Effects of Glutamine and Alanine Supplementation on Central Fatigue Markers in Rats Submitted to Resistance Training.
Recent evidence suggests that increased brain serotonin synthesis impairs performance in high-intensity intermittent exercise and specific amino acids may modulate this condition, delaying fatigue. This study investigated the effects of glutamine and alanine supplementation on central fatigue markers in rats submitted to resistance training (RT). Wistar rats were distributed in: sedentary (SED), trained (CON), trained and supplemented with alanine (ALA), glutamine and alanine in their free form (G + A), or as dipeptide (DIP). Trained groups underwent a ladder-climbing exercise for eight weeks, with progressive loads. In the last 21 days, supplementations were offered in water with a 4% concentration. Albeit without statistically significance difference, RT decreased liver glycogen, and enhanced the concentrations of plasma glucose, free fatty acids (FFA), hypothalamic serotonin, and ammonia in muscle and the liver. Amino acids affected fatigue parameters depending on the supplementation form. G + A prevented the muscle ammonia increase by RT, whereas ALA and DIP augmented ammonia and glycogen concentrations in muscle. DIP also increased liver ammonia. ALA and G + A reduced plasma FFA, whereas DIP increased this parameter, free tryptophan/total tryptophan ratio, hypothalamic serotonin, and the serotonin/dopamine ratio. The supplementations did not affect physical performance. In conclusion, glutamine and alanine may improve or impair central fatigue markers depending on their supplementation form.


High-Density Morphometric Analysis of Shape and Integration: The Good, the Bad, and the Not-Really-a-Problem.
The field of comparative morphology has entered a new phase with the rapid generation of high-resolution three-dimensional (3D) data. With freely available 3D data of thousands of species, methods for quantifying morphology that harness this rich phenotypic information are quickly emerging. Among these techniques, high-density geometric morphometric approaches provide a powerful and versatile framework to robustly characterize shape and phenotypic integration, the covariances among morphological traits. These methods are particularly useful for analyses of complex structures and across disparate taxa, which may share few landmarks of unambiguous homology. However, high-density geometric morphometrics also brings challenges, for example, with statistical, but not biological, covariances imposed by placement and sliding of semilandmarks and registration methods such as Procrustes superimposition. Here, we present simulations and case studies of high-density datasets for squamates, birds, and caecilians that exemplify the promise and challenges of high-dimensional analyses of phenotypic integration and modularity. We assess: (1) the relative merits of "big" high-density geometric morphometrics data over traditional shape data; (2) the impact of Procrustes superimposition on analyses of integration and modularity; and (3) differences in patterns of integration between analyses using high-density geometric morphometrics and those using discrete landmarks. We demonstrate that for many skull regions, 20-30 landmarks and/or semilandmarks are needed to accurately characterize their shape variation, and landmark-only analyses do a particularly poor job of capturing shape variation in vault and rostrum bones. Procrustes superimposition can mask modularity, especially when landmarks covary in parallel directions, but this effect decreases with more biologically complex covariance patterns. The directional effect of landmark variation on the position of the centroid affects recovery of covariance patterns more than landmark number does. Landmark-only and landmark-plus-sliding-semilandmark analyses of integration are generally congruent in overall pattern of integration, but landmark-only analyses tend to show higher integration between adjacent bones, especially when landmarks placed on the sutures between bones introduces a boundary bias. Allometry may be a stronger influence on patterns of integration in landmark-only analyses, which show stronger integration prior to removal of allometric effects compared to analyses including semilandmarks. High-density geometric morphometrics has its challenges and drawbacks, but our analyses of simulated and empirical datasets demonstrate that these potential issues are unlikely to obscure genuine biological signal. Rather, high-density geometric morphometric data exceed traditional landmark-based methods in characterization of morphology and allow more nuanced comparisons across disparate taxa. Combined with the rapid increases in 3D data availability, high-density morphometric approaches have immense potential to propel a new class of studies of comparative morphology and phenotypic integration.


[Active constituents from Aloe arborescens as BACE inhibitors].
To seek for new components as BACE inhibitors from Aloe arborescens. The chemical constituents were isolated by chromatographic methods and their structures were elucidated on the basis of spectral analysis. Eight compounds were isolated and their structures identified as 6'-O-isobutyryl aloenin A (1), aloenin A (2), aloe-emodin (3), (E)-2-acetonyl-8-(2'-O-feruloxyl)-beta-D-glucopyranosyl-7-methoxy-5-methyl-chromone (4), 7-O-methylaloeresin A (5), babarloin A (6), elgonica-dimer A (7), and elgonica-dimer B (8), separately. Compound 1 is a new compound, and compound 4 was isolated from A. arborescens for the first time. Pharmacological tests indicated that 2, 4, 5 and 6 have moderate inhibitory active on BACE.


Highly N2-Selective Activated Carbon-Supported Pt-In Catalysts for the Reduction of Nitrites in Water.
The catalytic reduction of nitrites over Pt-In catalysts supported on activated carbon has been studied in a semi-batch reactor, at room temperature and atmospheric pressure, and using hydrogen as the reducing agent. The influence of the indium content on the activity and selectivity was evaluated. Monometallic Pt catalysts are very active for nitrite reduction, but the addition of up to 1 wt% of indium significantly increases the nitrogen selectivity from 0 to 96%. The decrease in the accessible noble metal surface area reduces the amount of hydrogen available at the catalyst surface, this favoring the combination of nitrogen-containing intermediate molecules to promote the formation of N2 instead of being deeply hydrogenated into NH4+. Several activated carbon-supported Pt-In catalysts, activated under different calcination and reduction temperatures, have been also evaluated in nitrite reduction. The catalyst calcined and reduced at 400°C showed the best performance considering both the activity and the selectivity to nitrogen. This enhanced selectivity is ascribed to the formation of Pt-In alloy. The electronic properties of Pt change upon alloy formation, as it is demonstrated by XPS.


A protocol for initiation of nasal positive pressure ventilation.
Respiratory failure related to neuromuscular weakness has commonly been managed with long-term ventilation by tracheostomy. Currently, nasal positive pressure ventilation is being used with success in this patient population. It has been suggested that initiation of nasal positive pressure ventilation is best done in an intensive care setting. Nine patients were placed on nasal ventilation during a brief admission to a medical floor staffed by nurses trained in respiratory care. This process was facilitated by use of a standardized protocol for nursing staff that identified treatment objectives. Following the initiation of nasal positive pressure ventilation, this group of patients experienced near normalization of daytime measurements of partial pressure of arterial carbon dioxide, reported increases in daytime energy levels, and relief of nighttime signs and symptoms. These objectives were accomplished with no significant complications. Use of this protocol may also decrease length and cost of hospitalization and improve patient acceptance of noninvasive ventilatory assistance.


A review of emerging factor XI inhibitors.
Whilst the introduction of direct oral anticoagulants (DOACs) has improved the prevention of thromboembolic events, there is still a need for safer anticoagulants. This is particularly so, for specific populations of patients, such as those with an increased bleeding risk or those with severely reduced kidney function. People with Factor XI (FXI) deficiency are at reduced risk of thromboembolic events, without an increased risk of spontaneous bleeding. FXI inhibition, therefore, presents the ideal target for novel anticoagulants. In this review, we provide an overview of the currently available anticoagulants and the emerging FXIa inhibitors in clinical trials. The need for availability of novel anticoagulants and the potential issues that will hinder the development and marketing of factor XIa inhibitors is also discussed. Evidence suggests that FXI inhibition presents a promising drug target for novel anticoagulation therapies. The FXIa inhibitors in development have advantages over DOACs with lower renal clearance and long half-lives. Overall, FXI inhibition presents a promising target, it is likely that the clinical use of FXIa inhibitors is on the horizon.


Different Digitalization Techniques for 3D Printing of Anatomical Pieces.
The use of different technological devices that allow the creation of three-dimensional models is in constant evolution, allowing a greater application of these technologies in different fields of health sciences and medical training. The equipment for digitalization is becoming increasingly sophisticated allowing obtaining three-dimensional which are more defined and similar to real image and original object. In this work, different modalities of designing 3D anatomical models of bone pieces are presented, for use by students of different disciplines in Health Sciences. To do this we digitalized bone pieces, with different models of scanners, producing images that can be transformed for 3D printing, with a Colido X 3045 printer by digital treatment with different software.


miR-564 is downregulated in gastric carcinoma and targets E2F3.
Numerous aberrantly expressed microRNAs (miRNAs/miRs) have been identified in gastric cancer (GC); however, only a fraction of these have been functionally investigated and novel deregulated miRNAs in GC remain to be explored. Through examining two public miRNA expression profile datasets, the present study identified aberrantly expressed miRNAs in GC. One of these miRNA, miR-564, was identified to be downregulated in GC, which was validated in tissue samples from patients with GC by reverse transcription-quantitative polymerase chain reaction analysis. Targets of miR-564 were then predicted bioinformatically, including transcription factor E2F3 (E2F3), which was identified to be functionally enriched in several cancer signaling pathways. Furthermore, overexpression of miR-564 decreased the activity of a luciferase reporter carrying the 3'-untranslated region of E2F3, in addition to the mRNA and protein level of E2F3, indicating that miR-564 directly targets E2F3. These data suggest that by targeting E2F3, miR-564 may act as a tumor suppressor gene in gastric carcinogenesis.


Influence of TBX21 T-1993C variant on autoimmune hepatitis development by Yin-Yang 1 binding.
To investigated the mechanism of the association between the TBX21 T-1993C promoter polymorphism and autoimmune hepatitis type 1 (AIH-1) development. In vivo, In vivo, and reporter analyses were performed to determine the function of transcription factors binding to the T-1993C element of the TBX21 promoter in human CD4+ T and B cell lines. Flow cytometry and quantitative real-time PCR were used to analyze T-box transcription factor (T-bet) and interferon-γ (IFN-γ) expressions in CD4+ T cells, B cells and monocytes from the peripheral blood of AIH-1 patients including 5-1993TC and 15-1993TT genotype carriers, and healthy controls including 10-1993TC and 25-1993TT genotype carriers. Furthermore, a range of biochemical indices was measured simultaneously in the blood of AIH-1 patients. TBX21-1993C allele created a strong Yin-Yang 1 (YY1)-binding site and decreased transcriptional activity of TBX21 promoter in human CD4+ T and B cells. Higher levels of T-bet and IFN-γ were detected in the circulating CD4+ T cells and B cells of AIH-1 patients carrying the TBX21-1993 TT genotype compared with the patients carrying the -1993 TC genotype and controls with the -1993 TC genotype. T-bet expression levels of circulating T cells and B cells were positively correlated with AIH-1 disease activity. Knockdown of YY1 with siRNA caused increased expression of T-bet and IFN-γ in peripheral blood mononuclear cells in AIH-1 patients. The repression of TBX21 expression by high-affinity binding of YY1 to the -1993C allele may contribute to a decreased development of AIH-1 via suppression of type 1 immunity.


Origins of tmRNA: the missing link in the birth of protein synthesis?
The RNA world hypothesis refers to the early period on earth in which RNA was central in assuring both genetic continuity and catalysis. The end of this era coincided with the development of the genetic code and protein synthesis, symbolized by the apparition of the first non-random messenger RNA (mRNA). Modern transfer-messenger RNA (tmRNA) is a unique hybrid molecule which has the properties of both mRNA and transfer RNA (tRNA). It acts as a key molecule during trans-translation, a major quality control pathway of modern bacterial protein synthesis. tmRNA shares many common characteristics with ancestral RNA. Here, we present a model in which proto-tmRNAs were the first molecules on earth to support non-random protein synthesis, explaining the emergence of early genetic code. In this way, proto-tmRNA could be the missing link between the first mRNA and tRNA molecules and modern ribosome-mediated protein synthesis.


Draft genome sequences of Hirudo medicinalis and salivary transcriptome of three closely related medicinal leeches.
Salivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today. We annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis. Here we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.


KIR and Human Leukocyte Antigen Genotype Associated Risk of Cytomegalovirus Disease in Renal Transplant Patients.
Cytomegalovirus(CMV) infections have a significant effect on morbidity and mortality in kidney transplants. We conducted a study to ascertain the association of natural killer cell killer immunoglobulin-like receptors and human leukocyte antigen (HLA) genotype with risk of CMV disease. The 90 CMV-negative patients receiving a first renal transplantation from a CMV-positive donor in this study received triple immunosuppressive therapy and prophylactic CMV treatment for up to 3 months after transplantation. We observed a 43.3% incidence rate of CMV disease within the first year after transplantation. Twenty-seven recipients experienced a rejection episode, 14 of which had CMV disease, mostly after rejection, suggesting that in this group, CMV disease is not a risk factor for rejection. KIR gene or genotype distribution were similar between the CMV diseased and CMV disease-free group. Twenty-seven recipients (30%) carried KIR-AA genotype, of which nine (33%) had CMV disease. Of the remaining 63 (70%) recipients with KIR-BX genotype, 30 (48%) had CMV disease. There was no significant difference between the two genotype groups with regard to occurrence of CMV disease, although there was a trend toward a lower incidence of CMV disease in recipients carrying the KIR-AA genotype. For CMV disease, we found no significant risk associated with the number of activating or inhibitory KIRs. Neither was missing KIR ligands for the inhibitory KIRs (HLA-C1/C2/Bw4) in recipients associated with lower rates of CMV disease. In CMV-negative recipients, genotypic analysis of KIR repertoire and HLA ligands does not provide risk factors for primary CMV disease after renal transplantation.


Lipid peroxidation early after brain injury.
The role of lipid peroxidation after brain injury is still not completely understood, and results of different studies have been equivocal. In this study, three proposed peroxidation markers were determined in patients early after isolated head injury and results compared to healthy controls. Malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) were measured in plasma, and n-pentane was determined in patients' exhaled air. For MDA and TBARS no significant differences could be shown (0.267 vs. 0.358 ng/mL, and 0.896 vs. 0.814 ng/mL in patients vs. healthy volunteers, respectively). n-Pentane, however, was significantly increased in the expired air of patients (0.471 vs. 0.118 nmol/L in healthy volunteers). Similar results for n-pentane were obtained when only male patients and volunteers were considered (0.510 vs. 0.113 nmol/L). Stratification according to clinical outcome showed significantly higher values for n-pentane in male patients with poor outcome (0.656 nmol/L) in comparison with healthy male volunteers (0.113 nmol/L). No difference was found when patients were stratified according to the presence or absence of subarachnoid hemorrhage. It is concluded that, only in a sub-population of patients with brain injury, lipid-peroxidation is a crucial mechanism. n-Pentane seems to be a valuable marker to detect lipid peroxidation early after brain trauma. Malondialdehyde may be of value only later in the course of the disease. TBARS are not a specific marker and should therefore not be used.


Molecular cloning of complementary DNA to swine pepsinogen mRNA.
Poly(A)-containing RNA was isolated from total RNA of swine gastric mucosa by oligo(dT)-cellulose chromatography, and was translated in a wheat germ cell-free system. Analysis of the translation products by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that pepsinogen was a major translation product and was synthesized as two different molecular forms with apparent molecular weights of 45,000 and 43,000. The pepsinogen translated in the in vitro translation system had no autocatalytic activity. The pepsinogen mRNA was further purified by sucrose density gradient centrifugation, where the mRNA activity for pepsinogen was located around 15 S. At this stage, the translation product of the pooled fractions appeared to be almost exclusively pepsinogen. The peptide maps of the pepsinogen which was translated in vitro and digested by alpha-chymotrypsin and by Staphylococcus aureus V8 protease were nearly identical with the corresponding peptide maps of standard pepsinogen. The double-stranded complementary DNA which had been synthesized from the partially purified mRNA by avian myeloblastosis virus reverse transcriptase was cloned in Escherichia coli chi 1776, using plasmid pBR322 as a cloning vector. A colony carrying pepsinogen cDNA sequence was identified by in situ colony hybridization using the cDNA synthesized from the partially purified mRNA as a probe and further by a positive hybridization-translation assay. One of the recombinant clones (pSPcA1) had an insert of about 850 base pairs, and the nucleotide sequence analysis revealed that pSPcA1 codes for swine pepsinogen.


[Rosuvastatin in Coronary Bypass Surgery: Whether Only Secondary Prevention?]
The increasing number of coronary artery bypass grafting (CABG) is associated with a need for active introduction of methods improving immediate and long-term results of these interventions. Results of a number of studies conducted during recent years allow to consider high dose statin therapy one of such methods. In this article we present results of rosuvastatin administration to patients with ischemic heart disease (IHD) prior to surgery. Rosuvastatin (40 mg/day) was given for 4 weeks before CABG to patients who had previously taken simvastatin (20 mg/day). This regimen was assocaed with reduction of desquamation of endothelium of the intima, reduction of the number of smooth muscle cells in the media, as well as the proliferation index according to the immunohistochemical analysis in sections of the great saphenous vein selected for the coronary anastomosis. It is assumed that the antiproliferative effects of high-dose rosuvastatin therapy may have a positive impact in relation to the viability of a remote arterio-venous grafts.


Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency.
In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/−); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross-sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/− (age 15.3 ± 9.9 years) and 17 healthy controls (16.0 ± 7.2 years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6-sulphatoxymelatonin concentrations were measured by enzyme-linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13 years old. Pineal volume was fivefold lower in PAX6+/− versus controls (mean ± SD: 25 ± 15 versus 129 ± 50 μL, P < 0.001). Midnight serum cortisol was similar in PAX6+/− versus controls (P = 0.14). Midnight serum melatonin was > twofold lower in PAX6+/− versus controls [median (25th-75 th): 28 (22-42) versus 71 (46-88) pg mL-(1), P < 0.001]. First morning void urinary 6-sulphatoxymelatonin was fourfold lower in PAX6+/− versus controls [11 (6-26) versus 45 (34-61) ng mg(-1) Cr, P = 0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/− versus controls (48 ± 6 versus 41 ± 5, P = 0.03). The current findings suggest that PAX6+/− is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/−.


Effects of Activin in Embryoid Bodies Expressing Fibroblast Growth Factor 5.
Nodal/activin signaling is indispensable for embryonic development. We examined what activin does to the embryoid bodies (EBs) produced from mouse embryonic stem cells (mESCs) expressing an epiblast marker. The EBs were produced by culturing mESCs by the hanging drop method for 24 hours. The resulting EBs were transferred onto gelatin-coated dishes and allowed to further differentiate. The 24-hour EBs showed a stronger expression of fibroblast growth factor (FGF)5 and Brachyury (specific to the epiblast) in comparison with mESCs. Treating the transferred EBs with activin A maintained transcript levels of FGF5 and Oct4, while inhibiting definitive endoderm differentiation. The activin A treatment reversed the endoderm differentiation induced by retinoic acid (RA), while the inhibition of nodal/activin signaling promoted RA-induced endoderm differentiation. Inhibition of nodal/activin signaling in EBs, including epiblast-like cells, promotes differentiation into the endoderm, facilitating the transition from the pluripotent state to specification of the endoderm.


Multiple channel exposure therapy: combining cognitive-behavioral therapies for the treatment of posttraumatic stress disorder with panic attacks.
A large proportion of patients who present for treatment of posttraumatic stress disorder (PTSD) experience comorbid panic attacks, yet it is unclear to what extent currently available PTSD treatment programs address this problem. Here we describe a newly developed treatment, multiple-channel exposure therapy (M-CET), for comorbid PTSD and panic attacks. The treatment utilizes elements of cognitive processing therapy treatment for PTSD and elements of panic control treatment to target physiological, cognitive, and behavioral symptoms. Preliminary results suggest that M-CET may provide a promising treatment program for a subset of patients with PTSD who experience panic attacks. In addition, guidelines for conducting M-CET with clients who have been exposed to diverse traumatic events are provided.


Prevalence of Neisseria gonorrhoeae and Trichomonas vaginalis in Portuguese women of childbearing age.
The purpose of this study was to evaluate the prevalence of Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) in Portuguese women of childbearing age. Cervicovaginal self-collected samples of 680 childbearing-age women (15-44 years) were tested for NG and TV by polymerase chain reaction. Sociodemographic, clinical and behavioural data were assessed through an anonymous self-administered questionnaire. NG and TV prevalence was 1.3% (95% confidence interval (CI) 0.7-2.5%) and 1.0% (95% CI 0.5-2.1%), respectively. The prevalence of TV was significantly higher in women aged >22 years (p = .003), with >6 years after sexual intercourse (p = .003), and who reported previous pregnancy (p = .004). Our study suggests that NG and TV are rare in Portuguese women of childbearing age. However, larger epidemiological studies with a nationally representative sample of female subjects are warranted, to clarify the need for screening of these microorganisms in Portuguese women, since its prevalence is probably underestimated.IMPACT STATEMENTWhat is already known on this subject? Studies on the prevalence of NG and TV have been performed in several developed and developing countries. However, limited data is available in Portuguese women. The detection of NG and TV is necessary because, beside the risk of transmission to sex partners, these STIs may be associated with an increased risk of HIV acquisition and transmission, and ultimately with reproductive, pregnancy and perinatal complications.What do the results of this study add? Our study adds new findings to the body of knowledge on NG and TV prevalence in Portuguese women of reproductive age. As so, we found a low prevalence of both NG (1.3%) and TV (1.0%) in the studied population.What are the implications of these findings for clinical practice and/or further research? Our results may be a step ahead to encourage future nationally representative studies evaluating the prevalence of NG and TV genital infection and, consequently, to clarify the need for screening of these microorganisms. In clinical practice, it should be highlighted the appropriate management of NG and TV infection in specific situations, such as pregnancy. Also, sexual partners must be treated to prevent the recurrences in the index cases and reduce transmission to other partners.


Tomographic Aspects of Advanced Active Pulmonary Tuberculosis and Evaluation of Sequelae following Treatment.
Objectives. To evaluate tomographic changes in pulmonary tuberculosis (TB), degree of agreement among three radiologists regarding tomographic diagnoses, and sequelae following treatment. Methods. Cross-sectional and descriptive study of 74 TB patients confirmed by sputum culture and chest computed tomography before (CT1) and 6 months after (CT2) drug therapy. Results were performed by three radiologists blinded to clinical and laboratory results. Results. Main findings in CT1 included nodules indicating the presence of a tree-in-bud pattern in 93% of cases, ill-defined nodules in 84% of cases, consolidation in 77% of cases, architectural distortion in 71% of cases, cavitary lesions in 62% of cases, and ground glass opacities in 37% of cases. Airway involvement, characterized by increased thickness and dilatation of the bronchial walls, occurred in 93% of cases. Pleural involvement occurred in 54%. There was an agreement on active TB among the three radiologists in 85% of cases. The results in CT2 indicated the presence of architectural distortion in 91% of cases and cylindrical bronchiectasis in 86%. Conclusions. The study established a tomographic pattern for diagnosis of active TB characterized by the presence of airway nodules, consolidation, architectural distortion, and cavitary lesions, and an almost complete degree of agreement (Kappa) was observed among the radiologists (0.85). CT after treatment assists in defining the cure.


Renal anemia: from incurable to curable.
Renal anemia has been recognized as a characteristic complication of chronic kidney disease. Although many factors are involved in renal anemia, the predominant cause of renal anemia is a relative deficiency in erythropoietin (EPO) production. To date, exogenous recombinant human (rh)EPO has been widely used as a powerful drug for the treatment of patients with renal anemia. Despite its clinical effectiveness, a potential risk for increased mortality has been suggested in patients who receive rhEPO, in addition to the economic burden of rhEPO administration. The induction of endogenous EPO is another therapeutic approach that might have advantages over rhEPO administration. However, the physiological and pathophysiological regulation of EPO are not fully understood, and this lack of understanding has hindered the development of an endogenous EPO inducer. In this review, we will discuss the current treatment for renal anemia and its drawbacks, provide an overview of EPO regulation in healthy and diseased conditions, and propose future directions for therapeutic trials that more directly target the underlying pathophysiology of renal anemia.


Optimising uncertainty in physical sample preparation.
Uncertainty associated with the result of a measurement can be dominated by the physical sample preparation stage of the measurement process. In view of this, the Optimised Uncertainty (OU) methodology has been further developed to allow the optimisation of the uncertainty from this source, in addition to that from the primary sampling and the subsequent chemical analysis. This new methodology for the optimisation of physical sample preparation uncertainty (u(prep), estimated as s(prep)) is applied for the first time, to a case study of myclobutanil in retail strawberries. An increase in expenditure (+7865%) on the preparatory process was advised in order to reduce the s(prep) by the 69% recommended. This reduction is desirable given the predicted overall saving, under optimised conditions, of 33,000 pounds Sterling per batch. This new methodology has been shown to provide guidance on the appropriate distribution of resources between the three principle stages of a measurement process, including physical sample preparation.


Recent Advances of S-18F Radiochemistry for Positron Emission Tomography.
The click chemistry of sulfur(VI) fluoride exchange (SuFEx) has facilitated the widespread application of sulfur-fluoride compounds such as sulfonyl fluorides, fluorosulfates, and sulfamoyl fluorides in various fields, especially in the development of 18F ligands for PET (positron emission tomography) imaging. In recent years, the prominent progress of sulfur-[18F]fluoride compounds has been achieved through the combination of 18F and sulfur-fluoride chemistry. These compounds serve as potential 18F tracers, 18F synthons, and reagents for 18F-fluorination, thereby complementing the range of 18F ligands, typically C-18F structures, used in PET studies. This review aims to provide an overview of S-18F labeling reactions through examples of relevant 18F compounds and highlight the advancements and breakthroughs achieved in the past decade.


Pancreaticoduodenal artery aneurysm formation with superior mesenteric artery stenosis.
Celiac stenosis or occlusion is attributed partly to increase blood flow at pancreatic arcade from the superior mesenteric artery (SMA) system and may play a causal role in true aneurysm of pancreaticoduodenal artery (PDAA) formation. However, despite possible increased blood flow in the pancreatic arcades like celiac stenosis, PDAAs with a stenotic SMA are extremely rare, with only three cases have been reported in the literature. We report a case of PDAA with SMA stenosis and review the literature.


The cooling profile of hot-cooked mussels stored in domestic insulated coolers amongst food vendors in Prince Edward Island, Canada.
It is common during outdoor events on Prince Edward Island, Canada for vendors to store hot-cooked mussels in domestic coolers. Provincial legislation states that hot product should be maintained at a minimum of 60 °C. A study was conducted to ascertain how long mussels could be stored before the temperature decreased to less than 60 °C. Hot, cooked mussels were placed into coolers and the temperature measured every 10 min for 4 h. It was found that when the cooler was unopened, the mean temperature dropped to less than 60 °C in 56 min. For coolers opened every 10 min, the mean temperature decreased to less than 60 °C in 38 min. For coolers opened every 10 min with mussels removed, the mean temperature decreased to less than 60 °C in 52 min. It was concluded that mussels should not be stored for more than 30 min and temperature should be regularly monitored.


Prevalence and molecular characteristics of Listeria monocytogenes in cooked products and its comparison with isolates from listeriosis cases.
This study aimed to investigate the prevalence and molecular characteristics of Listeria monocytogenes in cooked products in Zigong City, China. The overall occurrence of the L. monocytogenes in the ready-to-eat (RTE) shops and mutton restaurants surveyed was 16.2% (141/873). An occurrence of 13.5% was observed in RTE pork, 6.5% in RTE vegetables, and more than 24.0% in either cooked mutton or cooked haggis. Serotype 1/2b (45.4%), 1/2a (33.3%), and 1/2c (14.2%) were the predominant types. By comparing the clonal complexes (CCs) based on multilocus sequence typing (MLST) of the L. monocytogenes from cooked foods in Zigong City and 33 listeriosis cases from different districts of China, CC87, CC9, CC8, and CC3 were showed to be prevalent in cooked products and CC87 and CC3 were the first two frequent types in the 33 clinic-source strains. All CC87 stains harbored the newly reported Listeria pathogenicity island 4 (LIPI-4) gene fragment ptsA, and all CC3 strains possessed the Listeria pathogenicity island 3 (LIPI-3) gene fragment llsX. These may increase the occurrence of the strains belonging to CC87 and CC3 in listeriosis cases in China and also underline the risk of infection owing to the consumption of the cooked products from Zigong. ST619 (serotype 1/2b) harbored both llsX and ptsA, indicating a potential hypervirulent sequence type in Zigong.


Fluorescent sensing layer for the determination of L-malic acid in wine.
An enzymatic method for determining L-malic acid in wine based on an L-malate sensing layer with nicotinamide adenine dinucleotide (NAD+), L-malate dehydrogenase (L-MDH) and diaphorase (DI), immobilized by sol-gel technology, was constructed and evaluated. The sol-gel glass was prepared with tetramethoxysilane (TMOS), water and HCl. L-MDH catalyzes the reaction between L-malate and NAD+, producing NADH, whose fluorescence (lambdaexc=340 nm, lambdaem=430 nm) could be directly related to the amount of L-malate. NADH is converted to NAD+ by applying hexacyanoferrate(III) as oxidant in the presence of DI. Some parameters affecting sol-gel encapsulation and the pH of the enzymatic reaction were studied. The sensing layer has a dynamic range of 0.1-1.0 g/L of L-malate and a long-term storage stability of 25 days. It exhibits acceptable reproducibility [sr(%) approximately 10] and allows six regenerations. The content of L-malic acid was determined for different types of wine, and polyvinylpolypyrrolidone (PVPP) was used as a bleaching agent with red wine. The results obtained for the wine samples using the sensing layer are comparable to those obtained from a reference method based on UV-vis molecular absorption spectrometry, if the matrix effect is corrected for.


Whole genome analysis of Aspergillus sojae SMF 134 supports its merits as a starter for soybean fermentation.
Aspergillus sojae is a koji (starter) mold that has been applied for food fermentation in Asia. The whole genome of A. sojae SMF 134, which was isolated from meju (Korean soybean fermented brick), was analyzed at the genomic level to evaluate its potential as a starter for soybean fermentation. The genome size was 40.1 Mbp, which was expected to be composed of eight chromosomes with 13,748 ORFs. Strain SMF 134 had a total of 151 protease genes, among which two more leucine aminopeptidase (lap) genes were found in addition to the previously known lap 1, and three γ-glutamyltranspeptidase (ggt) genes were newly identified. Such genomic characteristics of SMF 134 with many protease and flavor-related (lap and ggt) genes support its merits as a starter for soybean fermentation. In addition, this first complete genome of A. sojae will allow for further genetic studies to better understand the production of various enzymes, including proteases, LAPs, and GGTs, as well as other characteristics as a starter mold for soybean fermentation.


Parent-teacher disagreement regarding psychopathology in children: a risk factor for adverse outcome?
To investigate if parent-teacher discrepancies in reports of behavioral/emotional problems in children predict poor outcome. A total of 1154 4- to 12-year-old children from the general population were followed up. At the first assessment, parent and teacher ratings were obtained with the Child Behavior Checklist (CBCL) and Teacher's Report Form (TRF). Fourteen years later, DSM-IV diagnoses were assessed, and ratings of self-reported and parent-rated behavioral and emotional problems were obtained. CBCL and TRF scores predicted most of the outcomes, but in general, discrepancies between CBCL and TRF scores did not. There were some exceptions. For instance, higher parental vs. teacher ratings of aggressive behaviors increased the risk of suicide attempts/self-mutilation. Risk factors for self-mutilating behaviors may be supplemented with parent-reported aggressive behaviors that are not observed by the teachers. In general, whereas CBCL and TRF scale scores were useful predictors of outcome, parent-teacher discrepancies were not.


Drug-Porous Silicon Dual Luminescent System for Monitoring and Inhibition of Wound Infection.
Wound monitoring and curing is of great importance in biomedical research. This work created a smart bandage that can simultaneously monitor and inhibit wound infection. The main components of the smart bandage are luminescent porous silicon (LuPSi) particles loaded with ciprofloxacin (CIP). This dual luminescent system can undergo accelerated fluorescent color change from red to blue upon the stimulation of reactive oxygen species (ROS) and elevated pH, which are main biomarkers in the infected wound. The mechanism behind the chemical-triggered fluorescent color change was studied in detail. In vitro experiment showed that the ratiometric fluorescent intensity (IRed/IBlue) of CIP-LuPSi particles decreased from 10 to 0.03 at pH 7.5 after 24 h, while the value deceased from 10 to 2.15 at pH 7.0. Strong correlation can be also found between the IRed/IBlue value and ROS concentration ranging from 0.1 to 10 mM. In addition, the oxidation of LuPSi also simultaneously triggered the release of CIP molecules, which exhibited bacterial inhibition activity. Therefore, the ratiometric fluorescent intensity change at red and blue channels can indicate not only the wound infection status but also the release of antibiotics. In vivo test proved that the smart bandage could distinguish infected wounds from acute wounds, just relying on the naked eyes or a cell phone camera. On the basis of the Si nanotechnology established in this work, theranostic wound care will be realized in future.


New method for the rapid determination of lathyrogenic agents.
Salamander and toad embryos will develop grossly observable tumors of the notochord if they are placed for 3 or more days in a solution of the lathyrism-producing chemicals beta-aminopropionitrile or aminoacetonitrile. A technique for using tumorigenesis in amphibian embryos as a biological indicator for other lathyrogenic agents is presented.


Difficult-to-treat and severe asthma in adults: Towards a new treatment paradigm.
Asthma is a common yet complex airway disorder, comprising diverse phenotypes and pathophysiology. According to the Australian Institute of Health and Welfare, asthma affects 11% of the Australian population. Despite the availability of effective therapies and a national medicines subsidy scheme, a significant burden of disease still exists in Australia, with high mortality by international standards. This article discusses the challenges in managing patients with difficult-to-treat and severe asthma in primary care, how to distinguish between difficult-to-treat and severe asthma, when to refer, and the role of biologic therapy. Asthma that remains uncontrolled despite treatment with high-dose preventive therapies is not only challenging for clinicians but also imposes long-term, debilitating burdens on patients' quality of life. Recent advances in evidence-based guidelines for severe asthma, increasing evidence about phenotypic patterns and asthma biomarkers, and the availability of targeted biologic therapies offer hope for improving patient outcomes.


Augmented Reality-Assisted Deep Reinforcement Learning-Based Model towards Industrial Training and Maintenance for NanoDrop Spectrophotometer.
The use of augmented reality (AR) technology is growing in the maintenance industry because it can improve efficiency and reduce costs by providing real-time guidance and instruction to workers during repairs and maintenance tasks. AR can also assist with equipment training and visualization, allowing users to explore the equipment's internal structure and size. The adoption of AR in maintenance is expected to increase as hardware options expand and development costs decrease. To implement AR for job aids in mobile applications, 3D spatial information and equipment details must be addressed, and calibrated using image-based or object-based tracking, which is essential for integrating 3D models with physical components. The present paper suggests a system using AR-assisted deep reinforcement learning (RL)-based model for NanoDrop Spectrophotometer training and maintenance purposes that can be used for rapid repair procedures in the Industry 4.0 (I4.0) setting. The system uses a camera to detect the target asset via feature matching, tracking techniques, and 3D modeling. Once the detection is completed, AR technologies generate clear and easily understandable instructions for the maintenance operator's device. According to the research findings, the model's target technique resulted in a mean reward of 1.000 and a standard deviation of 0.000. This means that all the rewards that were obtained in the given task or environment were exactly the same. The fact that the reward standard deviation is 0.000 shows that there is no variability in the outcomes.


C. elegans MAGU-2/Mpp5 homolog regulates epidermal phagocytosis and synapse density.
Synapses are dynamic connections that underlie essential functions of the nervous system. The addition, removal, and maintenance of synapses govern the flow of information in neural circuits throughout the lifetime of an animal. While extensive studies have elucidated many intrinsic mechanisms that neurons employ to modulate their connections, increasing evidence supports the roles of non-neuronal cells, such as glia, in synapse maintenance and circuit function. We previously showed that C. elegans epidermis regulates synapses through ZIG-10, a cell-adhesion protein of the immunoglobulin domain superfamily. Here we identified a member of the Pals1/MPP5 family, MAGU-2, that functions in the epidermis to modulate phagocytosis and the number of synapses by regulating ZIG-10 localization. Furthermore, we used light and electron microscopy to show that this epidermal mechanism removes neuronal membranes from the neuromuscular junction, dependent on the conserved phagocytic receptor CED-1. Together, our study shows that C. elegans epidermis constrains synaptic connectivity, in a manner similar to astrocytes and microglia in mammals, allowing optimized output of neural circuits.


Assessing the Impact of Hands-Free Georgia on Serious Motor Vehicle Accidents.
Hands-Free Georgia Law (HB673) was designed to prevent motor vehicle collisions (MVCs) by banning drivers from using their hands for non-driving-related activities, including cell phone use. We investigate HB673 effect on trauma activations secondary to MVCs in Georgia. The Georgia Trauma Registry (GTR) was queried for MVCs from 2017 to 2019, representing the 18 months prior and following implementation of HB673. The number of MVCs for each period and severity of MVC designated by the average injury severity score (ISS) for each trauma activation were collected. Prior to implementation, a total of 43 080 traumas were recorded in GTR, 11 111 (25.8%) were attributed to an MVC. Following implementation, 12 130 (23.6%) occurred secondary to MVCs. Statewide MVC-related traumas per 1000 residents increased from 1.07 to 1.14 with increased mortality rate and unchanged median ISS per MVC. The Hands-Free Georgia Law seems to have not had a major reduction in mortality in its early implementation.


Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP.
Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh2(cap)4] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.


Structural and psychological empowerment and organizational commitment among staff nurses in Jordan.
The purpose of this study was to examine the relationships between structural empowerment, psychological empowerment, and organizational commitment in Jordanian staff nurses. Empowering nurses is one of the most effective strategies for increasing efficiency. Therefore, studying the contribution of structural and psychological empowerment to organizational commitment will provide a base for future interventions to improve nurses' working environment. This cross-sectional study used snowball sampling to recruit staff nurses working in Jordanian public and private hospitals. The sample consisted of 180 nurses. Data were collected using three valid and reliable self-reporting questionnaires that were distributed in electronic format. Nurses reported a moderate level of both structural and psychological empowerment, and a high level of organizational commitment. Significant positive relationships were found between structural empowerment and psychological empowerment and organizational commitment (r = .62, p < .001) and (r = .57, p < .001) respectively. Staff nurses reported moderate levels of both structural and psychological empowerment, and have a high level of organizational commitment. Positive relationships between structural empowerment, psychological empowerment, and organizational commitment were found among Jordanian staff nurses.


Reprint of: Equal egocentric bias in school-aged children with and without autism spectrum disorders.
Egocentric bias is a core feature of autism. This phenomenon has been studied using the false belief task. However, typically developing children who pass categorical (pass or fail) false belief tasks may still show subtle egocentric bias. We examined 7- to 13-year-old children with autism spectrum disorder (ASD; n=76) or typical development (n=113) using tasks with a continuous response scale: a modified false belief task and a visual hindsight bias task. All children showed robust egocentric bias on both tasks, but no group effects were found. Our large sample size, coupled with our sensitive tasks and resoundingly null group effects, indicate that children with and without ASD possess more similar egocentric tendencies than previously reported.


Is Interarterial Course a Requisite for Ischemia in Anomalous Origin of Coronary Arteries?
Anomalous origin of the left main coronary artery from the noncoronary sinus (LCANS) is a rare variant of anomalous aortic origin of a coronary artery that is not characterized by an interarterial course. Despite the absence of an interarterial course, there are rare reports of LCANS presenting with sudden death, life-threatening arrhythmia, exercise-induced myocardial ischemia, premature ventricular contractions, and syncope. We report a patient with LCANS presenting with acute myocardial infarction who recovered completely with emergent surgical unroofing of the coronary artery.


Nucleotide-dependent structural changes in dimeric NCD molecules complexed to microtubules.
Complexes consisting of motor domains of the kinesin-like protein ncd bound to reassembled brain microtubules were visualised using cryoelectron microscopy and helical image reconstruction. Different nucleotide-associated states of a dimeric construct (NDelta295-700) of ncd were analysed to reveal ADP-containing, AMP.PNP-containing and empty (rigor) conformations. In these three states, each thought to mimic a different stage in ATP turnover, the double-headed motors attach to the microtubules by one head only, with the free head tethered in relatively fixed positions. The three structures differ both in the way the attached heads interact with tubulin and in the position of the tethered heads. In the strongly binding rigor and AMP.PNP (ATP-like) states, the attached head makes close contact with both subunits of a tubulin heterodimer. In the weakly bound ADP state, the contact made by the attached head with the monomer closer to the plus end appears to be more loose. Also, in the ATP-like state, the free head tilts nearer to the plus end than in the other two states. The data argue against model mechanisms in which a conformational change in the bound head guides the free head closer to its next binding site; on the contrary, the transition from ADP-filled via rigor to the AMP.PNP (ATP-like) state of the bound head produces a small motion of the free head in the counter-productive direction. However, the observation that the tethered head points towards the minus end, in all three states, is consistent with the idea that the relative arrangement of the heads in a dimer is a major determinant of directionality.


Molecular Characterization of Mycobacterium tuberculosis Strains with TB-SPRINT.
We evaluated Tuberculosis-Spoligo-Rifampicin-Isoniazid Typing (TB-SPRINT), a microbead-based method for spoligotyping and detection of rifampicin and isoniazid resistance in Mycobacterium tuberculosis. For that, 67 M. tuberculosis complex strains were retrospectively selected. Membrane-based spoligotyping, restriction fragment length polymorphism, DNA sequencing/pyrosequencing of rpoB, katG, and inhA promoter, TB-SPRINT, and SNP typing were performed. Concordance between spoligotyping methods was 99.6% (2,785/2,795 spoligotype data points). For most of the discordant cases, the same lineage was assigned with both methods. Concordance between phenotypic drug susceptibility testing and TB-SPRINT for detecting rifampicin and isoniazid resistance was 98.4% (63/64) and 93.8% (60/64), respectively. Concordance between DNA sequencing/pyrosequencing and TB-SPRINT for detecting mutations in rpoB, katG, and inhA were 98.4% (60/61), 100% (64/64), and 96.9% (62/64), respectively. In conclusion, TB-SPRINT is a rapid and easy-to-perform assay for genotyping and detecting drug resistance in a single tube; therefore, it may be a useful tool to improve epidemiological surveillance.


A cross-sectional study confirms temporary post-COVID-19 vaccine menstrual irregularity and the associated physiological changes among vaccinated women in Jordan.
COVID-19 vaccines continue to save people's lives around the world; however, some vaccine adverse events have been a major concern which slowed down vaccination campaigns. Anecdotal evidence pointed to the vaccine effect on menstruation but evidence from the adverse event reporting systems and the biomedical literature was lacking. This study aimed to investigate the physiological changes in women during menstruation amid the COVID-19 vaccination. A cross-sectional online survey was distributed to COVID-19 vaccinated women from Nov 2021 to Jan 2022. The results were analyzed using the SPSS software. Among the 564 vaccinated women, 52% experienced significant menstrual irregularities post-vaccination compared to before regardless of the vaccine type. The kind of menstrual irregularity varied among the vaccinated women, for example, 33% had earlier menstruation, while 35% reported delayed menstruation. About 31% experienced heavier menstruation, whereas 24% had lighter menstrual flow. About 29% had menstruation last longer, but 13% had it shorter than usual. Noteworthy, the menstrual irregularities were more frequent after the second vaccine shot, and they disappeared within 3 months on average. Interestingly, 24% of the vaccinated women reported these irregularities to their gynecologist. The COVID-19 vaccine may cause physiological disturbances during menstruation. Luckily, these irregularities were short-termed and should not be a reason for vaccine hesitancy in women. Further studies are encouraged to unravel the COVID-19 vaccine adverse effect on women's health.


Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons: application of a new and sensitive flow cytometric technique to measure intracellular lead and calcium concentrations.
The distribution of intracellular ionized lead (Pb) and calcium in dissociated cerebellar cells of ten-day-old mice was measured by flow cytometry. There are no fluorescent probes specific for lead, whereas commonly used fluorescent calcium indicators bind heavy metals with greater affinity than they do calcium, which impedes discrimination of lead- and calcium-induced fluorescence changes. Therefore, we developed a method to determine [Pb2+]i and [Ca2+]i by employing a combination of the calcium indicator fluo-3 and the heavy-metal chelator TPEN. Using these methods, we studied the effects of multiple in vivo exposure (five subcutaneous injections over 10 days) to lipopolysaccharide (LPS, 100 ng/g), recombinant mouse interleukin-6 (IL-6, 5 ng/g) and/or inorganic lead (lead, 2.5 micrograms/g) on lead and calcium concentrations. Control cells had [Cai] of 112 nM. Lead exposure alone had little effect on [Ca2+]i and resulted in a mean [Pb2+]i of about 7 pM, and did not alter cell volume. A significant fraction of cells (about 44% of living cells) from animals treated with lead plus LPS were swollen, as determined by analysis of the light scattering pattern, and there was a small increase in the number of dead cells, identified with the nucleic acid stain, 7-aminoactinomycin. While [Ca2+]i was not significantly increased in animals treated with either only LPS or IL-6, lead and calcium concentrations were increased in animals exposed to lead and LPS or IL-6 in both the non-swollen and swollen cells, with a mean value of (Pb2+)i of 32 pM and (Ca2+)i of 155 nM in cells not swollen. Electrophysiological analysis showed that LPS injections caused decreases in the membrane potential of endothelial cells of the blood-brain barrier (BBB) and lead potentiated the effect of LPS. IL-6 mimicked the effects of LPS, but was less potent. Thus these experiments indicate a synergistic interaction between lead and cytokines on biophysical properties of both neurons and endothelial cells of the BBB.


Handheld device quantifies breath acetone for real-life metabolic health monitoring.
Non-invasive breath analysis with mobile health devices bears tremendous potential to guide therapeutic treatment and personalize lifestyle changes. Of particular interest is the breath volatile acetone, a biomarker for fat burning, that could help in understanding and treating metabolic diseases. Here, we report a hand-held (6 × 10 × 19.5 cm3), light-weight (490 g), and simple device for rapid acetone detection in breath. It comprises a tailor-made end-tidal breath sampling unit, connected to a sensor and a pump for on-demand breath sampling, all operated using a Raspberry Pi microcontroller connected with a HDMI touchscreen. Accurate acetone detection is enabled by introducing a catalytic filter and a separation column, which remove and separate undesired interferents from acetone upstream of the sensor. This way, acetone is detected selectively even in complex gas mixtures containing highly concentrated interferents. This device accurately tracks breath acetone concentrations in the exhaled breath of five volunteers during a ketogenic diet, being as high as 26.3 ppm. Most importantly, it can differentiate small acetone changes during a baseline visit as well as before and after an exercise stimulus, being as low as 0.5 ppm. It is stable for at least four months (122 days), and features excellent bias and precision of 0.03 and 0.6 ppm at concentrations below 5 ppm, as validated by proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS). Hence, this detector is highly promising for simple-in-use, non-invasive, and routine monitoring of acetone to guide therapeutic treatment and track lifestyle changes.


How boron nitride forms a regular nanomesh on Rh(111).
Boron nitride forms nearly perfectly regular films with a thickness of precisely one atom on various metal surfaces. Here, we follow the formation of boron nitride layers on Rh(111) with scanning tunneling microscopy (STM) under realistic growth conditions, up to 1200 K. Our STM movies demonstrate in detail how the structure grows and how defects are introduced. Based on these observations we arrive at the optimal recipe for a high-quality overlayer.


[A case of locally advanced pancreatic cancer with hepatic artery invasion treated with neoadjuvant chemoradiotherapy].
A 64-year-old man with a high serum level of cancer antigen 19-9 (CA19-9) was diagnosed with pancreatic head cancer by computed tomography. Because the tumor was found to have directly invaded the hepatic artery for long segment on laparotomy, we diagnosed it as an unresectable locally advanced pancreatic cancer. Radiation therapy( 50.4 Gy/28 Fr) with gemcitabine( GEM)( 1,000 mg/m2 on days 1, 8, and 15, every 4 weeks) for 3 courses was administered. Subsequently, additional systemic chemotherapy with GEM( 800 mg/m2 on days 1 and 15, every 3 weeks) and S-1( 100 mg/body on days 1-14, every 3 weeks) was administered for 4 courses. After the treatment, the main tumor shrunk without distant metastasis. Thus, we performed pancreaticoduodenectomy with resection of the common hepatic artery. An end-to-end microvascular anastomosis was made between the left gastric artery and the right hepatic artery. Pathological examination revealed that > 90% of the tumor cells had disappeared and confirmed a negative margin status (R0). Eight months postoperatively, the patient is healthy and shows no signs of recurrence.


Environmental factors, reproductive history, and selective fertility in farmers' sibships.
In a national study of births to farmers in Norway, grain farming was associated with short gestational age (21-24 weeks). An impact of selective fertility and maternal heterogeneity on the association was suspected but could not be assessed further in a traditional birth-based design. Thus, analyses based on the mother as the observational unit were performed. A total of 45,969 farmers with a first birth in 1967-1981 were followed for subsequent births and perinatal mortality. A perinatal loss increased farmers' likelihood to continue to another pregnancy, but this selective fertility was less dominant than in the general population due to a higher baseline fertility. The effect of the mother's reproductive history on the grain farming-midpregnancy delivery association was analyzed in 59,338 farmers with more than one single birth in 1967-1991. A history of preterm birth (< 37 weeks) in previous or subsequent pregnancies both was an independent determinant of midpregnancy delivery and also increased the effect of grain exposure. Nongrain farmers with a history of only term births had 1.3 midpregnancy deliveries per 1,000 births; grain farmers with a history of only term births had 1.8 cases per 1,000 (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.0-1.9); nongrain farmers with a history of preterm birth had 6.8 cases per 1,000 (OR 5.5, 95% CI 4.0-7.6), whereas grain farmers with a history of preterm birth had 13.7 cases per 1,000 (OR 11.0, 95% CI 7.7-15.9). Selective fertility had only a marginal impact on the association. The study demonstrates that a maternally based design can contribute in the assessment of joint effects of environmental and maternal factors.


Coronary flow rate dependent enzyme release rate from normoxic and anoxic rat hearts in vitro.
To study the relation between coronary flow rate (CFR) and the rate of enzyme release from isolated perfused rat hearts which were either normoxic or anoxic, we measured the total activity of lactate dehydrogenase (LDH) released from the heart during a 3 h test period and mean CFR during that period. The test period consisted of (under)perfusion in the presence of oxygen and sodium pyruvate (normoxic ischaemia) or (under)perfusion in the absence of oxygen and metabolic substrates (anoxic ischaemia). Activity of LDH released during the 3 h test period correlated positively with mean CFR during anoxic ischaemia for the whole range of CFR from 0 to 17 ml X min-1, and during normoxic ischaemia when CFR was in the range 0 to 7 ml X min-1. At a CFR higher than 7 ml X min-1, the activity of LDH released during 3 h of normoxic ischaemia correlated negatively with CFR. Mean CFR was negatively correlated with coronary vascular resistance at the end of the 3 h period of perfusion. In the hearts subjected to normoxic ischaemia, coronary vascular resistance correlated positively with the percentage of myocardium unperfused. This study shows that a low CFR leads to unhomogeneous myocardial perfusion, which inhibits leakage of enzymes from myocytes into the perfusate.


Cemental tear: Literature review, proposed classification and recommendations for treatment.
Cemental tears are an important condition of relevance to Endodontics but are often overlooked. A cemental tear is the partial or complete detachment of the cementum from the cemento-dentinal junction or along the incremental line within the body of cementum. The limited attention received is most likely due to the limited awareness amongst dental professionals and challenges in accurately diagnosing them, resulting in misdiagnosis and erroneous treatment. The aim of this review is to describe the: (i) epidemiology and predisposing factors; (ii) clinical, radiographic and histological features and (iii) the clinical management and treatment outcomes of cemental tear. The review included 37 articles published in English that comprised eight observational studies and 29 case reports. The prevalence of cemental tears was reported to be lower than 2%; whilst the incidence remains unknown. Internal factors due to the inherent structural weakness of cementum and its interface with the dentine, and external factors that are associated with stress have been proposed as the two mechanisms responsible for the development and propagation of cemental tears. Predisposing factors that have been implicated were tooth type, gender, age, previous root canal treatment, history of dental trauma, occlusal trauma and excessive occlusal force; however, evidence is limited. Common clinical and radiographic manifestations of cemental tears resemble the presentations of primary endodontic diseases, primary periodontal diseases and combined endodontic-periodontal lesions. Clinical management tended to focus on complete removal of the torn fragments and periodontal treatment, often combined with regenerative treatment. In this article, a new classification for cemental tears is developed that consists of classes 0 to 6 and stages A, B, C and D based on the: (i) location and accessibility of the torn cemental fragment; (ii) the pattern and extension of the associated bony defect in relation to the root length and (iii) the number of root surface/s affected by the cemental tear/s and the associated bony defect. Recommendations for treatment strategies are also provided and linked to the classification to aid in streamlining the process of treatment decision making.


[6-unit clinico-physical complex].
The article is devoted to the results of application of high energy proton beams, negative pi-mesons and neutrons in biomedical and clinical investigations carried out at the 680 MeV phasotron (the JINR Laboratory of Nuclear Problems) before its conversion. A six-compartment clinico-physical facility is described. It has been constructed at the converted phasotron in order to continue and expand investigations for application of heavy nuclear particles in radiation therapy. The first physical and dosimetric characteristics of medical proton beams produced in the converted accelerator and guided to chambers 1 and 2 of the new clinico-physical facility are discussed. The future of radiobiological and clinical investigations with high energy proton, negative pion and neutron beams of this facility is also discussed.


Development of an "object category recognition" task for mice: Involvement of muscarinic acetylcholine receptors.
Recent research suggests that rats are capable of object categorization-like processes. To study whether mice possess similar abilities, we developed a spontaneous one-trial object category recognition (OCR) task. Based on the spontaneous object recognition paradigm, mice discriminated between two otherwise equally novel objects, one from a novel category and one from a studied category. During the sample phase, mice were exposed to two different exemplars from the same category. After a retention delay, they explored a third (i.e., novel) object from that sampled category and an object from a novel category in a choice phase. Mice preferentially explored the novel category object, taken as an index of category recognition, in this OCR task when a 30-min retention delay was used. Extensive preexposure to category exemplar objects also enhanced subsequent task performance across a longer (1-h) retention delay at which mice without preexposure did not demonstrate evidence for category recognition. Prechoice administration of the acetylcholine muscarinic receptor antagonist, scopolamine, disrupted OCR performance with or without preexposure, implicating acetylcholine in category recognition. The current study presents a valuable new rodent task for the study of the mechanistic basis of categorization-like processes and its potential relevance to common cognitive disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Ultrasonography of umbilical structures in clinically normal foals.
The umbilical arteries, urachus, and umbilical vein were scanned ultrasonographically in 13 clinically normal foals that ranged in age from 6 hours to 4 weeks. Sonograms were obtained using a 7.5-MHz sector scanner transducer placed across the midline of the ventral portion of the foal's abdominal wall. The umbilical vein was scanned from the umbilical stalk to its entrance into the hepatic parenchyma. The mean (+/- SD) diameter of the umbilical vein was 0.61 +/- 0.20 cm immediately cranial to the umbilical stalk, 0.52 +/- 0.19 cm midway between the umbilicus and liver, and 0.6 +/- 0.19 cm at the liver. The urachus and umbilical arteries were scanned from the umbilical stalk to the apex of the urinary bladder and had a mean total diameter of 1.75 +/- 0.37 cm at the bladder apex. The umbilical arteries also were scanned along either side of the bladder and had a mean diameter of 0.85 +/- 0.21 cm. These measurements and the ultrasonographic appearance of the internal umbilical structures from clinically normal foals can be used as references to diagnose abnormalities of the umbilical structures in neonatal foals.


Molecular Events in the Natural History of Pancreatic Cancer.
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads.


The Association between Alcohol Consumption and Grip Strength in a Nationwide Survey.
Handgrip strength (HGS) is an important predictor of long-term health and physical function. Studies have associated alcohol consumption with HGS but based on inconsistent findings. The Korea National Health and Nutrition Examination Survey (KNHANES) data were analyzed to examine the association between alcohol consumption levels and HGS based on sociodemographic and health-related factors. Using the 2014 to 2018 KNHANES data, alcohol consumption levels (abstinence, moderate, binge, and heavy consumption) and HGS levels (normal vs. weak) were determined in 8,556 men and 10,054 women (age, 49±16 years). Logistic regression analyses were conducted after adjusting for sociodemographic and health-related factors and in subgroups of those factors. Binge or heavy consumption was reported in 50.2% of men and 22.7% of women, and weak HGS was found in 4.6% of men and 9.9% of women. In the fully adjusted model, weak HGS was associated with binge consumption (odds ratio [OR], 0.51, 95% confidence interval [CI], 0.37-0.71) and heavy consumption (OR, 0.37, 95% CI, 0.22-0.63) in men, and moderate consumption (OR, 0.79, 95% CI, 0.67-0.93) and binge consumption (OR, 0.65, 95% CI, 0.52-0.83) in women. An association between consumption levels and weak HGS was found in both sexes regardless of age (<65 vs. ≥65 years), education/income level, exercise endurance level, presence/absence of co-morbid illness, weight, and the presence/absence of metabolic syndrome. Alcohol consumption may be inversely associated with weak HGS, regardless of sociodemographic and health-related factors using the 2014 to 2018 KNHANES data. Further prospective studies are necessary to examine the causality of the association.


Blind Poissonian images deconvolution with framelet regularization.
We propose a maximum a posteriori blind Poissonian images deconvolution approach with framelet regularization for the image and total variation (TV) regularization for the point spread function. Compared with the TV based methods, our algorithm not only suppresses noise effectively but also recovers edges and detailed information. Moreover, the split Bregman method is exploited to solve the resulting minimization problem. Comparative results on both simulated and real images are reported.


New Acorane-Type Sesquiterpene from Acorus calamus L.
A new sesquiterpene, named neo-acorane A (1), and two known ones, acoric acid (2) and calamusin D (3), were isolated from a 95% ethanol extract of the rhizome parts of Acorus calamus L. Their structures were elucidated by spectroscopic methods, and the absolute configurations were determined by single-crystal X-ray diffraction analysis. Compounds 1 and 2 are nonisoprenoid sesquiterpenoids, likely biosynthesized from an acorane-type sesquiterpene by oxidative fission of the six- or five-membered ring. Moreover, compounds 1 (10 μM), 2 (5 μM and 10 μM) and 3 (10 μM) showed cell proliferation activity on the SK-N-BE (2) cell line.


Differential activation of primary and memory "B" lymphocytes.
Immunization of certain strains of mice with the tobacco mosaic virus protein (TMVP) elicits antibodies capable of binding with a decapeptide representing residues 103-112 of TMVP. However, immunization of mice with decapeptide conjugated to a variety of carriers failed to elicit antibodies to the decapeptide in spite of the fact that antibodies were induced to the carriers or to nonrelated peptides similarily conjugated to the carriers. In contrast to the conjugates inability to induce a primary anti-decapeptide response, the conjugates were able to elicit a secondary anti-decapeptide response. Thus, when irradiated mice were transplanted with syngeneic TMVP-primed B cells and carrier-primed T cells, secondary challenge with the decapeptide on the carrier elicited an excellent secondary anti-decapeptide response. Furthermore, the titer and specificity of the antibodies so induced were the same as that induced by secondary challenge with TMVP. These results suggest a difference between primary and memory B cells in their requirements for activation.


Influence of environmental enrichment on the behavior and physiology of mice infected by Trypanosoma cruzi.
Enriched environments normally increase behavioral repertoires and diminish the expression of abnormal behaviors and stress-related physiological problems in animals. Although it has been shown that experimental animals infected with microorganisms can modify their behaviors and physiology, few studies have evaluated how environmental enrichment affects these parameters. This study aimed to evaluate the effects of environmental enrichment on the behavior and physiology of confined mice infected with Trypanosoma cruzi. The behaviors of 20 T. cruzi-infected mice and 20 non-infected mice were recorded during three treatments: baseline, enrichment, and post-enrichment. Behavioral data were collected using scan sampling with instantaneous recording of behavior every 30s, totaling 360h. Plasma TNF, CCL2, and IL-10 levels and parasitemia were also evaluated in infected enriched/non-enriched mice. Behavioral data were evaluated by Friedman's test and physiological data by one-way ANOVA and area under the curve (AUC) analysis. Results showed that environmental enrichment significantly increased exploratory behaviors and diminished inactivity. The use of environmental enrichment did not diminish circulating levels of TNF and IL-10 but diminished circulating levels of CCL2 and parasitemia. Positive behavioral and physiological effects of environmental enrichment were observed in mice living in enriched cages. Thus, environmental enrichment improved the welfare of these animals.


ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2.
Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.


Nitrilase and its application as a 'green' catalyst.
Hydrolase-catalyzed reactions have been widely applied in organic synthesis. Nitrilases are an important class of hydrolase that converts naturally occurring, as well as xenobiotically derived, nitriles to the corresponding carboxylic acids and ammonia. Because of their inherent enantio- and regioselectivities and other benefits, nitrilases are attractive as 'green', mild, and selective catalysts for setting stereogenic centers in fine-chemical synthesis and enantiospecific synthesis of a variety of carboxylic acid derivatives. In this review, the literature has been surveyed to provide a comprehensive coverage of the application of nitrilases in organic synthesis. Literature has also been cited to describe the isolation and/or characterization of nitrilases and related enzymes.


Excited states and spin-orbit coupling in chalcogen substituted perylene diimides and their radical anions.
While spin-orbit coupling does not play a decisive role in the photophysics of unsubstituted perylene diimides (PDI), this changes dramatically when two phenylselenyl or phenyltelluryl substituents were attached to the PDI bay positions. In the series of PhO-, PhS-, PhSe-, and PhTe-substituted PDIs we observed strongly decreasing fluorescence quantum yield as a consequence of strongly increasing intersystem crossing (ISC) rate, measured by transient absorption spectroscopy with fs- and ns-time resolution as well as by broadband fluorescence upconversion. Time-dependent density functional calculations suggest increasing spin-orbit coupling due to the internal heavy-atom effect as the reason for fast ISC. In case of the selenium PDI derivative we found significant singlet oxygen sensitization via the PDI triplet state. The corresponding radical anions of the chalcogen substituted PDIs were also prepared and investigated by optical and EPR spectroscopy. Here, the increasing SOC results in an increase of the g-tensor anisotropy, and of the isotropic g-value in solution, albeit quasirelativistic density functional calculations show only a relatively small fraction of the spin density to be located on the chalcogen atom.


[Role of reactive oxygen species, nitric oxide and mitochondrial K(ATP) channels in TNF-alpha induced cardioprotection].
To explore the cardiac effect of TNF-alpha in postischemic heart and the possible mechanism. Langendorff perfused rat heart was used to evaluate the contractile properties of myocardium by intraventricular pressure measurement. The isolated rat heart underwent 20 min of global ischemia followed by 20 min of reperfusion. The level of lactate dehydrogenase (LDH) in the coronary effluent was measured to evaluate the cardiac injury. And the activity of manganese superoxide dismutase (Mn-SOD) in myocardium was measured. Perfusion with TNF-alpha (104 U/L) attenuated the inhibitory effects induced by ischemia/reperfusion on left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure(LVEDP), maximal rise/fall rate of left ventricular pressure (+/- dP/dtmax) and rate pressure product (LVDP multiplied by heart rate, LVDP x HR). TNF-alpha significantly decreased the release of LDH (P < 0.05) and increased the activity of Mn-SOD in the myocardium (P < 0.05). Antioxidant 2-MPG (0.3 mmol/L), NOS inhibitor L-NAME (0.5 mmol/L) or mitochondrial selective KATP channel inhibitor 5-HD (100 micromol/L) attenuated the increase in LVDP, +/- dP/dtmax and LVDP x HR, and decrease in LVEDP induced by TNF-alpha in ischemia/reperfusion heart, respectively. And the effects of TNF-alpha in reducing the levels of LDH and increasing the Mn-SOD activity were also attenuated by 2-MPG, L-NAME or 5-HD, respectively. TNF-alpha pretreatment attenuates the myocardial injury induced by ischemia/reperfusion, which coincides with the increasing of myocardial Mn-SOD activity. Reactive oxygen species, nitric oxide and mitochondrial KATP channels are involved in the cardioprotection induced by TNF-alpha.


[Subcutaneous myxoid liposarcoma].
Although myxoid liposarcomas (MLS) are the most common type of soft-tissue sarcomas in adults, their primary location in the superficial tissues is rare. So sarcomas are classified as superficial and deep-seated. They are distinct based on their location and their frequency as well as their prognosis which is relatively better in superficial sarcomas. We here report the case of a patient with subcutaneous liposarcoma in the right thigh. The diagnosis was confirmed by histology after clinical symptoms had evolved over 1 year. Treatment involved wide surgical resection followed by locoregional radiation therapy. Patient's evolution was marked by complete remission maintained after 32 months follow-up. This study highlights that superficial sarcomas are rare and this can cause a delay in diagnosis compromising their prognosis.


Redesigning protein pKa values.
The ability to re-engineer enzymatic pH-activity profiles is of importance for industrial applications of enzymes. We theoretically explore the feasibility of re-engineering enzymatic pH-activity profiles by changing active site pK(a) values using point mutations. We calculate the maximum achievable DeltapK(a) values for 141 target titratable groups in seven enzymes by introducing conservative net-charge altering point mutations. We examine the importance of the number of mutations introduced, their distance from the target titratable group, and the characteristics of the target group itself. The results show that multiple mutations at 10A can change pK(a) values up to two units, but that the introduction of a requirement to keep other pK(a) values constant reduces the magnitude of the achievable DeltapK(a). The algorithm presented shows a good correlation with existing experimental data and is available for download and via a web server at http://enzyme.ucd.ie/pKD.


The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters.
Precise homoeostasis of the intracellular concentration of Cl- is achieved via the co-ordinated activities of the Cl- influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl- co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr1048)]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of 86Rb+ uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr5 in KCC1/KCC3 and Thr6 in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser96). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl- influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl- extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states.


Knockdown of desmin in zebrafish larvae affects interfilament spacing and mechanical properties of skeletal muscle.
Skeletal muscle was examined in zebrafish larvae in order to address questions related to the function of the intermediate filament protein desmin and its role in the pathogenesis of human desminopathy. A novel approach including mechanical and structural studies of 4-6-d-old larvae was applied. Morpholino antisense oligonucleotides were used to knock down desmin. Expression was assessed using messenger RNA and protein analyses. Histology and synchrotron light-based small angle x-ray diffraction were applied. Functional properties were analyzed with in vivo studies of swimming behavior and with in vitro mechanical examinations of muscle. The two desmin genes normally expressed in zebrafish could be knocked down by ~50%. This resulted in a phenotype with disorganized muscles with altered attachments to the myosepta. The knockdown larvae were smaller and had diminished swimming activity. Active tension was lowered and muscles were less vulnerable to acute stretch-induced injury. X-ray diffraction revealed wider interfilament spacing. In conclusion, desmin intermediate filaments are required for normal active force generation and affect vulnerability during eccentric work. This is related to the role of desmin in anchoring sarcomeres for optimal force transmission. The results also show that a partial lack of desmin, without protein aggregates, is sufficient to cause muscle pathology resembling that in human desminopathy.


Current Scenario of Postcholecystectomy Bile Leak and Bile Duct Injury at a Tertiary Care Referral Centre of Nepal.
With the adoption of safe cholecystectomy principles at an academic institute, the risk of major bile duct injury has decreased. This study aims at evaluating the present status of bile duct injury, compared to the study published in 2013 by index centre. This is a retrospective review of a prospectively maintained database of bile leak and bile duct injury from 2014 to 2019. Patients who completed postcholecystectomy bile leak or bile duct injury treatment and were on regular follow-up were included. Eighteen patients (0.78%) among 2,300 consecutive cholecystectomies presented with bile duct injury, including 8 (0.35%) major bile duct injuries and 10 (0.43%) bile leaks compared to major bile duct injury rate of 0.68% (92/11,345 cholecystectomies) between 2001 and 2010. Injuries were classified as Strasberg's type A (52.9%), type D (5.9%), and type E (41.1%). Eight patients (47%) of bile leak were managed conservatively with drains, while two required laparotomy and lavage. The mean time for spontaneous closure of bile leak was 11 days. Intraoperative repair was done in three cases: Roux en Y hepaticojejunostomy in 2 and end-to-end repair over T-tube in 1 for sharp transection of the duct. Delayed repair (Roux-en-Y hepaticojejunostomy) was done in five patients. The median postcholecystectomy hospital stay was 8 days, with no mortality. There was no restricture at a median follow-up of 13 months. With the adoption of a safe culture of cholecystectomy, the major bile duct injury rate has decreased currently. Repair of bile duct injury by experienced hepatobiliary surgeon results in excellent outcome.


Aqueous choline amino acid deep eutectic solvents.
We have investigated the structure and phase behavior of biocompatible, aqueous deep eutectic solvents by combining choline acetate, hydrogen aspartate, and aspartate amino acid salts with water as the sole molecular hydrogen bond donor. Using contrast-variation neutron diffraction, interpreted via computational modeling, we show how the interplay between anion structure and water content affects the hydrogen bond network structure in the liquid, which, in turn, influences the eutectic composition and temperature. These mixtures expand the current range choline amino acid ionic liquids under investigation for biomass processing applications to include higher melting point salts and also explain how the ionic liquids retain their desirable properties in aqueous solution.


The sequence determinant causing different folding behaviors of insulin and insulin-like growth factor-1.
Although insulin and insulin-like growth factor-1 (IGF-1) belong to the insulin superfamily and share highly homologous sequences, similar tertiary structure, and a common ancestor molecule, amphioxus insulin-like peptide, they have different folding behaviors: IGF-1 folds into two thermodynamically stable tertiary structures (native and swap forms), while insulin folds into one unique stable structure. To further understand which part of the sequence determines their different folding behavior, based on previous reports from the laboratory, two peptide models, [B9A][1-4]porcine insulin precursor (PIP) and [B10E][1-4]PIP, were constructed. The plasmids encoding the peptides were transformed into yeast cells for expression of the peptides; the results showed that the former peptide was expressed as single component, while the latter was expressed as a mixture of two components (isomer 1 and isomer 2). The expression results together with studies of circular dichoism, disulfide rearrangement, and refolding lead us to deduce that isomer 1 corresponds to the swap form and the isomer 2 corresponds to the native form. We further demonstrate that the sequence 1-4 plus B9 of IGF-1 B-domain can make PIP fold into two structures, while sequence 1-5 of insulin B-chain can make IGF-1 fold into one unique structure. In other words, it is the IGF-1 B-domain sequence that 1-4 allows IGF-1 folding into two thermodynamically stable tertiary structures; this sequence plus its residue B9E can change PIP folding behavior from folding into one unique structure to two thermodynamically stable structures, like that of IGF-1.


Renal Denervation After Symplicity HTN-3 - Back to Basics. Review of the Evidence.
Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment resistant hypertension, a condition defined as office blood pressure elevation despite prescription of at least three antihypertensive drugs including a diuretic. However, the impressive fall in blood pressure reported after RDN in Symplicity HTN-2, the first randomised study, and multiple observational studies has not been confirmed in the US sham-controlled trial Symplicity HTN-3 and four subsequent prospective randomised studies, all published or presented in 2014. The blood pressure reduction documented in earlier studies may be largely due to non-specific effects such as improvement of drug adherence in initially poorly adherent patients (Hawthorne effect), placebo effect and regression to the mean. The overall blood pressure lowering effect of RDN seems rather limited and the characteristics of true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparent drug-resistant hypertension, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment and with true resistant hypertension who may respond to RDN.


Teaching ethics in nursing.
Being a professional nurse requires ethical decision making and this in turn necessitates an effective learning process. The active participation of students in the teaching of ethics will contribute to this process. This study was conducted at Hacettepe University School of Nursing, Ankara, Turkey, to determine the views of students about the nursing ethics content in the curriculum, the examination system, and some educational characteristics of the teachers responsible for the course. The sample comprised 113 students who participated voluntarily. In general, the students expressed a positive view relating to the course content and the teachers. The majority stated that the discussions on case study analysis by using ethical principles, rights, legal aspects and the use of the International Council of Nurses Code of Ethics were very useful in developing ethical decision-making skills. We believe that the results of this study will enhance our efforts in amending this course and improving the ethical decision-making skills of our students.


A PBPK Model of Ternary Cyclodextrin Complex of ST-246 Was Built to Achieve a Reasonable IV Infusion Regimen for the Treatment of Human Severe Smallpox.
ST-246 is an oral drug against pathogenic orthopoxvirus infections. An intravenous formulation is required for some critical patients. A ternary complex of ST-246/meglumine/hydroxypropyl-β-cyclodextrin with well-improved solubility was successfully developed in our institute. The aim of this study was to achieve a reasonable intravenous infusion regimen of this novel formulation by a robust PBPK model based on preclinical pharmacokinetic studies. The pharmacokinetics of ST-246 after intravenous injection at different doses in rats, dogs, and monkeys were conducted to obtain clearances. The clearance of humans was generated by using the allometric scaling approach. Tissue distribution of ST-246 was conducted in rats to obtain tissue partition coefficients (K p ). The PBPK model of the rat was first built using in vivo clearance and K p combined with in vitro physicochemical properties, unbound fraction, and cyclodextrin effect parameters of ST-246. Then the PBPK model was transferred to a dog and monkey and validated simultaneously. Finally, pharmacokinetic profiles after IV infusion at different dosages utilizing the human PBPK model were compared to the observed oral PK profile of ST-246 at therapeutic dosage (600 mg). The mechanistic PBPK model described the animal PK behaviors of ST-246 via intravenous injection and infusion with fold errors within 1.2. It appeared that 6h-IV infusion at 5 mg/kg BID produced similar Cmax and AUC as oral administration at 600 mg. A PBPK model of ST-246 was built to achieve a reasonable regimen of IV infusion for the treatment of severe smallpox, which will facilitate the clinical translation of this novel formulation.


The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.
This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.