Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density.
Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.


Computed tomography-guided percutaneous drainage of splenic abscesses.
The aim of the study is to evaluate the role of computed tomography (CT)-guided percutaneous drainage in the management of solitary splenic abscesses. Sonography and CT were used in the initial diagnosis of splenic abscess in patients with vague left upper quadrant pain and/or fever. Solitary splenic abscesses of nine male patients whose ages varied between 21 and 27 years (mean age: 24.7 years) were percutaneously drained under CT guidance. Puncture with 18-gauge Chiba needles and coaxial guidewire technique was used for insertion of six or eight French pigtail catheters. Antibiotics in accordance with the microbiological results were also given adjuvant to drainage. Follow-up examinations were performed by sonography, daily for the first week and weekly for the next 7 weeks, and by CT at the end of first, fourth and eighth weeks. All patients tolerated the intervention well, except for one complicating with splenic rupture and hemorrhage, who underwent emergency splenectomy. The remaining eight patients recovered within 4 weeks without any splenic sequela. A mean of 3.9 days was needed before removing the drainage catheter based on regression criteria. CT-guided percutaneous drainage of splenic abscesses may be proven effective and is superior to splenectomy in selected cases, as it preserves host immunity.


Changes of skin electrical potential in acupoints from Ren Mai and Du Mai conduits during Qigong practice: Documentation of a clinical phenomenon.
Qigong is a therapeutic method of traditional Chinese medicine (TCM) that combines slow, soft movements and postures with breath control and a special mental state of 'awareness'. TCM holds that the practice of Qigong promotes the 'circulation of qi' in the human body, the 'flow' of upward yang qi and downward yin qi to establish 'balance'. In Western terms, this may be generally equivalent to vegetative homeostasis and the emotionally balanced state induced thereby. Researchers have often attempted to evaluate the functional movements of qi using measurements of the skin's electrical resistance. However, these methodologies have proven difficult to gauge, validate, repeat, and interpret. We aimed to overcome these limitations by measuring the skin's electrical potential between two points of the same system. The main goal of this study was to assess the skin's electrical potential changes in acupoints from the Ren Mai and Du Mai conduits, or meridians, as well as in other points of interest, during Qigong practice. While participants performed a specific Qigong exercise called 'White Ball', we observed significant changes in the skin electrical potential on Mìngmén (GV 4), Shèndáo (GV 11) and Baihuì (GV 20), from the Du Mai conduit, as well as on Huiyin (CV 1), Qìhai (CV 6), Zhongwan (CV 12) and Dànzhong (CV 17), from Ren Mai. These observations are in accordance with TCM theory and may contribute to the explanation of the vegetative physiological changes that are associated with 'qi flow' in TCM.


Mechanisms of action of rabbit CAP18 on monolayers and liposomes made from endotoxins or phospholipids.
We have investigated the mechanism of action of the cationic antimicrobial protein (18 kDa) CAP18 on liposomes and monolayers made from phospholipids and enterobacterial lipopolysaccharides (LPS). CAP18 intercalates into lipid matrices composed of LPS from sensitive strains, weaker into those made of LPS from a resistant strain (Proteus mirabilis strain R45) or negatively charged phospholipids, but not into those composed of neutral phosphatidylcholine. From the combination of data obtained with fluorescence resonance energy transfer and Fourier-transform infrared spectroscopy and film balance measurements, it can be concluded that structural differences in the LPS determine the depth of intercalation of CAP18 into the respective lipid matrices. Thus, we identified the L-Arap4N linked to the first Kdo of the LPS of P. mirabilis strain R45 to be responsible for the CAP18 resistance of this strain. These data provide insight into CAP18-mediated effects on the integrity of the outer membrane of Gram-negative bacteria and led to an improved model for rabbit CAP18 membrane interaction.


Clostridium difficile and Laparoscopic Bariatric Surgery: an Analysis of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program Database.
Obesity is associated with disturbances in the gut microbiota which is a risk factor for Clostridium difficile infection (CDI). Bariatric surgery can induce substantive changes to the gut microbiota which may affect the risk of developing CDI. The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program captures variables specific to bariatric surgery from 832 centers. Patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) in 2016 and 2017 were identified. Primary outcomes included the prevalence and predictors of CDI after bariatric surgery. A multivariable logistic regression model determined preoperative factors predictive of 30-day CDI. A total of 78,222 LRYGB and 222,968 LSG were included. The overall incidence of CDI was low with 0.13% developing CDI. Rates of CDI were two times higher after LRYGB compared to LSG (0.2 vs 0.1%, p < 0.001). Although CDI rates were low, CDI was associated with increased post-operative complications. Multivariable analysis identified chronic kidney disease (OR 2.37, 95%CI 1.09-5.15, p = 0.03) and history of venous thromboembolism (OR 2.06, 95%CI 1.29-3.29, p = 0.002) as being most predictive of developing CDI with more than a twofold increase in risk. Patients undergoing LRYGB had an increased risk of CDI compared to LSG (OR 1.65, 95%CI 1.31-2.09, p < 0.001). White race, female sex, and obstructive sleep apnea also increased risk of CDI. The incidence of CDI following bariatric surgery is relatively low with LRYGB having a higher risk than LSG. Furthermore, CDI is associated with significant adverse outcomes post-operatively but had no increased risk of mortality.


Exoskeleton-Assisted Anthropomorphic Movement Training for the Upper Limb After Stroke: The EAMT Randomized Trial.
Robot-assisted arm training is generally delivered in the robot-like manner of planar or mechanical 3-dimensional movements. It remains unclear whether integrating upper extremity (UE) natural coordinated patterns into a robotic exoskeleton can improve outcomes. The study aimed to compare conventional therapist-mediated training to the practice of human-like gross movements derived from 5 typical UE functional activities managed with exoskeletal assistance as needed for patients after stroke. In this randomized, single-blind, noninferiority trial, patients with moderate-to-severe UE motor impairment due to subacute stroke were randomly assigned (1:1) to receive 20 sessions of 45-minute exoskeleton-assisted anthropomorphic movement training or conventional therapy. Treatment allocation was masked from independent assessors, but not from patients or investigators. The primary outcome was the change in the Fugl-Meyer Assessment for Upper Extremity from baseline to 4 weeks against a prespecified noninferiority margin of 4 points. Superiority would be tested if noninferiority was demonstrated. Post hoc subgroup analyses of baseline characteristics were performed for the primary outcome. Between June 2020 and August 2021, totally 80 inpatients (67 [83.8%] males; age, 51.9±9.9 years; days since stroke onset, 54.6±38.0) were enrolled, randomly assigned to the intervention, and included in the intention-to-treat analysis. The mean Fugl-Meyer Assessment for Upper Extremity change in exoskeleton-assisted anthropomorphic movement training (14.73 points; [95% CI, 11.43-18.02]) was higher than that of conventional therapy (9.90 points; [95% CI, 8.15-11.65]) at 4 weeks (adjusted difference, 4.51 points [95% CI, 1.13-7.90]). Moreover, post hoc analysis favored the patient subgroup (Fugl-Meyer Assessment for Upper Extremity score, 23-38 points) with moderately severe motor impairment. Exoskeleton-assisted anthropomorphic movement training appears to be effective for patients with subacute stroke through repetitive practice of human-like movements. Although the results indicate a positive sign for exoskeleton-assisted anthropomorphic movement training, further investigations into the long-term effects and paradigm optimization are warranted. URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100044078.


Fluorescence resonance energy transfer across a mechanical bond of a rotaxane.
Fluorescence transfer across a donor-acceptor tagged rotaxane was studied and a small conformational change of the rotaxane observed using fluorescent spectroscopy and ROESY NMR.


KLP-7 acts through the Ndc80 complex to limit pole number in C. elegans oocyte meiotic spindle assembly.
During oocyte meiotic cell division in many animals, bipolar spindles assemble in the absence of centrosomes, but the mechanisms that restrict pole assembly to a bipolar state are unknown. We show that KLP-7, the single mitotic centromere-associated kinesin (MCAK)/kinesin-13 in Caenorhabditis elegans, is required for bipolar oocyte meiotic spindle assembly. In klp-7(-) mutants, extra microtubules accumulated, extra functional spindle poles assembled, and chromosomes frequently segregated as three distinct masses during meiosis I anaphase. Moreover, reducing KLP-7 function in monopolar klp-18(-) mutants often restored spindle bipolarity and chromosome segregation. MCAKs act at kinetochores to correct improper kinetochore-microtubule (k-MT) attachments, and depletion of the Ndc-80 kinetochore complex, which binds microtubules to mediate kinetochore attachment, restored bipolarity in klp-7(-) mutant oocytes. We propose a model in which KLP-7/MCAK regulates k-MT attachment and spindle tension to promote the coalescence of early spindle pole foci that produces a bipolar structure during the acentrosomal process of oocyte meiotic spindle assembly.


Effects of a Neonicotinoid on Indigenous Earthworm Perionyx excavatus Biochemical and Histopathological Alterations.
Acetamiprid is a broad-spectrum insecticide, belonging to the neonicotinoid compounds group, which has been extensively applied throughout the globe. Recently, indiscriminate use of these compounds was reported to cause fatal impacts on non-targeted soil organisms. Hence, the present study aimed to examine the impact of acetamiprid on Indian indigenous earthworm, Perionyx excavatus. Acute toxicity revealed an LC50 concentration of 0.25 µg/cm2 for filter paper test/72 h and 400 µg/kg for artificial soil test/14 days. Oxidative stress (ROS) and various biomarkers including superoxide dismutase, catalase, glutathione S-transferase, malondialdehyde content and DNA damage were measured. The results of the biomarker responses confirmed the acetamiprid exposure can cause toxicity to P. excavatus. In addition, cell density (20 × 102 cell mL/mg) and cell viability (40%) were significantly (p < 0.05) reduced. Further, the ecotoxicological assessment made through this study can be utilized as good evidence to toxicity of neonicotinoids to non-targeted indigenous organisms.


Disorders of glycoprotein degradation.
The intracellular degradation of glycoproteins occurs predominantly in the lysosomes through the concerted action of proteases and glycosidases. Genetic defects in any of the enzymes cleaving the oligosaccharide side chains lead to specific diseases because of an excessive lysosomal accumulation of partially degraded material, mostly oligosaccharides. This paper presents an overview of the biochemistry and the clinical spectrum of this group of diseases including sialidosis, galactosialidosis, alpha- and beta-mannosidosis, fucosidosis, aspartylglucosaminuria, and alpha-N-acetylgalactosaminidase deficiency (Schindler disease). In addition, the sialic acid storage disorder (Salla disease) which is caused by a defect in the lysosomal transport of this acidic monosaccharide is included because of functional and clinical correlations.


Repair of Superior Vena Caval Perforation during Pacemaker Placement with Video-Assisted Limited Thoracotomy.
Abstract We report a case of a patient who sustained superior vena cava perforation just proximal to the innominate-caval confluence during pacemaker implantation. Because this complication was recognized early and the dilator was left in place, the patient remained hemodynamically stable and successfully underwent a videoscopically assisted repair of the superior vena caval perforation through a limited thoracotomy incision.


Skin cells, but not T cells, are resistant to indoleamine 2, 3-dioxygenase (IDO) expressed by allogeneic fibroblasts.
We have previously demonstrated that indoleamine 2, 3-dioxygenase (IDO) expressed by dermal fibroblasts generated a tryptophan deficient environment in which immune cells, but not skin cells, undergo apoptosis. However, the mechanism by which primary skin cells such as fibroblasts and keratinocytes are resistant to this culture environment is not elucidated. Here, we asked the question of whether the activity of the general control nondepressing-2 (GCN2) kinase pathway in primary immune and skin cells is differently regulated in response to IDO-induced tryptophan deficient environment. Before addressing this question, the expression of IDO in IDO-adenoviral infected fibroblasts, as a source of IDO expression, was validated. We then demonstrated a significant immunosuppressive effect of IDO expression in primary human T cells co-cultured with IDO expressing fibroblasts in the presence of allogeneic pieces of either epidermis or full thickness skin. Evaluating the mechanism by which skin cells, but not T cells, are resistant to IDO induced low tryptophan environment, we then co-cultured IDO-expressing fibroblasts with bystander human T cells, the fibroblasts, or keratinocytes for 3 days. The results showed a significant activation of apoptotic pathway as analyzed by caspase-3 induction as well as the expression of CHOP, a downstream effector of GCN2 kinase pathway in T cells, but not in skin cells.


Wastewater compounds in urban shallow groundwater wells correspond to exfiltration probabilities of nearby sewers.
Wastewater compounds are frequently detected in urban shallow groundwater. Sources include sewage or reclaimed wastewater, but origins are often unknown. In a prior study, wastewater compounds were quantified in waters sampled from shallow groundwater wells in a small coastal California city. Here, we resampled those wells and expanded sample analyses to include sewage- or reclaimed water-specific indicators, i.e. pharmaceutical and personal care product chemicals or disinfection byproducts. Also, we developed a geographic information system (GIS)-based model of sanitary sewer exfiltration probability--combining a published pipe failure model accounting for sewer pipe size, age, materials of construction, with interpolated depths to groundwater--to determine if sewer system attributes relate to wastewater compounds in urban shallow groundwater. Across the wells, groundwater samples contained varying wastewater compounds, including acesulfame, sucralose, bisphenol A, 4-tert-octylphenol, estrone and perfluorobutanesulfonic acid (PFBS). Fecal indicator bacterial concentrations and toxicological bioactivities were less than known benchmarks. However, the reclaimed water in this study was positive for all bioactivity tested. Excluding one well intruded by seawater, the similarity of groundwater to sewage, based on multiple indicators, increased with increasing sanitary sewer exfiltration probability (modeled from infrastructure within ca. 300 m of each well). In the absence of direct exfiltration or defect measurements, sewer exfiltration probabilities modeled from the collection system's physical data can indicate potential locations where urban shallow groundwater is contaminated by sewage.


Neuroradiology.
Neuroradiographs are an invaluable part of the diagnostic plan in most cases involving nervous system dysfunction in companion animals. High MAS, low KvP techniques used on standard radiographic equipment available in most veterinary practices will provide good-quality neuroradiographs of the skull and spine. Proper positioning of the animal, which necessitates use of general anesthesia, is required to obtain neuroradiographs of good diagnostic quality. A working knowledge of the normal anatomy of the skull and spine is required to make correct interpretations of the neuroradiographs.


Analysis of antimicrobial agents in pig feed by liquid chromatography coupled to orbitrap mass spectrometry.
The emerging trend towards full scan mass spectrometry alternatives was evaluated for the identification of a wide range of anti-bacterial compounds in animal feed. The high resolving power of the orbitrap exactive provides precise mass accuracy, resulting in high selectivity which enables qualitative and quantitative analysis in complex matrices such as feed. A simple generic sample preparation procedure was applied, including extraction of the feed samples with a combination of organic solvents. The mass spectrometer was operated in full scan with polarity switching between positive and negative modes, using heated electrospray ionization (H-ESI). The detection was carried out using automatic control of the number of ions entering the mass analyzer and with the combination of the ion injection time, accurate quantitative analysis was achieved. Due to the complexity of the feed samples the resolving power proved to be the key for the discrimination between interfering masses from the matrix and the exact masses of the compounds in order to achieve mass accuracy of 5ppm. Furthermore, the use of narrow mass windows (±5ppm) improved the selectivity of the method, increasing the signal-to-noise ratio for the compounds. A thoroughly validation study was successfully performed and evaluated in pig feed. The utilization of liquid chromatography to the high resolution orbitrap exactive proved to be a powerful tool for routine analysis of undesirable anti-bacterial compounds in feed control, ensuring food safety under the EU food chain legal framework.


Nociception Coma Scale-Revised Allows to Identify Patients With Preserved Neural Basis for Pain Experience.
The Nociception Coma Scale-Revised (NCS-R) was developed to help assess pain in patients with disorders of consciousness (DOC). Several studies have shown its sensitivity in assessing response to acute noxious stimuli. However, they failed to determine a reliable cut-off score that could be used to infer pain processing in these patients. This retrospective cross-sectional study aimed to determine a NCS-R cut-off score supporting preserved neural basis for pain experience, based on brain metabolism preservation as measured by fluorodeoxyglucose positron emission tomography (FDG-PET). We included patients in unresponsive wakefulness syndrome (UWS) confirmed by the FDG-PET and examined the NCS-R total scores. As the highest score was 4, we defined the cut-off to be 5 and compared the brain metabolism of these patients to matched patients with DOC and a NCS-R cut-off score ≥5 (ie, potential pain), as well as healthy subjects. We found a higher global cerebral metabolism in healthy subjects compared to both patient groups and also in patients with potential pain compared with FDG-PET confirmed UWS. We observed a preserved metabolism in the left insula in patients with potential pain compared with FDG-PET confirmed UWS. PERSPECTIVES: Our data suggest that using the cut-off score of 5 could be helpful to improve pain management in patients with DOC. Future studies should focus on patients showing scores below this cut-off to better characterize their profile and improve care.


LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.
Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.


Structure of the Fc fragment of the NIST reference antibody RM8671.
As the link between antigen binding and immune activation, the antibody Fc region has received extensive structural study. In this report, the structure of the Fc fragment of the NIST IgG1 mAb (reference material 8671) is described at 2.1 Å resolution in space group P212121, with approximate unit-cell parameters a = 50, b = 80, c = 138 Å. Prior Fc structures with a wide variety of modifications are also surveyed, focusing on those in the same crystal form. To facilitate the analysis of conformations, a reference frame and a two-parameter metric are proposed, considering the CH2 domains as mobile with respect to a fixed dimeric CH3 core. Over several human Fc structures, a significant variation in Fc elbow conformations is observed, which may serve to facilitate the regulation of Fc effector signaling.


Influence of rubber's viscoelasticity and damping on vertical dynamic stiffness of air spring.
Using the diaphragm-type air spring as the research object. The ratio of the vertical stiffness change caused by compressed air to the total vertical stiffness change was calculated, and it was determined that the nonlinearity of air spring vertical stiffness was mainly caused by the deformation stiffness of the rubber airbag. The variation law of vertical dynamic stiffness of air spring was predicted by theory: due to the material's viscoelasticity, the vertical dynamic stiffness rises as the excitation frequency rises, and the vertical dynamic stiffness decreases with the increase of excitation amplitude due to the damping of the material. An air spring finite element analysis (FEA) and experiment were conducted. The results show that the vertical dynamic stiffness obtained through simulation and experiment is consistent with the theoretical prediction, when various factors such as material nonlinearity, element coupling, and stiffness value sensitivity were considered. This proves that the predicted vertical dynamic stiffness variation law is reliable. The vertical dynamic stiffness obtained from both simulation and experiment showed a strong correlation in numerical values, which verified the accuracy of the FEA model of air spring established in this paper.


An individual with McLeod syndrome and the Kell blood group antigen K(K1).
McLeod syndrome is an X-linked condition in which individuals of McLeod blood group phenotype have weak Kell antigens, acanthocytic red cells, and a muscular disorder. We now report a family in which two brothers have McLeod syndrome. One is K:-1, while the other is the first known K:1 person with McLeod syndrome. The K1 gene in the latter is expressed weakly and was inherited from the father, in whom it is expressed normally. The brothers have the same clinical and laboratory manifestations of McLeod syndrome but have different Kell genes. Therefore, the Kell gene is unlikely to have any positive input into development of McLeod syndrome; its role is one of passive involvement in which its expression is modified.


Approach to the management of coronary artery disease in the elderly.
Atherosclerotic coronary artery disease is an important problem in the elderly and is the leading cause of death. It is a diagnosis that is often difficult to make; signs and symptoms of angina pectoris and myocardial infarction can be atypical in the elderly patient for a variety of reasons. The chest radiograph, electrocardiogram, and echocardiogram can provide diagnostic clues as to the presence of coronary artery disease. Exercise testing is foremost among the noninvasive diagnostic modalities, but it has significant limitations particular to the elderly patient. These include a decreased ability to exercise in the elderly, difficulty in interpretation because of an abnormal resting electrocardiogram, and the nature of an imperfect test that provides a statement of probability rather than an unequivocal diagnosis. Cardiac catheterization can be performed with minimal risk in selected, particularly unstable patients, in whom a surgical alternative is contemplated. The elderly patient can benefit as much from coronary artery bypass graft surgery as younger counterparts, albeit with a modestly increased risk. The medical therapy of coronary artery disease, stable and unstable angina, and myocardial infarction is not substantially different in the older patient. Nitrates, beta blockers, and calcium antagonists provide relief of anginal symptoms. The older patient stands to derive the same benefits from CCU monitoring as does the younger patient. An increased awareness of adverse drug reactions is necessary, however, and as for patients of any age, the particular goals of therapy may differ substantially and require an individualized approach.


Integrating K and P co-doped g-C3N4 with ZnFe2O4 and graphene oxide for S-scheme-based enhanced adsorption coupled photocatalytic real wastewater treatment.
Recently, there has been a significant increase in the interest of using photocatalysis for environmental clean-up applications. In this research, potassium, and phosphorus co-doped graphitic carbon nitride (KPCN) photocatalyst modified with graphene oxide (GO) and heterostructured with ZnFe2O4 was synthesized via the hydrothermal method (KPCN/GO/ZnFe2O4). The photoactivity of KPCN/GO/ZnFe2O4 photocatalyst was examined for the photocatalytic degradation of target pollutants such as methylene blue (MB) dye, rhodamine B (RhB) dye, and tetracycline (TC) antibiotic. Furthermore, the chemical oxygen demand (COD) removal efficiency for real wastewater was determined to explore the practical application of KPCN/GO/ZnFe2O4 photocatalyst. The degradation efficiencies of bare graphitic carbon nitride, KPCN, KPCN/GO, and KPCN/GO/ZnFe2O4 photocatalysts for tetracycline antibiotics were 30%, 42%, 57%, and 87% within 60 min, respectively. Moreover, KPCN/GO/ZnFe2O4 photocatalyst showed 71% COD removal efficiency within 240 min. The •OH and •O2- were the major reactive species in the photocatalytic process. Results showed that the degradation efficiencies of graphitic carbon nitride were greatly enhanced upon doping and further improved with the addition of GO and ZnFe2O4. Doping improved light harvesting, GO enhanced the adsorption ability and heterojunction with ZnFe2O4 enhanced the charge separation as well as the reusability of synthesized KPCN/GO/ZnFe2O4 photocatalyst.


Topographic analysis in brain mapping can be compromised by the average reference.
The average reference introduces ghost potential fields at the latencies for which the integral of scalp-recorded potentials differs from zero. These spurious effects occur because the average reference is computed from a limited number of (scalp) electrodes which do not survey the bottom half of the head. By arbitrarily re-setting the zero at each latency in the maps to be compared, it can also obliterate or even reverse topographical differences in the case of focal brain potentials enhancements thereby defeating the purpose of brain mapping.


Is the RAND-36 an Adequate Patient-reported Outcome Measure to Assess Health-related Quality of Life in Patients Undergoing Bariatric Surgery?
The RAND-36 is the most frequently used patient-reported outcome measure (PROM) to evaluate health-related quality of life (HRQoL) in bariatric surgery. However, the RAND-36 has never been adequately validated in bariatric surgery. The purpose of this study was to validate the RAND-36 in Dutch patients undergoing bariatric surgery. To validate the RAND-36, the following measurement properties were assessed in bariatric surgery patients: validity (the degree to which the RAND-36 measures what it purports to measure (HRQoL)), reliability (the extent to which the scores of the RAND-36 are the same for repeated measurement for patients who have not changed in HRQoL), responsiveness (the ability of the RAND-36 to detect changes in HRQoL over time). Two thousand one hundred thirty-seven patients were included. Validity was not adequate due to the irrelevance of some items and response options, the lack of items relevant to patients undergoing bariatric surgery, and the RAND-36 did not actually measure what it was intended to measure in this study (HRQoL in bariatric surgery patients). Reliability was insufficient for the majority of the scales (the scores of patients who had not changed in HRQoL were different when the RAND was completed a second time (intraclass correlation coefficient (ICC) values 0.10-0.69)). Responsiveness was insufficient. The RAND-36 was not supported by sufficient validation evidence in patients undergoing bariatric surgery, which means that the RAND-36 does not adequately measure HRQoL in this patient population. Future research studies should use PROMs that are specifically designed for assessing HRQoL in patients undergoing bariatric surgery.


Protection of isolated rat heart from oxidative stress by exogenous creatine phosphate.
The influence of exogenous creatine phosphate (CP) on peroxidative heart injury was investigated in two experimental models: isolated working rat hearts and myocardial membrane preparations. In the first model the addition of 190 microM hydrogen peroxide to the perfusion buffer caused a marked decrease of aortic flow, minute work and peak aortic pressure, and leakage of intracellular enzymes. In the presence of 10 mM CP the hemodynamic damage produced by the same concentration of hydrogen peroxide was significantly lower and enzyme release was also remarkably reduced. The protection was concentration-dependent and the whole structure of the molecule was required since creatine was found to be ineffective. In the absence of hydrogen peroxide, CP and creatine did not affect heart performance. In microsomal membrane preparations CP decreased the formation of thiobarbituric acid-reactive material (malonaldehyde) induced by hydrogen peroxide in the presence of ferrous ions. This protection was concentration-dependent and occurred at physiological concentrations of CP. Also in this experimental model creatine had no effect and creatine plus inorganic phosphate was much less active than CP. The influence of CP on oxidative heart stress could account for the beneficial effect of this substance in different models of ischemic injury.


Novel poricoic acids attenuate renal fibrosis through regulating redox signalling and aryl hydrocarbon receptor activation.
Renal fibrosis is the final manifestation of chronic kidney disease (CKD). Renal fibrosis is largely driven by oxidative stress and inflammation. The aim of the current study was to identify novel poricoic acids from Poria cocos and investigated their antifibrotic effects and the underlying mechanism. In this study, we identified six novel poricoic acids from Poria cocos and examined their antifibrotic effect using transforming growth factor-β1- (TGF-β1-) induced cultured human kidney proximal tubular epithelial cells (HK-2) and mice with unilateral ureteral obstruction (UUO). Treatment with six poricoic acids significantly inhibited TGF-β1-induced α-smooth muscle actin expression at both mRNA and protein levels in HK-2 cells. Three compounds with an intact carboxyl group at C-3 position showed a stronger inhibitory effect than that of other three compounds with esterified carboxyl group at the C-3 position. Mechanistically, poricoic acid ZM (PZM) and poricoic acid ZP (PZP) attenuate renal fibrosis through the modulation of redox signalling including the inhibition of proinflammatory nuclear factor kappa B (NF-κB) signalling and its target genes as well as the activation of antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) signalling and its downstream target gene in both TGF-β1-induced HK-2 cells and UUO mice. PZM treatment and PZP treatment inhibit the upregulated aryl hydrocarbon receptor and they target the gene expression in UUO mice. Intriguingly, PZM treatment exhibits a stronger inhibitory effect than that of the PZP treatment. Structure-function relationship reveals that the carboxyl group at C-3 position is the most important bioactive function group in secolanostane tetracyclic triterpenoids against renal fibrosis. PZM and PZP attenuated renal fibrosis through the modulation of redox signalling and the aryl hydrocarbon receptor signalling pathway. Our findings will provide several promising leading compounds against renal fibrosis.


Determination of prognostic predictors in patients with solitary hepatocellular carcinoma: histogram analysis of multiparametric MRI.
To evaluate the histogram parameters of preoperative multiparametric magnetic resonance imaging (MRI) and clinical-radiological (CR) characteristics as prognostic predictors in patients with solitary hepatocellular carcinoma ≤ 5 cm and to determine the optimal time window for histogram analysis. We retrospectively included 151 patients who underwent preoperative MRI between January 2012 and December 2017. All patients were randomly separated into training and validation cohorts (n = 105 and 46). Eight whole-lesion histogram parameters were extracted from T2-weighted images, apparent diffusion coefficient maps, and dynamic contrast-enhanced images. Univariate and multivariate logistic regression analyses were performed to evaluate these histogram parameters and CR variables related to early recurrence (ER) and recurrence-free survival. A nomogram was derived from the clinical-radiological-histogram (CRH) model that incorporated these risk factors. Kaplan-Meier survival analysis was performed to evaluate the prognostic performance of the CRH model. In total, 151 patients (male: female, 130: 21; median age, 54.46 ± 9.09 years) were evaluated. Multivariate logistic regression analysis revealed that the significant risk factors of ER were Mean Absolute Deviation and Minimum in the histogram analysis of the delayed phase images, as well as three important CR variables: albumin-bilirubin grade, microvascular invasion, and tumor size. The nomogram built by incorporating these risk factors showed satisfactory predictive ability in the training and validation cohorts with AUC values of 0.747 and 0.765, respectively. Furthermore, the prognostic nomogram can effectively classify patients into high- and low-risk groups (p < 0.05). Multiparametric MRI-derived histogram parameters provide additional value in predicting patient prognosis. The CRH model may be a useful and noninvasive method for achieving prognostic stratification and personalized disease management.


Virulence without catalysis: how can a pseudokinase affect host cell signaling?
A hallmark of the pathogenic lifestyle is the secretion of enzymes and other effectors that dysregulate host signaling. Intriguingly, the most potent virulence locus identified in the intracellular parasite Toxoplasma gondii encodes a family of related catalytically inactive protein kinases, or pseudokinases. Toxoplasma has in its kinome among the highest percentage of pseudokinases among all sequenced organisms, and the majority of these appear to be secreted into the host cell. We posit that the pseudokinase fold represents a particularly well-suited domain for functional diversification, discuss the relevance of gene expansion at these loci, and outline potential mechanisms by which a pseudokinase might affect host signaling.


Light intensity and spectral quality modulation for improved growth kinetics and biochemical composition of Chlamydomonas reinhardtii.
Effective strategies to optimize algal growth and lipid productivity are critical for the sustainable production of biomass for various applications. Light management has emerged as a promising approach, but the intricate relationship between light intensity, spectral quality, and algal responses remains poorly understood. This study investigated the effects of different light qualities (blue, red-orange, and white-yellow) and intensities (45-305 μmol/m2·s) on Chlamydomonas reinhardtii. Red-orange light exhibited the highest promotion of biomass growth and lipid productivity, with specific growth rates of 1.968 (d-1) and biomass productivity of 0.284 (g/L/d) at 155 μmol/m2·s and 205 μmol/m2·s, respectively. Within the intensity range of 205 μmol/m2·s to 305 μmol/m2·s, lipid mass fractions ranged from 10.5% w/w to 11.0% w/w, accompanied by lipid concentrations ranging from 68.6 mg/L to 74.9 mg/L. Red-orange light positively influenced carbohydrate accumulation, while blue light promoted protein synthesis. These findings highlight the importance of optimizing light quality and intensity to enhance algal biomass productivity and manipulate biochemical composition. Understanding the complex relationship between light parameters and algal physiology will contribute to sustainable algal cultivation practices and the use of microalgae as a valuable bioresource.


[Current standards in the treatment of pancreatic cancer].
The poor prognosis of pancreatic adenocarcinoma on the one hand side is due to the fact that early symptoms are nonspecific, often misdiagnosed and the disease is on the other hand side rapidly progressive, so that at diagnosis in about 80 % of cases already locally advanced inoperable, or metastatic cancer stages are present. In these cases the 1 year survival rate ranged from 20 % to 50 % depending of performance status and the used regimen. Thus, symptomatic supportive treatment is as important as palliative chemotherapy. Today several evidence-based chemotherapies are available - and others are expected soon - resulting in a highly significant overall survival benefit. Individual patient characteristics have to be considered for the selection of treatment. Even after successful surgery with curative intention, the 5-year survival rate is about 10 %. By adjuvant chemotherapy the survival probability as well as cure rate can be more than doubled. Since the preparation of the S3 guidelines for pancreatic cancer additional options in the care of patients with pancreatic cancer have become available to be incorporated in clinical practice.


The application of fluorescein sodium for the resection of medulloblastoma.
Surgical resection of medulloblastoma (MB) remains a challenge. At present, a variety of tracers have been used for intraoperative tumor visualization. However, there are few reports on the intraoperative visualization of MB. Hence, we reported our experience of applying fluorescein sodium (FS) in MB surgery. We retrospectively analyzed the clinical information of patients with MB confirmed by surgery and pathology from January 2016 to December 2020 from Sun Yat-sen University Cancer Center. A total of 62 patients were enrolled, of which 27 received intraoperative FS and 35 did not. The intraoperative dose of FS was 3 mg/kg. Among the 62 patients, 42 were males, and twenty were females. The age of onset in the FS group was 9.588 ± 7.322, which in the non-fluorescein sodium group was 13.469 ± 10.968, p = 0.198. We did not find significant differences in tumor location, tumor size, tumor resection, tumor histology, and preoperative symptoms (hydrocephalus, headache, vomit, balance disorder) between the groups. There was no significant difference in the postoperative symptoms (hydrocephalus, headache, vomiting, balance disorder, and cerebellar mutism). However, patients in the FS group had a relatively low incidence of balance disorder and cerebellar mutism. There was definite fluorescence of tumor in all cases of the FS group, and even the tiny metastatic lesion was visible. No case had side effects related to the use of FS. FS is safe and effective in MB surgery. Whether the application of FS for surgery can reduce complications remains to be studied in the future.


The effect of COVID-19: Adopted changes and their impact on management of musculoskeletal oncology care at a tertiary referral centre.
COVID-19 pandemic has disrupted access to healthcare. Delay in diagnosis and onset of care increases cancer related mortality. We aim to analyse its impact on patient profile, hospital visits, morbidity in surgically treated patients and process outcomes. We analysed an ambi-directional cohort from 16th March to June 30, 2020 (Pandemic cohort, PC) as compared to 2019 (Pre-pandemic cohort, PPC). We measured, new patient registrations, proportion of 'within state' patients vs 'rest of India', median time to treatment decision, proportion of patients seeking 'second opinions', modality of initial treatment (surgery/radiotherapy/chemotherapy), 30-day post-operative morbidity/mortality and conversion of inpatient-to 'teleconsult' in the PC. Between the 2 cohorts, new registrations declined from 235 to 69 (70% reduction). The percentage of 'within state' patients increased from 41.7% to 53.6% (11.9% increase). There was a decline in second opinion consults from 25% to 16%. The median time to decision-making decreased to 16 days in PC vs 20 days in PPC (20% reduction). Surgery was the first line of treatment in 40% as compared to 34% in the PPC with a mean time to surgery of 24 days in PC compared to 36 days in PPC (33% reduction). 66 surgeries were performed in the PC compared to 132 in the PPC. Thirty day post operative morbidity needing readmission remained similar (18% PC, vs 17% PPC). Perioperative intensive care remained similar in both cohorts. Teleconsultation was deemed medically safe in 92.8% (439/473 patients). The COVID 19 pandemic has substantially reduced access and onset to cancer care. Post operative morbidity and mortality did not seem to worsen with triage. Teleconsultation is an effective tool in optimizing follow up strategy.


Marine bacterial chitinase as sources of energy, eco-friendly agent, and industrial biocatalyst.
Chitin is the richest renewable polymer carbohydrate in the marine environment and is an energetic source of nitrogen and carbon for marine organisms. Marine chitinolytic bacteria play a basic role in the nutrient cycling in the oceans by biodegradation of chitinous waste to useful form. Chitinase-producing bacteria from marine wastes increasing attention has received, and it serves two purposes: (i) reduce environmental hazards by waste management and (ii) increases generation of industrially important value-added products. This review aims to present the environmental pitfalls caused by marine waste and successes of chitinase-producing bacteria in employ waste for the generation of functional and valuable products, as well as to present importance role of chitinase-producing bacteria in industry. The focus is on isolation, purification, biochemical and enzymatic characteristics of chitinolytic bacteria in the oceans.


Force in numbers: high-throughput screening approaches to unlock microbial transport.
Biological membranes are inherently complex, making transport processes in microbial cell factories a significant bottleneck. Lack of knowledge on transport proteins' characteristics and the need for advanced technical equipment often hamper transporter identification and optimization. For these reasons, moving away from individual characterization and towards high-throughput mining, engineering, and screening of transporters is an increasingly attractive approach. Superior transporters can be selected from large libraries by coupling their activity to growth, for substrates that function as feedstocks or toxic compounds. Other compounds can be screened thanks to recent advances in the design and deployment of synthetic genetic circuits (biosensors). Furthermore, novel strategies are rapidly increasing the repertoire of biomolecule transporters susceptible to high-throughput selection methods.


Radiation-induced apoptosis of tumor cells is facilitated by inhibition of the interaction between Survivin and Smac/DIABLO.
To investigate the mechanism of radioresistance of solid tumor cells, we created two expression vectors encoding Survivin mutants, T34A and D53A. When T34A and D53A were overexpressed in NIH3T3, A549 and HeLa cells, radiation-induced apoptosis was significantly enhanced. Furthermore, we examined the binding capability of Survivin with Smac/DIABLO in the cells that overexpressed these mutants. Coimmunoprecipitation analysis revealed that mutant form of Survivin, D53A and T34A could bind to Smac/DIABLO, but with much less affinity compared to the authentic form. These results suggest that radiation-induced apoptosis of tumor cells is increased by inhibition of the interaction between Survivin and Smac/DIABLO through overexpression of T34A and D53A.


Management of Upper Gastrointestinal Bleeding in Children: Variceal and Nonvariceal.
Upper gastrointestinal (UGI) bleeding is generally defined as bleeding proximal to the ligament of Treitz, which leads to hematemesis. There are several causes of UGI bleeding necessitating a detailed history to rule out comorbid conditions, medications, and possible exposures. In addition, the severity, timing, duration, and volume of the bleeding are important details to note for management purposes. Despite the source of the bleeding, acid suppression with a proton-pump inhibitor has been shown to be effective in minimizing rebleeding. Endoscopy remains the interventional modality of choice for both nonvariceal and variceal bleeds because it can be diagnostic and therapeutic.


Expiratory flow limitation in a cohort of highly symptomatic COPD patients.
Small airway collapse during expiration, known as expiratory flow limitation (EFL), can be detected using oscillometry and is associated with worse clinical outcomes in COPD. This study investigated the prevalence of EFL in a cohort of highly symptomatic patients, evaluated clinical and lung function characteristics of patients with EFL and studied the repeatability of EFL over 6 months. 70 patients were recruited. Clinical characteristics and lung function metrics were collected at baseline and 6 months. Impulse oscillometry was used to detect the presence of EFL. Patients were defined as EFLHigh (change in reactance measured at 5 Hz (ΔX 5) ≥0.28 kPa·L-1·s-1); EFLIntermediate (ΔX 5 0.1-0.27 kPa·L-1·s-1) and EFLNone (ΔX 5 <0.1 kPa·L-1·s-1). EFLHigh was present in 47.8% of patients at baseline. ΔX 5 showed excellent repeatability over 6 months (ρ=0.78, p<0.0001, intraclass correlation coefficient (ICC) 0.88), with the best repeatability observed in EFLNone and EFLHigh patients (ICC 0.77 and 0.65, respectively). Compared to EFLNone patients, EFLHigh had a higher body mass index, worse health-related quality of life and increased peripheral airway resistance. EFLIntermediate was more variable over time with less severe physiological impairment. Overall, these data indicate that EFLHigh is a common, and relatively stable, component of disease pathophysiology in highly symptomatic COPD patients. EFLHigh was also associated with worse quality of life and obesity.


Further observations on the fine structure of cellular cementum from deciduous teeth of pigs.
Examination of microradiographs from the deciduous teeth of pigs revealed large lacunae or radiolucent zones close to the cemento-dentinal junction. Electron microscopic studies of the ground sections showed areas of irregularly shaped zones devoid of mineral and filled with collagen fibers. In the wide unmineralized zones, spherical clusters of crystallites were noted. Several cementum lacunae bordered by a broad rim of unmineralized collagen fibers were noted and some lacunae also contained zones of a moderately electron dense material. This material did not yield a diffraction pattern, while the mineralized part of the cementum gave the diffraction pattern typical of hydroxyapatite.


Brain functional changes in individuals with bulimia nervosa: a protocol for systematic review and meta-analysis.
Bulimia nervosa (BN) is a disorder with high health and socioeconomic burdens that typically arises in late adolescence and early adulthood. Previous neuroimaging studies have found functional brain changes in patients with BN. This study aims to review the latest neurobiological evidence from studies of individuals with BN, examine the consistency of these findings and evaluate the food addiction hypothesis of the disease. A systematic search will be performed using the Cochrane Library, PubMed, Embase and Web of Science databases, covering the period from database inception to 30 November 2021. Two researchers will be responsible for study selection, quality assessment and data extraction. The anisotropic effect size version of the signed differential mapping method will be used to conduct a coordinate-based meta-analysis. Publication bias will be examined with the Egger test. The quality of studies will be evaluated using the Newcastle-Ottawa Scale. No ethics approval is required for this is a systematic review protocol and does not require the collection of primary data. Findings will be disseminated through peer-reviewed journal or related conferences. CRD42022307233.


[Problems of hygiene of children and adolescents in the military health care].
The article presents the current issues hygiene mechanical prevention of disease in the younger generation in re-formation of the Russian Armed Forces, the economy, health, education and ecological trouble.


A structural blueprint for interleukin-21 signal modulation.
Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity.


Epidemiology of sexually transmitted infections on the Anangu Pitjantjatjara Yankunytjatjara Lands: results of a comprehensive control program.
To assess the impact of a long-term comprehensive control program for sexually transmitted infections (STIs) in remote Aboriginal communities in Central Australia, and to investigate a recent rise in gonorrhoea prevalence. STI prevalence was determined from annual, cross-sectional, population-wide, age-based screening, 1996-2006. During 2006, gonococcal isolates were obtained by on-site culture and tested for antimicrobial susceptibility. Six remote clinics on the Anangu Pitjantjatjara Yankunytjatjara (APY) Lands, South Australia, which are served by Nganampa Health Council, an Aboriginal community-controlled health service. All resident Aboriginal people aged 14-40 years at the commencement date of each annual population-wide screen. Multivariable logistic regression models were used to compare prevalence of chlamydial infection, gonorrhoea and syphilis measured during each annual population-wide screen; antimicrobial susceptibility of gonococcal isolates obtained in 2006. Between 1996 and 2003, there was a significant reduction in prevalence of gonorrhoea and chlamydial infection, by 67% and 58%, respectively. Subsequently, chlamydia prevalence rate plateaued, but there was a rapid rise in prevalence of gonorrhoea. Syphilis prevalence decreased linearly over the study period (odds ratio, 0.81; P < 0.001). During the first 6 months of 2006, 89 gonococcal isolates were obtained, 39 through on-site culture during the 6-week screening period, and all were sensitive to penicillin (in the less-sensitive category). The decrease in STI prevalence associated with the program was maintained until 2006 for chlamydial infection and syphilis, but not for gonorrhoea, which rose in prevalence after 2003. There was no change in antimicrobial resistance to explain this rise, and gonorrhoea transmission dynamics and travel of core transmitters to regions without STI control programs might be responsible.


Environmental control of gas exchange in some savanna woody species : I. Controlled environment studies of Terminalia sericea and Grewia flavescens.
The effects of temperature, radiation, water stress and humidity on net photosynthesis, transpiration and leaf resistances of the two savanna woody species, Grewia flavescens and Terminalia sericea were studied under controlled environmental conditions. Both species have developed morphological and physiological features resulting in low rates of transpiration even under non-stress conditions and are able to tolerate quite severe water stress. Grewia seemed particularly well adapted in this regard and prestressed plants of Grewia were able to photosynthesise down to leaf water potentials of-42 bars. The photosynthetic responses of both species to all the environmental parameters studied were predominantly under stomatal control. The mechanisms employed for maintaining production and conserving water are examined.


Synthesis and computational studies of highly selective inhibitors of human recombinant tissue non-specific alkaline phosphatase (h-TNAP): A therapeutic target against vascular calcification.
In this study, we have discovered small druglike molecules as selective inhibitors of human tissue-nonspecific alkaline phosphatase (h-TNAP), an enzyme critical for the regulation of extracellular matrix calcification. The upregulation of h-TNAP is associated with various pathologies particularly the vascular calcification (VC). Selective inhibition of h-TNAP over h-NPP1 may serve as a useful therapeutic strategy against vascular calcification. A series of novel triazolyl pyrazole derivatives (10a-y) in which thiol bearing triazole moiety as the zinc binding functional group was introduced to a pyrazole based pharmacophore was synthesized and evaluated as potent and selective inhibitors of h-TNAP over h-NPP1. The biological screening against h-TNAP, h-IAP, h-NPP1 and h-NPP3 showed that many of the synthesized compounds are selective inhibitors of TNAP. Particularly, the compounds 10a-h, 10j, 10m-q, 10u, 10w and 10x displayed high potency and complete selectivity towards h-TNAP over h-NPP1. Compound 10q emerged as a highly potent inhibitor (IC50 = 0.16 µM or 160 nM) against h-TNAP with 127-fold increased inhibition compared to levamisole. On the other hand, compound 10e was found to be most selective inhibitor against the tested APs and NPPs (IC50 = 1.59 ± 0.36 µM). Binding sites architecture analysis, molecular-docking and molecular dynamics simulations (MDS), revealed the basis for h-TNAP and h-IAP ligand selectivity as well as selectivity towards h-TNAP over h-NPP1. These newly discovered inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target VC.


17 beta-estradiol induces L-type Ca2+ channel activation and regulates redox function in macrophages.
17 beta-estradiol induces rapid effects on cells of the immune system via plasma membrane surface receptor but the ways in which delayed signals involving intracellular receptors affect the same functions are not well understood. To study the delayed but sustained events in estradiol signaling, we have investigated macrophage Ca(2+) signaling, detected specific Ca(2+) ion channel activated and found a relationship between intracellular calcium [Ca(2+)](i) and macrophage release of reactive oxygen species (ROS) and nitric oxide (NO) during delayed 17 beta-estradiol activity. We found evidence of additional effect of estradiol on capacitative entry of Ca(2+), Ca(2+) entry through L-type channel and a direct relationship between [Ca(2+)](i) and generation of ROS and NO. This study demonstrates that 17 beta-estradiol exhibits a delayed phase of Ca(2+) influx involving L-type channel and regulates macrophage immune redox function.


Gastrointestinal and liver lesions in primary childhood Sjögren syndrome.
Sjögren syndrome (SS) is characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands, leading to keratoconjunctivitis sicca and xerostomia. SS is one of the most common autoimmune rheumatic diseases in adults; however, few cases of primary childhood SS with gastrointestinal and liver lesions have been reported in the literature. We report five cases of primary childhood SS with gastrointestinal and liver lesions. Multiple gastric biopsies in four cases revealed atrophic gastritis in the antrum of the stomach or chronic gastritis. Liver biopsies in two cases revealed nonalcoholic steatohepatitis. Careful clinical approach and follow-up for gastrointestinal and liver lesions are required.


Inflammatory response to cardiopulmonary bypass using two different types of heparin-coated extracorporeal circuits.
Previous reports have highlighted the disparity in biocompatibility of two differently engineered heparin coatings during the cardiopulmonary bypass (CPB) procedure. The aim of this prospective study was to evaluate the impact of the difference in haemocompatibility provided by either the Duraflo II equipment or the Carmeda equipment in the terminal inflammatory response observed after coronary artery surgery. Thirty patients were randomly allocated to two groups to be operated on using either Duraflo II equipment (group I) or Carmeda equipment (group 2) for extracorporeal circulation (ECC). Initial inflammatory response was assessed by terminal complement complex activation (SC5b-9). The late inflammatory response observed in the postoperative period was assessed by measuring cytokine production (tumour factor necrosis (TNF alpha), interleukin IL-6, interleukin IL-8) and circulating concentrations of adhesion molecules (ELAM-1, ICAM-1). The release of SC5b-9 after CPB and after protamine administration was lower in group 2 than in group 1 (p = 0.0002 and p = 0.006, respectively). A significant production of cytokines was detected in both groups with peak values observed within the time range of 4-6 h after the start of CPB.


Modeling single versus multiple systems in implicit and explicit memory.
It is currently controversial whether priming on implicit tasks and discrimination on explicit recognition tests are supported by a single memory system or by multiple, independent systems. In a Psychological Review article, Berry and colleagues used mathematical modeling to address this question and provide compelling evidence against the independent-systems approach.


Mass spectrometry and ion mobility study of poly(ethylene glycol)-based polyurethane oligomers.
Commercial-grade polymer synthesis is performed via melt polymerization, which leads to polydispersion. The work reported herein provides a synthetic strategy to produce mono-dispersive polyurethane oligomers and an analytical strategy to distinguish these oligomers, providing chemists with the tools necessary to synthesize and identify specific polymer structures that exhibit a desired property. Three isomeric poly(ethylene glycol)-polyurethane (PEG-PUR) oligomers were synthesized and analyzed via flow-injection ion mobility mass spectrometry (IM-MS). Each polymer oligomer was injected and run independently via flow injection at 100 μL•min-1 and analyzed in positive ion mode on a drift tube quadrupole time-of-flight (QTOF) instrument. Mobility measurements were determined using a single-field approach. For tandem mass spectrometry (MS/MS) experiments, the sodium-adducted singly charged precursor ion was isolated in the quadrupole and subjected to a range of collision energies. In MS experiments, both +1 and +2 sodium-adducted species were observed for each oligomer at m/z 837.4 and 430.2, respectively. When isolated and fragmented via MS/MS, the +1 precursor yielded distinct product ions for each of the three isomeric oligomers. Fragmentation generally occurred at urethane linkages via 1,3- and 1,5-H shift mechanisms. IM was also used to distinguish the three isomers, with greater IM separation observed for the +2 versus the +1 species. Mono-disperse PEG-PUR oligomers were synthesized and analyzed. Although the polymeric oligomers analyzed in this study are quite small and structurally simple, this work serves as a model system for the synthesis and structural characterization of larger, more complex block copolymers.


Golgi partitioning controls mitotic entry through Aurora-A kinase.
At the onset of mitosis, the Golgi complex undergoes a multistep fragmentation process that is required for its correct partitioning into the daughter cells. Inhibition of this Golgi fragmentation results in cell cycle arrest at the G2 stage, suggesting that correct inheritance of the Golgi complex is monitored by a "Golgi mitotic checkpoint." However, the molecular basis of this G2 block is not known. Here, we show that the G2-specific Golgi fragmentation stage is concomitant with centrosome recruitment and activation of the mitotic kinase Aurora-A, an essential regulator for entry into mitosis. We show that a block of Golgi partitioning impairs centrosome recruitment and activation of Aurora-A, which results in the G2 block of cell cycle progression. Overexpression of Aurora-A overrides this cell cycle block, indicating that Aurora-A is a major effector of the Golgi checkpoint. Our findings provide the basis for further understanding of the signaling pathways that coordinate organelle inheritance and cell duplication.


Binding of Cu(II) ions to peptides studied by fluorescence spectroscopy and isothermal titration calorimetry.
Steady-state and time-resolved fluorescence quenching measurements supported by Isothermal Titration Calorimetry (ITC) were used to study the interactions of Cu(2+) with four peptides. Two of them were taken from the N-terminal part of the FBP28 protein (formin binding protein) WW domain: Tyr-Lys-Thr-Ala-Asp-Gly-Lys-Thr-Tyr-NH2 (D9) and its mutant Tyr-Lys-Thr-Ala-Asn-Gly-Lys-Thr-Tyr-NH2 (D9_M) as well as two mutated peptides from the B3 domain of the immunoglobulin binding protein G derived from Streptococcus: Asp-Val-Ala-Thr-Tyr-Thr-NH2 (J1) and Glu-Val-Ala-Thr-Tyr-Thr-NH2 (J2). The measurements were carried out at 298.15K in 20mM 2-(N-morpholino)ethanesulfonic acid (MES) buffer solution with a pH of 6. The fluorescence of all peptides was quenched by Cu(2+) ions. The stoichiometry, conditional stability constants and thermodynamic parameters for the interactions of the Cu(2+) ions with D9 and D9_M were determined from the calorimetric data. The values of the conditional stability constants were additionally determined from fluorescence quenching measurements and compared with those obtained from calorimetric studies. There was a good correlation between data obtained from the two techniques. On the other hand, the studies revealed that J1 and J2 do not exhibit an affinity towards metal ions. The obtained results prove that fluorescence quenching experiments may be successfully used in order to determine stability constants of complexes with fluorescent ligands. Finally, based on the obtained results, the coordinating properties of the peptides towards the Cu(2+) ions are discussed.


Effects of pterygium on the biomechanical properties of the cornea: a pilot study.
To investigate the changes induced by a pterygium or its surgical removal on the biomechanical properties of the cornea and to determine factors that might affect these parameters. This prospective pilot interventional, non-randomized, observer-masked study included 20 eyes of 20 patients with a unilateral primary pterygium (pterygium group) and 19 fellow healthy eyes (control group). The bare sclera technique with one-minute application of 0.02% mitomycin C intraoperatively was performed in all cases. The follow-up period was one month. The preoperative and postoperative biomechanical properties of the cornea were measured using the Reichert ocular response analyzer (ORA). The corneal hysteresis (CH) decreased significantly (P<.01) in eyes with a pterygium compared to the control eyes, while surgery did not significantly change the CH compared to preoperatively. There were no significant changes in the corneal resistance factor or the central corneal thickness. Primary active pterygium (grades 1 or 2) induce a reduction of corneal biomechanical features. Further studies are needed in populations, with longer follow-ups and bigger pterygium that may involve wider keratectomy to confirm our results.


Brain 5-HT1 binding sites in depressed suicides.
5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suicides, with definite evidence of depression, and 19 sex and age-matched controls. Thirteen of the depressed suicides had not been prescribed psychoactive drugs recently (drug-free suicides); six had been receiving antidepressant drugs, alone or in combination with other drugs (antidepressant-treated suicides). No significant differences were found in the number or affinity of 5-HT1 and 5-HT1A binding sites in frontal or temporal cortex between drug-free suicides and controls. The number of 5-HT1 sites was significantly lower (by 20%), affinity unaltered, in hippocampus and the affinity significantly lower (by 33%), number unaltered, in amygdala of drug-free suicides than controls. The number of 5-HT1 binding sites tended to be higher and the affinity lower in the antidepressant-treated compared to drug-free suicides, and significantly so in hippocampus. The present results, together with our previous studies, provide no evidence of altered cortical 5-HT markers in depressed suicides, but further emphasise abnormalities in the hippocampus.


Minority report: The minor spliceosome as a novel cancer vulnerability factor.
The minor spliceosome regulates the removal of a conserved subset of introns present in genes with regulatory functions. In this issue of Molecular Cell, Augspach et al.1 report that elevated levels of U6atac snRNA, a key minor spliceosome component, contribute to prostate cancer cell growth and can be a novel therapeutic target.


MR features of high-pressure injection injuries caused by grease and paints.
This study investigates the magnetic resonance (MR) features of high-pressure injection injuries (HPII) caused by grease and paints to detect the presence of foreign material and associated complications. Sixteen rat models with HPII were established by injecting industrial grease and marine paints (n = 8 each) into their thighs. All the rats underwent a 3.0 T MR scanning, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), Fat-suppressed T2-weighted imaging (FST2WI), Susceptibility-weighted imaging (SWI), and Diffusion-weighted imaging (DWI). Follow-up MR scanning was performed from 1st to 4th weeks. Acute subcutaneous grease and paints appeared as different signal intensity characteristics (grease: T1WI ↑, T2WI =, FST2WI ↓, SWI ↓, DWI ↓; paints: T1WI ↑, T2WI ↑, FST2WI ↑↓, SWI ↓, DWI ↓). As time progressed, the signal intensity of HPII lesions caused by both grease and paints became inhomogeneous. Impurity components of the foreign material appeared as marked low signal intensity on SWI. The signal intensity on DWI significantly increased subsequently due to purulent fluids (confirmed surgically). HPII caused by grease and paints have a characteristic appearance on MR imaging. SWI can detect impurity components of the foreign material, while DWI is highly sensitive to abscesses and helpful in monitoring infections.


Minimal marker: an algorithm and computer program for the identification of minimal sets of discriminating DNA markers for efficient variety identification.
DNA markers are frequently used to analyze crop varieties, with the coded marker data summarized in a computer-generated table. Such summary tables often provide extraneous data about individual crop genotypes, needlessly complicating and prolonging DNA-based differentiation between crop varieties. At present, it is difficult to identify minimal marker sets--the smallest sets that can distinguish between all crop varieties listed in a marker-summary table--due to the absence of algorithms capable of such characterization. Here, we describe the development of just such an algorithm and MinimalMarker, its accompanying Perl-based computer program. MinimalMarker has been validated in variety identification of fruit trees using published datasets and is available for use with both dominant and co-dominant markers, regardless of the number of alleles, including SSR markers with numeric notation. We expect that this program will prove useful not only to genomics researchers but also to government agencies that use DNA markers to support a variety of food-inspection and -labeling regulations.


A novel Candida albicans skin test antigen: efficacy and safety in man.
Yeast phase Candida albicans (ATCC No. 10231) was grown in a nonantigenic medium, harvested and lyophilized. Ammonium sulfate fractions of an aqueous extract of the lyophilized cells were evaluated and the fraction yielding the highest specific delayed cutaneous reactivity in sensitized guinea-pigs was used to prepare a C. albicans skin test antigen (CASTA). The safety of the antigen was evaluated by measuring immediate and delayed (0.25, 6, 24, 48 and 72 h) cutaneous reactions in atopic and nonatopic human subjects. The outcome of three repetitive monthly Mantoux skin tests with 0.01-1 microgram antigen doses was used to test for booster effects in 14 subjects and to estimate a safe initial test antigen dose. The utility of a single skin test as a measure of cell-mediated immunity was evaluated in 40 healthy subjects. Reactor rates (greater than or equal to 2 mm, 48 h) of 40% and 85% were detected, respectively, with doses of 0.0316 and 1 microgram. Using a skin test reaction diameter greater than or equal to 5 mm at 48 h, the reactor rate was 50% for the 1-microgram dose. The only adverse reaction (45 mm, 0.25 h) was detected with the 1-microgram dose in an atopic subject who also exhibited exquisite scratch test reaginic hypersensitivity to C. albicans allergen. The prevalence of other adverse reactions to this antigen compared favorably with that to other antigens used for recall antigen testing. These studies suggest the 1-microgram CASTA dose can be used for effective, safe recall antigen skin tests.


A novel binding site between the voltage-dependent calcium channel CaV1.2 subunit and CaVβ2 subunit discovered using a new analysis method for protein-protein interactions.
We developed a new method to analyze protein-protein interactions using a dual-inducible prokaryotic expression system. To evaluate protein-protein binding, a chimeric fusion toxin gene was constructed using a DNase-treated short DNA fragment (epitope library) and CcdB, which encodes a DNA topoisomerase II toxin. Protein-protein interactions would affect toxin activity, resulting in colony formation. Using this novel system, we found a new binding site in the voltage-dependent calcium channel α1 subunit (CaV1.2) for the voltage-dependent calcium channel β2 subunit. Prokaryotic expression screening of the β2 subunit using an epitope library of CaV1.2 resulted in two overlapping clones of the C-terminal sequence of CaV1.2. In vitro overlay and immunoprecipitation analyses revealed preferential binding of the C-terminal sequences of CaV1.2 and β2.


SGK2 is overexpressed in colon cancer and promotes epithelial-mesenchymal transition in colon cancer cells.
Human cancers often related to signal pathway variation, the phosphoinositide-3-kinase (PI3K) pathway is one of it. AKT kinase family is the most common downstream of PI3K pathway. The serum and glucocorticoid kinase 2(SGK2) is similar to AKT as the downstream of PI3K pathway. Up to now, we have few understanding of SGK2 in colon cancer. We determined the 20 colon cancer samples mRNA level. Later, we silence SGK2 in colon cancer cells. We found that SGK2 is up-regulated in colon cancer tissue/cells and have positive correlation with cell migration and invasive potential in human colon cancer cell line CACO2 and HCT116. The expression level of SGK2 have positive correlation with expression of mesenchymal marker N-cadherin and Vimentin and negative correlation with the expression of epithelial marker E-cadherin in CACO2 and HCT116 cells. In short, our research indicate that SGK2 is overexpressed in colon cancer and promotes EMT in colon cancer cells.


Safety of 13-valent pneumococcal conjugate vaccine in infants and children: meta-analysis of 13 clinical trials in 9 countries.
Meta-analyses enable summarization and interpretation of data across clinical trials. When applied to safety data they allow for detection of rare events. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) was approved in multiple countries worldwide for routine immunization of infants and young children. This meta-analysis was conducted to identify potentially clinically important rare safety events associated with PCV13. To summarize the safety of PCV13 compared with 7-valent pneumococcal conjugate vaccine (PCV7) administered to infants and toddlers. A meta-analysis was performed of integrated safety data from 13 infant studies (PCV13 n=4729 and PCV7 n=2760) conducted in 9 North American, European, and Asian countries. Local reactions at the vaccine injection site and systemic events were collected for 4-7 days after each dose into electronic diaries. Adverse events (AEs) were collected after each vaccination. Overall, rates of local reactions after any dose of the infant series were similar between PCV13 and PCV7 groups: tenderness (46.7% vs 44.8%, respectively); swelling (28.5% vs 26.9%); and redness (36.4% vs 33.9%). After the toddler dose, tenderness was significantly higher among PCV7 subjects than PCV13 subjects (54.4% vs 48.8%; P=0.005). Frequencies of fever (≥38°C) were similar in both groups and mostly mild (≤39°C); incidence of moderate fever (>39°C to ≤40°C) with PCV13 was ≤2.8% after any infant dose and 5.0% after the toddler dose, compared with ≤2.6% and 7.3%, respectively, with PCV7. Fever >40°C was uncommon in both groups. Frequencies of decreased appetite, irritability, and sleep disturbances were similar in both groups. AEs were the types of conditions and symptoms expected in infants and children, and clinically significant differences between vaccine groups were not observed. PCV13 has a favorable safety profile similar to that of PCV7, a vaccine for which there is >10 years clinical experience.


Folic acid dependent hypersarcosinaemia.
Hypersarcosinaemia is a rare inborn error of metabolism, caused by a deficiency of the sarcosine dehydrogenase complex with tetrahydrofolate as a formaldehyde acceptor needed for the sarcosine-glycine conversion. Prolonged therapy with folic acid on a hypersarcosinaemic patient resulted in a significant effect on the urinary excretion of sarcosine, leading to the conclusion that the patient has a folic acid dependent hypersarcosinaemia.


Mesenchymal Stem Cells and Stromal Vascular Fraction for Hair Loss: Current Status.
The current state of the applicability of cell therapy for the treatment of various conditions of hair loss reveals a promising and potentially effective role. Further research, based on published work to date, is indicated to further explore the potential roles of autologous fat grafting, mesenchymal stem cells, and stromal vascular fraction therapy. The authors' evolving experience matches these promising scientific findings.


Epidemiology of adult acute myeloid leukemia: Impact of exposures on clinical phenotypes and outcomes after therapy.
An increased risk of adult myeloid leukemia (AML) has recently been associated with lifestyle and environmental exposures, including obesity, smoking, some over the counter medications, and rural/farm habitats in case control studies. The association of these exposures with AML cytogenetic categories, outcomes after therapy, and overall survival is unknown. Relevant exposures were evaluated in a cohort of 295 consecutive AML patients diagnosed and treated at Mayo Clinic in Florida and Arizona. Standard cytogenetic risk categories were applied and reviewed in a central cytogenetic laboratory. The association of epidemiologic exposures with cytogenetic risk, complete remission after therapy, and overall survival was evaluated using logistic and Cox regression models. A significant association between obesity and intermediate-abnormal cytogenetics was identified (OR: 1.94, P=0.025). Similarly, those with secondary AML were more likely to have poor risk (OR: 2.55, P<0.001) and less likely to have intermediate normal (OR: 0.48, P=0.003) cytogenetics. In multivariate analysis, overall survival was improved for patients ≥ 60 years receiving intensive (RR: 0.21, P<0.001) and non-intensive therapy (RR: 0.40, P<0.001 compared to no treatment, and was lower for users of tobacco (RR 1.39, P=0.032), and those with poor risk cytogenetics (RR: 3.96, P=0.002) or poor performance status (RR: 1.69, P<0.001). Furthermore, an association between statin use at the time of diagnosis (OR: 2.89, P=0.016) and increased complete remission after intensive chemotherapy was identified, while prior solid organ transplantation was associated with significantly lower complete remission rate after therapy (OR: 0.10, P=0.035). Our results provide evidence that specific epidemiologic exposures, including obesity, are significantly associated with unique AML cytogenetic risk categories and response to therapy. This supports a link between patient lifestyles, clinical exposures, and leukemogenesis.


Calcitonin and calcitonin gene-related peptide alter the excitability of neurons in rat forebrain.
Individual neurons in the hypothalamus, thalamus, cortex, and other forebrain areas of urethane-anesthetized, male rats were iontophoretically tested for their membrane sensitivity to salmon calcitonin (CT), human CT, and CT gene-related peptide (CGRP). Extracellular recording of unit activity revealed that depression of neuronal firing was the predominant effect of iontophoretically applied salmon CT (35 of 74 cells tested). Few neurons responded to salmon CT with an increase in firing rate (N = 3). When CGRP was iontophoretically applied a pattern of response resembling that of salmon CT was observed. CGRP was predominantly inhibitory and excited those neurons whose firing rate was increased by salmon CT. Inhibition was also the predominant effect of human CT. However, no neurons were excited by human CT. The results clearly demonstrate that a subpopulation of neurons with membrane sensitivity to salmon CT, human CT, and CGRP are present in the rat forebrain. This finding suggests that modulation of neuronal activity may underlie the behavioral and biochemical effects of these peptides when administered centrally. Endogenous CGRP and CT-like peptides in rat brain may be capable of regulating these events as neurotransmitters or neuromodulators.


Effect of non-digestible gluco-oligosaccharides on glucose sensitivity in high fat diet fed mice.
Non digestible dietary carbohydrates have been reported to modify lipaemia and post-prandial glycaemia and insulinaemia. The aim of this study was to investigate the effect of a non-digestible gluco-oligosaccharides (GOS) diet on glucose, insulin, triglycerides and free fatty acid blood levels and glucose sensitivity in high fat diet fed mice (a high fat diet composed of 45% fat, 35% carbohydrate and 20% protein). Female C57B16/J mice were divided into two groups fed a high fat diet (HF) for 20 weeks supplemented or not with 1.5 g/kg/day of GOS (HF-GOS). The GOS supplementation did not change body weight nor fat pad mass, nor any of the blood parameters measured (glucose, insulin, leptin, triglycerides, and free fatty acids). However, mice which received the GOS supplemented diet showed an increased glucose utilization after a 1 g/kg load of glucose compared with the mice fed the high fat diet alone. Our results suggest a role for non-digestible GOS in the regulation of carbohydrate metabolism.


Inhibiting guanine oxidation and enhancing the excess-electron-transfer efficiency of a pyrene-modified oligonucleotide by introducing an electron-donating group on pyrene.
The introduction of an electron-donating group (e.g., methoxy or piperidinyl) onto the pyrene moiety of 5-(pyrenylethynyl)-2'-deoxyuridine (PyU) increases its DNA-mediated reductive electron-transfer efficiency. In addition, these modifications dramatically inhibit photoinduced guanine oxidation.


Kaiser Permanente's New Technologies Committee: an approach to assessing technology.
Kaiser Permanente's New Technologies Committee reviews emerging technologies, evaluates their status as experimental or nonexperimental, and recommends coverage under specified circumstances. Kaiser Permanente developed a model for consensus and policy formation in its handling of the case of chorionic villus sampling, a now preferred alternative to amniocentesis for the detection of fetal defects.


Integration of a Simulation Curriculum Across Semesters in an Acute Care Pediatric Nurse Practitioner Program.
Simulation is a common strategy for health care education. Research regarding simulation for nurse practitioner education is sparse. This paper describes the integration of a nine simulation session curriculum into a nurse practitioner program, including motivating factors, process description, and lessons learned. Students report high satisfaction and improved perception of confidence and competence of knowledge, skills, and performance. Integrated learning experiences and outcomes that span an educational program are needed in thetransition to competency-based education. This description serves as a guide for other programs seeking to incorporate simulation-based education.


Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells.
Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level forces. Whether cell tension regulates development by modifying morphogen signaling is less clear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization, which motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that recapitulate the biophysical properties of the early embryo and mediate the self-organization of "gastrulation-like" nodes in cultured hESCs. Tissue geometries that generated local nodes of high cell-adhesion tension directed the spatial patterning of the BMP4-dependent "gastrulation-like" phenotype by enhancing phosphorylation and junctional release of β-catenin to promote Wnt signaling and mesoderm specification. Furthermore, direct force application via mechanical stretching promoted BMP-dependent mesoderm specification, confirming that tissue-level forces can directly regulate cell fate specification in early human development.


Teleological Perspectives in Child and Adolescent Development.
The way adults think about children is of enormous consequence. Around the world, adults are "in charge" of children, claiming responsibility for their safety and lives. This may seem natural and intuitive, but adult concepts of youth, including in the sciences of development, can lead to a worldview in which the adult is seen as better, more important, more complex, and more valuable than the child.1.


Overcoming proteasome inhibitor resistance in the immunotherapy era.
Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.


Characterization of nuclear localization and nuclear export signals of yeast actin-binding protein Pan1.
Pan1 is an actin patch-associated protein involved in endocytosis. Our studies revealed that in oleate-grown cells Pan1 is located in the nucleus as well as in patches. One of three putative nuclear localization signals (NLS) of Pan1, NLS2, directed beta-galactosidase (beta-gal) to the nucleus. However, GFP-Pan1(886-1219), containing NLS2, was found in the cytoplasm indicating that it may contain a nuclear export signal (NES). A putative Pan1 NES, overlapping with NLS3, re-addressed NLS(H2B)-NES/NLS3-beta-gal from the nucleus to the cytoplasm. Inactivation of the NES allowed NLS3 to be effective. Thus, Pan1 contains functional NLSs and a NES and appears to shuttle in certain circumstances.


Severe familial cholestasis in North American Indian children: a clinical model of microfilament dysfunction?
Studies of 14 North American Indian children with a familial type of severe neonatal cholestasis are described. Jaundice occurred during the neonatal period in 9 children, but disappeared before the end of the 1st yr. Progressive liver damage was documented by the persistence of high levels of alkaline phosphatase, moderate elevation of transaminases, and severe pruritus. Serum bile acids were constantly elevated (3.0-119.5 microgram/ml). Early portal hypertension and variceal bleeding necessitated portal-systemic shunts in 7 children. By light microscopy, the early stage was characterized by hepatitis with giant-cell transformation and biliary stasis. Later on, portal fibrosis became evident and was followed by cirrhosis. By electron microscopy bile canaliculi appeared slightly dilated with preservation or only partial loss of microvilli. They were surrounded by a prominent pericanalicular filamentous web. Immunofluorescence studies indicated the presence of action-containing microfilaments. This group of children might represent a human model of microfilament dysfunction-induced cholestasis.


Does femoral stem choice influence fracture type or incidence for direct anterior approach total hip arthroplasty?
Despite similar fracture rates, the incidence of intraoperative and post-operative fractures between standard (ST) length and short (SH) femoral stems remains unclear. Therefore, this study compared the incidence of intraoperative and early postoperative fractures between three ST and a single tapered-wedge SH femoral stem. Data were retrospectively collected on 1113 patients (1306 hips) having undergone total hip arthroplasty, via the anterior approach on a fracture table, between 2014 and 2019. One surgeon completed all ST procedures (314 hips), using one of three implants without discretion. One surgeon completed all SH procedures (992 hips), using one implant design. Differences between ST and SH groups were evaluated by independent t tests (continuous variables) and Chi-square tests (categorical variables). Patients in the SH group were significantly older (p < 0.001) and had a lower body mass index (p = 0.001) compared to the ST group. The total number of fractures was 12 (3.8%) and 14 (1.4%) in the ST and SH groups, respectively. The 12 ST fractures occurred intraoperatively, compared to two (0.2%) in the SH group. The remaining seven (0.7%) SH fractures occurred post-operatively. There was no difference in fracture rate between the three ST designs (p = 0.882). Interestingly, five (0.5%) insufficiency fractures were diagnosed in the SH group. The risk of intraoperative and post-operative fractures following anterior total hip arthroplasty may be biased toward ST and SH implants, respectively. These results, along with the presence of five insufficient fractures, identify potential fracture risks and mechanisms for specific implant designs.


Seroprevalence of Crimean-Congo Hemorrhagic Fever Virus and Rift Valley Fever Virus in human population in Senegal from October to November 2020.
Rift Valley Fever and Crimean-Congo Hemorrhagic Fever are two infections classified among the emerging diseases to be monitored with highest priority. Studies undertaken in human and animals have shown endemicity of these two arboviruses in several African countries. However, most of the investigations were carried out on domestic cattle and the studies conducted on human populations are either outdated or limited to a small number of well-known endemic areas. It is then critical to better evaluate the burden of these viruses in Senegal at a national scale. This work relies on a previous seroprevalence survey undertaken in all regions of Senegal at the end of 2020. The existing biobank was used to determine the immunoglobulin G [IgG] Rift Valley Fever and Crimean-Congo Hemorrhagic Fever seroprevalences by indirect enzyme-linked immunosorbent assay. The crude seroprevalences of Rift Valley Fever and Crimean-Congo Hemorrhagic Fever were 3.94% and 0.7% respectively, with the northern and central part of the countries as the main exposed areas. However, acute infections reported in both high and low exposed regions suggest sporadic introductions. This study gives updated information and could be of interest to support the stakeholders in the management of these zoonoses.


Surgical Treatment of the Twisted Nose.
The twisted nose is a challenging procedure in rhinoplasty. The goal of surgery is to realign the nasal skeleton to create symmetry in the face and restore nasal patency. Key in the surgical procedure is that all structures of the nasal skeleton be dissected free, mobilized, repositioned, and stabilized. Important surgical steps are intermediate osteotomies on the contralateral side of the deviation for the upper nasal third; for the mid nasal third, a unilateral spreader graft or splint on the nondeviated side, and for the lower nasal third, fixation of the caudal septum to the anterior nasal spine.


Association of ANKRD55 Gene Polymorphism with HT: A Protective Factor for Disease Susceptibility.
Recent studies have shown that Ankyrin Repeat Domain 55 (ANKRD55) gene polymorphism is a risk factor for multiple autoimmune diseases, but its association with autoimmune thyroid diseases (AITDs) has not been reported. The purpose of this study was to investigate the potential relationship between polymorphism of the ANKRD55 gene and AITDs. For this study, we enrolled 2050 subjects, consisting of 1220 patients with AITD and 830 healthy subjects. Five loci (rs321776, rs191205, rs7731626, rs415407, and rs159572) of the ANKRD55 gene were genotyped using Multiplex PCR combined with high-throughput sequencing. The results showed that the allele frequencies of rs7731626 and rs159572 loci in HT patients were lower than those in normal controls (P=0.048 and P=0.03, respectively). In different genetic model analyses, rs7731626 and rs159572 were also significantly correlated with HT in allele, dominant and additive models before and after age and sex adjustment. There were no differences in rs321776, rs191205, or rs415407 of the ANKRD55 gene in allele frequency or genotype frequency between AITDs patients and controls. This study for the first time found that rs7731626 and rs159572 of ANKRD55 were significantly correlated with HT, and individuals carrying the A allele at these two loci had a lower probability of developing HT.


Gastrointestinal bleeding due to idiopathic early onset of vitamin K deficiency bleeding in a girl baby 50 min after birth: a rare case.
The incidence of early-onset vitamin K deficiency bleeding (VKDB) in at-risk neonates who did not receive vitamin K supplementation varied from 6 to 12%. This case report aims to show that VKDB can occur abruptly after birth despite vitamin K1 1 mg IM being given immediately after birth. A term female baby was born through vaginal delivery of a 28 years old mother, G1P0A0, 39-40 weeks gestation with normal APGAR score, and birth weight was 3445 g, birth length was 52 cm. During pregnancy, the mother did not take any drugs except vitamins. There are no abnormalities on the baby's physical examination. The anus is patent. Immediately after birth, the baby received a vitamin K1 1 mg intramuscularly. Abruptly, 50 min after delivery, there was meconium with lots of fresh blood. Laboratory results showed hemoglobin, 19.6 g/dL; leukocytes, 25,010/uL; platelets, 390,000/uL, with increased PT and aPTT. A peripheral blood smear showed a normal blood morphology. When 7 h old, the baby had much hematochezia. Laboratory results showed decreased hemoglobin to 17.5 g/dL and increased PT, aPTT, and INR. No abnormalities were found on the babygram and abdominal ultrasound. The working diagnosis was gastrointestinal bleeding due to idiopathic early-onset VKDB. The baby received vitamin K1 2 mg IM, Fresh Frozen Plasma, and a Packed Red Cells transfusion. The patient returned home in good clinical condition. Vitamin K1 1 mg IM prophylaxis should be given immediately after birth to prevent early-onset VKDB. In addition, pregnant women who receive drugs that interfere with vitamin K metabolism (anti-epileptic drugs, anti-tuberculosis drugs, vitamin K antagonist drugs) should be given prophylactic vitamin K1, 20 mg/d orally, for at least two weeks before the expected time of delivery.


Correlation of pharmacokinetics and brain penetration data of adult zebrafish with higher mammals including humans.
Adult zebrafish pharmacology is evolving rapidly for creating efficacy and safety models for drug discovery. However, there is very limited research in understanding pharmacokinetics (PK) in adult zebrafish. Methods for understanding PK will help in conducting pharmacokinetic - pharmacodynamic (PK-PD) correlations and improving the quality and applicability of data obtained using zebrafish. We conducted adult zebrafish PK and brain penetration studies on two known compounds (irinotecan and lorcaserin) with distinct PK and brain penetration properties using validated LCMS/MS method. Irinotecan was studied at a dose of 100mg/kg i.p. and levels of the parent drug and active metabolite SN-38 were measured. Loracserin was studies at a dose of 10mg/kg by two routes i.p. and p.o. Zebrafish PK and brain penetration profiles for both compounds were very similar to that of higher mammals including humans. Irinotecan was metabolised to SN-38 in ratios similar to ratios seen in other species and the compound had long half life with very low brain penetration in our studies. Loracasin was highly permeable in brain as compared to the exposure in blood, with long half life and high relative bioavailability, similar to other mammalian species including humans. Adult zebrafish PK studies are relatively an unexplored area of zebrafish research. The zebrafish data for key parameters of irinotecan and loracserin shows a high correlation to the data from higher species, including human. This report explores and discusses the use of adult zebrafish as a predictive PK tool for higher animal studies.