbial growth. Additionally, the alkaline small intestinal pH on a high fiber diet may enhance digestion.


Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics.
Pancreatic beta-cells in the islet of Langerhans produce the hormone insulin, which maintains blood glucose homeostasis. Perturbations in beta-cell function may lead to impairment of insulin production and secretion and the onset of diabetes mellitus. Several essential beta-cell factors have been identified that are required for normal beta-cell function, including six genes that when mutated give rise to inherited forms of diabetes known as Maturity Onset Diabetes of the Young (MODY). However, the intracellular signaling pathways that control expression of MODY and other factors continue to be revealed. Post-transplant diabetes mellitus in patients taking the calcineurin inhibitors tacrolimus (FK506) or cyclosporin A indicates that calcineurin and its substrate the Nuclear Factor of Activated T-cells (NFAT) may be required for beta-cell function. Here recent advances in our understanding of calcineurin and NFAT signaling in the beta-cell are reviewed. Novel therapeutic approaches for the treatment of diabetes are also discussed.


Psychosocial risk factors for increased emergency hospital utilization by sickle cell disease patients: a systematic review protocol.
To assess psychosocial risk factors for increased emergency hospital utilization by sickle cell patients. Emergency hospital utilization by sickle cell disease patients is high but heterogeneous between patients and in a given patient over time. Psychosocial factors affect emergency hospital utilization and are a possible target to improve the management of sickle cell disease. This review will include all original quantitative studies evaluating the impact of psychosocial risk factors on emergency hospital utilization by sickle cell disease patients. There will be no language restriction. PubMed, Embase, CINAHL, PubPsych, LiSSa, and Web of Science will be searched using a peer-reviewed search strategy. Study selection and extraction of data will be performed independently by two authors. Discrepancies will be solved by consensus or, if needed, by a third author. The authors will assess study quality, as well as perform a narrative synthesis of included studies, and where possible, meta-analyses with evaluation of heterogeneity and publication bias. PROSPERO CRD42019140435.


Endocardial pacing in infants and children 15 kg or less in weight: medium-term follow-up.
Twenty-four children 15 kg or less in weight (range 2.8-15 kg) underwent implantation of a permanent pacemaker using the transvenous technique of lead placement. During a follow-up period of 2 months to 6 years 1 month (median 3 years 6 months) eight children suffered complications, six of which necessitated reoperation. These included: lead fracture in two, infection in two, transient myocardial dysfunction in one, generator migration in one, premature battery depletion in one, and threshold rise in one. A loop of redundant ventricular lead positioned in the atrium at the time of implant is successfully unravelling in all children. One child died during the follow-up period of a pneumonia unrelated to her pacemaker. The other children are growing and developing normally and the cosmetic appearance has proved acceptable in all cases.


Effects of respiratory alkalosis and acidosis on myocardial excitation.
In anesthetized dogs electrocardiogram and monophasic action potentials (MAPs) were recorded from the right atrium and the right ventricle by intracardiac suction electrode technique. The animals were subjected, by means of ventilation with CO2 and hyperventilation, to periods of respiratory acidosis and respiratory alkalosis, respectively. Pronounced respiratory acidosis induced an increased sympathetic activity followed by a decrease in heart rate and prolongation of the A-V conduction time whereas the shape and duration of the atrial and ventricular MAPs remained unaltered. Arterial hypoxia in combination with pronounced respiratory acidosis did not influence the MAP durations. Respiratory alkalosis resulted in an increased sympathetic influence on the heart activity whereas the shape and duration of the atrial and the ventricular MAPs remained unaffected. During pronounced hyperventilation with increasing central venous pressure an increased parasympathetic influence on the heart activity with decrease in the heart rate, prolongation of the A-V conduction time and shortening of the atrial MAP duration was recorded.


Intensive epidermal adsorption and specific venous deposition of carboxyl quantum dots in zebrafish early-life stages.
To properly assess the environmental risk of quantum dots (QDs), it is necessary to determine their fate in living organisms, including adsorption, distribution and bioaccumulation under representative environmental or physiological conditions. We comprehensively investigated the fate of QDs with carboxyl terminal functional groups (carboxyl-QDs) in zebrafish (Danio rerio) embryo and larvae subjected to either waterborne exposure or cardiovascular system microinjection. On waterborne exposure, carboxyl-QDs exhibited an intensive adsorption and accumulation in the chorion of embryos, and their predominate target organs were the gill and intestinal tract in larvae. On microinjection, carboxyl-QDs were rapidly delivered into the cardiovascular system and specifically deposited in veins and the capillary network system of zebrafish larvae, but not in the arterial system. Taken together, we found that the exact tissue condition including epidermal structures, mucus secretion and vascular microstructures strongly affected the adsorption, uptake and distribution of carboxyl-QDs in zebrafish. This work highlights the intensive tissue epidermal adsorption and accumulation of carboxyl-QDs and their specific vein and capillary deposition in the cardiovascular system in zebrafish early-life stages.


Variation in the practice of laparoscopic sacrohysteropexy and laparoscopic sacrocolpopexy for the treatment of pelvic organ prolapse: a Dutch survey.
Laparoscopic techniques for pelvic organ prolapse surgery using mesh are gaining interest. A standard approach or published guideline for the laparoscopic sacrohysteropexy (LSH) or laparoscopic sacrocolpopexy (LSC) is lacking. The purpose of this study is to assess the variation between Dutch gynecologists in executing LSH and LSC. A questionnaire was developed to evaluate the technique of LSH and LSC. All members of the Dutch Society for Gynecological Endoscopy and Minimally Invasive Surgery and the Dutch Society for Urogynecology were invited by email to participate in a web-based survey. With 357 respondents, the response rate was 71%. Of the respondents, a total of 49 gynecologists (13.7%) perform LSH and/or LSC. Gynecologists who perform both procedures use the same surgical technique for LSH and LSC. There are variations among gynecologists on several key points such as the level of dissection along the anterior and posterior walls of the vagina, the type of mesh used, the type of sutures used, the tension of the implanted mesh and reperitonealization of the mesh. There is a high practice variation in LSH and LSC performed by a selected group of Dutch gynecologists. Different methods have been described in the literature and there is no consensus on how to perform these procedures. A well-designed prospective study or randomized controlled trial with regard to the specific parts of these procedures is needed to provide evidence for the best surgical technique. The outcomes of these studies will help to establish evidence-based guidelines.


Effects of Acupuncture on CCL2 and CXCL8 Expression and the Subset of uNK Cells in Rats with Embryo Implantation Failure.
The present study was designed to investigate the efficacy and mechanism of acupuncture treatment on embryo implantation failure in rats. The pregnant rats were randomized into normal group (N), implantation failure group (M), acupuncture treatment group (A), and progestin treatment group (W). The embryo implantation failure model was established by mifepristone. Efficacy of acupuncture treatment was evaluated by the number of implanted embryos. The expression of CCL2 and CXCL8 and the subset of uterine natural killer cells in the endometrium were detected. We demonstrated that the number of implanted embryos was dramatically reduced after mifepristone (M group) treatment, while the acupuncture (A group) and progestin (W group) treatments significantly rescued impaired embryo implantation. The protein and mRNA expressions of CCL2 and CXCL8 were significantly reduced by mifepristone treatment, but the attenuated expression of CCL2 and CXCL8 was markedly reversed by acupuncture or progestin treatment. More importantly, acupuncture and progestin could markedly increase the subset of uNK cells in rats with embryo implantation failure. These evidences suggest that acupuncture is able to modulate the endometrial immune microenvironment and thus improve embryo implantation in pregnant rats, which provides solid experimental evidence for the curative effect of acupuncture treatment on infertility.


Assessing the severity of perinatal hypoxia-ischemia in piglets using near-infrared spectroscopy to measure the cerebral metabolic rate of oxygen.
Reduced cerebral function after neonatal hypoxia-ischemia is an early indicator of hypoxic-ischemic encephalopathy. Near-infrared spectroscopy offers a clinically relevant means of detecting impaired cerebral metabolism from the measurement of the cerebral metabolic rate of oxygen (CMRO2). The purpose of this study was to determine the relationship between postinsult CMRO2 and duration of hypoxia-ischemia in piglets. Twelve piglets were subjected to randomly selected durations of hypoxia-ischemia (5-28 min) and five animals served as controls. Measurements of CMRO2 were taken before and for 24 h after hypoxia-ischemia. Histology was carried out in nine piglets (six insults, three controls) to estimate brain injury. In the first 4 h after the insult, average CMRO2 of the insult group was significantly depressed (33 +/- 3% reduction compared with controls) and by 8 h, a significant correlation developed, which persisted for the remainder of the study, between CMRO2 and the duration of ischemia. Histologic staining suggested little brain damage resulted from shorter insult durations and considerable damage from more prolonged insults. This study demonstrated that near-infrared spectroscopy could detect early changes in CMRO2 after hypoxia-ischemia for a range of insult severities and CMRO2 could be used to distinguish insult severity by 8 h after the insult.


Intestinal transport of 5-methyltetrahydrofolate.
The mechanism of intestinal absorption of 5-methyltetrahydrofolate (5- CH3THF ) has been the topic of some controversy. In the present study, we have used enzymatically prepared 5- CH3THF to characterize transport by rat intestinal loops in vivo and everted jejunal sacs in vitro. Transport of 5- CH3THF is saturable (Km = 5.2 microM) and highly pH dependent, with the rate of maximal transport occurring at pH 5.8. Transport is competitively inhibited by folic acid (Ki = 4.2 microM) and methotrexate (Ki = 4.65 microM). Metabolic poisons and anaerobiosis greatly reduce 5- CH3THF transport. We conclude that 5- CH3THF transport in the rat intestine occurs by the same structure-specific mechanism responsible for the transport of unreduced folic acid and other monoglutamyl folates.


Preparation of Zirconium Phosphate Nanomaterials and Their Applications as Inorganic Supports for the Oxygen Evolution Reaction.
Zirconium phosphate (ZrP) nanomaterials have been studied extensively ever since the preparation of the first crystalline form was reported in 1964. ZrP and its derivatives, because of their versatility, have found applications in several fields. Herein, we provide an overview of some advancements made in the preparation of ZrP nanomaterials, including exfoliation and morphology control of the nanoparticles. We also provide an overview of the advancements made with ZrP as an inorganic support for the electrocatalysis of the oxygen evolution reaction (OER). Emphasis is made on how the preparation of the ZrP electrocatalysts affects the activity of the OER.


ED revamp: team approach to care reduces errors, boosts patient and clinician satisfaction.
With a poor safety record and long waits for care, the ED at St. Vincent's Medical Center in Bridgeport, CT, launched a comprehensive improvement effort that has slashed door-to-doctor times, drastically improved patient satisfaction, and reduced serious safety events to zero during the past year. Key to the approach is a team-based operations system that makes care teams responsible for specific zones in the ED. Patient satisfaction has gone from the single digits to above 90% in almost all areas, but high satisfaction is now harder to sustain because of elevated patient expectations. Door-to-doctor times have been reduced from 126 minutes to less than 25 minutes. Team approach to care improves clinician satisfaction while reducing errors. A streamlined triage system has eliminated several steps for low-acuity patients.


Multistate vibronic interactions in difluorobenzene radical cations. II. Quantum dynamical simulations.
The multistate vibronic dynamics in the X-D electronic states of all three difluorobenzene radical cations are investigated theoretically by an ab initio quantum dynamical approach. The vibronic coupling scheme and the ab initio values of the system parameters are adopted from Paper I [S. Faraji and H. Koppel, J. Chem. Phys. 129, 074310 (2008)]. Extensive calculations by wave-packet propagation have been performed with the aid of the multiconfiguration time-dependent Hartree method. Five coupled electronic potential energy surfaces and 10 (11 in the case of the orthoisomer) vibrational degrees of freedom have been included in these calculations. The nonadiabatic interactions lead to the restructuring of the photoelectron spectral envelopes. Ultrafast internal conversion processes within the electronic manifolds in question demonstrate the strength of the nonadiabatic coupling effects and complement the analogous findings for the electronic spectra. The internal conversion dynamics is characterized by a stepwise transfer of the electronic population to the lowest electronic state on a time scale of femtoseconds to picoseconds. A difference between the three isomers is found to be related to the weaker interaction between the sets of X-A and B-C-D states (with high-energy conical intersections) in the meta isomer, as compared to the other isomers. The implications of these findings for the qualitative understanding of the fluorescence dynamics of fluorinated benzene radical cations are discussed.


Motor and secretory effects of nerves on the parotid gland of rat.
The influence of parasympathetic and sympathetic nerves on the parotid gland of the rat was investigated. It was found that both divisions of the autonomic nerves evoke secretion and probably also motor effects in this gland. Secretion elicited on sympathetic stimulation was mediated both via alpha- and beta-adrenoceptors, while motor effects were mediated via alpha-adrenoceptors. On stimulation of the autonomic nerves a lower duct pressure was reached in the parotid than in the submaxillary gland, and on sympathetic nerve stimulation the flow of saliva always started later from the parotid than the submaxillary gland. These findings are discussed in the view of the different arrangement of the myoepithelial cells in the 2 glands.


Effect of all-trans-retinoic acid on the hypercoagulable state of patients with breast cancer.
To evaluate whether all-trans-retinoic acid (ATRA) is able to modulate the hemostatic system in patients with solid tumors, we studied patients with locally advanced breast cancer who were enrolled in a Phase Ib study of ATRA +/- Tamoxifen (Tam). In this study, two groups of 15 patients/each were treated for 21 days before operation with ATRA at three doses (15, 45, or 75 mg/m(2)/day on alternate days) given alone (group 1) or in combination with Tam (group 2). One additional group received Tam alone. Plasma samples were evaluated for hypercoagulation markers (FVIIa, F1+2, TAT, D-dimer), fibrinolysis proteins (t-PA, PAI-1), and coagulation inhibitors (protein C, AT). At baseline, cancer patients had FVIIa, F1+2, TAT, and PAI-1 significantly greater than control subjects. During treatment, in the patients given ATRA alone, hypercoagulation markers appeared unmodified. Instead, subjects given Tam alone had a significant elevation of FVIIa, F1+2, and TAT versus baseline. However, in the ATRA + Tam groups, hypercoagulation markers were decreased compared with Tam alone. These results suggest that in selected conditions, pre-operative ATRA may modulate the hypercoagulable state of breast cancer patients.


ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy.
The hemoglobinopathies are a heterogeneous group of single-gene disorders that includes the structural hemoglobin variants and the thalassemias. More than 270 million people worldwide are heterozygous carriers of hereditary disorders of hemoglobin, and at least 300,000 affected homozygotes or compound heterozygotes are born each year. The purpose of this document is to review the most common hemoglobinopathies and to provide recommendations for screening and clinical management of hemoglobinopathies during pregnancy.


Application of Food-specific IgG Antibody Detection in Allergy Dermatosis.
The application of food-specific IgG antibody detection in allergy dermatoses was explored. 181 patients with allergy dermatoses were diagnosed from January to September 2014 and 20 healthy subjects were selected. Fourteen kinds of food-specific IgG antibodies were detected by ELISA method among all the subjects. The positive rates of IgG antibody of the patient group and the healthy group were respectively 65.2% and 5.0%. The positive rates of IgG antibody of egg, milk, shrimp and crab took a large proportion in three groups of patients with three kinds of allergy dermatoses of urticaria, eczema and allergic dermatitis, the proportion of which was respectively 70.2%, 77.8% and 71.7%. Among urticaria and allergic dermatitis patients with positive antibody, the positive rate of children was significantly higher than that of adults (p<0.05) while there was no significant difference between children and adults among eczema patients with positive antibody (p>0.05). Allergy dermatoses are closely related to food-specific IgG antibodies, and the allergy dermatoses patients have a high incidence rate of food intolerance; detecting IgG antibody in the serum of patients is of great significance for the diagnosis and treatment of allergy dermatoses.


Mechanisms for the near-UV photodissociation of CH3I on D2O/Cu(110).
The system of CH3I adsorbed on submonolayer, monolayer, and multilayer thin films of D2O on Cu(110) has been studied by measuring the time of flight (TOF) distributions of the desorbing CH3 fragments after photodissociation using linearly polarized λ = 248 nm light. For multilayer D2O films (2-120 ML), the photodissociation is dominated by neutral photodissociation via the "A-band" absorption of CH3I. The polarization and angle dependent variation in the observed TOF spectra of the CH3 photofragments find that dissociation is largely via the (3)Q0 excited state, but that also a contribution via the (1)Q1 excitation can be identified. The photodissociation results also indicate that the CH3I adsorbed on D2O forms close-packed islands at submonolayer coverages, with a mixture of C-I bond axis orientations. For monolayer and submonolayer quantities of D2O we have observed a contribution to CH3I photodissociation via dissociative electron attachment (DEA) by photoelectrons. The observed DEA is consistent with delocalized photoelectrons from the substrate causing the observed dissociation- we do not find evidence for an enhanced DEA mechanism via the temporary solvation of photoelectrons in localized states of the D2O ice.


Risk of coronary heart disease in women after menopause.
An increase in the incidence of coronary heart disease risk has commonly been reported in postmenopausal women. The study population comprised 263 adult healthy men and 237 women (104 premenopausal and 133 postmenopausal) ranging in age group of 21-70 years who were examined for coronary heart disease risk factors from Nellore district in Andhra Pradesh. Anthropometric measurements, blood pressure and serum lipids were analysed using standard procedures. There were no significant differences for anthropometric variables between postmenopausal and premenopausal women. Postmenopausal women had significantly higher levels of blood pressure, pulse rate, serum total cholesterol, triglycerides, low-density lipoprotein cholesterol and ratios of total cholesterol:high-density lipoprotein cholesterol and low-density lipoprotein cholesterol:high-density lipoprotein cholesterol as atherogenic indices than premenopausal women and the corresponding age group of male counterparts. However, the variation of high-density lipoprotein cholesterol levels between these groups were not statistically significant. The prevalence of hypertension, hypercholesterolaemia, hypertriglyceridaemia and atherogenic indices was significantly greater in postmenopausal women than in premenopausal women. This study confirms a higher prevalence of risk factors for coronary heart disease among women in older age group and suggests that when oestrogen production ceases in menopausal women, the risk of coronary heart disease increases.


When a caesarean section is necessary: Analysis of cesarean sections performed in the Republic of Turkey in 2022 in accordance with the World Health Organization Multi-Country Research Guidelines.
The aim of our study, in light of the World Health Organization Multi-Country Survey (WHO-MCS) data examining the data of the Ministry of Health for the year 2022, comparing the cesarean sections (C/S) performed in the Republic of Turkey (TR) with the WHO-MCS data, and comparing the number of cesarean sections applied more than the reference values. According to the database of the Turkish Ministry of Health, in 2022, 1166175 deliveries took place in the Republic of Turkey, and 706370 (60.5%) cesarean section deliveries were recorded as 365764 (51%) primary C/S. Using the Ministry of Health registration system based on the Robson classification. The number and rate of C/S operations performed per birth in 2022 in TR (n=706370; 60.50%) were found to be significantly higher when compared to the number and rate of C/S on a global scale (n=246062; 21.10%), (p<0.001). When cesarean section operations performed in the Ministry of Health hospitals, private institutions, foundation universities, public universities and other public unit hospitals were compared with WHO MCS reference values and C/S ratios, 44.2% versus 24.7% (p=0.05), versus 77.4%, versus 34.2% (p<0.001), 74.3% versus 29.5% (p<0.001), 75% versus 35.8% (p<0.001), 69.3% versus 35.9% (p<0.001). The amount of cesarean sections performed according to the total number of births in the Turkish Republic is relatively high and its cost nearly 1 billion 750 million TL.


Time-resolved measurement of plasma parameters by means of triple probe.
Triple Langmuir probe (TLP) diagnostic system with its necessary driving circuit is developed and successfully applies for time-resolved measurement of plasma parameters in the negative glow region of pulsating-dc discharge. This technique allows the instantaneous measurement of electron temperature [T_], electron number density [n_] as well as plasma fluctuations without any voltage or frequency sweep. In TLP configuration two probes are differentially biased and serve as a floating symmetric double probe whereas the third probe is simply floating into plasma to measure floating potential as a function of time and thus incorporates the effect of plasma fluctuations. As an example of the application to time-dependent plasmas, basic plasma parameters such as floating potential, electron temperature, and electron number density in low pressure air discharge are determined as a function of time for different fill pressure. The results demonstrate temporal evolution of plasma parameters and thus plasma generation progression for different fill pressures.


Characterization of colloidal nanocrystal surface structure using small angle neutron scattering and efficient Bayesian parameter estimation.
Complete structural characterization of colloidal nanocrystals is challenging due to rapid variation in the electronic, vibrational, and elemental properties across the nanocrystal surface. While electron microscopy and X-ray scattering techniques can provide detailed information about the inorganic nanocrystal core, these techniques provide little information about the molecular ligands coating the nanocrystal surface. Moreover, because most models for scattering data are parametrically nonlinear, uncertainty estimates for parameters are challenging to formulate robustly. Here, using oleate-capped PbS quantum dots as a model system, we demonstrate the capability of small angle neutron scattering (SANS) in resolving core, ligand-shell, and solvent structure for well-dispersed nanocrystals using a single technique. SANS scattering data collected at eight separate solvent deuteration fractions were used to characterize the structure of the nanocrystals in reciprocal space. Molecular dynamics simulations were used to develop a coarse-grained form factor describing the scattering length density profile of ligand-stabilized nanocrystals in solution. We introduce an affine invariant Markov chain Monte Carlo method to efficiently perform nonlinear parameter estimation for the form factor describing such dilute solutions. This technique yields robust uncertainty estimates. This experimental design is broadly applicable across colloidal nanocrystal material systems including emergent perovskite nanocrystals, and the parameter estimation protocol significantly accelerates characterization and provides new insights into the atomic and molecular structure of colloidal nanomaterials.


High thoracic epidural anesthesia does not alter airway resistance and attenuates the response to an inhalational provocation test in patients with bronchial hyperreactivity.
The functional relevance of an intact pulmonary sympathetic innervation for airway resistance is unknown. We therefore evaluated whether or not pulmonary sympathetic denervation by thoracic epidural anesthesia decreases the threshold of an inhalational provocation with acetylcholine in 20 patients with documented bronchial hyperreactivity scheduled for elective upper abdominal or thoracic surgery. Baseline inhalational provocation with acetylcholine was performed 2-4 days before surgery. The acetylcholine threshold concentration for a hyperreactivity response (i.e., for a 20% decrease in forced expiratory volume in 1 s and a 100% increase in total respiratory resistance by oscillometry) was determined. On the day of surgery a second inhalative provocation with acetylcholine was performed 45 min after the patients had received 6-8 ml epidural bupivacaine 0.75% (n = 10), intravenous bupivacaine (1.2 mg.min-1, n = 6), or 6-8 ml epidural saline (n = 4). The acetylcholine threshold concentration for a hyperreactive response was again determined. We also measured vital capacity, forced expiratory volume in 1 s as a percentage of vital capacity, spread of sensory blockade (pin prick), skin temperature on hand and foot (telethermography). During thoracic epidural anesthesia, C4-T8 skin temperature increased significantly on hand and foot indicating widespread sympathetic blockade including the lungs. Compared to values obtained immediately before pulmonary sympathetic blockade, forced expiratory volume in 1 s as a percentage of vital capacity, and total respiratory resistance by oscillometry remained unchanged, while vital capacity decreased. Compared to baseline the acetylcholine threshold concentration for the hyperreactive response increased threefold after epidural as well as after intravenous bupivacaine. Epidural saline evoked no directional changes in the acetylcholine threshold concentration. We conclude that in patients with bronchial hyperreactivity 1. blockade of pulmonary sympathetic innervation seems to be of no relevance for airway resistance and 2. both epidural and intravenous bupivacaine substantially attenuate the response to an inhalational provocation with acetylcholine.


The acceptability of the AMBITION-cm treatment regimen for HIV-associated cryptococcal meningitis: Findings from a qualitative methods study of participants and researchers in Botswana and Uganda.
The AMBITION-cm trial for HIV-associated cryptococcal meningitis demonstrated that a single, high-dose of liposomal amphotericin (AmBisome) plus 14-days of oral flucytosine and fluconazole was non-inferior in terms of all-cause mortality to 7-days of amphotericin B deoxycholate and flucytosine followed by 7-days of fluconazole (Control). The AmBisome regimen was associated with fewer adverse events. We explored the acceptability of the AmBisome regimen from the perspective of participants and providers. We embedded a qualitative methods study within the AMBITION-cm sites in Botswana and Uganda. We conducted in-depth interviews with trial participants, surrogate decision makers, and researchers and combined these with direct observations. Interviews were transcribed, translated, and analysed thematically. We interviewed 38 trial participants, 20 surrogate decision makers, and 31 researchers. Participant understanding of the trial was limited; however, there was a preference for the AmBisome regimen due to the single intravenous dose and fewer side effects. More time was required to prepare the single AmBisome dose but this was felt to be acceptable given subsequent reductions in workload. The AmBisome regimen was reported to be associated with fewer episodes of rigors and thrombophlebitis and a reduction in the number of intravenous cannulae required. Less intensive monitoring and management was required for participants in the AmBisome arm. The AmBisome regimen was highly acceptable, being simpler to administer despite the initial time investment required. The regimen was well tolerated and associated with less toxicity and resultant management. Widespread implementation would reduce the clinical workload of healthcare workers caring for patients with HIV-associated cryptococcal meningitis.


12-step approaches for the dually diagnosed: mechanisms of change.
Existing data indicate that 12-step program involvement is associated with improved outcomes in the dually diagnosed, but there are questions concerning the magnitude and mechanisms of this effect in various dually diagnosed populations. Publications identified in a comprehensive review of the literature pertaining to 12-step programs and patients with addictions and co-occurring psychiatric disorders were reviewed for any content relevant to understanding the process of change involving dually diagnosed patients involved with 12-step programs. Dually diagnosed individuals attend 12-step programs at rates comparable to the nondually diagnosed, although specific diagnoses may have some effect on attendance. The benefits of 12-step attendance do not appear to be markedly different for those with psychiatric disorders. Specialized 12-step programs could have benefits for the dually diagnosed over and above those of traditional 12-step programs. Existing data suggest that nonspecific change mechanisms (self-efficacy, social support) are similar to those found in the general AA literature. Based on existing data, the change mechanisms are broadly similar to those found in the general 12-step literature, but additional factors related to mental illness may also play a significant role. Further work is necessary to test the components of this model and to achieve a firm empirical foundation for understanding the processes of 12-step recovery in the dually diagnosed.


Cognitive and Physiologic Reserve Independently Relate to Superior Neurocognitive Abilities in Adults Aging With HIV.
To investigate joint contributions of cognitive and physiologic reserve to neurocognitive SuperAging in older persons with HIV (PWH). Participants included 396 older PWH (age range: 50-69 years) who completed cross-sectional neuropsychological and neuromedical evaluations. Using published criteria, participants exhibiting global neurocognition within normative expectations of healthy 25-year-olds were classified as SuperAgers (SA; n = 57). Cognitively normal (CN; n = 172) and impaired (n = 167) participants were classified with chronological age-based norms. Cognitive reserve was operationalized with an estimate of premorbid verbal intelligence, and physiologic reserve was operationalized with a cumulative index of 39 general and HIV-specific health variables. Analysis of variance with confirmatory multinomial logistic regression examined linear and quadratic effects of cognitive and physiologic reserve on SA status, adjusting for chronological age, depression, and race/ethnicity. Univariably, SA exhibited significantly higher cognitive and physiologic reserve compared with CN and cognitively impaired ( d s ≥ 0.38, p s < 0.05). Both reserve factors independently predicted SA status in multinomial logistic regression; higher physiologic reserve predicted linear increases in odds of SA, and higher cognitive reserve predicted a quadratic "J-shaped" change in odds of SA compared with CN (ie, odds of SA > CN only above 35th percentile of cognitive reserve). Each reserve factor uniquely related to SA status, which supports the construct validity of our SA criteria and suggests cognitive and physiologic reserve reflect nonoverlapping pathways of neuroprotection in HIV. Incorporation of proxy markers of reserve in clinical practice may improve characterization of age-related cognitive risk and resilience among older PWH, even among PWH without overt neurocognitive impairment.


Defining benchmarks for tolerable risk thresholds in cancer screening: Impact of HPV vaccination on the future of cervical cancer screening.
The performance of cervical cancer screening will decline as a function of lower disease prevalence-a consequence of successful human papillomavirus (HPV) vaccination. Replacement of cytology with molecular HPV testing as the primary screening test and adoption of risk-based screening, with less intense screening of vaccinated individuals and initiated at older ages is expected to improve efficiency. However, policy officials may decide to further reduce or eliminate screening as the ratio of benefits to harms continues to decline. To evaluate the level of risk currently tolerated for different cancers in the United States (ie, for which clinical guidelines do not recommend secondary prevention though effective screening methods exist), we used US cancer registry data to compare incidence (2008-2012) and survival (1988-2011) associated with different cancers for which organized screening is recommended and not recommended. The most common cancer at ages 70 to 74 years (ie, age group with highest cancer incidence and reasonable life expectancy to consider screening in the US) satisfying Wilson and Jungner's classic screening criteria was vulvar cancer (incidence = 9/100 000 females). In comparison, the incidence of cervical cancer among females 65 years of age (the upper recommended age limit for screening) was 13 cases per 100 000 females (low as a reflection of effective screening), whereas 10-year survival was 66% (similar to vulvar cancer at 67%). Our approach of defining tolerable risk in cancer screening could help guide future decisions to modify cervical screening programs.


[Moyamoya disease associated with persistent primitive trigeminal artery--a case report and review of literature].
A case of moyamoya disease associated with the persistent primitive trigeminal artery (PTA) is reported. 5 such cases reported in literature are reviewed. A 16-year-old female patient was admitted to our clinic, having complained of right hemiparesis for 8 years. CT scan revealed multiple low density areas in the left frontal, temporal and parietal lobes. In left carotid angiogram, the internal carotid artery was occluded at the C3 portion and basal moyamoya (stage IV) was found. In right carotid angiogram, the internal carotid artery was occluded at the C3 portion and basal moyamoya (stage V) was found. Furthermore the persistent primitive trigeminal artery was seen with marked moyamoya vessels from the posterior cerebral artery. In vertebral angiogram, the posterior cerebral artery was seen bilaterally with moyamoya vessels. In 133Xe-rCBF study, compared with the mean flow in each hemisphere, the flow decreased at the temporal lobe, but, in contrast, increased at the parieto-occipital lobes. Reviewing the literature, the following conclusions are suggested. 1. Persistent primitive trigeminal artery will promote the stage of moyamoya disease. 2. It will protect the brain from hemorrhage and/or ischemia in moyamoya disease.


Congenital partial pericardial defect: surgical correction by partial pericardiectomy through a median sternotomy.
A case of symptomatic congenital pericardial defect with herniation of the left atrial appendage is reported. The patient had experienced increasing fatigue, chest pain, shortness of breath, and slight cyanosis. A partial pericardiectomy through a median sternotomy was performed and the patient made an uneventful recovery.


Testing and Confidence Intervals for High Dimensional Proportional Hazards Model.
This paper proposes a decorrelation-based approach to test hypotheses and construct confidence intervals for the low dimensional component of high dimensional proportional hazards models. Motivated by the geometric projection principle, we propose new decorrelated score, Wald and partial likelihood ratio statistics. Without assuming model selection consistency, we prove the asymptotic normality of these test statistics, establish their semiparametric optimality. We also develop new procedures for constructing pointwise confidence intervals for the baseline hazard function and baseline survival function. Thorough numerical results are provided to back up our theory.


On the inhibition of GABA release from a preparation of rat brain nerve-endings by SKF 89976-A, a GABA uptake inhibitor.
Fractions enriched in nerve-terminals were made in order to investigate the release of gamma-aminobutyric acid (GABA). A P2-preparation made from whole rat brain was pre-labeled with [3H]GABA and thereafter incubated in high concentrations (1 mM) of the GABA uptake inhibitor SKF 89976-A. The nerve-terminals were thereafter incubated in depolarizing concentrations of KCl and finally the medium and nerve-terminals separated by a filtration procedure. The amount of [3H]GABA present on the filter and in the supernatant was measured by liquid scintillation counting and used to assess the release rate. SKF 89976-A reduced the KCl-induced efflux of [3H]GABA from the nerve-terminals. The inhibition was as effective against KCl-induced [3H]GABA efflux in the presence as well as in the absence of Ca2+. Our finding may demonstrate an inhibition of the inside-out activity of the GABA transporter.


Plasma gonadotropin (LH and FSH) concentrations in repubertal and pubertal children upon stimulation by LH-releasing hormone.
The simultaneous determination of LH and FSH were carried out in a single plasma sample by double antibody radioimmunoassays in a total of 26 prepubertal and pubertal children. The blood samples were taken before and after i.v. application of 25 mug synthetic LH-RH. Plasma LH and FSH concentrations found in prepubertal boys and girls at beginning of the test and at the time of maximum response were compared with those measured in pubertal boys and girls. The mean basal levels of LH and FSH are in group I (8 prepubertal girls): LH 0.6+/-0.7 (SD) mIU/ml, FSH 1.5+/-0.8 mIU/ml; in group II (6 prepubertal boys): LH 1.8+/-1.0 mIU/ml, FSH 2.0+/-0.8 mIU/ml; in group III (6 pubertal girls): LH 4.1+/-2.0 mIU/ml, FSH 4.7+/-2.8 mIU/ml; in group IV (6 pubertal boys): LH 3.5+/-2.3 mIU/ml, FSH2.0+/-1.2 mIU/ml. The mean maximum response of LH and FSH after stimulation are in group I: LH 4.1+/-2.3 mIU/ml, FSH 11.7+/-3.7 mIU/ml; in group II: LH 4.2+/-1.0 mIU/ml, FSH 6.0+/-1.1 mIU/ml; in group III: LH 19.7+/-10.6 mIU/ml, FSH 12.8+/-5.7 mIU/ml; in group IV: LH 13.4+/-5.7 mIU/ml, FSH 3.8+/-0.9 mIU/ml. It is suggested that without stimulation of the pituitary with LH-RH, plasma LH and FSH levels are not reliable parameters to test the pituitary gonadotropin reserve.


Long-term graft outcome with mycophenolate mofetil and azathioprine: A paired kidney analysis.
Randomized controlled trials and U.S. Registry data have demonstrated that mycophenolate mofetil (MMF) reduces acute rejection rates and improves graft survival. We undertook the first paired kidney analysis comparing the effects of MMF and azathioprine on graft outcome in the United Kingdom. In all, 238 deceased donors from 1999 to 2002 who donated one kidney to a patient treated with MMF and the other kidney to a patient treated with azathioprine were identified from the national transplant database held by U.K. Transplant. Graft function and rates of change of graft function were compared using multiple linear regression analyses adjusting for covariates on an intention-to-treat basis. Incidence of acute rejection and delayed graft function were studied using logistic regression. Patient and graft survival censored for death were evaluated with Cox regression analyses. The MMF-treated patients exhibited a nonsignificant trend towards improved graft function but with increased rejection rates (44% versus 31%, P < 0.01). Treatment with MMF did not reduce delayed graft function rates. Univariate analysis showed that graft survival was inferior in MMF-treated patients (90% versus 95%, log-rank, P = 0.02) but in multivariate Cox regression models, MMF treatment was not a significant factor. Surprisingly, in the first year 32% of patients achieved daily doses of less than 2 g of MMF compared to 18% of patients who received less than 100 mg of azathioprine (P < 0.01). In this real-life study, there was no difference in patient or graft outcome between MMF and azathioprine treated groups despite increased rejection rates in patients receiving MMF therapy.


Transcriptome Profiling Identifies Multiplexin as a Target of SAGA Deubiquitinase Activity in Glia Required for Precise Axon Guidance During Drosophila Visual Development.
The Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex is a transcriptional coactivator with histone acetylase and deubiquitinase activities that plays an important role in visual development and function. In Drosophila melanogaster, four SAGA subunits are required for the deubiquitination of monoubiquitinated histone H2B (ubH2B): Nonstop, Sgf11, E(y)2, and Ataxin 7. Mutations that disrupt SAGA deubiquitinase activity cause defects in neuronal connectivity in the developing Drosophila visual system. In addition, mutations in SAGA result in the human progressive visual disorder spinocerebellar ataxia type 7 (SCA7). Glial cells play a crucial role in both the neuronal connectivity defect in nonstop and sgf11 flies, and in the retinal degeneration observed in SCA7 patients. Thus, we sought to identify the gene targets of SAGA deubiquitinase activity in glia in the Drosophila larval central nervous system. To do this, we enriched glia from wild-type, nonstop, and sgf11 larval optic lobes using affinity-purification of KASH-GFP tagged nuclei, and then examined each transcriptome using RNA-seq. Our analysis showed that SAGA deubiquitinase activity is required for proper expression of 16% of actively transcribed genes in glia, especially genes involved in proteasome function, protein folding and axon guidance. We further show that the SAGA deubiquitinase-activated gene Multiplexin (Mp) is required in glia for proper photoreceptor axon targeting. Mutations in the human ortholog of Mp, COL18A1, have been identified in a family with a SCA7-like progressive visual disorder, suggesting that defects in the expression of this gene in SCA7 patients could play a role in the retinal degeneration that is unique to this ataxia.


Structural varieties in heterobimetallic lanthanide disiloxanediolates: "inorganic metallocenes" versus in-plane metallacrowns.
The previously proposed concept of "inorganic metallocenes" of group 3 and rare-earth elements has been tested by preparing a series of novel disiloxanediolates with metals displaying different ionic radii. For the smaller scandium and yttrium, approximately planar arrangements of the disiloxanediolate frameworks with solvent and chloride ligands in trans positions were found. Thus, the compounds [{(Ph2SiO)2O}2{Li(DME)}2]ScCl(THF/DME) (2; DME=1,2-dimethoxyethane and THF=tetrahydrofuran) and [{(Ph2SiO)2O}2{Li(THF)2}2]YCl(THF) (3) can be described as heterobimetallic inorganic ring systems or metallacrown complexes with "in-plane" coordination of the metal. In contrast, "out-of-plane" geometries with cis coordination of additional ligands were identified in the praseodymium derivatives [{(Ph2SiO)2O}2{Li(THF)2}{Li(THF)}]Pr(micro-Cl)2Li(THF)2 (4) and [{(Ph2SiO)2O}2{Li(DME)}2]PrCl(DME) (5). These compounds can be viewed as analogues of the known metallocene derivatives (C5Me5)2Pr(micro-Cl)2Li(THF)2 and (C5Me5)2PrCl(THF). The molecular structures of 2-5 have been determined by X-ray diffraction.


Using Video-recorded Laryngoscopy to Evaluate Laryngoscopic Blade Approach and Adverse Events in Children.
Using recordings of endotracheal intubation attempts obtained with a video-enabled laryngoscope with Miller and Macintosh blades, the authors sought to evaluate the association between laryngoscopic approach (right-sided vs. midline) and intubation success, as well as adverse event rates in the pediatric emergency department (ED). This was a retrospective cohort study of children younger than 21 years who underwent endotracheal intubation with a C-MAC video laryngoscope in a tertiary care ED between August 2009 and May 2013. The primary outcome was successful endotracheal intubation on the first attempt. The secondary outcomes included time to intubation, video-recorded adverse events (oropharyngeal mucosal injury and aspiration), and physiologic adverse events. Multivariate regression models were used to determine the relationship between laryngoscope blade position and outcome measures adjusted for patient and provider factors. The cohort consisted of complete video recordings for 105 of 143 (73%) patient encounters with intubations. The first-pass success rate did not significantly differ based on laryngoscopic approach (adjusted odds ratio [aOR] = 0.76, 95% confidence interval [CI] = 0.29 to 2.0). Among patients successfully intubated on the first attempt, the median time to intubation was longer for the right-sided approach compared to the midline approach (42 seconds vs. 31.5 seconds; p < 0.05). The odds of mucosal injury and aspiration were higher among patients intubated using a right-sided approach compared to a midline approach (aOR = 4.1, 95% CI = 1.2 to 14.5; aOR = 7.7, 95% CI = 1.5 to 39.5, respectively). Rates of physiologic adverse events did not differ based on approach. First-pass success rate did not differ based upon laryngoscopic approach type; however, a right-sided approach was associated with a longer time to intubation, as well as higher rates of mucosal injury and aspiration among patients undergoing video-enabled intubation in a pediatric ED.


Structural insights into the substrate recognition and reaction specificity of the PLP-dependent fold-type I isoleucine 2-epimerase from Lactobacillus buchneri.
The isoleucine 2-epimerase from Lactobacillus buchneri has been previously identified and characterized to catalyze the pyridoxal 5'-phosphate (PLP)-dependent racemization and epimerization of a broad spectrum of nonpolar amino acids from L- to D-form and vice versa, in particular isoleucine. In this study, crystal structures of both native and PLP-complex forms of this racemase are presented at 2.6 and 2.15 Å resolution, respectively. Both structures show that the protein belongs to the fold-type I subgroup of PLP-dependent enzymes and is very close to aminobutyrate aminotransferases family, as it has been suspected because of their sequence homology. The extensive structural comparison with fold-type I enzymes with known amino acid racemization activities, including the α-amino-ε-caprolactam racemase from Achromobacter obae and the cystathionine β-lyase from Escherichia coli, allows us to identify the active site residues responsible for its nonpolar amino acid recognition and reactivity specificity. Our observations also suggest that the racemization reaction by the fold-type I racemases may generally occur thanks to a revised two-base mechanism. Lastly, both structures reveal details on the conformational changes provoked by PLP binding that suggest an induced fit of the active site "entrance door", necessary to accommodate PLP and substrate molecules.


[Emergency intubation with the Combitube in a patient with persistent vomiting].
Prompt establishment of a patient airway and effective ventilation are the major goals during initiation of cardiopulmonary resuscitation in patients with cardiac arrest. Endotracheal intubation is the definitive method to maintain an optimal airway. However, endotracheal intubation is not always possible, even for the skilled physician. The Combitube has been developed to overcome this disadvantage. Studies have proved the effectivity of ventilation with this device. A case is reported where a patient suffered from acute respiratory failure and attempts at endotracheal intubation failed due to continued vomiting rendering fibre-optical visualisation of the vocal cords impossible. Blind insertion of the Combitube led to successful ventilation, and hence replacement by an endotracheal airway could be performed without danger of aspiration.


Threat credibility and weapons of mass destruction.
Individual or collective preparedness for an attack involving weapons of mass destruction (WMD) must be based on an analysis of the threat. In threat assessment one takes many factors into account, including the physical and psychological parameters of the attacker. Although the potential devastation caused by WMD is significant, there are many limitations to the effective use of such weapons. Casualty rates will likely be measured in the thousands rather than millions because of factors that will be discussed. The psychological ramifications, it should be noted, the permutations of which have not yet been defined, will be much longer lasting. In this paper the author discusses these and other characteristics of the current threat.


Maturation and integration of tissue-engineered cartilages within an in vitro defect repair model.
This study compared the behavior of four different engineered cartilages in a hybrid culture system. First, the growth and maturation of tissue-engineered cartilages in isolation were compared to those grown in an in vitro articular cartilage defect repair model. Tissue-engineered cartilages using fibrin, agarose, or poly(glycolic acid) scaffolds were implanted into annular explants of articular cartilage and cultured for 20 or 40 days. Native tissue had a substantial influence on the DNA, sulfated glycosaminoglycan, and hydroxyproline content of the engineered tissues, suggesting that the presence of living tissue in the culture significantly altered cell proliferation and matrix accumulation. Second, the adhesion strength of various engineered cartilages to native tissue was measured and compared with the biochemical content of the engineered tissues. All scaffold treatments adhered to the native cartilage, but there were statistically significant differences in adhesive strength between the different scaffolds. The adhesive strength of all engineered scaffolds was significantly lower than that of native tissue to itself. In the engineered tissues, neither failure stress nor energy to failure correlated with gross biochemical content, suggesting that adhesion between native and engineered tissues is not purely a function of gross matrix synthesis.


Inactivation of spores of Bacillus anthracis Sterne, Bacillus cereus, and Bacillus thuringiensis subsp. israelensis by chlorination.
Three species of Bacillus were evaluated as potential surrogates for Bacillus anthracis for determining the sporicidal activity of chlorination as commonly used in drinking water treatment. Spores of Bacillus thuringiensis subsp. israelensis were found to be an appropriate surrogate for spores of B. anthracis for use in chlorine inactivation studies.