Assessment of hemodialysis adequacy by ionic dialysance: comparison to standard method of urea removal.
The hemodialysis adequacy is one of the most important issues influencing the survival of patients on maintenance hemodialysis (HD). Assessment of measuring the delivered dialysis dose using clearance x time/volume (Kt/V) index requires multiple blood sampling. New methods for assessment of dialysis dose based on ionic dialysance (ID) have been suggested. Online conductivity monitoring (using sodium flux as a surrogate for urea) allows the repeated noninvasive measurement of Kt/V on each HD treatment. In this study we have compared this method with the standard method of estimating Kt/V. We studied 24 established HD patients over a 4 week time period. Patients were dialyzed using Fresenius 4008S dialysis monitors, equipped with modules to measure ID. Data were manually collected and analyzed using the appropriate statistical software. Urea removal (UR) was measured once a week by a two-pool calculation, estimating an eKt/V. The Kt/V measured by ID highly correlated with the one derived from the measurement of the UR (r=0.8959, p< 0.0001). The ID underestimated UR by the mean of 6%. The ID varied greatly within individual patients with a median of 1.29 +/- 0.22. If the eKt/V > or = 1.2 is considered adequate, 33% of the patients would have been inadequately dialyzed. The mean HD duration to achieve an adequate dialysis was 4 hours and 47 minutes with high interpatient variability. The ID seems to be an easily obtained measure of the delivered dialysis dose, correlating well with standard UR method. Substantial individual variations imply that repeated measures (ideally for all treatments) are necessary to obtain a real answer to the mean treatment dose being delivered to the patients.


Protease signalling: the cutting edge.
Protease research has undergone a major expansion in the last decade, largely due to the extremely rapid development of new technologies, such as quantitative proteomics and in-vivo imaging, as well as an extensive use of in-vivo models. These have led to identification of physiological substrates and resulted in a paradigm shift from the concept of proteases as protein-degrading enzymes to proteases as key signalling molecules. However, we are still at the beginning of an understanding of protease signalling pathways. We have only identified a minor subset of true physiological substrates for a limited number of proteases, and their physiological regulation is still not well understood. Similarly, links with other signalling systems are not well established. Herein, we will highlight current challenges in protease research.


Cross-stream diffusion under pressure-driven flow in microchannels with arbitrary aspect ratios: a phase diagram study using a three-dimensional analytical model.
This article presents a three-dimensional analytical model to investigate cross-stream diffusion transport in rectangular microchannels with arbitrary aspect ratios under pressure-driven flow. The Fourier series solution to the three-dimensional convection-diffusion equation is obtained using a double integral transformation method and associated eigensystem calculation. A phase diagram derived from the dimensional analysis is presented to thoroughly interrogate the characteristics in various transport regimes and examine the validity of the model. The analytical model is verified against both experimental and numerical models in terms of the concentration profile, diffusion scaling law, and mixing efficiency with excellent agreement (with <0.5% relative error). Quantitative comparison against other prior analytical models in extensive parameter space is also performed, which demonstrates that the present model accommodates much broader transport regimes with significantly enhanced applicability.


Clinical characteristics and patterns of failure in the parotid region after intensity-modulated radiotherapy for nasopharyngeal carcinoma.
To discuss the clinical characteristics and patterns of failure in the parotid region after intensity-modulated radiotherapy for nasopharygeal carcinoma. We retrospectively reviewed the charts of 716 patients with nasopharygeal carcinoma who underwent intensity-modulated radiotherapy in our centre from January 2005 to December 2010. Disease recurred in a spared parotid gland in 10 patients (1.4%). There were 2 females and 8 males with a median age of 38.5 (34-53) years. The most common presenting symptom was a swelling in pre-auricular region (7/10). Parotid glands were spared bilaterally in these patients. None of these patients had undergone previous radiotherapy or surgical treatment of the head and neck. The location of periparotid failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. The median time from day 1 of radiotherapy to periparoid recurrence was 17.4 (4.4-40.5) months. The median survivial after periparoid recurrence was 25.1 (5.0-74.5) months. There were 9 (90%) patients with lateral retropharyngeal lymphadenopathy. Seven of the periparotid failures were marginal. Of the 7 marginal failures, 6 occurred at the ipslateral parotid of the primary tumor centre. The average mean dose of the ipslateral parotid was 38.1 (32.3-44.1) Gy. Periparotid recurrence is an uncommon pattern of failure after definitive intensity-modulated radiotherapy for nasopharygeal carcinoma. To reduce the risk of periparotid recurrence,one possible strategy is to lessen the dose constraint criteria to ipslateral parotid of the primary tumor centre especially for nasopharygeal carcinoma with lateral retropharyngeal lymphadenopathy.


Investigation of confined placental mosaicism by CGH in IVF and ICSI pregnancies.
Assisted reproductive technologies include in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). It has been shown that embryos derived from ART have higher rates of aneuploidy. Although the majority of ART pregnancies are genetically normal, it is suspected that aneuploid embryos may persist as mosaics and lead to confined placental mosaicism (CPM). Due to the greater risks of sperm aneuploidy in infertile men, CPM may be more prevalent in ICSI than IVF pregnancies. In this report, we investigated the prevalence of CPM in IVF and ICSI pregnancies using comparative genomic hybridization and flow cytometry. The placenta and umbilical cord blood were collected after birth. To determine the presence of CPM, karyotypes of umbilical cord blood were compared to the results of placental analyses. For each placenta, multiple villous sites were investigated for DNA gains/losses and polyploidy using comparative genomic hybridization and flow cytometry. Detected abnormalities were further confirmed by fluorescent in-situ hybridization (FISH). In total, 134 IVF/ICSI cases were investigated. CPM was detected in five of these cases (5/134) giving an overall rate of 3.73%. CPM was detected in one IVF case (1/31; 3.23%) and four ICSI cases (4/103; 3.88%). The prevalence of CPM in IVF and ICSI pregnancies was not statistically different from each other. CPM was not observed in 13 ICSI and 6 IVF cases that were determined to be small for gestational age (SGA). The prevalence of CPM in ICSI pregnancies is not greater than IVF pregnancies. In addition, the overall prevalence of CPM in ART pregnancies (IVF and ICSI) is similar to that of the general population. CPM was not observed in the limited cases that were affected by small for gestational age. Our results suggest that ART pregnancies are not at a greater risk for CPM.


Information flow after a positive newborn screening for cystic fibrosis.
To provide a model of the information processes instigated by a positive result on a newborn screening for cystic fibrosis and to analyze their implications for future research. We reviewed research conducted at Wisconsin and elsewhere. We identified 6 distinct phases of information flow. Although continued attention to genetic counseling is clearly warranted, research on information flow after newborn screening should: 1) look beyond genetic counseling to include a variety of information sources including family, friends, and the Internet; 2) appreciate that families vary in their willingness to acquire cystic fibrosis-related information; and 3) should seek to better understand how this information moves through social networks.


The Spectrum of Hypereosinophilia and Associated Clonal Disorders - A Real-World Data Based on Combined Retrospective and Prospective Analysis from a Tropical Setting.
To determine the frequency, etiological spectrum and treatment outcome of hypereosinophilia (HE) and hypereosinophilic syndromes (HES) in a tropical setting. A retrospective analysis of hospital data of five years (January 2009 to December 2013) and a comprehensive prospective evaluation of patients presenting with HE/HES over a period of 33 months (January 2014 to September 2016) was performed. HE/HES was diagnosed in a total of 125 patients during the study period with an estimated prevalence of 0.5-1 case per 100,000 population in our hospital settings. 41 patients were excluded from the final analysis due to lack of sufficient data. Infections, especially helminths were the commonest cause (34%) followed by primary/clonal HE/HES (24%) and reactive HE/HES secondary to various clonal disorders (14.3%). A lymphocytic variant of HES and FIP1L1-PDGFRA positive HES were diagnosed in 3.6% each. Imatinib-responsive BCR-ABL1 negative HE/HES constitute 7.1% in our patients. None of the clinical or routine laboratory features including the age of patients, duration of HE, presence or absence of organomegaly, hemoglobin levels, eosinophil %, absolute eosinophil count, total leukocyte count, platelet counts, serum IgE levels or presence of myelofibrosis could predict or exclude malignancy in patients with HE/HES. The absence of blasts in peripheral blood or the absence of >5% blasts in bone marrow does not exclude primary/clonal HES. An underlying malignancy (Primary HE/HES and neoplasms leading to reactive HES; 35.7%) is diagnosed with nearly equal frequency compared to infections (34.5%) in tropical settings. There are no hematological or serological parameters, which can reliably be used to exclude an underlying malignancy, necessitating a thorough follow-up and comprehensive work-up in patients with HE/HES.


Fine mapping, phenotypic characterization and validation of non-race-specific resistance to powdery mildew in a wheat-Triticum militinae introgression line.
Introgression of several genomic loci from tetraploid Triticum militinae into bread wheat cv. Tähti has increased resistance of introgression line 8.1 to powdery mildew in seedlings and adult plants. In our previous work, only a major quantitative trait locus (QTL) on chromosome 4AL of the line 8.1 contributed significantly to resistance, whereas QTL on chromosomes 1A, 1B, 2A, 5A and 5B were detected merely on a suggestive level. To verify and characterize all QTLs in the line 8.1, a mapping population of double haploid lines was established. Testing for seedling resistance to 16 different races/mixtures of Blumeria graminis f. sp. tritici revealed four highly significant non-race-specific resistance QTL including the main QTL on chromosome 4AL, and a race-specific QTL on chromosome 5B. The major QTL on chromosome 4AL (QPm.tut-4A) as well as QTL on chromosome 5AL and a newly detected QTL on 7AL were highly effective at the adult stage. The QPm.tut-4A QTL accounts on average for 33-49 % of the variation in resistance in the double haploid population. Interactions between the main QTL QPm.tut-4A and the minor QTL were evaluated and discussed. A population of 98 F(2) plants from a cross of susceptible cv. Chinese Spring and the line 8.1 was created that allowed mapping the QPm.tut-4A locus to the proximal 2.5-cM region of the introgressed segment on chromosome 4AL. The results obtained in this work make it feasible to use QPm.tut-4A in resistance breeding and provide a solid basis for positional cloning of the major QTL.


Membrane trafficking and phagosome maturation during the clearance of apoptotic cells.
Apoptosis is a cellular suicide process that quietly and efficiently eliminates unwanted or damaged cells. In metazoans, cells that undergo apoptosis are swiftly internalized by phagocytes and subsequently degraded inside phagosomes through phagosome maturation, a process that involves the fusion between phagosomes and multiple kinds of intracellular organelles and the gradual acidification of phagosomal lumen. In recent years, rapid progress has been made, in particular, through studies conducted in the model organism, the nematode Caenorhabditis elegans, in understanding the membrane trafficking events and molecular mechanisms that govern the degradation of apoptotic cells through phagosome maturation. These studies revealed the novel and essential functions of a large number of proteins, including the large GTPase dynamin, multiple Rab small GTPases and their regulatory proteins, the lipid second messenger PtdIns(3)P and its effectors, and unexpectedly, the phagosomal receptors for apoptotic cells, in promoting phagosome maturation. Further, novel signaling pathways essential for phagosome maturation have been delineated. Here, we discuss these exciting new findings, which have significantly deepened and broadened our understanding of the mechanisms that regulate the interaction between intracellular organelles and phagosomes.


Maintenance shelf-life quality of cocktail tomatoes by using UV-C illumination and Arabic gum coating.
The aim of the study was to investigate the effects of Arabic gum (AG) coating, UV-C illumination and its combinations on postharvest quality parameters of cocktail tomatoes (Solanum lycopersicum L. cv. Ipekce F1 ). After harvest, mature green tomatoes were treated with 10% Arabic gum (AG10), 20% AG (AG20), 3.6 kJ m-2 ultraviolet-C (UV-C) illumination, 3.6 kJ m-2 UV-C+AG10 and 3.6 kJ m-2 UV-C+AG20, and stored at 20 °C for 20 days. The highest titratable acidity (TA), total soluble solids (TSS) and the lowest weight loss were obtained in AG20 treatments. Maximum fruit firmness and L* value were in AG20 and UV-C+AG20 treatment. The greatest h° values were recorded in AG20, UV-C+AG20 and control group. The highest vitamin C content were obtained from AG20, UV-C+AG10 and UV-C+AG20 treated tomatoes. Minimum lycopene content was determined from AG10, AG20, UV-C+AG10 and UV-C+AG20 treatments. Maximum chlorophyll content was determined from UV-C+AG20-treated tomatoes. AG10, AG20, UV-C+AG10 and UV-C+AG20 treatments resulted in lower ethylene emissions as compared to control and UV-C-treated tomatoes. AG20, UV-C+AG10 and UV-C+AG20 treatments generally had lower values than control and UV-C in term of respiration rates. It is concluded that AG20 treatment effectively maintained the postharvest quality and biochemical properties of cocktail tomatoes as compared to other tested treatments. © 2021 Society of Chemical Industry.


Cause of chest pain in a patient with previous myocardial infarction: look outside the heart for extracardiac mass.
We report a case of thymic carcinoma that was initially detected by echocardiography in an 80-year-old male who visited the emergency room for chest pain and had a history of myocardial infarction and percutaneous coronary intervention. Transthoracic echocardiography showed a huge extracardiac mass that was located in the anterior mediastinum and was diagnosed as a thymic carcinoma by biopsy.


Drastically enhanced ultrasonic decolorization of methyl orange by adding CCl4.
Effects of CCl(4) were investigated on the ultrasonic decolorization of azo dye methyl orange (MO). The decolorization of MO was observed to behave as a pseudo-first reaction in kinetics under all the conditions tested in the present work. The apparent rate constant of the decolorization was demonstrated to be dependent on CCl(4) concentration, MO concentration and the solution pH value. Under appropriate conditions, the rate constant of the ultrasonic decolorization of MO was able to be increased more than 100 times by adding CCl(4) into the MO solution. A reaction mechanism was proposed to explain the promoting effect of CCl(4) on the ultrasonic decolorization of MO, which was attributed to the generation of highly-oxidizing such as (*)Cl radical and HClO species, and then their attack at the azo bond of MO.


Phase angle predicts physical function in older adults.
Phase angle (PhA) is recognized as an indicator of cellular health and may be a useful marker of physical functions in geriatric populations. We aim to analyse the ability of the Phase angle (PhA) to predict the physical function in older adults. 113 healthy older adults (67 female and 46 male) performed physical tests using the Fullerton Battery - Senior Fitness Test, to assess their physical fitness. Bioelectrical impedance spectroscopy was used to determine PhA at 50KHz and dual-energy x-ray absorptiometry to assess body composition. PhA was positively associated with functional fitness composite, chair stand, arm curl and 6 min walk test and negatively related with chair sit-and-reach and 8-foot and go (p < 0.05). Even after adjusting for potential confounding variables such as age, sex and appendicular lean soft tissue, PhA showed an association with arm curl (ß = 0.23,p = 0.038), and 8-foot and go (ß=-0.214,p = 0.042). Higher values of PhA are related with a better physical function. Regardless of sex, age, and skeletal muscle, PhA predicts body strength, agility and dynamic balance in healthy older adults.


Effect of long-term paired associative stimulation on the modulation of cortical sensorimotor oscillations after spinal cord injury.
A prospective interventional case series. To explore changes in the modulation of cortical sensorimotor oscillations after long-term paired associative stimulation (PAS) in participants with spinal cord injury (SCI). BioMag Laboratory, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. Five patients with chronic incomplete SCI received unilateral spinal PAS to upper limb for 16-22 days. Changes in the modulation of sensorimotor oscillations in response to tactile stimulus and active and imaginary hand movements were assessed with magnetoencephalography recorded before and after the intervention. PAS restored the modulation of sensorimotor oscillations in response to active hand movement in four patients, whereas the modulation following tactile stimulation remained unaltered. The observed change was larger in the hemisphere that received PAS and preceded the clinical effect of the intervention. Long-term spinal PAS treatment, which enhances the motor functions of SCI patients, also restores the modulation of cortical sensorimotor oscillations.


[Necessity of No.13 lymph node dissection in advanced gastric carcinoma].
To investigate the feasibility and necessity of No.13 lymph node dissection for advanced gastric carcinoma. Clinical data of 144 cases who were diagnosed as TNMII-III stage gastric carcinoma were collected from January 2007 to December 2009 in the Department of General Surgery at the First Affiliated Hospital of Nanchang University. Seventy-two cases who received D2 radical gastrectomy plus No.13 lymph node dissection were selected as the study group, and they were matched 1:1 to 72 cases who received D2 Radical gastrectomy (the control group) for TNMII-III stage gastric carcinoma. The differences in the intraoperative and postoperative parameters and survival time were compared, and the factors associated with No.13 lymph node metastasis were analyzed. There were no significant differences between the two groups in operative time [(2.8 ± 0.4) h vs. (2.7 ± 0.4) h], blood loss [(191.9 ± 81.5) ml vs. (186.0 ± 81.7) ml], the incidence of postoperative complications (18.1% vs. 15.3%), length of hospital stay [(12.3 ± 4.2) d vs. (11.9 ± 3.2) d] and 3-year survival rate (63% vs. 57%) (all P>0.05). In the study group, there were 15 patients (20.8%) with positive No.13 lymph nodes, and the 3-year survival rate was 13%, significantly lower compared to those with negative No.13 lymph node (73%, n=57) (P<0.05). Multivariate analysis showed that N stage (P<0.01) and histological type (P<0.05) were independently associated with No.13 lymph node metastasis. No.13 lymph node dissection for TNMII-III stage gastric cancer is feasible and necessary.


Relation between the response to iron supplementation and sickle cell hemoglobin phenotype in preschool children in western Kenya.
Iron supplementation has been associated with greater susceptibility to malaria and lower hematologic responses in pregnant Gambian women with sickle cell trait (HbAS) than in similar women with the normal (HbAA) phenotype. It is not known whether a similar interaction exists in children. Our aim was to determine the influence of the HbAS phenotype on hematologic responses and malaria after iron supplementation in anemic (hemoglobin: 70-109 g/L) children aged 2-35 mo. We conducted a double-blind, randomized, placebo-controlled trial (HbAS, n = 115; HbAA, n = 408) of intermittent preventive treatment with sulfadoxine pyrimethamine (IPT-SP) at 4 and 8 wk and daily supervised iron for 12 wk. The mean difference in hemoglobin concentrations at 12 wk between children assigned iron and placebo iron, after adjustment for the effect of IPT-SP, was 9.1 g/L (95% CI: 6.4, 11.8) and 8.2 g/L (4.0, 12.4) in HbAA and HbAS children, respectively (P for interaction = 0.68). Although malaria parasitemia and clinical malaria occurred more often in HbAS children in the iron group than in those in the placebo iron group, this difference was not significant; incidence rate ratios were 1.23 (95% CI: 0.64, 2.34) and 1.41 (0.39, 5.00), respectively. The corresponding incidence rate ratios in HbAA children in the same groups were 1.07 (95% CI: 0.77, 1.48) and 0.59 (0.35, 1.01), respectively. The corresponding interactions between the effects of iron and hemoglobin phenotype were not significant. There was no evidence for a clinically relevant modification by the hemoglobin S phenotype of the effects of iron supplementation in the treatment of mild anemia. The benefits of iron supplementation are likely to outweigh possible risks associated with malaria in children with the HbAA or HbAS phenotype.


The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma.
N6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive. In this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A "readers". Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice. Here, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression in vitro and in vivo. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of DDX58 mRNA. Moreover, RIG-I, encoded by the DDX58 mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of DDX58 mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients. These findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.


Calcium-independent, pH-regulated effects of S-100 proteins on assembly-disassembly of brain microtubule protein in vitro.
At alkaline pH, Ca2+ is no longer required for S-100 proteins to inhibit the assembly and to promote the disassembly of brain microtubules in vitro, though the presence of Ca2+ significantly favors the S-100 effects. These effects are inversely related to the microtubule protein concentration and directly related to the S-100 concentration and the pH. Ca2+-independent, pH-regulated inhibition of assembly of phosphocellulose-purified tubulin by S-100 is also described. The microtubule disassembling effect of S-100 is additive to that of alkali (used to raise the pH), and S-100 further disassembles microtubules after alkalinization. Thus the larger inhibitory effect of S-100 on microtubule assembly at alkaline versus acid pH depends on both a decrease in the assembly rate and an increase in the disassembly rate. Together with previous data on this topic, the present findings indicate that S-100 proteins act on microtubule protein in vitro primarily by binding to tubulin, this event being Ca2+-regulated at a given pH, and pH-regulated at a given free Ca2+ concentration.


The interaction between G-quadruplex-forming oligonucleotide and cationic surfactant monolayer at the air/water interface.
We report on the interactions between a 21-mer quadruplex-forming oligonucleotide bearing human telomere sequence of dG(3)(T(2)AG(3))(3) (G4 DNA) and a positively charged dioctadecyldimethylammonium bromide (DODAB) monolayer at the air-aqueous interface, studied by surface film balance measurements. In the presence of G4 DNA, the π-A isotherm of the cationic Langmuir film shifted to lower molecular areas when compared with the reference isotherm recorded on the subphase containing only 50 mM triethylamine-acetate (TEAA) buffer. The presence of quadruplex-stabilizing metal cations (K(+) or Na(+)) further affected profiles of π-A isotherms. Further insight into processes related to the G4 DNA-monolayer interactions was provided by recording time profiles of the surface pressure of monolayer at a constant mean molecular area. In these experiments G4 DNA and/or metal ions were sequentially injected under the monolayer surface. Results indicated that multistranded assemblies of G4 DNA were formed at the monolayer interface even in the absence of metal ions, which suggested that the charged cationic surface of Langmuir monolayer induced aggregation of guanine-rich DNA strands. The presence of sodium and potassium ions inhibited formation of multi-stranded assemblies through the competitive G-quadruplex formation but to different extent that might be related to the differences in stability and topology of both quadruplexes.


Topical tacrolimus does not negatively impact acute skin wound healing.
Despite the increasing use of topical tacrolimus, there is little information about its effect on skin wound healing. To determine effects on acute cutaneous wound healing, two full-thickness skin wounds were imparted on the backs of 45 hairless mice, which were then divided into vehicle-, topical tacrolimus- and topical steroid-treated group. Each drug was topically applied once daily. The wound area was assessed by using dermoscopic images every two days after wounding. At 3, 7 and 11 days after wounding, 10 wounds in each group were collected for semi-quantitative analysis of histological features including re-epithelialization, polymorphonuclear leucocytes, fibroblasts and collagen. We also checked the mRNA expression levels of EGF, TGF-β, TNF-α and IL-1α. While topical application of clobetasol propionate was found to delay re-epithelialization and infiltration of polymorphonuclear leucocyte, topical treatment with tacrolimus showed patterns similar to that of the vehicle. In the tacrolimus-treated group, mRNA expression levels of IL-1α and TGF-β were slightly decreased, while the others were similar with the vehicle-treated group. Unlike steroid, topical tacrolimus, therefore, did not disturb the wound healing process in a murine skin wound model.


Discussions on Implantable Cardioverter-Defibrillator Deactivation in Patients Receiving Radiation Therapy: A Missed Opportunity.
Established guidelines discuss end-of-life care in patients with implantable cardioverter-defibrillators (ICDs). It is not known how frequently these discussions take place in patients who have ICDs and are receiving active treatment for cancer. Chart review from a large regional cardiac and cancer center from 2005 to 2019 highlighted that discussions on ICD deactivation were infrequent (28% of patients). Receipt of a palliative care consultation increased the likelihood of patients having discussions on ICD deactivation during this time. Collaboration with palliative care teams may facilitate discussions on ICD deactivation during this opportune time.


Characteristics of the corpus callosum in chronic schizophrenia treated with clozapine or risperidone and those never-treated.
The corpus callosum (CC) deficits have been well documented in chronic schizophrenia. However, the long-term impacts of antipsychotic monotherapies on callosal anatomy remain unclear. This cross-sectional study sought to explore micro- and macro-structural characteristics of the CC in never-treated patients and those with long-term mono-antipsychotic treatment. The study included 23 clozapine-treated schizophrenia patients (CT-SCZ), 19 risperidone-treated schizophrenia patients (RT-SCZ), 23 never-treated schizophrenia patients (NT-SCZ), and 35 healthy controls (HCs). High resolution structural images and diffusion tensor imaging (DTI) data for each participant were obtained via a 3.0 T MR scanner. FreeSurfer was used to examine the volumes and fractional anisotropy (FA) values of the CC for each participant. There were significant deficits in the total and sub-regional CC volume and white matter integrity in NT-SCZ in comparison with healthy subjects. Compared with NT-SCZ, both CT-SCZ and RT-SCZ showed significantly increased FA values in the anterior CC region, while only RT-SCZ showed significantly increased volume in the mid-anterior CC region. Moreover, the volume of the mid-anterior CC region was significantly smaller in CT-SCZ compared to HCs. No correlations of clinical symptoms with callosal metrics were observed in schizophrenia patients. Our findings provide insight into micro- and macro-structural characteristics of the CC in chronic schizophrenia patients with or without antipsychotics. These results suggest that the pathology itself is responsible for cerebral abnormalities in schizophrenia and that chronic exposure to antipsychotics may have an impact on white matter structure of schizophrenia patients, especially in those with risperidone treatment.


Molecular dynamics of the cryo-EM CFTR structure.
Cystic fibrosis (CF), a lethal monogenic disease, is caused by mutant variants of the CF transmembrane conductance regulator (CFTR). Recent advances in single molecule cryo-EM methods enabled structural determination of full-length human and zebrafish CFTR, achieving an important milestone for CF drug development. To relate these structures to the gating cycle, we examined its dynamic features using molecular dynamics simulations. Our results show that the nucleotide binding domains (NBDs) in this bottom-open apo conformation exhibit motions related to dimerization and the bottom-closed apo CFTR model indicates opening of NBDs in contrast to transporters. These observations help in understanding the properties of CFTR chloride channel distinct from transporters and in proper interpretation of available structural information on this ABC protein.


Gallbladder cancer invading the perimuscular connective tissue: results of reresection after prior non-curative operation.
Most T2 gallbladder cancers are diagnosed at final pathology after cholecystectomy. Reoperations including liver resection and regional lymph node dissection are needed to achieve better long-term results. The aim of this study is to evaluate long-term results of reresections after prior non-curative surgery for T2 carcinomas. Retrospective study from January 1985 to July 2001. Twelve out of 14 pT2 cancers were found postoperatively. All but one underwent reresection: these 11 patients are the basis of our series. The in-hospital mortality rate was 0%. Overall 5-year survival was 63.5% with a median survival of 25 months. Median and 5-year survival of the eight cases without preoperative signs of disease (Group A) were 46.7 months and 100%. These results were significantly better than those obtained in the subset (Group B: three cases) with preoperative signs of disease (P = 0.01): all these patients died of recurrence within 25 months from the reoperation. Mean time between cholecystectomy and reresection was 2.2 and 11.3 months in the Group A and B (P = 0.01), respectively. T2 cancers discovered incidentally after simple cholecystectomy should be reoperated on as soon as possible, as the appearance, before reoperation, of a recurrence is significantly related to a dismal prognosis.


Maximal sfermion flavour violation in super-GUTs.
We consider supersymmetric grand unified theories with soft supersymmetry-breaking scalar masses [Formula: see text] specified above the GUT scale (super-GUTs) and patterns of Yukawa couplings motivated by upper limits on flavour-changing interactions beyond the Standard Model. If the scalar masses are smaller than the gaugino masses [Formula: see text], as is expected in no-scale models, the dominant effects of renormalisation between the input scale and the GUT scale are generally expected to be those due to the gauge couplings, which are proportional to [Formula: see text] and generation independent. In this case, the input scalar masses [Formula: see text] may violate flavour maximally, a scenario we call MaxSFV, and there is no supersymmetric flavour problem. We illustrate this possibility within various specific super-GUT scenarios that are deformations of no-scale gravity.


Site-directed mutagenesis of core sequence elements 9R', 9L, 9R, and 2 in self-splicing Tetrahymena pre-rRNA.
The intron within the Tetrahymena thermophila nuclear large rRNA precursor is the best studied example of group I self-splicing introns. In this paper, we examine the structural and functional roles of four internal sequence elements which are characteristic of group I introns in the RNA-catalyzed processing reactions. Oligonucleotide-directed mutagenesis was used to generate mutations in sequence elements 9R', 9L, 9R and 2 of the Tetrahymena intervening sequence. Self-splicing activities of variant precursor RNAs were characterized by in vitro splicing following transcription with T7 or SP6 RNA polymerase. First, we confirm the proposed base pairing of sequence elements 9R and 9R' by construction and analysis of compensatory mutations. Mutations in elements 9R (G272A C274G) and 9R' (G100C C102U) each disrupt the pairing and eliminate self-splicing activity. A compensatory 9R/9R' mutation (G100C C102U G272A C274G) restores pairing and normal splicing activity. We conclude that 9R X 9R' pairing is a requirement for self-splicing. Second, we show that self-splicing activity is very sensitive to both nucleotide sequence and RNA secondary structure in the pairing segments of elements 9L and 2. Mutations within these regions at positions 266, 268, 307, and 309 can increase as well as decrease activity relative to wild type. Third, a mutation in the highly conserved nonpairing segment of element 9L (U259A A261C) increases KM for GTP from 29 to 120 microM, but does not otherwise affect splicing activity. The primary consequence of this mutation is a decrease in GTP binding energy of approximately 0.9 kcal/mol. Last, we show that a mutation in the highly conserved nonpairing segment of element 2 (A301C A302G G303C) eliminates transesterification activity, but does not affect 3' splice site hydrolysis.


[Determination of the ammonia content in the atmosphere of biosatellite mock-ups and approaches to its standardization].
The concentrations of ammonia having an irritating and acute effect on intact rats and hypokinetic rats were determined. The thresholds of the chronic effect were calculated for each group of animals. The 30-day hypokinesia increased the animal sensitivity to ammonia: the threshold of the irritating effect decreased twice. The atmosphere in an enclosure equipped with an automatic life support system was examined during 30-day integrated animal experiments. Ammonia proved to be the major contaminant. Its concentration increased gradually, remaining for the longest part of the experiments (28 days) below the threshold of the chronic effect (40 mg/m3).


A new simplified assay for evaluation of motile activity of human polymorphonuclear leucocytes.
We studied the adaptation of a filtration instrument to an assay for cell migration experiments. The commercially available Nuclepore filter holders were modified so that isolated human polymorphonuclear leucocytes (PMNs) were allowed to penetrate a porous filter membrane and to enter a compartment under the membrane. The total number of PMNs which had passed the pores during an hour of incubation could be counted. In this way we carried out experiments using Shigella sonnei lipopolysaccharide and dilutions of E. coli culture supernatant as chemoattractants for healthy human PMNs. These studies showed that the method can distinguish between random and directed movements of PMNs and it is sensitive to the concentrations of chemoattractant. Furthermore, the data obtained using PMNs from the same subject on different days seem to be comparable.


Single photon emission computed tomography (SPECT) using N-isopropyl-p-(123I) iodoamphetamine (IMP) in the evaluation of patients with epileptic seizures.
To evaluate the clinical usefulness of IMP SPECT in the diagnosis of epilepsy, 6 normals and 52 patients in the interictal phase were studied. Thirty min after an intravenous injection of 111 MBq IMP, SPECT was performed using a rotating gamma camera. Of 21 patients with simple partial seizures, a localized decrease of uptake was shown in 16, and an increase in 3. Topologically, these findings corresponded well to the ictal symptoms. Nine of 13 patients with localized epileptic EEG had a good correspondence between the findings on EEG and IMP SPECT. In 20 of 23 with complex partial seizures, the coronal images showed laterality of uptake in the temporal lobes, whereas the CT was normal in 14. However, these findings on IMP SPECT agreed with the EEG in the temporal leads in only 5 cases. Of 8 patients with primary generalized seizures, a diffuse cerebral decrease was shown in 3 of 4 patients with convulsive seizures (grand mal), and a normal uptake in 3 of 4 patients with non-convulsive seizures (petit mal). However, 2 patients showed a localized decrease, therefore, we determined that they suffered from partial seizures evolving to secondarily generalization. From these data, we concluded that IMP SPECT could be a useful method in the diagnosis of epilepsy.


A clinicopathological study of malignant odontogenic tumours.
Malignant odontogenic tumours (MOTs) are rare neoplasms occurring primarily within the jaw. The objective of this study was to determine the incidence, demographics and clinicopathological features of the MOTs from two institutions. The records of the Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand and the Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, USA were searched from 1991 to 2010; we identified 17 cases of previously diagnosed MOTs. All cases were reviewed independently of the previous diagnosis by two blinded oral pathologists and reclassified based on the 2005 World Health Organization classification of head and neck tumours. In this study we describe in detail these 17 cases which presented with an average age of 50.29 years and a male to female ratio of 2.4:1. These cases included five ameloblastic carcinomas, four atypical ameloblastomas, three primary intraosseous squamous cell carcinomas, three intraosseous mucoepidermoid carcinomas and two clear cell odontogenic carcinomas. All cases were treated by surgical resection and one patient with ameloblastic carcinoma received postoperative radiotherapy. Malignant odontogenic tumours are considered rare central odontogenic lesions. Awareness of their existence, rapid diagnosis and successful treatment using surgery, radiation and/or chemotherapy is critical to patient survival.


Association between cardiometabolic disease multimorbidity and all-cause mortality in 2 million women and men registered in UK general practices.
Myocardial infarction (MI), stroke and diabetes share underlying risk factors and commonalities in clinical management. We examined if their combined impact on mortality is proportional, amplified or less than the expected risk separately of each disease and whether the excess risk is explained by their associated comorbidities. Using large-scale electronic health records, we identified 2,007,731 eligible patients (51% women) and registered with general practices in the UK and extracted clinical information including diagnosis of myocardial infarction (MI), stroke, diabetes and 53 other long-term conditions before 2005 (study baseline). We used Cox regression to determine the risk of all-cause mortality with age as the underlying time variable and tested for excess risk due to interaction between cardiometabolic conditions. At baseline, the mean age was 51 years, and 7% (N = 145,910) have had a cardiometabolic condition. After a 7-year mean follow-up, 146,994 died. The sex-adjusted hazard ratios (HR) (95% confidence interval [CI]) of all-cause mortality by baseline disease status, compared to those without cardiometabolic disease, were MI = 1.51 (1.49-1.52), diabetes = 1.52 (1.51-1.53), stroke = 1.84 (1.82-1.86), MI and diabetes = 2.14 (2.11-2.17), MI and stroke = 2.35 (2.30-2.39), diabetes and stroke = 2.53 (2.50-2.57) and all three = 3.22 (3.15-3.30). Adjusting for other concurrent comorbidities attenuated these estimates, including the risk associated with having all three conditions (HR = 1.81 [95% CI 1.74-1.89]). Excess risks due to interaction between cardiometabolic conditions, particularly when all three conditions were present, were not significantly greater than expected from the individual disease effects. Myocardial infarction, stroke and diabetes were associated with excess mortality, without evidence of any amplification of risk in people with all three diseases. The presence of other comorbidities substantially contributed to the excess mortality risks associated with cardiometabolic disease multimorbidity.


Three-Dimensional Quantitative Analysis of the Brainstem Safe Entry Zones Based on Internal Structures.
Brainstem safe entry zones (EZs) are gates to access the intrinsic pathology of the brainstem. We performed a quantitative analysis of the intrinsic surgical corridor limits of the most commonly used EZs and illustrated these through an inside perspective using 2-dimensional photographs, 3-dimensional photographs, and interactive 3-dimensional model reconstructions. A total of 26 human brainstems (52 sides) with the cerebellum attached were prepared using the Klingler method and dissected. The safe working areas and distances for each EZ were defined according to the eloquent fiber tracts and nuclei. The largest safe distance corresponded to the depth for the lateral mesencephalic sulcus (4.8 mm), supratrigeminal (10 mm), epitrigeminal (13.2 mm), peritrigeminal (13.3 mm), lateral transpeduncular (22.3 mm), and infracollicular (4.6 mm); the rostrocaudal axis for the perioculomotor (11.7 mm), suprafacial (12.6 mm), and transolivary (12.8 mm); and the mediolateral axis for the supracollicular (9.1 mm) and infracollicular (7 mm) EZs. The safe working areas were 46.7 mm2 for the perioculomotor, 21.3 mm2 for the supracollicular, 14.8 mm2 for the infracollicular, 33.1 mm2 for the supratrigeminal, 34.3 mm2 for the suprafacial, 21.9 mm2 for the infrafacial, and 51.7 mm2 for the transolivary EZs. The largest safe distance in most EZs corresponded to the depth, followed by the rostrocaudal axis and, finally, the mediolateral axis. The transolivary had the largest safe working area of all EZs. The supracollicular EZ had the largest safe area to access the midbrain tectum and the suprafacial EZ for the floor of the fourth ventricle.


A female-specific attractant for the codling moth, Cydia pomonella, from apple fruit volatiles.
Host plant-derived esters were investigated as potential female-specific attractants for the codling moth (CM), Cydia pomonella (L.), a key pest of apples worldwide. The behavioural effects of single and combined volatile compounds and of a natural odour blend were examined using olfactometry and wind-tunnel bioassays. The apple-derived volatile butyl hexanoate attracted mated females while it was behaviourally ineffective for males over a dosage range of more than three orders of magnitude in olfactometer assays. Female CM preferred this kairomone to the headspace volatiles from ripe apples. Both no-choice and choice trials in the wind-tunnel suggested that female moths might be effectively trapped by means of this compound. In contrast, headspace volatiles collected from ripe apple fruits as well as a blend containing the six dominant esters from ripe apples were behaviourally ineffective. A female-specific repellency was found for the component hexyl acetate in the olfactometer, but this ester had no significant effect in the wind-tunnel. Butyl hexanoate with its sex-specific attraction should be further evaluated for monitoring and controlling CM females in orchards.


The arches and spandrels of maize domestication, adaptation, and improvement.
People living in the Balsas River basin in southwest México domesticated maize from the bushy grass teosinte. Nine thousand years later, in 2021, Ms. Deb Haaland - a member of the Pueblo of Laguna tribe of New Mexico - wore a dress adorned with a cornstalk when she was sworn in as the Secretary of Interior of the United States of America. This choice of garment highlights the importance of the coevolution of maize and the farmers who, through careful selection over thousands of years, domesticated maize and adapted the physiology and shoot architecture of maize to fit local environments and growth habits. Some traits such as tillering were directly selected on (arches), and others such as tassel size are the by-products (spandrels) of maize evolution. Here, we review current knowledge of the underlying cellular, developmental, physiological, and metabolic processes that were selected by farmers and breeders, which have positioned maize as a top global staple crop.


[Biological activity of follicle-stimulating hormone in the pituitary gland of human fetuses].
Biological methods were used to study the changes in the folliculo-stimulating hormone (FSH) level in the hypophysis of human fetuses. FSH was found to be present in the hypophysis of fetuses during the whole period of investigation: from the 8th to the 34th week. Marked sex differences both in the total and in the relative FSH content were revealed in the adenohypophysis from the 17th to the 34th weeks of gestation.


Cuticle-degrading proteases from the entomopathogen Metarhizium flavoviride and their distribution in secreted and intracellular fractions.
The aim of this study was to analyse a native isolate of Metarhizium flavoviride (CG423) which is being developed as a myco-insecticide against grasshoppers in Brazil for the production of the cuticle-degrading subtilisin-like (Pr1), and trypsin-like (Pr2) proteases. The results show that Pr1 activity occurred only in medium supplemented with grasshopper cuticle (Schistocerca pallens). In contrast, Pr2 was detected in higher amounts on defined growth substrate than on cuticle-supplemented medium. Both activities were detected after 48 h of growth, suggesting that in S. pallens cuticle-containing medium these protease types are not co-ordinately expressed. Low levels of enzyme activity were detected when pre-grown mycelium was used to investigate the induction of Pr1 proteases. The analysis of Pr1 and Pr2 distribution in both secreted and intracellular fractions revealed high percentage of extracellular activity, which may suggest the occurrence of an efficient mechanism of protein secretion by this fungus, probably related to substrate degradation which provides nutrients for fungal growth.


Preparation of selective magnetic dispersive solid-phase sorbent and its application for recognition clenbuterol from bovine urine.
A new kind of selective magnetic dispersive solid-phase sorbent based on multiple Fe3O4 nanospheres as the core structure and molecular imprinted material as the shell structure was synthesized with tert-butylamine and 2-chloroaniline as the templates. The obtained multicore-shell-structured sorbent was spherical (diameter distribution 25-90μm) with porous morphologies, thus incorporating strong magnetic properties and specific molecular recognition coupled with rapid adsorption and dynamic equilibrium. The sorbent was applied for rapid and selective screening of clenbuterol (CLB) in bovine urine samples. Good linearity was obtained in the range 1.25-200ngmL(-1) with the average recovery at three spiked levels ranging from 91.4% to 105.3%. The proposed method significantly improved the purification and extraction efficiency of CLB in urine samples and eliminated the effect of template leakage during quantitative analysis.


Radioactive carbon-14 as an indicator of energy flow in litter decomposition studies.
A method for uniformly labeling kilogram amounts of plant litter with 14C is described. Data obtained from field decomposition of tagged fescue litter prepared by this method suggest that 14C flux can be a reliable indicator of energy flow, as measured directly by bomb calorimetry and indirectly by ashfree weight.


Perhexiline maleate-induced cirrhosis.
The authors report the cases of 2 patients who died from cirrhosis after receiving perhexiline maleate, a drug widely used in Europe for the treatment of angina pectoris. Perhexiline maleate had been ingested for 24 and 28 mo, respectively. Manifestations of cirrhosis included jaundice, hepatic encephalopathy, ascites, and portal hypertension. Associated manifestations of intolerance to perhexiline maleate included peripheral neuropathy in 1 patient and marked weight loss in both. Histologic lesions resembled those observed in patients with alcoholic liver disease. Ultrastructural lesions included numerous enlarged lysosomes containing myeloid figures. Histochemical stains demonstrated increased phospholipid content of the hepatocytes. These findings are consistent with the view that prolonged administration of perhexiline maleate may induce both histologic lesions resembling those of alcoholic liver disease and ultrastructural and histochemical lesions resembling those of phospholipidosis.


Comparison of Long-run Trends in 30-day Readmission by Degrees of Medicare Payment Cuts.
The Affordable Care Act enacted significant Medicare payment reductions to providers, yet long-term effects of such major reductions on patient outcomes remain uncertain. Using the 1997 Balanced Budget Act (BBA) as an experiment, we compare long-run trends in 30-day readmission across hospitals with different amount of payment cuts. Using 100% Medicare claims between 1995 and 2011 and instrumental variable hospital fixed-effects regression models, we compared changes in 30-day readmission trends for 5 leading Medicare conditions between urban hospitals facing small, moderate, and large BBA payment reductions across 4 periods [1995-1997 (pre-BBA period), 1998-2000, 2001-2005, 2006-2001]. Patient sample includes Medicare patients who were admitted to general, acute, urban, short-stay hospitals in the United States 1995-2011. Sample size ranges from 1.4 million patients for acute myocardial infarction to 3 million for pneumonia. We found that 30-day readmission trends diverged post-BBA (2001-2005) between hospitals facing small and large payment cuts, where large-cut hospitals experience slower improvement in readmission rates relative to small-cut hospitals. The gap between small-cut and large-cut hospitals readmission trend was 6% for acute myocardial infarction, 4% for congestive heart failure and pneumonia (all P<0.01) in the 2001-2005 period. The gaps between hospitals were eliminated by the 2006-2011 period as the effect of BBA naturally dissipated over time. Although payment-cut differences are associated with widening gaps in readmission rates across hospitals, the negative association appears to dissipate in the long run.


Traveling Salesman Finds Random Walk: A Curve Reconstruction Algorithm for Supercoiled DNA.
DNA supercoiling plays an important role in a variety of cellular processes, including transcription, replication, and DNA compaction. To fully understand these processes, we must uncover and characterize the dynamics of supercoiled DNA. However, supercoil dynamics are difficult to access because of the wide range of relevant length and timescales. In this work, we present an algorithm to reconstruct the arrangement of identical fluorescent particles distributed around a circular DNA molecule, given their three-dimensional trajectories through time. We find that this curve reconstruction problem is analogous to solving the traveling salesman problem. We demonstrate that our approach converges to the correct arrangement with a sufficiently long observation time. In addition, we show that the time required to accurately reconstruct the fluorophore arrangement is reduced by increasing the fluorophore density or reducing the level of supercoiling. This curve reconstruction algorithm, when paired with next-generation super-resolution imaging systems, could be used to access and thereby advance our understanding of supercoil dynamics.


Subsidized veterinary extension services may reduce antimicrobial resistance in aquaculture.
Antibiotic use in aquaculture has become very controversial vis-à-vis driving antimicrobial resistance (AMR) in aquatic bacterial populations. The AMR trends in fish pathogens in Hong Kong over a four-year period suggests that providing small stakeholder farmers with free veterinary advice on fish health issues and treatments, as well as subsidized quality-assured medicines, likely reduced AMR. We observed a dramatic reduction in the proportion of bacteria resistant to oxolinic acid, oxytetracycline, and florfenicol on local aquaculture farms between 2018 and 2021. These decreases coincided with either a change in antibiotic use practices on farms (i.e. with oxytetracycline), or the reduction in the use of specific drugs (i.e. oxolinic acid and florfenicol). We did not observe a similar decline in the resistance pattern to commonly used antibiotics in human medicine in the same fish bacteria. Resistance to these products, which were unlikely to be used by the farmers in our study, was very high. Our finding suggests that both human and veterinary use of antibiotics in Hong Kong may have an influence on the AMR of bacteria in the aquatic environment.


Attenuation of diacylglycerol signal in the primordial human placenta: role of phosphatidylcholine formation.
Metabolic conversion of the synthetic DAG, dioctanoylglycerol (DOCG) into the dioctanoyl species of phosphatidic acid (PADOCG) and phosphatidylcholine (PCDOCG) in minced human primordial placenta incubated with [32P]phosphate was studied. Time-course experiments performed with 0.25 mM DOCG revealed a much higher capacity of the placenta to synthetize PCDOCG than PADOCG and indicated the rapid metabolism of PCDOCG. In addition, DOCG stimulated the labeling of PC whereas no such effects on the labeling of lyso-PC and PA were observed. This effect of DOCG is not related to the synthesis of PC de novo, because DOCG did not exhibit any stimulating effect on the synthesis of PC from [3H]glycerol or [3H]glucose. Experiments with varying concentrations of DOCG (0.025-0.5 mM) showed increasing rate of formation of PCDOCG over a concentration range from 0.05 to 0.5 mM whereas 0.5 mM DOCG was the lowest concentration where significant formation of PADOCG was found. Labeling of PC was about 30% over control at 0.125 mM as well as at 0.25 mM DOCG, and decreased below the control level at 0.5 mM DOCG. Labeling of PA and PI was not influenced by these DOCG concentrations. Labeling of PC, either stimulated by DOCG or not, was more sensitive to the inhibitory effect of 1 mM of the DAG analog: dioctanoylethyleneglycol (DOEG) than that of PA. Moreover, 1 mM DOEG inhibited the formation of PCDOCG without such an effect on the labeling of PADOCG. These findings indicate that in the primordial human placenta PC synthesis represents a more efficient attenuation pathway of DAG signal than the formation of PA by DAG kinase.


Enteric glial cells are major contributors to formation of cyclic AMP in myenteric plexus cultures from adult guinea-pig small intestine.
Cultures derived from ganglia isolated from the small intestine of adult guinea-pigs were used to determine relative contribution of neurons and glial cells to stimulation of cAMP formation by forskolin in myenteric ganglia. In untreated cultures (8-12 days), the ratio of glial cells to neurons was 5-fold higher than the ratio in intact myenteric plexus preparations. Treatment with cytosine arabinoside virtually eliminated the glia by the 12th day. Microelectrode recording of excitatory responses to forskolin in AH/Type 2 neurons confirmed the viability of cultured neurons in cytosine arabinoside. Forskolin elevated the cAMP content of cultures and cytosine arabinoside reduced this effect by 80-90%. This suggests that enteric glial cells are the major contributors to cAMP formation in the cultures and that glial cells contribute significantly to elevation of cAMP levels seen in intact myenteric ganglia.


The exposure-response relationship for mesothelioma among asbestos-cement factory workers.
Forty-five deaths from mesothelioma have occurred among production workers in an asbestos-cement factory. This analysis examines the fit of the cubic residence time model to the incidence of mesothelioma using a case-control method proposed by de Klerk and colleagues. The cubic residence time model was found to provide a good description of the data.


Molecular Pathways: Increased Susceptibility to Infection Is a Complication of mTOR Inhibitor Use in Cancer Therapy.
As one of the earliest examples of "chemical biology," the M: echanistic T: arget of R: apamycin (mTOR) protein and its chemical inhibitors have been extensively studied across a spectrum of physiologic and pathologic processes at the molecular, organismal, and patient population levels. There are several FDA-approved mTOR inhibitors (sirolimus, everolimus, and temsirolimus) with indications for cancer treatment and for prevention of solid organ rejection. Dozens of mTOR inhibitors are currently being evaluated in hundreds of ongoing clinical trials across a spectrum of diseases, including numerous cancer indications, autoimmune diseases, and a number of congenital disorders. As many of the approved and investigational indications for mTOR inhibitors require long-term treatment, the magnitude and incidence of particular side effects differ from those observed in shorter-term treatments. Here, we focus on the increased risk of infections in patients being treated with mTOR inhibitors. While increased infection rates might be expected from a class of drugs approved as posttransplant immunosuppressants, we review reports from clinical, mechanistic, and genetically engineered mouse model studies detailing a much more nuanced view of mTOR inhibitor drug action and target biology.


The presence of free D-amino acids in mouse tissues.
The presence of free D-amino acids in mouse kidney, liver, brain, heart, lung, thymus and serum has been shown with an enzymic microdetermination method. The D-amino acid levels were higher in the extracts of kidney and liver than in those from other organs.


A machine learning approach for hypertension detection based on photoplethysmography and clinical data.
High blood pressure early screening remains a challenge due to the lack of symptoms associated with it. Accordingly, noninvasive methods based on photoplethysmography (PPG) or clinical data analysis and the training of machine learning techniques for hypertension detection have been proposed in the literature. Nevertheless, several challenges arise when analyzing PPG signals, such as the need for high-quality signals for morphological feature extraction from PPG related to high blood pressure. On the other hand, another popular approach is to use deep learning techniques to avoid the feature extraction process. Nonetheless, this method requires high computational power and behaves as a black-box approach, which impedes application in a medical context. In addition, considering only the socio-demographic and clinical data of the subject does not allow constant monitoring. This work proposes to use the wavelet scattering transform as a feature extraction technique to obtain features from PPG data and combine it with clinical data to detect early hypertension stages by applying Early and Late Fusion. This analysis showed that the PPG features derived from the wavelet scattering transform combined with a support vector machine can classify normotension and prehypertension with an accuracy of 71.42% and an F1-score of 76%. However, classifying normotension and prehypertension by considering both the features extracted from PPG signals through wavelet scattering transform and clinical variables such as age, body mass index, and heart rate by either Late Fusion or Early Fusion did not provide better performance than considering each data type separately in terms of accuracy and F1-score.


Repetitive sex change in the stony coral Herpolitha limax across a wide geographic range.
Sex change has been widely studied in animals and plants. However, the conditions favoring sex change, its mode and timing remain poorly known. Here, for the first time in stony corals, we report on a protandrous (youngest individuals are males) repetitive sex change exhibited by the fungiid coral Herpolitha limax across large spatial scales (the coral reefs of Japan, Jordan and Israel) and temporal scales (2004-2017). In contrast to most corals, this species is a daytime spawner (08:00-10:00 AM) that spawned at the same time/same date across all the study sites. The sporadically scattered populations of H. limax among the coral reefs of Eilat (Israel) and Aqaba (Jordan) exhibited significantly slower growth, earlier sex change, and lower percentages of reproduction and sex change in comparison to the densely aggregated populations in Okinawa (Japan). At all sites, sex ratio varied among years, but was almost always biased towards maleness. Growth rate decreased with size. We conclude that comparable to dioecious plants that display labile sexuality in response to energetic and/or environmental constraints, the repetitive sex change displayed by H. limax increases its overall fitness reinforcing the important role of reproductive plasticity in the Phylum Cnidaria in determining their evolutionary success.


Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide.
Cyanide was detected as a product of cyanamide oxidation by bovine liver catalase in vitro under conditions that also produced an active aldehyde dehydrogenase (AlDH) inhibitor. Cyanide formation was directly related to both cyanamide and catalase concentrations and was also dependent on incubation time. The apparent Km for this reaction was 172 microM. Cyanide formation was blocked by ethanol, a known substrate for catalase Compound I. The toxic effects of cyanamide in the dog, a species with limited capacity to conjugate cyanamide by N-acetylation, may be causally related to enhancement of this catalase-mediated pathway for cyanamide metabolism.


Three approaches to improving performance of liquid chromatography using contour maps with pressure, time, and number of theoretical plates.
Attempts to improve HPLC performance often focus on increasing the speed or separation performance. In this article, both the flow rate and column length are optimized as separation conditions, while observing the number of theoretical plates and hold-up time with isocratic elutions. In addition, the upper pressure limit must be simultaneously considered as the boundary condition. Approaches based on the optimal velocity (Opt.) are often adopted; but the kinetic performance limit (KPL) in Desmet's method can also be utilized for three-dimensional graphing with axes of pressure, time, and number of theoretical plates. Here, two approaches involving pressure increase are introduced, beginning with the condition of optimal linear velocity: one aimed at greater speed and the other at higher resolution. Coefficients of pressure-application are derived to measure the effectiveness of the intermediate conditions between the Opt. and KPL methods. In the third approach, the hold-up time is extended while maintaining a fixed pressure. Coefficients of time-extension are also derived, to determine the effectiveness to improve the separation performance.


The burden of medication overuse headache and patterns of switching and discontinuation among triptan users: a systematic literature review.
A synthesis of real-world discontinuation and switching patterns among triptan users and rates of acute medication use among patients with medication overuse headache (MOH) is needed to better understand the burden among patients with migraine. The study objectives were to: (1) synthesize rates of switching and discontinuation from triptans; (2) characterize acute medication use among patients with MOH; and (3) describe the associated burden. A systematic literature review was conducted, under the Preferred Reporting Items for Systematic Review guidelines, using MEDLINE/EMBASE from database inception to July 2019. The search strategy targeted studies of adults with migraine, and included terms related to migraine and its treatment. Continuous variables were summarized using means, standard deviations, and ranges. Dichotomous and categorical variables were summarized using the number and proportion of individuals. Twenty studies were included; seven describing patterns of switching and discontinuation among triptan users, and 13 characterizing triptan overuse among patients with MOH. High rates of switching to non-specific acute medications and low two-year retention rates were reported; among US samples switching to opioids at the first refill (18.2%) or after 1-year (15.5%) was frequent. Compared to persistent use of triptans, switchers experienced greater headache related impact and either no improvement or increased headache-related disability. Rates of medication overuse by agent among patients with MOH varied greatly across the included studies, and only one study described factors associated with the risk of MOH (e.g. duration of medication overuse). Medication agent, increased headache frequency (p = .008), and increased disability (p = .045) were associated with unsuccessful withdrawal; patients overusing triptans were more successful at withdrawal than those overusing opioids or combination analgesics (P < .0001). The evidence summarized here highlights that rates of WCS are low and many patients turn to other acute medication at their first refill. Patients may experience no improvement in disability when switching from one triptan agent to another, or experience increasing disability and/or increasing migraine frequency when turning to traditional acute treatment for migraine. Variability in health care settings, patient severity, and study design contributed to heterogeneity across the synthesis.


Structure of human neutrophil collagenase reveals large S1' specificity pocket.
The crystal structure of the catalytic domain of human neutrophil collagenase complexed with a peptide transition state analogue has been determined to a resolution of 2.1 A. The structure of the neutrophil enzyme, when compared with the three dimensional structure of the corresponding human fibroblast collagenase, shows differences in the first, S1', of the three enzyme specificity subsites on the carboxy-terminal side of the substrate scissile bond. The S1' pocket in the neutrophil collagenase is significantly larger than the equivalent site in the fibroblast enzyme, suggesting that the former enzyme has a broader range of possible substrates. Such differences also suggest approaches for the design of selective matrix metalloproteinase inhibitors.


Protective cardiovascular benefits of exercise training as measured by circulating endothelial cells and high-density lipoprotein in adults.
This study aims to determine the protective cardiovascular effect of aerobic exercise training by measuring cluster of differentiation 146 (CD146), circulating endothelial cell (CEC), and high-density lipoprotein-cholesterol (HDL-C) levels in adults. This study was an experimental pre-post-test without a control group. Forty-five participants were divided into three groups based on aerobic exercise training intensity: low, moderate, and high. Whole blood samples were measured for HDL-C levels. In addition, CEC was isolated from Peripheral Blood Mononuclear Cells (PBMC) samples, then identified by CD146 marker using flow cytometry. CEC percentage and HDL-C increase after aerobic exercise training. There was a significant difference in CEC percentage between the intensity groups. However, there was no difference in HDL-C levels. Aerobic exercise training can protect cardiovascular health by stimulating CEC mobilization, identified by CD146. In addition, an HDL-C level increase also contributes to cardiovascular protection by decreasing inflammation levels, inhibiting low-density lipoprotein-cholesterol oxidation, improving endothelial regeneration capabilities, and lowering blood glucose.


Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29.
The role and regulation of signal transduction pathways in proliferation and differentiation of intestinal epithelial cells are still poorly understood. However, growing evidences have been recently accumulated demonstrating that mitogen-activated protein kinases (MAPKs) play a pivotal function in the normal development of intestine. We have investigated, in the intestinal cell line HT-29, the regulation (namely activity and phosphorylation degree) of MAP kinases ERK 1 (p44) and ERK 2 (p42) during differentiation. Addition of fetal calf serum to HT-29 undifferentiated resting cells caused a rapid phosphorylation of both ERKs and an increase of their specific kinase activity. Moreover, nuclear translocation of ERK 1 and ERK 2 occurred concurrently to their activation, leading to the conclusion that ERK 1 and ERK 2 are classically regulated when quiescent HT-29 cells are induced to proliferate. Butyrate addition to the intestinal cell line resulted in terminal differentiation and in a selective down-regulation of ERK 2 activity (and phosphorylation degree) without any effect on ERK 1. Conversely, when HT-29 cells were differentiated by repeated passages in a glucose-free medium, we observed a progressive dephosphorylation and inactivation of p42 and p44 kinases along with the failure of serum to activate both the enzymes. Our findings suggest that, during the differentiation of intestinal cells, remarkable changes occur in ERK 1 and ERK 2 control mechanisms leading to an unresponsiveness of MAP kinase pathway.


A Systematic Review on Complications of Tissue Preservation Surgical Techniques in Percutaneous Bone Conduction Hearing Devices.
To investigate skin-related postoperative complications from tissue preservation approaches in percutaneous bone conduction device (BCD) implantations. PubMed, Embase, and Cochrane Library. We identified studies on BCDs including the opted surgical technique and derived complications. Retrieved articles were screened using predefined inclusion criteria. Critical appraisal included directness of evidence and risk of bias. Studies that successfully passed critical appraisal were included. Outcome measures included patient demographics, surgery time, follow-up time, and complications reported by Holgers classification. We selected 18 articles for data extraction; encompassing 381 BCDs implanted using non-skin thinning approaches. Four studies reported an implantation technique using the punch method (81 implants), 13 studies applied the linear incision technique without soft tissue reduction (288 implants) and one study used the Weber technique (12 implants). Holgers 3 was described in 2.5% following the punch technique, in 5.9% following the linear incision technique, and in no implants following the Weber technique. One patient was mentioned having Holgers 4, skin overgrowth was reported in 6 patients, and 10 studies compared their non-skin thinning technique with a skin-thinning technique. Overall, the soft tissue preservation technique had a similar or superior complication rate, shorter surgical time, and better and faster healing, compared with the soft tissue reduction technique. Tissue preservation surgical techniques for percutaneous BCDs have limited postoperative skin complication rates. Moreover, these techniques are suggested to have at least similar complications rates compared with skin-thinning techniques.


Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction.
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling.


Enzyme-triggered smart antimicrobial drug release systems against bacterial infections.
The rapid emergence and spread of drug-resistant bacteria, as one of the most pressing public health threats, are declining our arsenal of available antimicrobial drugs. Advanced antimicrobial drug delivery systems that can achieve precise and controlled release of antimicrobial agents in the microenvironment of bacterial infections will retard the development of antimicrobial resistance. A variety of extracellular enzymes are secreted by bacteria to destroy physical integrity of tissue during their invasion of host body, which can be utilized as stimuli to trigger "on-demand" release of antimicrobials. In the past decade, such bacterial enzyme responsive drug release systems have been intensively studied but few review has been released. Herein, we systematically summarize the recent progress of smart antimicrobial drug delivery systems triggered by bacteria secreted enzymes such as lipase, hyaluronidase, protease and antibiotic degrading enzymes. The perspectives and existing key issues of this field will also be discussed to fuel the innovative research and translational application in the future.


Animal models of Parkinson׳s disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535).
Antagonism of the adenosine A2A receptor represents a promising strategy for non-dopaminergic treatment of Parkinson׳s disease (PD). Previously, the adenosine A2A receptor antagonist ST1535 was shown to possess potential beneficial effects in animal models of PD. Two metabolites of ST1535, namely ST3932 and ST4206, were tested in vitro to assess their affinity and activity on cloned human A2A adenosine receptors, and their metabolic profile. Additionally, ST3932 and ST4206 were investigated in vivo in animal models of PD following oral/intraperitoneal administration of 10, 20 and 40mg/kg using ST1535 as a reference compound. ST3932 and ST4206 displayed high affinity and antagonist behaviour for cloned human adenosine A2A receptors. The Ki values for ST1535, ST3932 and ST4206 were 8, 8 and 12nM, respectively, and their IC50 values on cyclic AMP were 427, 450 and 990nM, respectively. ST1535, ST3932 and ST4206 antagonized (orally) haloperidol-induced catalepsy in mice, potentiated (intraperitoneally) the number of contralateral rotations induced by l-3,4-dihydroxyphenylalanine (l-DOPA) (3mg/kg) plus benserazide (6mg/kg) in 6-Hydroxydopamine hydrobromide (6-OHDA)-lesioned rats, and increased mouse motor activity by oral route. Thus, ST3932 and ST4206, two ST1535 metabolites, show a pharmacological activity similar to ST1535, both in vitro and in vivo, and may be regarded as an interesting pharmacological alternative to ST1535.


Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience.
To evaluate the growth, development, and medical histories of children with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening. Chart review of patients diagnosed with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiency at our center. There were 16 children with short-chain acyl-CoA dehydrogenase deficiency, including 10 with two pathogenic mutations, and 8 with isobutyryl-CoA dehydrogenase deficiency. All but one patient has had normal growth and development, and that patient also had the 22q deletion syndrome. Our data and previous reports suggest that the majority of individuals with short-chain acyl-CoA dehydrogenase or isobutyryl-CoA dehydrogenase deficiencies have normal growth and development.


Nuclear import: a tale of two sites.
The recently determined crystal structure of a nuclear localization sequence receptor has revealed an exquisitely specific interaction between ligand and receptor, and explains how simple and complex nuclear localization signals can both be recognized specifically by the same molecule.


Human stem cell models: lessons for pancreatic development and disease.
A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed to decipher mechanisms of pancreatic development, congenital defects of the pancreas, as well as genetic forms of diabetes and exocrine diseases. In this review, we summarize recent insights gained from studies of pancreatic hPSC models. We discuss how genome-scale analyses of the differentiation system have helped elucidate roles of chromatin state, transcription factors, and noncoding RNAs in pancreatic development and how the analysis of cells with disease-relevant mutations has provided insight into the molecular underpinnings of genetically determined diseases of the pancreas.


Cell-mediated immune reactions to clinical neuroblastoma.
Immunotherapy may be an effective treatment for neuroblastoma. It is of importance to delineate changes in various parameters of tumor immunity over an extended period, before and during the course of treatment, in any given case. In our patients with neuroblastoma, tumor-associated cell-mediated immune-reaction showed a good responsiveness before treatment. However, delayed cutaneous hypersensitivity reactions were shown to be negative in many cases, particularly in those with advanced tumor, and T gamma cells were enormously increased in some cases. During the course of therapy, the tumor-associated cellular immune responsiveness showed a tendency to become negative when the patient was tumor free or was in remission, but showed a tendency to become positive on regrowth, recurrence or metastasis of tumor. The T gamma cells showed much the same fluctuations as did the tumor-associated cellular immune responsiveness.


The effect of light on stomatal control of gas exchange in Douglas fir (Pseudotsuga menziesii) saplings.
Attached twigs of young Pseudotsuga menziesii (Mirb.) Franco plants were subjected to variations in irradaince. Stomatal responsiveness to irradiance, measured in an open type gas exchange system, varied seasonally. During the autumn and winter, stomatal conductance was relatively unresponsive to changes in irradiance, but during the summer stomatal conductance decreased in response to reduced irradiance. The summer stomatal response to irradiance was such that a nearly constant ratio of stomatal conductance to net photosynthesis was maintained as irradiance was varied. This caused intercellular CO2 concentration (c i) and water use efficiency (net CO2 uptake/transpiration) to also remain relatively constant. At constant irradiance, stomatal conductance was relatively insensitive to experimentally-induced changes in c i. This, and the observation that c i remained relatively constant as irradiance was varied, suggest that changes in c i played a minor role in mediating the stomatal response to light.The ecological significance of the seasonal changes in stomatal response to light is discussed.


Analysis of the clinicopathological characteristics and prognosis of adenoid cystic carcinoma of the intraoral minor salivary glands: a retrospective study of 40 cases.
The clinicopathological aspects and prognostic factors of 40 patients with adenoid cystic carcinoma (ACC) of the intraoral minor salivary glands, treated between 2007 and 2017 at a single institution, were evaluated retrospectively. Twenty-six were female and 14 were male, and they ranged in age from 26 to 81 years (median 55 years). ACC occurred mainly in the palate, with 54.8% of cases presenting T3-T4 lesions. Curative surgery was performed in all patients, and 62.5% of patients were treated with postoperative adjuvant radiotherapy. In the final analysis, positive surgical margins were noted in 57.5% of cases and perineural invasion in 70%. Follow-up was at least 13 months (range 13-141 months, median 59 months). Nineteen patients (47.5%) developed recurrent disease after initial surgery and nine patients had died at the end of follow-up. The 5- and 10-year overall survival rates were 88.3% and 25.6%, respectively. The 5- and 10-year disease-free survival rates were 75.6% and 34.0%, respectively. Patients with a tumour size >4cm and those with positive surgical margins showed a significantly higher risk of local recurrence. Elective neck dissection is suggested for patients with clinically positive lymph nodes or a locally advanced tumour, especially those undergoing microvascular reconstruction. The survival analysis results are similar to those reported previously in the literature.


Epidemic renal disease of unknown etiology in the Zuni Indians.
An epidemic of renal disease is occurring among the Zuni Indians in western New Mexico. In 1985, 1.6% of Zunis had clinically recognized renal disease and 1% had renal insufficiency. The incidence of end-stage renal disease (ESRD) in 1984 and 1985 was 14 times the rate for US whites, and three times the rates of other Indians in ESRD network 6. One third of the cases of renal disease and ESRD is due to type 2 diabetes, but the etiology of disease in most of the remainder is unknown. Affected subjects range from early childhood to old age. Early signs are hematuria, mild to moderate proteinuria, normal BP, and low total hemolytic complement, normal or low C3 and C4 levels, in about 40% of the cases. The clinical course varies from benign to rapidly progressive renal failure. Biopsies usually reflect an immune-complex mediated mesangiopathic glomerulonephritis, with IgA, IgG, IgM, and C3 variably present in the mesangium. In some cases, there is a very strong familial pattern suggesting autosomal dominant inheritance or a marked communal exposure effect. This may be a genetic disease educed by the consanguinity in the ethnically homogeneous Zuni population. Mesangiopathic renal disease is common in some Oriental populations, and this phenomenon may reflect the American Indians' Oriental ancestry. This disease may also be due to toxic exposures related to jewelry-making, potting, Zuni water, Zuni salt, or herbal or other products used for medicinal or religious purposes. This epidemic is much morbidity and generating huge costs for ESRD treatment. Further study is needed to better understand its etiology.


Eagle Claw II: A novel endosuture device that uses a curved needle for major arterial bleeding: a bench study.
Control of bleeding from major arteries in the upper-GI tract remains difficult with currently available endoscopic devices. We designed an endosuture device that uses a curved needle and extracorporeal knotting, and assessed the device in stopping arterial bleeding in a bench model. Harvested porcine splenic arteries (2-mm diameter) were tunneled submucosally in pig stomach with the open end protruding into an artificially created mucosal defect. The outer end of the vessel was connected to a pulsatile pump, and red ink was infused at a pressure of about 100 mm Hg. The stomach was installed on an Erlangen endo-training model. The suturing device (Eagle Claw II), mounted outside an endoscope, has an eyed, curved needle that carries a 3-0 nylon thread. After puncture, the thread was retrieved by using a hook. Three-throw square knots were tied at the thread extracorporeally and were pushed into place by using a knotting cap. The criteria of successful plication was defined as hemostasis after knotting, no leakage at pressures of >200 mm Hg, and the vessel was completely encircled by the suture. A total of 25 sutures were made with the mean time of 9.38 minutes (standard deviation 1.51). Control of the bleeding was obtained with 17 sutures (68%). The causes for failure were the following: a suture was too shallow (4), a loose knot (2), incorrect suture position (1), and stomach-wall edema (1). Control of bleeding from large arteries by using endoscopic suturing is possible. Continued refinements of the device are required.


Just how strapping was KNM-WT 15000?
For over twenty years, the young, male Homo erectus specimen KNM-WT 15000 has been the focus of studies on growth and development, locomotion, size, sexual dimorphism, skeletal morphology, and encephalization, often serving as the standard for his species. Prior research on KNM-WT 15000 operates under the assumption that H. erectus experienced a modern human life history, including an adolescent growth spurt. However, recent fossil discoveries, improvements in research methods, and new insights into modern human ontogeny suggest that this may not have been the case. In this study, we examine alternative life history trajectories in H. erectus to re-evaluate adult stature estimates for KNM-WT 15000. We constructed a series of hypothetical growth curves by modifying known human and chimpanzee curves, calculating intermediate growth velocities, and shifting the age of onset and completion of growth in stature. We recalculated adult stature for KNM-WT 15000 by increasing stature at death by the percentage of growth remaining in each curve. The curve that most closely matches the life history events experienced by KNM-WT 15000 prior to death indicates that growth in this specimen would have been completed by 12.3 years of age. These results suggest that KNM-WT 15000 would have experienced a growth spurt that had a lower peak velocity and shorter duration than the adolescent growth spurt in modern humans. As a result, it is likely that KNM-WT 15000 would have only attained an adult stature of 163 cm (∼ 5'4 ″), not 185 cm (∼ 6'1 ″) as previously reported. KNM-WT 15000's smaller stature has important implications for evolutionary scenarios involving early genus Homo.


Nerve Surgeons' Assessment of the Role of Eduard Pernkopf's Atlas of Topographic and Applied Human Anatomy in Surgical Practice.
(Reprinted with permission from NEUROSURGERY, Volume 84, Number 2, February 2019).


[Killing effect of human pulmonary adenocarcinoma cells with TK + CD/5-Fc + GCV coexpression suicide gene systems].
To investigate the different killing effect to human pulmonary adenocarcinoma cell line cells GLC-82 with coexpressed double suicide genes compared with single gene. Recombinant expression vectors containing CD (cytosine deaminase) and/or TK (thymidine kinase) gene under CMV promoter were constructed successfully. The vectors were transfected to GLC-82 tumor cell lines by use of lipofectamine. The clones were picked out after G418 selection. Extraneous gene integration and expression were confirmed by PCR and semi-quantitative RT-PCR. The cytotoxicity to these transgenic cells under treatment with 5-Fc and GCV were measured by MTT assays. Double and single suicide gene transfer were both stably expressed in GLC-82 cells. The cytotoxic effects of co-expressed TK-CD genes were superior than that of the single gene. The CD + TK/5-Fc + GCV co-expression system is more effective for killing effect of tumor cells than CD/5-Fc or TK/GCV system alone.


Bone scan artifact caused by hyperhidrosis: case report.
An unusual unilateral axillary concentration of radioactivity was observed in a bone scan. The cause was contamination of the patient's undershirt due to localized hyperhidrosis.


Abdominal sepsis patients have a high incidence of chronic critical illness with dismal long-term outcomes.
As hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes. Review of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis. Of the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p < 0.05). Over 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.


Preoperative pregabalin does not reduce propofol ED(50): a randomized controlled trial.
In many studies, gabapentinoids, such as pregabalin, have been shown to reduce preoperative anxiety. This anxiolysis is often accompanied by sedation, one of the most frequent side effects of pregabalin. We hypothesized that pregabalin taken preoperatively could reduce propofol requirements for induction of general anesthesia. A randomized double-blind placebo-controlled trial was conducted after approval by the local ethics committee. Fifty women aged 18-40 yr, American Anesthesiologists Society physical status I and II, and scheduled to undergo elective laparoscopic gynecologic procedures were enrolled after written consent. Treatment group patients were given pregabalin 150 mg po one hour before surgery while patients in the control group received a placebo. The primary outcome was the propofol dose required to achieve a targeted anesthetic depth in 50% of the population, i.e., effective dose (ED)50. The ED50 was estimated using Dixon's up-and-down methodology. The targeted anesthetic depth was defined based on predetermined entropy monitoring values (State Entropy [SE] < 50 and Response Entropy [RE]-SE < 10). As a secondary outcome, we tested if pregabalin reduced pre-induction anxiety levels which were measured on a 0-100 scale. The propofol ED50 was not statistically different between the pregabalin group (mean 1.33 mg·kg(-1); 95% confidence interval [CI] 1.23 to 1.43) vs the placebo group (mean 1.37 mg·kg(-1); 95% CI 1.28 to 1.46); P = 0.19. Also, pre-induction anxiety level was not different between groups (median 31; interquartile range [IQR] [10-52] vs median 42; IQR [4-71], respectively; P = 0.41). Preoperative pregabalin does not reduce propofol requirements in a population of healthy young women undergoing laparoscopic gynecologic procedures. This study failed to show a pre-induction anxiolytic effect of pregabalin in such a population. This trial was registered at www.clinicaltrials.gov (NCT01158859).


Induction of cytotoxic T lymphocytes by dendritic cells pulsed with murine leukemic cell RNA.
Peptide-pulsed dendritic cells can stimulate T cells showing specific cytotoxicity in chronic myelogenous leukemia. We tried to induce a specific cytotoxic T-cell response stimulated by RNA-pulsed dendritic cells in acute myelogenous leukemia. The total RNA of WEHI-3BD+, a myelomonocytic leukemia cell line derived from BALB/c mice, was transfected into dendritic cells induced from bone marrow nucleated cells of BALB/c mice with granulocyte macrophage colony-stimulating factor (GM-CSF) and lipopolysaccharide (LPS) using liposome. RNA-pulsed dendritic cells were injected into the peritoneal cavity of BALB/c mice, and splenic T cells were isolated for antigen-stimulated proliferation and leukemia-specific cytotoxicity assay. Cultured bone marrow nucleated cells expressed dendritic cell markers including MHC class II antigen, CD80, CD86, and CD11c. T cells stimulated by RNA-pulsed dendritic cells showed enhanced proliferation than those stimulated by unpulsed dendritic cells (P = 0.05) and showed dose-dependent specific cytotoxicity against WEHI-3BD+ cells. We concluded total RNA-pulsed dendritic cells could induce a specific T-cell cytotoxicity in acute myelogenous leukemia.


Allergen carriage by atmospheric aerosol. I. Ragweed pollen determinants in smaller micronic fractions.
Outdoor air-bearing natural ragweed pollen burdens were drawn through 5 microns membrane filters during 24 hr periods; aerosols penetrating these barriers were collected on individual, in-line, 0.8 microns filters. The 0.8 microns filters were free of intact pollen grains and grain fragments when scanned in toto by transmitted light. Aqueous extracts of 0.8 microns filters were found to elicit wheal-and-flare skin test reactions in a ragweed pollen-sensitive subject but not in nonatopic controls. The same extracts produced significant inhibition of an IgG-ELISA system by use of ragweed pollen protein conjugated to polystyrene plate wells and pooled serum of patients on ragweed immunotherapy. No inhibition resulted from preincubation of serum with an unrelated allergen (hickory pollen extract). These data indicate the presence of airborne ragweed pollen allergen in aerosol fractions below 5 microns during seasonal periods of ragweed pollination, confirming the report of Busse et al. Potential sources of such aerosols are prominent in nature, and their occurrence may help explain existing dose-response disparities in pollinosis.


Brain-derived neurotrophic factor (BDNF)-like immunoreactivity localization in the retina and brain of Cichlasoma dimerus (Teleostei, Perciformes).
Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the development and maintenance of vertebrate nervous systems. Although there were several studies in classical animal models, scarce information for fish was available. The main purpose of this study was to analyze the distribution of BDNF in the brain and retina of the cichlid fish Cichlasoma dimerus. By immunohistochemistry we detected BDNF-like immunoreactive cells in the cytoplasm and the nuclei of the ganglion cell layer and the inner nuclear layer of the retina. In the optic tectum, BDNF-like immunoreactivity was detected in the nucleus of neurons of the stratum periventriculare and the stratum marginale and in neurons of the intermediate layers. In the hypothalamus we found BDNF-like immunoreactivity mainly in the cytoplasm of the nucleus lateralis tuberis and the nucleus of the lateral recess. To confirm the nuclear and cytoplasm localization of BDNF we performed subcellular fractionation, followed by Western blot, detecting a 39 kDa immunoreactive-band corresponding to a possible precursor form of BDNF in both fractions. BDNF-like immunoreactivity was distributed in areas related with photoreception (retina), the integration center of retinal projections (optic tectum) and the control center of background and stress adaptation (hypothalamus). These results provide baseline anatomical information for future research about the role of neurotrophins in the adult fish central nervous system.