All-Inside Anterior Cruciate Ligament Reconstruction Using Quadrupled Semitendinosus: Comparable 2-Year Outcomes in Male and Female Patients.
To determine 2-year functional outcomes using an all-inside quadrupled semitendinosus anterior cruciate ligament (ACL) reconstruction technique in male and female patients. A total of 100 patients who underwent quadrupled semitendinosus all-inside hamstring ACL reconstruction by a single surgeon were enrolled. Patient-reported outcome scores collected preoperatively and postoperatively included visual analog scale, Veterans Rand 12-Item Health Survey (VR-12; Physical and Mental), Marx Activity Scale, Knee Injury and Osteoarthritis Outcome Scores (KOOS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A total of 100 ACL reconstructions comprising 62 female, and 38 male patients were included in this study. Mean graft diameter was 9.4 mm in female and 9.8 mm in male patients (range, 9-11). Outcome scores demonstrated improvement from preoperative to 2-year postoperative respectively: visual analog scale pain 3.18, 1.07, VR-12 physical 36.35, 52.64, VR-12 mental 53.96, 54.65, KOOS pain 59.17, 89.03, KOOS symptoms 52.64, 80.79, KOOS Activities of Daily Living 69.38, 95.4, KOOS Sport 28.97, 81.25, KOOS Quality of Life 27.54, 71.56, WOMAC Pain 71.56, 92.65, WOMAC Stiffness 60.55, 84.13, and WOMAC Function 69.38, 95.4. Marx activity score decreased from baseline (10.98) to 2 years' postoperatively (8.75). At 2 years, patient expectations were met or exceeded with regards to pain (94%), motion and strength (91%), normal function of daily living (95%), and return to sport (79%). Anatomic all-inside quadrupled semitendinosus ACL reconstruction improves functional outcomes similarly to previous studies between baseline and clinical follow-up at 1-year and 2-years postoperatively and is comparable in both male and female patients. Level III, retrospective comparative study.


Contact times of change-of-direction manoeuvres are influenced by age and the type of sports: a novel protocol using the SpeedCourt® system.
Side-to-side asymmetry in side-cutting manoeuvres is a known risk factor for severe knee injury. Potential leg asymmetry during ground contact times of different change-of-direction manoeuvres was evaluated in athletes by means of the recently developed SpeedCourt® system. The hypotheses were that ground contact times and the limb symmetry index are affected by age and the type of sports. One-hundred and sixty-five athletes (149 men, 16 women, age 16.5 ± 5.1) of popular team sports such as football, team handball and baseball were assessed by means of three different tests [side-hop, lateral change-of-direction (COD) and diagonal COD] using the SpeedCourt® system. Analysis included the factors age, sex, type of sports, ground contact time, leg symmetry index and limb dominance. During lateral but not diagonal COD tests, football players had shorter contact times than players of team handball (p = 0.026) and baseball (p = 0.015) of the same age group. The side-hop tests yielded differences in the leg symmetry index between players < 16 years and players > 16 years (p < 0.01). Mean ground contact time differed in each of the side-hop, lateral COD and diagonal COD tests (143.5 ± 20.0 vs. 256.2 ± 66.1 vs. 320.4 ± 55.0). Contact times and test durations of side-hop, lateral COD and diagonal COD tests were shorter for older players (p < 0.01). Ground contact times of side-hop and change-of-direction manoeuvres are influenced by age, the type of sports and limb dominance. Such information is fundamental for future sports medicine research and needs to be considered in pre-season screening or when used as a criterion for return-to-competition of players with previous severe knee injury. Assessment of change-of-direction manoeuvres should be included in future return-to-competition test batteries. III.


Thrombophlebitis and pseudothrombophlebitis in the ED.
The patient presenting to the emergency department (ED) with a painful swollen lower extremity is considered to have deep venous thrombosis (DVT) until this diagnosis can be ruled out. This clinical presentation, however, is far from specific and the differential diagnosis includes symptomatic Baker's cyst, also known as pseudothrombophlebitis syndrome (PTP). This article presents two cases of PTP and reviews the literature relevant to diagnosis of DVT and PTP. Ultrasonography is now the diagnostic test of choice for both DVT and PTP, being safe, accurate, noninvasive, and rapid, and should ideally be available for use in the ED.


Recontact: a survey of current practices and BRCA1/2 testing in Japan.
Genetic testing advances have enabled the provision of previously unavailable information on the pathogenicity of genetic variants, frequently necessitating the recontact of former patients by clinicians. In Japan, national health insurance coverage was extended to BRCA1/2 testing for the diagnosis of hereditary breast and ovarian cancer for patients who meet certain criteria in 2020, and conditions necessitating recontact were expected to increase. Studies and discussions regarding recontact have been conducted in the U.S. and Europe; however, in Japan, the national discussion around recontact remains undeveloped. We conducted a cross-sectional study by interviewing 73 facilities accredited by the Japanese Organization of Hereditary Breast and Ovarian Cancer regarding the practice of recontacting patients at these facilities. Sixty-six facilities responded that they recontact patients, but only 17 facilities had a protocol for this. The most common reason for recontact was that it could benefit the patient. Facilities that did not recontact stated that they lacked the necessary personnel or services. Most facilities indicated that a recontact system should be implemented in their practice. The increased burden on too few medical personnel, unestablished systems, patient confusion, and the right not to know were cited as barriers to implementing recontact. Although developing recommendations on recontact would be useful for providing equitable healthcare in Japan, there is an urgent need to deepen the discussion on recontacting, as negative opinions about recontacting patients were observed.


Single cell activity in ventral prefrontal cortex of behaving monkeys.
Single unit activity was recorded extracellularly from ventral prefrontal cortex (VPC) of monkeys during performance of two short-term memory tasks: spatial delayed response and delayed matching to sample. The tasks required perception, retention and recognition of visual cues differing in either color or spatial location. Two separate areas of VPC were explored: a lateral area in the lower prefrontal convexity and a medial area around the medial orbital sulcus. Two categories of unit activity were distinguished on the basis of frequency changes to the cue. One was characterized by non-specific discharge independent upon which cue was presented, the other by discriminative discharge related not only to visual qualities of the cue but to the animal's subsequent use of it. Nearly one-half of all units showed altered firing during the retention (delay) period as compared with intertrial control firing. Eighteen per cent displayed delay activity related to the quality of the preceding cue. The lateral and medial segments of VPC were not distinguished by differences of unit activity in cue or delay periods. Post-trial activity was related to presence or absence of reward. Type I cells showed firing changes following choice reinforcement as well as gratuitous reward; some showed changes in opposite direction following unreinforced choices. They may encode the availability of reward. Type II cells showed changes of activity after unreinforced trials and, in some cases, opposite changes after unexpected reward; they were not affected by the reward of normal correct-choice trials. These cells appear to react to deviations from expectancy of reward. Type III cells exhibited comparable firing changes following reinforced and unreinforced choices. They may encode termination of a trial sequence. Type I was more common in lateral than medial VPC, whereas the opposite was true for type II; type III did not clearly predominant in either area. Ablation studies have shown that the two areas of VPC differ in behavioral functions. This study of their cellular properties revealed topographic differences only during the post-trial period. It is therefore possible that the combination of cue and delay activity (related to exteroceptive input) with post-trial activity (related to interoceptive input) constitutes the neuronal basis for the two areas' differences in behavioral function.


Industry-Specific Profile of COVID-19-Related Workers' Compensation Claims in New York State.
This study aimed to characterize the distribution and award status of COVID-19-related workers' compensation (WC) claims in New York State (NYS) for 2020 and 2021. Characteristics and filing rates of COVID-19 claims were described by industry, time of illness, and award status. Nursing care facilities' claims were compared with the recorded nursing home staff COVID-19 infections and deaths reported by the Centers for Medicare & Medicaid Services (CMS) during the same period. Of 29,814 COVID-19 claims, 21.9% were awarded benefits, although 86.8% of the claimants worked in essential industries. Of the 46,505 CMS-recorded COVID-19 infections, 1.4% resulted in a claim and 7.2% of the 111 CMS-recorded deaths received death benefits. The NYS WC program has provided very modest support to essential workers for the likely work-related burden of the pandemic in NYS.


Multivariate adaptive regression splines: a powerful method for detecting disease-risk relationship differences among subgroups.
In a wide variety of medical research scenarios one is interested in the question whether regression curves differ for subgroups in the sample. Examples are gender differences in the effect of drug treatment or the study of genotype-environment interactions. To address this question exploratory techniques are often required because detailed knowledge concerning the shape of the regression curves and how that shape differs across subgroups is lacking. In this article we explored the power of two such exploratory techniques: multivariate adaptive regression splines (MARS) and least squares curve fitting using polynomials. For this purpose simulations were performed using linear, logistic, and complex non-linear curves. The power obtained from MARS was on average 1.4 times higher than with polynomials. It was shown that power was higher even if the regression curve was linear, that gains increased with the complexity of the curve, and that for highly non-linear curves model-free methods such as MARS might be the only alternative.


Epsilon aminocaproic acid is associated with acute kidney injury after life-threatening hemorrhage in children.
Antifibrinolytic medications have been associated with reduced mortality in pediatric hemorrhage but may contribute to adverse events such as acute kidney injury (AKI). We conducted a secondary analysis of the MAssive Transfusion in Children (MATIC), a prospectively collected database of children with life-threatening hemorrhage (LTH), and evaluated for risk of adverse events with either antifibrinolytic treatment, epsilon aminocaproic acid (EACA) or tranexamic acid (TXA). The primary outcome was AKI and secondary outcomes were acute respiratory distress syndrome (ARDS) and sepsis. Of 448 children included, median (interquartile range) age was 7 (2-15) years, 55% were male, and LTH etiology was 46% trauma, 34% operative, and 20% medical. Three hundred and ninety-three patients did not receive an antifibrinolytic (88%); 37 (8%) received TXA and 18 (4%) received EACA. Sixty-seven (17.1%) patients in the no antifibrinolytic group developed AKI, 6 (16.2%) patients in the TXA group, and 9 (50%) patients in the EACA group (p = .002). After adjusting for cardiothoracic surgery, cyanotic heart disease, preexisting renal disease, lowest hemoglobin pre-LTH, and total weight-adjusted transfusion volume during the LTH, the EACA group had increased risk of AKI (adjusted odds ratio 3.3 [95% CI: 1.0-10.3]) compared to no antifibrinolytic. TXA was not associated with AKI. Neither antifibrinolytic treatment was associated with ARDS or sepsis. Administration of EACA during LTH may increase the risk of AKI. Additional studies are needed to compare the risk of AKI between EACA and TXA in pediatric patients.


Controlled acute and follow-up trial of cognitive therapy and pharmacotherapy in out-patients with recurrent depression.
We report a randomised controlled trial, in both the acute and maintenance stage of treatment, in 75 out-patients with recurrent major depression. Patients were allocated to three groups: 16 weeks of acute treatment and two years' maintenance treatment in the following way: antidepressants and maintenance antidepressants; cognitive therapy and maintenance cognitive therapy; antidepressants and maintenance cognitive therapy. Both completers' and end-point data were analysed. In the acute phase of treatment, all patients improved significantly and there was no significant difference among treatments, or in the pattern of improvement over time. In the maintenance stage of treatment, patients kept improving over time in all three groups and there was no significant difference among treatments. Cognitive therapy was consistently superior to medication. The results indicate that maintenance cognitive therapy has a similar prophylactic effect to maintenance medication and is a viable option for maintenance after acute treatment with medication in recurrent depression.


Effects of Lactobacillus plantarum and Saccharomyces cerevisiae co-fermentation on the structure and flavor of wheat noodles.
Although traditional fermented noodles possess high eating quality, it is difficult to realize large-scale industrialization as a result of the complexity of spontaneous fermentation. In present study, commercial Lactobacillus plantarum and Saccharomyces cerevisiae were applied in the preparation of fermented noodles. The changes in the structural characteristics and aroma components of noodles after fermentation were investigated via scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), low-field magenetic resonance imaging, electronic nose, and simultaneous distillation and extraction/gas chromatography-mass spectrometry (GC-MS) analysis. SEM images revealed that co-fermentation of the L. plantarum and S. cerevisiae for 10-40 min enhanced the continuity of the gluten network and promoted the formation of pores. FTIR spectra analysis showed that the co-fermentation increased significantly (P < 0.05) the proportion of α-helices of noodles gluten protein, enhancing the orderliness of the molecular structure of protein. After fermentation for 10-40 min, the signal density of hydrogen protons increased from the surface to the core, indicating that the water in the noodles migrated inward during a short fermentation process. The results of multivariate statistical analysis demonstrated that the main aroma differences between unfermented and fermented noodles were mainly in hydrocarbons, aromatic compounds and inorganic sulfides. GC-MS analysis indicated that the main volatile compounds detected were 2, 4-di-tert-butylphenol, bis (2-ethylhexyl) adipate, butyl acetate, dibutyl phthalate, dioctyl terephthalate, bis (2-ethylhexyl) phthalate, pentanol and 2-pentylfuran, etc. CONCLUSION: Co-fermentation with L. plantarum and S. cerevisiae improved the structure of gluten network and imparted more desirable volatile components to wheat noodles. © 2022 Society of Chemical Industry.


4-Salicylideneamino-3-methyl-1,2,4-triazole-5-thione as a sensor for aniline recognition.
Tridentate triazole based Schiff base 4-salicylideneamino-3-methyl-1,2,4-triazole-5-thione has been found to selectively detect toxic aromatic amines such as aniline and benzene-1,4-diamine by simple titration techniques like UV-visible, fluorescence spectral studies (PL) and 1H NMR titrations. The Schiff base receptor utilizes, thione sulfur, NH-thione and the phenolic hydroxyl group to form hydrogen bonded adduct of aniline and benzene-1,4-diamine with high binding affinity, followed by a slow removal of the corresponding hydrogens thus providing a promising candidate and an unique receptor for toxic aromatic amines.


Effects of ginsenosides, active components of ginseng, on nicotinic acetylcholine receptors expressed in Xenopus oocytes.
We investigated the effects of ginsenosides, the active ingredient of ginseng, on neuronal or muscle-type nicotinic acetylcholine receptor channel activity expressed in Xenopus oocytes after injection of cRNA encoding bovine neuronal alpha3beta4, alpha7 or human muscle alphabetadeltavarepsilon subunits. Treatment with acetylcholine elicited an inward peak current (I(ACh)) in oocytes expressing nicotinic acetylcholine receptor subtypes. Cotreatment with ginsenoside Rg2 and acetylcholine inhibited I(ACh) in oocytes expressing with alpha3beta4 or alphabetadeltavarepsilon but not in oocytes expressing alpha7 nicotinic acetylcholine receptors. The inhibition of I(ACh) by ginsenoside Rg2 was reversible and dose-dependent. The half-inhibitory concentrations (IC50) of ginsenoside Rg2 were 60.2+/-14.1 and 15.7+/-3.5 microM in oocytes expressing alpha3beta4 and alphabetadeltavarepsilon nicotinic acetylcholine receptors, respectively. The inhibition of I(ACh) by ginsenoside Rg2 was voltage-independent and noncompetitive. Other ginsenosides besides ginsenoside Rg2 also inhibited I(ACh) in oocytes expressing alpha3beta4 or alphabetadeltavarepsilon nicotinic acetylcholine receptors. The order of potency for the inhibition of I(ACh) was ginsenoside Rg2>Rf>Re>Rg1>Rc>Rb2>Rb1 in oocytes expressing alpha3beta4 nicotinic acetylcholine receptors and was ginsenoside Rg2>Rf>Rg1>Re>Rb1>Rc>Rb2 in oocytes expressing alphabetadeltavarepsilon nicotinic acetylcholine receptors. These results indicate that ginsenosides might regulate nicotinic acetylcholine receptors in a differential manner and this regulation might be one of the pharmacological actions of Panax ginseng.


Process of differentiation of cerebellar Purkinje neurons in the chick embryo.
The microscopic and ultrastructural differentiation of Purkinje neurons has been studied in 40 chicken embryo cerebella, from the 10th incubation day to hatching, and the transverse diameter of the cell body measured, for each developmental stage, on 30 electron micrographs of sagittally cut Purkinje cells. The developing Purkinje cell bodies, bipolar, at first, given the presence of two processes emerging from the opposite poles of the oval perikaryon, grow progressively in size. After the 12th incubation day, they develop a branched dendritic tree, and, shortly before hatching time, the cells acquire the characteristic flask or pear-shaped configuration. On the 10th incubation day, microtubules are already detectable together with Golgi complexes and a few vesicles of rough endoplasmic reticulum; on the 14th incubation day, RER cisterns are recognizable in the supranuclear cytoplasm, later extending into the whole perikaryon, and attaining their definitive distribution by the 18th incubation day. Pinocytotic and coated vesicles, as well as subsurface cisterns are seen during the whole embryonic life. In the earliest stages of development, three distinct types of junctional contacts between Purkinje cells and surrounding axons are described, and their functional role in relation to synaptogenetic processes is discussed. Beginning with the 16th incubation day, some Purkinje neurons undergo degenerative changes similar to those described in other types of neurons of the central and peripheral nervous system.


The impact of cost-sharing on appropriate utilization and health status: a review of the literature on seniors.
This article provides a review of research that has addressed the impact of patient cost sharing on the use of services and resulting health status impacts, among the population age 65 and older. Nearly all of the 22 relevant studies examined that have been published since 1990-16 focusing on cost-sharing for prescription drugs and 6 on cost-sharing for medical services--conclude that increased cost-sharing reduces either or both the utilization and health status of seniors. Most of the studies, however, rely on cross-sectional and self-reported data. Further research, employing stronger study designs as well as clinical and administrative data, is necessary before drawing more definitive conclusions.


Relation between mental stress-induced prefrontal cortex activity and skin conditions: a near-infrared spectroscopy study.
Although psychological stress affects skin condition, the neurophysiological mechanism involved is unclear. In this study, we evaluated the relationship between skin condition and left/right asymmetry in prefrontal cortex (PFC) activity during mental stress tasks since recent studies have suggested that the right PFC dominates the regulation of the stress response system, including the hypothalamic-pituitary-adrenal (HPA) axis. Using near-infrared spectroscopy, we measured hemoglobin concentration changes in the bilateral PFC during a mental arithmetic task in normal adults and evaluated the laterality scores (i.e., [(right-left)/(right+left)]) of oxyhemoglobin concentration changes. Elicitation of stress was verified by the State-Trait Anxiety Inventory (STAI) and heart rate. The sebum levels and Propionibacterium acnes populations in the facial skin were measured before the task. The task significantly increased the STAI-II scores (p=0.00079) and heart rate (p=0.0000049). The oxyhemoglobin concentration increased in the bilateral PFC during the task, associated with a decrease in deoxyhemoglobin concentration. The laterality scores of oxyhemoglobin concentration changes were positively correlated with sebum levels (r=+0.50, p=0.026) and P. acnes populations (r=+0.49, p=0.029) in the facial skin before the task. There was a significant positive correlation between heart rate changes and the laterality scores of oxyhemoglobin concentration changes (r=+0.54, p=0.015). These results demonstrate that the subjects with higher sebum levels and higher P. acnes populations in the facial skin have a right dominant PFC activity during a mental stress task and suggest that such subjects are sensitive to mental stress associated with hyperactivity of the stress response system, including the HPA axis system.


Evaluation of virucidal activity of three commercial disinfectants and formic acid using bovine enterovirus type 1 (ECBO virus), mammalian orthoreovirus type 1 and bovine adenovirus type 1.
A modified version of the test method of the Comité Européen de Normalisation (CEN) was developed using formic acid and three commercial disinfectants to evaluate virucidal activity against three non-enveloped viruses, bovine enterovirus type 1 (ECBO virus), mammalian orthoreovirus type 1 and bovine adenovirus type 1 (BAV 1). Determination of the effects of temperature was carried out at 20 and 10 degrees C. All tests with protein load used bovine serum albumin (BSA) and yeast extract. The investigations were performed in suspension tests and in carrier tests using poplar wood virus carriers. The carrier tests showed that ECBO virus could be inactivated at 20 degrees C with 1% formic acid within a 60 min reaction time. For disinfection of ECBO virus at 10 degrees C within 60 min, a 2% concentration of formic acid was necessary. Formic acid was ineffective against reovirus and bovine adenovirus and cannot be recommended as a reference disinfectant. Inactivation of ECBO virus and adenovirus type 1 using a disinfectant containing aldehydes and alcohols could be achieved, but only at room temperature. The disinfection of reovirus type 1 at room temperature with this product was possible without a protein load. This disinfectant exhibited disinfection ability at 10 degrees C at a concentration of more than 2% or with a longer exposure time. A disinfectant containing aldehydes was effective at room temperature but its effect was reduced in the presence of organic matter. Inactivation at 10 degrees C was found only against adenovirus. The fourth disinfectant, which contained peroxiacetic acid, inactivated all test viruses at a concentration of 0.5% within 15 min independent of temperature and protein load.


Labeling of monoclonal antibodies with a 67Ga-phenolic aminocarboxylic acid chelate. Part I. Chemistry and labeling technique.
As a chelating agent for labeling antibodies (Abs) with metallic radionuclides, a propionic acid substituted ethylenediamine N,N'-di-[(o-hydroxyphenyl) acetic acid] (P-EDDHA), which tightly complexes 67Ga, was synthesized. The 67Ga-P-EDDHA chelate was coupled in aqueous solution to IgG at a molar ratio of 1:1 via carbodiimide. The average coupling yield was 15%. A specific activity of 4 mCi/mg IgG could be obtained with commercially supplied 67Ga. In vitro stability was evaluated in human serum at 37 degrees C and showed a half-life of about 120 h for the release of 67Ga from the labeled Ab during the initial phase of incubation. This in vitro halflife is similar to that measured for 111In-DTPA labeled Abs. Because of the high stability of the 67Ga-P-EDDHA chelate, the in vivo formation of radioactive labeled transferrin by transchelation, as described for 111In-DTPA labeled Abs, should, however, be reduced by this labeling technique.


Encapsulation of Bunium persicum essential oil using chitosan nanopolymer: Preparation, characterization, antifungal assessment, and thermal stability.
The present study reports the antifungal, aflatoxin B1 inhibitory, and free radical scavenging activity of chitosan-based nanoencapsulatedBunium persicum Boiss. essential oil (Ne-BPEO). The chemical profile ofBPEO was identified through Gas chromatography mass spectrometry analysis where cuminaldehyde (21.23%), sabinene (14.66%), and γ-terpinen (12.49%) were identified as the major compounds. Ne-BPEO was prepared using chitosan and characterised by Scanning electron microscope (SEM), Atomic force microscope (AFM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) assay. Ne-BPEO completely inhibited the growth and aflatoxin B1 production at a concentration of 0.3 μL/mL. The antifungal and aflatoxin B1 inhibitory effects were related to decreasing in ergosterol content, leakage of membrane ions (Ca2+, K+, and Mg2+), impairment in carbohydrate catabolism, and functioning of ver-1 gene of A. flavus exposed to Ne-BPEO over the control. In addition, Ne-BPEO exhibited promising free radical scavenging activity through DPPH assay (IC50 12.64 μL/mL) with high thermo-stability. Therefore, chitosan could be used as a carrier agent of plant-based preservative to enhance the shelf-life of food products against A. flavus and aflatoxin B1 contamination.


Expression of immunoreactivities to 75 kDa nerve growth factor receptor, trk gene product and phosphotyrosine in granular cell tumors.
Nineteen granular cell tumors (GCT) of adults, two congenital granular cell epulides and five epulides fibrosae were immunohistochemically examined to detect the expression of 75 kDa nerve growth factor receptor (NGFR), trk gene product, phosphotyrosine (PT), protein gene product 9.5 (PGP9.5) and S-100 protein. The NGFR-immunoreactivity (IR) and trk gene product-IR were expressed on almost all granular cells of GCT. PT-IR was also demonstrated on granular cells of all GCT examined, although the frequency of positive cells was low. Congenital granular cell epulides and epulides fibrosae were negative for NGFR-IR, trk gene product-IR and PT-IR. S-100 protein was localized in granular cells of adult GCT but not in the granular cells of congenital epulis. On the other hand, PGP9.5 was detected in granular cells of both conditions and in fibroblastic cells of epulis fibrosa. The present results further indicate that GCT is of peripheral nerve Schwann cell origin, while the congenital granular cell epulides are not of neural origin. NGFR and trk gene product expressed on GCT seems to be functional in terms of phosphorylation of the tyrosine residue in the receptor or downstream protein in signal transduction.


Insights into biogenic and diagenetic lead exposure in experimentally altered modern and archaeological bone: Synchrotron radiation X-ray fluorescence imaging.
Bones represent a valuable biological archive of environmental lead (Pb) exposure for modern and archaeological populations. Synchrotron radiation X-ray fluorescence imaging (SR-XFI) generates maps of Pb in bone on a microstructural scale, potentially providing insights into an individual's history of Pb exposure and, in the context of archaeological bone, the biogenic or diagenetic nature of its uptake. The aims of this study were to (1) examine biogenic spatial patterns for Pb from bone samples of modern cadavers compared with patterns observed archaeologically, and (2) test the hypothesis that there are spatial differences in the distribution of Pb for diagenetic and biogenic modes of uptake in bone. To address these aims, this study used inductively coupled plasma-mass spectrometry (ICP-MS) and SR-XFI on unaltered and experimentally altered cadaveric bone samples (University of Saskatchewan, Saskatoon, SK) and archaeological bone samples from 18th to 19th century archaeological sites from Antigua and Lithuania. Bone concentrations of modern individuals are relatively low compared to those of archaeological individuals. SR-XFI results provide insights into modern Saskatchewan Pb exposure with some samples demonstrating a pattern of relatively low Pb exposure with higher levels of Pb exposure occurring in bone structures of a relatively older age that formed earlier in life, likely during the era of leaded gasoline (pre-1980s), and other samples demonstrating a pattern of fairly consistent, low-level exposure. Results support hypotheses for the spatial distribution of Pb corresponding to biogenic vs. diagenetic uptake. Diagenetic Pb is mainly confined to the periosteal surface of each sample with some enrichment of cracks and sub-periosteal canals. This may be useful in the future for differentiating diagenetic from biogenic Pb accumulation, analyzing environmental contamination, and informing sampling strategies in archaeological or fossil bone.


Coating in vitro of erythrocytes with Tamm Horsfall-protein.
A method is described to coat isolated peripheral blood erythrocytes in vitro with Tamm-Horsfall Protein (THP, uromodulin). Coating of erythrocytes with THP was accomplished by incubation of the cells in the presence of THP, made monomeric by incubation in a high urea concentration. THP-coating of erythrocytes was dependent on the THP-concentration, maximal coating being obtained at a protein concentration > or = 250 mg/ml. The best coating results were obtained if, during the co-incubation of erythrocytes with THP, urea was removed while the sodium chloride concentration was increased up to a physiologic concentration by means of dialysis. This alteration in chemical conditions promotes THP-polymerisation. Erythrocytes coated in this way could be preserved for at least 5 weeks in preserving solution, making them an interesting source of testing and control material. Coating of erythrocytes with THP could also be accomplished under conditions in which THP was preserved in a monomeric form, which suggests that peripheral blood erythrocytes having binding-sites for THP.


Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells.
Oxidative stress is a known mechanism induced, among other things, by arsenic toxicity. As a response, the cell triggers the synthesis of antioxidant and stress response elements like glutathione and heme oxygenase. Alpha-lipoic acid (ALA) is a well-known antioxidant that confers protection to oxidative stress conditions. We analyzed the effect of ALA pretreatment on Nrf2-responsive gene expression of HepG2 cells exposed to As(3+). Cells were treated with 5mM ALA and 8h later exposed to 50μM As(3+) for 24h, analyzing MTT-activity, glutathione content, Nrf2 induction and antioxidant gene expression. As(3+) increased glutathione (154%), heme oxygenase, glutamate cystein ligase, modifier subunit and metallothionein (35-fold, 10-fold and 9-fold, respectively). ALA prevented the strong expression of heme oxygenase by As(3+) exposure (from 35- to 5-times of control cells), which correlated with the reduction of Nrf2 observed in As(3+) group. ALA pretreatment can down-modulate the response mediated by Nrf2 and provide protection to As(3+) exposed HepG2 cells.


Effects of actinomycin D and puromycin on colchicine-induced endoreduplication in Chinese hamster cells in vitro.
Experiments were carried out to study the events through which the process of endoreduplication occurs after treatment with colchicine in Chinese hamster cells cultivated in vitro, and to analyse the differences between the processes leading to normal mitosis and those leading to endoreduplication. Chinese hamster cells (line C-125) were treated with colchicine (10(-4) M) for 1 h, in order to induce endoreduplication. Before and after colchicine treatment the cultures were treated at various intervals with actinomycin D and puromycin. For preparation of mitosis specific RNA synthesis is required, and also synthesis of a specific protein, which is not required for endoreduplication. Moreover this suggests not only that the cells that endoreduplicate do not need new RNA and protein synthesis, but that inhibition of their synthesis apparently favours the processes of endoreduplication.


Platform switching in two-implant bar-retained mandibular overdentures: 1-year results from a split-mouth randomized controlled clinical trial.
The concept of platform switching is widely applied in current implant dentistry; however, the influence on peri-implant bone-level alterations (ΔIBL), especially in the field of implant overdentures (IODs), remains inconclusive. Therefore, the present study aimed to test the alternative hypothesis that there is an equivalent ΔIBLs at platform-switching and platform-matching implant abutments in 2-implant bar-retained IODs. Two interforaminal implants were placed in 32 subjects, who were randomly assigned to either an immediate- or a 3-month post-placement loading group. Furthermore, one implant in each subject was randomly assigned to receive a platform-switched abutment (test), and one a platform-matching abutment (control). The implants were splinted with prefabricated, chairside customized bars. ΔIBL was recorded by using customized radiograph holders at implant placement, implant loading, 3 months, 6 months, and 12 months after loading. After 1 year, equivalent ΔIBL could be identified (test: -0.51 mm ± 0.49 versus control: -0.56 mm ± 0.52; p < .001). ΔIBL increased over time and was more pronounced in the delayed-loaded implants (-0.87 mm ± 0.61) relative to the immediately loaded implants (-0.35 mm ± 0.43; p = .022). The prosthetic concept of platform switching does not necessarily lead to reduced bone loss. Immediate-loading of implants, primarily splinted with a bar, might be beneficial regarding peri-implant bone-level alterations over a short-term period.


Atomic insights into ML-SI3 mediated human TRPML1 inhibition.
Transient receptor potential mucolipin 1 (TRPML1) regulates lysosomal calcium signaling, lipid trafficking, and autophagy-related processes. This channel is regulated by phosphoinositides and the low pH environment of the lysosome, maintaining calcium levels essential for proper lysosomal function. Recently, several small molecules specifically targeting the TRPML family have been demonstrated to modulate channel activity. One of these, a synthetic antagonist ML-SI3, can prevent lysosomal calcium efflux and has been reported to block downstream TRPML1-mediated induction of autophagy. Here, we report a cryo-electron microscopy structure of human TRPML1 with ML-SI3 at 2.9-Å resolution. ML-SI3 binds to the hydrophobic cavity created by S5, S6, and PH1, the same cavity where the synthetic agonist ML-SA1 binds. Electrophysiological characterizations show that ML-SI3 can compete with ML-SA1, blocking channel activation yet does not inhibit PI(3,5)P2-dependent activation of the channel. Consequently, this work provides molecular insight into how ML-SI3 and native lipids regulate TRPML1 activity.


Traumatic tracheobronchial stricture treated with the Eder-Puestow dilator.
A case of tracheobronchial stenosis secondary to trauma is presented. Primary reconstruction resulted in stricture in the distal part of the trachea. Resection and anastomosis was followed by restenosis, which had to be treated endoscopically. Endobronchial resections and forceful dilatations with stiff bronchoscopes were done weekly for about 11 months without lasting benefit. After changing to Eder-Puestow dilators, the dilatations could be done at steadily increasing intervals. This method of dilatation was found to be safe, effective and less traumatic.


The transcriptional regulator GON4L is required for viability and hematopoiesis in mice.
The Gon4l gene encodes a putative transcriptional regulator implicated in the control of both cell differentiation and proliferation. Previously, we described a mutant mouse strain called Justy in which splicing of pre-mRNA generated from Gon4l is disrupted. This defect severely reduces, but does not abolish, GON4L protein expression and blocks the formation of early B-lineage progenitors, suggesting Gon4l is required for B-cell development in vertebrates. Yet, mutations that disable Gon4l in zebrafish impair several facets of embryogenesis that include the initiation of primitive hematopoiesis, arguing this gene is needed for multiple vertebrate developmental pathways. To better understand the importance of Gon4l in mammals, we created mice carrying an engineered version of Gon4l that can be completely inactivated by Cre-mediated recombination. Breeding mice heterozygous for the inactivated Gon4l allele failed to yield any homozygous-null offspring, indicating Gon4l is an essential gene in mammals. Consistent with this finding, as well previously published results, cell culture studies revealed that loss of Gon4l blocks cell proliferation and compromises viability, suggesting a fundamental role in the control of cell division and survival. Studies using mixed bone marrow chimeras confirmed Gon4l is required for B-cell development but also found it is needed to maintain definitive hematopoietic stem/progenitor cells that are the source of all hematopoietic cell lineages. Our findings reveal Gon4l is an essential gene in mammals that is required to form the entire hematopoietic system.


Flow cytometric detection of leukemic blasts in cerebrospinal fluid predicts risk of relapse in childhood acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology study.
Central nervous system (CNS) involvement by cytospin is associated with increased risk of relapse in childhood acute lymphoblastic leukemia. We investigated if flow cytometric analysis of cerebrospinal fluid (CSF) at diagnosis improves the prediction of relapse. This prospective cohort study included patients (1.0-17.9 years) treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. CSF flow cytometry samples were obtained at 17 centers, preserved with Transfix®, and analyzed at a central laboratory. One-hundred and seventy-one (25.4%) of 673 patients were positive by flow cytometry (CNSflow+). The 4-year cumulative incidence of relapse was higher for patients with cytospin positivity (CNScyto+) (17.1% vs. 7.5%), CNSflow+ (16.5% vs. 5.6%), and cytospin and/or flow positivity (CNScomb+) (16.7% vs. 5.1%). In Cox regression analysis stratified by immunophenotype and minimal residual disease day 29 and adjusted by sex, predictors of relapse were age (hazard ratio [HR] 1.1, 95% CI 1.1-1.2, P < 0.001), white blood cell count at diagnosis (HR 1.4, 95% CI 1.1-1.6, P < 0.001), and CNScomb+ (HR 2.2, 95% CI 1.0-4.7, P = 0.042). Flow cytometric analysis of CSF improves detection of CNS leukemia, distinguishes patients with high and low risk of relapse, and may improve future risk stratification and CNS-directed therapy.


Two clones obtained from Urabe AM9 mumps virus vaccine differ in their replicative efficiency in neuroblastoma cells.
A high rate of post-vaccinal aseptic meningitis for Urabe AM9 mumps virus strain is well documented. This strain is composed of two virus variants differing at the nt 1081 (A/G) region in the hemagglutinin-neuraminidase (HN) gene. An association of HN-A(1081) variant with neurovirulence has been proposed. In order to test for neurotropism we isolated the HN-A(1081) and HN-G(1081) virus variants from Urabe AM9 mumps virus vaccine. Sequential passages were performed in monkey kidney Vero cells and human neuroblastoma SH-SY5Y cells. Viral replication was determined by conventional and real-time RT-PCR. The results show that clone HN-A(1081) can replicate efficiently in both cell types. However, a defective replication of clone HN-G(1081), lacking its genetic marker, was observed after the third passage in neuroblastoma cells. Kinetics assays showed that clone HN-A(1081) replicates faster than clone HN-G(1081). Viral clones were also inoculated into the brains of newborn rats. Clone HN-A(1081) replicated 14 times, while clone HN-G(1081) merely duplicated its level over the initial inoculum. These results suggest that there is a selective replication of HN-A(1081) mumps virus variants in cells of nervous origin.


Prophylactic pegfilgrastim to prevent febrile neutropenia among patients receiving biweekly (Q2W) chemotherapy regimens: a systematic review of efficacy, effectiveness and safety.
Pegfilgrastim, a long-acting granulocyte colony-stimulating factor (G-CSF), is commonly used to prevent febrile neutropenia (FN), a potentially life-threatening complication, following myelosuppressive chemotherapy. The FDA label for pegfilgrastim specifies that it should not be administered 14 days before or within 24 h of administration of myelosuppressive chemotherapy, precluding the use of pegfilgrastim in biweekly (Q2W) regimens. The National Comprehensive Cancer Network and the European Organisation for Research and Treatment of Cancer guidelines support the use of prophylactic pegfilgrastim in patients receiving Q2W regimens. The objective of this study was to systematically review evidence from randomized clinical trials (RCTs) and observational studies that describe the effectiveness and safety of prophylactic pegfilgrastim in preventing FN among patients receiving Q2W regimens. An Ovid MEDLINE, Embase, and Cochrane Library literature search was conducted to evaluate the evidence regarding efficacy, effectiveness, and safety of prophylactic pegfilgrastim versus no prophylactic pegfilgrastim or prophylaxis with other G-CSF in patients who were receiving Q2W chemotherapy regimens with high (> 20%) or intermediate (10-20%) risk of FN for a non-myeloid malignancy. Studies that addressed absolute or relative risk of FN, grade 1-4 neutropenia, all-cause or any hospitalization, dose delays or dose reductions, adverse events, or mortality were included. Studies where the comparator was a Q3W chemotherapy regimen with primary prophylactic pegfilgrastim were also included. The initial literature search identified 2258 publications. Thirteen publications met the eligibility criteria, including eight retrospective, one prospective, one phase 1 dose escalation study, and three RCTs. In nine of the 13 studies reporting incidence of FN, and in seven of the nine studies reporting incidence of neutropenia, administration of prophylactic pegfilgrastim in patients receiving Q2W regimens resulted in decreased or comparable rates of FN or neutropenia compared with patients receiving filgrastim, no G-CSF, lipefilgrastim or pegfilgrastim in Q3W regimens. In six of the nine studies reporting safety data, lower or comparable safety profiles were observed between pegfilgrastim and comparators. In a variety of non-myeloid malignancies, administration of prophylactic pegfilgrastim was efficacious in reducing the risk of FN in patients receiving high- or intermediate-risk Q2W regimens, with an acceptable safety profile. PROSPERO registration no: CRD42019155572 .


"How to measure the outcome in the surgical treatment of vertebral compression fractures? A systematic literature review of highly cited level-I studies".
The economic burden of vertebral compression fractures (VCF) caused by osteoporosis was estimated at 37 billion euros in the European Union in 2010. In addition, the incidence is expected to increase by 25% in 2025. The recommendations for the therapy of VCFs (conservative treatment versus cement augmentation procedures) are controversial, what could be partly explained by the lack of standardized outcomes for measuring the success of both treatments. Consensus on outcome parameters may improve the relevance of a study and for further comparisons in meta-analyses. The aim of this study was to analyze outcome measures from frequently cited randomized controlled trials (RCTs) about VCF treatments in order to provide guidance for future studies. We carried out a systematic search of all implemented databases from 1973 to 2019 using the Web of Science database. The terms "spine" and "random" were used for the search. We included: Level I RCTs, conservative treatment or cement augmentation of osteoporotic vertebral fractures, cited ≥50 times. The outcome parameters of each study were extracted and sorted according to the frequency of use. Nine studies met the inclusion criteria. In total, 23 different outcome parameters were used in the nine analyzed studies. Overall, the five most frequently used outcome parameters (≥ 4 times used) were the visual analogue scale (VAS) for pain (n = 9), European Quality of Life-5 Dimensions (EQ-5D; n = 4) and Roland-Morris Disability Questionnaire (RMDQ, n = 4). With our study, we demonstrated that a large inconsistency exists between outcome measures in highly cited Level I studies of VCF treatment. Pain (VAS), followed by HrQoL (EQ-5D) and disability and function (RMDQ), opioid use, and radiological outcome (kyphotic angle, VBH, and new VCFs) were the most commonly used outcome parameters.


Seasonal Effects on Body Condition and Characteristics of the Estrous Cycle in Captive Asian Elephants (Elephas maximus) in Thailand: A Retrospective Study.
The aim of this study was to investigate the effects of season on the body condition score (BCS), the characteristics of the estrous cycle (luteal phase [LPL], follicular phase [FPL], estrous cycle [ECL] lengths, and the start of the luteal phase [SLP] and follicular phase [SFP]), and progesterone levels (baseline and peak) of eight captive Asian elephants (Elephas maximus) in Thailand. From 2014 to 2019, blood samples were collected weekly for serum progesterone enzyme immunoassays (EIAs). Estrous cycles (n = 70), including the luteal and follicular phases, and BCS (n = 70) were recorded. Based on the BCS, the LPL, FPL, and ECL were assigned to the following two groups: normal (BCS = 3.0-4.0, n = 38) and overweight (BCS = 4.5-5.0, n = 32). The findings demonstrated that there was no difference in LPL between the groups. However, in the normal group, the ECL was one week longer (14.9 ± 1.7 vs. 13.9 ± 1.7 weeks; p < 0.05), and the FPL also tended to be one week longer (7.2 ± 1.7 vs. 6.4 ± 1.5 weeks; p = 0.06) than in the overweight group. The mean progesterone level during the rainy, hot, and cool seasons was not statistically different. Based on the yearly averaged BCS from three seasons, the baseline and peak levels of progesterone were classified into the normal (n = 16) and overweight (n = 12) groups. Females with a normal BCS tended to exhibit higher progesterone peak levels (p = 0.08). The majority of peaks appeared during the rainy season (53.57%). The BCS was highest during the hot (4.47) and rainy (4.38) seasons, but not during the cool (4.12) season. The LPL, FPL, and ECL were not affected by the season in which the luteal phase occurred. On the other hand, the rainy season had a significant effect on the SFP, resulting in a longer LPL (p < 0.05) and ECL (p = 0.01); both were the longest during the rainy season. In conclusion, the effects of season on BCS may be related to characteristics of the estrous cycle and peak progesterone levels. Ultimately, these findings provide ground knowledge to assist elephant managers and owners in planning breeding activities using seasonal effects and BCS measurements in tropical climates.


ABCB1 and ABCG2 limit brain penetration and, together with CYP3A4, total plasma exposure of abemaciclib and its active metabolites.
Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast cancer and currently under investigation for other malignancies, including brain cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice. In vitro, abemaciclib was efficiently transported by hABCB1 and mAbcg2, and slightly by hABCG2, but the active metabolites were transported even better. Upon oral administration of 10 mg/kg abemaciclib, absence of Abcg2 and especially Abcb1a/1b significantly increased the plasma AUC0-24 h and Cmax of M2 and M18. Furthermore, the relative brain penetration of abemaciclib, M2 and M20 was dramatically increased by 25-, 4- and 60-fold, respectively, in Abcb1a/1b;Abcg2-/- mice, and to a lesser extent in single Abcb1a/1b- or Abcg2-deficient mice. The recovery of all active compounds in the small intestine content was profoundly reduced in Abcb1a/1b;Abcg2-/- mice, with smaller effects in single Abcb1a/1b-/- and Abcg2-/- mice. Our results indicate that Abcb1a/1b and Abcg2 cooperatively and profoundly limit the brain penetration of abemaciclib and its active metabolites, and likely also participate in their hepatobiliary or direct intestinal elimination. Moreover, transgenic human CYP3A4 drastically reduced the abemaciclib plasma AUC0-24 h and Cmax by 7.5- and 5.6-fold, respectively, relative to Cyp3a-/- mice. These insights may help to optimize the clinical development of abemaciclib, especially for the treatment of brain malignancies.


Two genera Foersteria Szépligeti, 1896 and Polydegmon Foerster, 1862 (Hymenoptera, Braconidae, Brachistinae) from China, with description of a new species.
The genera Foersteria Szépligeti, 1896 and Polydegmon Foerster, 1862 (Hymenoptera, Braconidae, Brachistinae) are recorded for the first time from China. A new species, Foersteria xinjiangensis Yan & Chen, sp. nov., is described and illustrated. A key to the Palaearctic species of Foersteria is given. In addition, Polydegmon sinuatus Foerster, 1862 is illustrated in detail for the first time.


Echocardiographic diagnosis of an aortic root abscess after Mycobacterium fortuitum prosthetic valve endocarditis.
A patient with an aortic root abscess complicating Mycobacterium fortuitum prosthetic endocarditis is described. The correct diagnosis had been made preoperatively by echocardiography and was confirmed subsequently at surgery.


Incontinence-related quality of life and sexual function following the tension-free vaginal tape versus the "inside-out" tension-free vaginal tape obturator.
The objective of this cohort study was to compare morbidity, quality of life, and sexual function in stress-incontinent women treated with tension-free vaginal tape (TVT) versus tension-free vaginal tape obturator (TVT-O) in a group of 329. Preoperative scores of the Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7) were compared to those from a mailed, postoperative questionnaire. The Pelvic Organ Prolapse/Incontinence Sexual Questionnaire (PISQ-12) and three additional questions were also included in the mailing. Of the initial 329 patients, 239 (73%) completed the questionnaire with a mean follow-up of 14.7 months. Complications, return to normal voiding, and operative time were less in the TVT-O group. Postoperative PISQ-12 scores and improvements in the UDI-6 and IIQ-7 were comparable between groups. The TVT-O procedure appears to be as effective in improving incontinence-related quality of life as the TVT. No differences in sexual function were demonstrated between groups.


Clinical experiences with left gastric vena caval shunt in patients with esophageal varices.
Left gastric vena caval shunt (Inokuchi) was performed in four patients with liver cirrhosis; electively in two and prophylactically in two cases. The overall results have been satisfactory in terms of the effect on esophageal varices and postoperative complications. This procedure appeared to be superior to distal splenorenal shunt or other direct surgical procedures in several aspects. Since left gastric vena caval shunt does not require particularly elaborate surgical techniques and can be performed safely even in patients with considerably impaired hepatic function, it can be recommended as an ideal surgical procedure to be performed in elective and prophylactic surgical candidates.


Thymoma: inter-relationships among World Health Organization histology, Masaoka staging and myasthenia gravis and their independent prognostic significance: a single-centre experience.
In thymomas, World Health Organization (WHO) histology, Masaoka stage and myasthenia gravis (MG) have long been considered important for patient management and outcome. Their role has been independently investigated in the past. Few studies, however, focussed on the correlations among these variables. The aim of the present study was to retrospectively evaluate, in our patient population of resected thymomas, the inter-relationships among MG, WHO histology and Masaoka stage, and to look at how and to what extent one variable is associated with the other two in terms of clinical presentation and survival. From January 1990 to October 2008, 255 patients received resection of thymoma. MG was present in 105 cases (41%). Histology by WHO was: 25 A (10%), 72 AB (28%), 65 B1 (25%), 69 B2 (27%) and 24 B (9%). Masaoka staging was stage I, 54 cases (21%), stage II, 86(34%), stage III 79 (31%), and stage IVA 36 (14%). Ordinal and logistic regression models were undertaken to analyse correlations among ordinal (WHO histology and Masaoka stage) and categorical (MG, A vs B WHO types) variables. Univariate and multivariate survival analysis were also performed using the same covariates. Overall survival (OS) and disease-free survival (DFS) were calculated. MG was associated with early Masaoka stages (odds ratio (OR) 0.45, 95% confidence interval (CI) 0.33-0.62) and B-type thymomas (OR 1.59, 95% CI 1.23-2.05). B-type thymomas were associated with high Masaoka stage (OR 0.46, 95% CI 0.36-0.60). High Masaoka stage was associated with non-MG (OR 3.27; 95% CI 2.00-5.34). In univariate survival analysis, MG (p = 0.01) and Masaoka stage (p = 0.0001) were significant prognostic indicators using OS. Using DFS, WHO histology (A/AB vs B1/B2/B3 types) (p = 0.05) and Masaoka stage (p = 0.0001) had a prognostic significance. In multivariate analysis, only Masaoka stage was an independent prognostic covariate using OS (hazard ratio (HR) 2.57, 95% CI 1.46-4.52, p = 0.001) and DFS (HR 3.18, 95% CI 1.56-6.52, p = 0.001). In thymomas, MG, WHO histology and Masaoka stage are inter-related. MG has an influence on histology and stage at presentation, while two clinical/histologic patterns are more likely: early Masaoka stage A/AB WHO type and high Masaoka stage/B WHO type. Among the three factors, only Masaoka stage had a prognostic significance on OS and DFS. Our results suggest that a consistent staging system for thymomas should take into account all three variables.


Forum One: Current recommendations about intensification of metabolic control in non-insulin-dependent diabetes mellitus.
To review issues about intensive management of non-insulin-dependent diabetes mellitus (NIDDM) and to formulate recommendations for goals and general approaches to implementation of intensive management. A panel of clinical scientists and practitioners specializing in diabetes initially used a formal nominal process to identify the points of agreement on major issues. These points were further refined in a general conference discussion. 1) On the basis of data from intervention trials in IDDM that prove that intensive glycemic control reduces microvascular and neuropathic complications, coupled with epidemiologic and basic scientific data that support the strong likelihood of a similar benefit in NIDDM, the goal of treatment in NIDDM should be near-normal glycemia (glycohemoglobin level no higher than 1.0% above the upper normal limit); 2) glycemic targets should be adjusted individually according to clinical factors such as increased risk for hypoglycemia, advanced age, or reduced life expectancy from comorbid conditions; 3) some degree of comprehensive and repetitive instruction about diet and exercise and the use of blood glucose self-monitoring for all patients is essential to achieve the chosen targets; 4) intensive management of hyperglycemia should be instituted early and should initially emphasize diet and exercise therapy; staged introduction of oral hypoglycemic agents and finally insulin regimens of increasing complexity are recommended as needed to achieve glycemic targets; 5) comprehensive care must also include aggressive attempts to reduce cardiovascular risk factors (particularly hypertension, smoking, dyslipidemia, and obesity) as well as prevention of nephropathy and neuropathy; 6) the complex interaction among treatment regimens for hyperglycemia, dyslipidemia, obesity, and hypertension ideally requires a team approach, using a physician, diabetes educator, nurse, dietitian, and other health professionals; health insurers should make these resources available to generalists who currently care for most diabetic patients.


[Lightning strike and lesions outside the brain: Clinical cases and a review of the literature].
Every year, 240,000 people are struck by lightning worldwide, causing injuries leading to significant handicaps. Most of the symptoms involve brain lesions; neuromuscular sequelae and myelopathy are less common. We describe five cases of patients struck by lightning with various clinical presentations. The first patient presented painful paresthesias in both upper limbs that disappeared 18 months later; the injury was a plexopathy. The second patient developed proximal weakness in the upper-left limb due to a myopathy. Two patients presented with various motor weaknesses in the lower limbs due to motor neuron disease and myelopathy. The last patient had a transient tetraplegy, which resolved in 5minutes; the diagnosis was keraunoparalysis. Lightning injuries can have many consequences depending on the different mechanisms involved. The clinical presentation is often due to a very focal lesion without any secondary extension. Motor neuron disease probably results from post-traumatic myelopathy. We discuss the ALS-electrocution association, frequently described in the literature. Various peripheral nerve and spinal cord lesions can be seen in lightning strike victims involving myelopathy, motor neuron, muscle and plexus. Clinical syndromes are often atypical but outcome is often favorable.


Iranian nurses' perception of essential competences in disaster response: A qualitative study.
Today disasters, natural and man-made, are a part of many people's lives. Iran has a long history of disaster events. Nurses are one of the most significant groups within Iranian disaster relief operations, providing immediate and longer term care for those affected by the disaster. However, the competence of Iranian nurses and their training for this work has received little attention. This paper presented the results of a study aimed to explore the context. A qualitative study was performed in 2012 in Iran. Interviews were conducted with 35 nurses. The sampling of participants was purposeful and continued until data saturation was achieved. Themes were identified using inductive qualitative content analysis. Trustworthiness of the study was supported considering auditability, neutrality, consistency, and transferability. Data analysis undertaken for the qualitative study resulted in the identification of five main themes included 1-management competences, 2- ethical and legal competences, 3-team working, 4-personal competences, and specific technical competences that presented in this report. This report presents an overview of nursing competences required for Iranian nurses in disaster relief. It is argued that additional competencies are required for nurses who care in high-risk situations, including disaster. Nurses need to prepare themselves more effectively to be responsible and effective in the nursing care.


The multitargeted receptor tyrosine kinase inhibitor sunitinib induces resistance of HER2 positive breast cancer cells to trastuzumab-mediated ADCC.
Despite recent advances in the development of novel personalized therapies, breast cancer continues to challenge physicians with resistance to various advanced therapies. The anticancer action of the anti-HER2 antibody, trastuzumab, involves antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. Here, we report a repurposing screen of 774 clinically used compounds on NK-cell + trastuzumab-induced killing of JIMT-1 breast cancer cells. Using a calcein-based high-content screening (HCS) assay for the image-based quantitation of ADCC that we have developed and optimized for this purpose, we have found that the multitargeted tyrosine kinase inhibitor sunitinib inhibits ADCC in this model. The cytoprotective effect of sunitinib was also confirmed with two other assays (lactate dehydrogenase release, and electric cell substrate impedance sensing, ECIS). The drug suppressed NK cell activation as indicated by reduced granzyme B deposition on to the target cells and inhibition of interferon-γ production by the NK cells. Moreover, sunitinib induced downregulation of HER2 on the target cells' surface, changed the morphology and increased adherence of the target cells. Moreover, sunitinib also triggered the autophagy pathway (speckled LC3b) as an additional potential underlying mechanism of the cytoprotective effect of the drug. Sunitinib-induced ADCC resistance has been confirmed in a 3D tumor model revealing the prevention of apoptotic cell death (Annexin V staining) in JIMT-1 spheroids co-incubated with NK cells and trastuzumab. In summary, our HCS assay may be suitable for the facile identification of ADCC boosting compounds. Our data urge caution concerning potential combinations of ADCC-based immunotherapies and sunitinib.


Classification of established atopic dermatitis in children with the in vivo imaging methods.
Atopic dermatitis (AD) is a cutaneous disease resulting from a defective barrier and dysregulated immune response. The severity scoring of atopic dermatitis (SCORAD) is used to classify AD. Noninvasive imaging approaches supplementary to SCORAD were investigated. Cr:forsterite laser-based microscopy was employed to analyze endogenous third-harmonic generation (THG) and second-harmonic generation (SHG) signals from skin. Imaging parameters were compared between different AD severities. Three-dimensional reconstruction of imaged skin layers was performed. Finally, statistic models from quantitative imaging parameters were developed for predicting disease severity. Our data demonstrate that THG signal intensity of lesional skin in AD were significantly increased and was positively correlated with AD severity. Characteristic gray level co-occurrence matrix (GLCM) values were observed in more severe AD. In the 3D reconstruction video, individual dermal papilla and obvious fibrosis in the upper papillary dermis were easily identified. Our estimation models could predict the disease severity of AD patients with an accuracy of nearly 85%. The THG signal intensity and characteristic GLCM patterns are associated with AD severity and can serve as quantitative predictive parameters. Our imaging approach can be used to identify the histopathological changes of AD objectively, and to complement the SCORAD index, thus improving the accuracy of classifying AD severity.


Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration.
The protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32 +/- 2 years, n = 5) and elderly (73 +/- 6 years, n = 5) male and female humans, and young (8 weeks, n = 4) and elderly (60 weeks, n = 3) male Sprague-Dawley rats. Serum samples were collected and immediately frozen at -20 degrees C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL-1 and 500 ng mL-1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut-off), capped, equilibrated to 37 degrees C, and centrifuged at 1850g for 1.5 h at 37 degrees C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non-stereoselective.


Improved 3-Year Cardiac Survival After IVUS-Guided Long DES Implantation: A Patient-Level Analysis From 2 Randomized Trials.
The present study aimed to evaluate long-term cardiac survival benefit for intravascular ultrasound (IVUS)- versus angiography-guided long drug-eluting stent (DES) implantation. Although the long-term benefit of IVUS guidance for DES implantation has been reported from recent randomized trials, this benefit was primarily driven by the reduction in repeat revascularization. Thus, it remains uncertain whether IVUS guidance improved survival during long-term follow-up. We pooled the data of 2 randomized trials (IVUS-XPL [Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions] and ULTIMATE [Intravascular Ultrasound Guided Drug Eluting Stents Implantation in All-Comers Coronary Lesions]) and compared IVUS guidance versus angiography guidance in 2,577 patients with long lesions treated with an implanted stent length ≥28 mm. The primary end point was cardiac death at 3 years. A 3-year clinical follow-up was completed in 96%. The primary end point of cardiac death occurred in 12 patients (1.0%) in the IVUS-guided group vs 28 patients (2.2%) in the angiography-guided group (HR: 0.43; 95% CI: 0.22-0.84; P = 0.011). In addition, target lesion-related myocardial infarction occurred in 3 patients (0.2%) in the IVUS-guided group and in 9 patients (0.7%) in the angiography-guided group (HR: 0.33; 95% CI: 0.09-1.22; P = 0.081), stent thrombosis developed in 3 patients (0.2%) in the IVUS-guided group and 9 patients (0.7%) in the angiography-guided group (HR: 0.33; 95% CI: 0.09-1.23; P = 0.082), and ischemia-driven target lesion revascularization was observed in 47 patients (3.8%) in the IVUS-guided group and 80 patients (6.5%) in the angiography-guided group (HR: 0.57; 95% CI: 0.40-0.82; P = 0.002). In this post hoc pooled patient-level analysis, the use of IVUS-guided long DES implantation compared with angiography-guided stent implantation improved long-term patient cardiac survival.


From the stochasticity of molecular processes to the variability of synaptic transmission.
The variability of the postsynaptic response following a single action potential arises from two sources: the neurotransmitter release is probabilistic, and the postsynaptic response to neurotransmitter release has variable timing and amplitude. At individual synapses, the number of molecules of a given type that are involved in these processes is small enough that the stochastic (random) properties of molecular events cannot be neglected. How the stochasticity of molecular processes contributes to the variability of synaptic transmission, its sensitivity and its robustness to molecular fluctuations has important implications for our understanding of the mechanistic basis of synaptic transmission and of synaptic plasticity.


Are our brains more prescriptive than our mouths? Experience with dialectal variation in syntax differentially impacts ERPs and behavior.
We investigated online auditory comprehension of dialectal variation in English syntax with event-related potential (ERP) analysis of electroencephalographic data. The syntactic variant under investigation was the double modal, comprising two consecutive auxiliary verbs (e.g., might could). This construction appears across subregional dialects of Southern United States English and expresses indirectness or uncertainty. We compared processing of sentences with attested double modals and single modals in two groups of young adult participants: listeners who were either familiar (Southern) or unfamiliar (Unmarked) with double modal constructions. Both Southern and Unmarked listeners engaged rapid error detection (early anterior negativity) and sentence-level reanalysis (P600) in response to attested double modals, relative to single modals. Offline acceptability and intelligibility judgments reflected dialect familiarity, contrary to the ERP data. We interpret these findings in relation to usage-based and socially weighted theories of language processing, which together capture the effects of frequency and standard language ideology.


Low-frequency suppression of auditory nerve responses to characteristic frequency tones.
The effects of low-frequency (50, 100, 200 and 400 Hz) 'suppressor' tones on responses to moderate-level characteristic frequency (CF) tones were measured in chinchilla auditory nerve fibers. Two-tone interactions were evident at suppressor intensities of 70-100 dB SPL. In this range, the average response rate decreased as a function of increasing suppressor level and the instantaneous response rate was modulated periodically. At suppression threshold, the phase of suppression typically coincided with basilar membrane displacement toward scala tympani, regardless of CF. At higher suppressor levels, two suppression maxima coexisted, synchronous with peak basilar membrane displacement toward scala tympani and scala vestibuli. Modulation and rate-suppression thresholds did not vary as a function of spontaneous activity and were only minimally correlated with fiber sensitivity. Except for fibers with CF < 1 kHz, modulation and rate-suppression thresholds were lower than rate and phase-locking thresholds for the suppressor tones presented alone. In the case of high-CF fibers with low spontaneous activity, excitation thresholds could exceed suppression thresholds by more than 30 dB. The strength of modulation decreased systematically with increasing suppressor frequency. For a given suppressor frequency, modulation was strongest in high-CF fibers and weakest in low-CF fibers. The present findings strongly support the notion that low-frequency suppression in auditory nerve fibers largely reflects an underlying basilar membrane phenomenon closely related to compressive non-linearity.


Serum amyloid A (SAA) protein and high-sensitivity C-reactive protein (hsCRP) in healthy newborn infants and healthy young through elderly adults.
To determine the levels of serum amyloid A (SAA) protein and high-sensitivity C-reactive protein (hsCRP) in different age groups. Serum samples from 70 healthy newborn infants, 80 blood donors and 81 healthy elderly individuals were analysed using a nephelometric method. The 231 samples were grouped as follows: 35 umbilical cords, 35 newborns, 48 young adults, 28 middle-aged adults, and 85 elderly adults. Serum levels of both SAA and hsCRP were lower in umbilical cords than in the newborns and young, middle-aged and elderly adults (p<0.0001). The SAA and hsCRP levels were comparable in newborns, and young and middle-age adults, but higher in elderly adults (p<0.0001-0.03). SAA (r2=0.159, p<0.0001) and hsCRP (r2=0.059, p<0.0001) were positively correlated with age and to each other (r2=0.385, p<0.0001). Serum levels of SAA and hsCRP in umbilical cord blood are close to the detection limit and lower than in the other age groups investigated. The elderly have generally higher levels than the younger age groups, which require higher decision levels in inflammatory diseases, including infections. In newborns and young and middle-aged adults, the lower decision levels of 10 mg/l for SAA and 5 mg/l for CRP are suggested.


Is resection of the tendon edge necessary to enhance the healing process? An evaluation of the expression of collagen type I, IL-1β, IFN-γ, IL-4, and IL-13 in the distal 1 cm of a torn supraspinatus tendon: part II.
Type I collagen proin pro-in expression in a damaged supraspinatus tendon is thought to be dependent on the distance from the edge of the tear and the local expression of pro-inflammatory, anti-proliferative, and pro-proliferative cytokines. The study evaluates the expression of type I collagen, pro-inflammatory interleukin (IL) 1β, anti-proliferative interferon-γ (IFN-γ), and pro-proliferative IL-4 and IL-13 cytokines along a 1-cm section taken from the edge of a torn supraspinatus tendon. Three sections were taken: 3 mm distal to the tear, 3 mm proximal to the tear, and the 4-mm middle section between them. Nine patients (average age, 58 years) were included in the study. All fulfilled strict inclusion criteria regarding tear morphology and reconstruction technique. Samples were taken from the ruptured supraspinatus tendon at the time of arthroscopic repair. Quantitative real-time polymerase chain reaction assay was used for analysis. The expression of type I collagen, IL-4, and IL-13 significantly increased and that of IL-1β and IFN-γ decreased from the distal to the proximal parts of the tendon edge (P < .05). The expression of type I collagen is dependent on the distance from the edge of the torn supraspinatus tendon, the balance between anti-proliferative IFN-γ and pro-proliferative IL-4 and IL-13, and the expression of pro-inflammatory IL-1β. Hence, whereas resection of the distal 3 mm of the torn supraspinatus tendon edge eliminates its least valuable part, resection between 4 and 7 mm may enhance the healing process by reaching a reasonable compromise between the mechanical features of the tendon characterized by collagen type I expression and the technical abilities of reconstruction.


Effects of maternal ethanol consumption in rats on basal and rhythmic pituitary-adrenal function in neonatal offspring.
Neonatal corticoid treatment delays development of the circadian rhythm of plasma corticosterone in rats. We therefore sought to determine whether fetal or neonatal exposure to ethanol, a substance which activates the hypothalamo-pituitary-adrenal axis, produces similar effects. Subjects were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric control diet during gestation weeks two and three or during postnatal week one. At birth (day 1), the fetal ethanol-exposed pups had significantly higher brain and plasma corticosterone levels than the pair-fed or normal controls; brain and body weights were unaffected. By day 3, brain and plasma corticosterone titers in the fetal ethanol-exposed pups declined to the levels of the pair-fed and normal controls, although brain weights were significantly reduced. Significantly higher p.m. than a.m. levels of plasma corticosterone first occurred on day 18 both in the fetal ethanol-exposed pups and in the pair-fed and normal controls. Thus, despite its causing elevated corticosterone levels at birth, fetal exposure to ethanol did not affect the onset of the pituitary-adrenal circadian rhythm. On the other hand, exposure to ethanol during the first neonatal week delayed the onset of the pituitary-adrenal rhythm from day 18 to day 21. However, even greater delays occurred in the neonatal pair-fed controls, suggesting that the delays following neonatal exposure were due to nutritional deficits rather than to alcohol per se. The developmental and long-term influences of elevated corticoid levels at birth in fetal ethanol-exposed rats on other aspects of pituitary-adrenal function remain to be determined.


[Experimental study of the gastric organogenesis of the Rabbit foetus : Normal development. Experimental localization of the presumptive area. Development of the cultured and grafted stomach].
1) An ultrastructural and optical examination of the "in utero" development of the stomach in Rabbit embryos, demonstrates that the epithelium increases by"vacuolisation". The intraepithelial vacuoles, formed by a secretory process, secondarily open into the gastric cavity, whence the constitution of primary villi. Then the mesenchyme buds chorionic evaginations under the epithelial crests and transforms the primary into secondary villi. As the villi grow longer the epithelium loses its pseudostratified structure in order to become simply unistratified. At the same time, the four types of gastric cells progressively accomplish their differentiation into parietal, mucous, peptic cells and surface epithelium. 2) The presumptive gastric area of a ten-day-old Rabbit embryo corresponds to the lower third of the entomesoblastic part of the embryonic pharynx, posteriorly amputated at the umbilical edge. This presumptive area, grafted in the Chick embryo, differentiates into characteristic gastric tissue. Finally the stomach is explanted ("in vitro" and"in ovo") at different stages of ontogenesis. Up to the thirteenth day it degenerates in culture but grows and accomplishes its morphogenesis as a graft. From the fifteenth day, the cultured and grafted stomach differentiates on both morphogenetic and cytochemical planes.


COVID-19 Pandemic and the Second Lockdown: The 3rd Wave of the Disease Through the Voice of Youth.
Around the beginning of the 2021 new year, Europe's COVID-19 third wave led many leaders to implement a new lockdown period, with the teaching-learning system returning to the online method once more. The present study aimed to understand the health consequences for adolescents and young adults (AYA) during the third wave's lockdown. This mixed-method study included 592 participants between 16 and 24 years old (M = 19.01, SD = 2.32), with the majority being female (70.9%) and students (82.3%) at high school (55.1%) or university (44.9%). Negative impacts are highlighted in the categories: relationships, physical activity (as well aseno impacts), screen time and academic stress; and no impactsin health and well-being, leisure activities, sleep, diet, academic performance and relationships with teachers and peers. Overall, when compared to the opposite gender, girls report more negative impacts on leisure activities and diet, although more positive impacts on diet, as well as on academic stress; boys stand out in the negative consequences on substance use. At the academic level, students in higher education show more negative impacts on relationships, leisure activities, sleep, diet, screen time and relationships with teachers and peers. Enlightened about the impacts of the second lockdown on their lives, and showing signs of "pandemic fatigue", this study draws attention to the need to associate psychological support measures with those implemented to contain the COVID-19 pandemic.


Recombinant Protein Purification using Composite Polyacrylamide-Nanocrystalline Cryogel Monolith Column and Carbohydrate-Binding Module Family 64 as Affinity Tag.
In the field of recombinant protein production, downstream processing, especially protein purification, is critical and often the most expensive step. Carbohydrate binding module 64 (CBM64) was shown in 2011 to bind efficiently to a broad range of cellulose materials. In this study, we developed a protein purification method using nanocrystalline cellulose embedded in a polyacrylamide monolith cryogel and CBM64 affinity tag linked by intein to PD1 as a model protein. The CBM64-Intein-PD1 gene cassette was expressed in E. coli. Following cell lysis, CBM64-Intein-PD1 protein bound to the monolith PA-NCC cryogel. After washing and reducing the pH from 8.0 to 6.5, the intein underwent self-cleavage, resulting in the release and elution of pure PD1 protein. The synthesized monolith column had a porous structure with an average pore size of 30 µm and a maximum binding capacity of 497 µg per gram of dried column. The yield of this purification method was 84%, while the yield of the His tag-acquired CBM64-Intein-PD1 method was 89%. We used cellulose as support for affinity chromatography, which can be used as a cost-effective method for protein purification.


Role of the lateral pterygoid muscle and meniscotemporomandibular frenum in spontaneous growth of the mandible and in growth stimulated by the postural hyperpropulsor.
Our experimental studies in young rats represent an attempt to elucidate the respective roles of the lateral pterygoid muscle (LPM), the temporomandibular frenum (TMF), and the postural hyperpropulsor (Hp) in the control of the growth rate, the growth direction, and the growth amount of the condylar cartilage. Even after surgical resection of the LPM, the growth of the condylar cartilage and the lengthening of the mandible continue but are significantly decreased. Also, the stimulating effect of postural hyperpropulsion on the condylar cartilage and mandibular growth is much less intense after resection of the LPM. The TMF, which has a blood-circulating and a biomechanical component, appears to be a mediator of the LPM in the control of the condylar cartilage growth. After the surgical resection of the TMF, the growth the condylar cartilage and the lengthening of the mandible continue but are significantly diminished.


Harleß' Apparatus of Will: 150 years later.
As the empirical study of action control via ideomotor effect anticipations continues to uncover more and more aspects of this fundamental process, it is time to look back to the 19th century roots of the theory to assess which classical ideas are supported by contemporary research. In turn, classic ideas might stimulate studies on aspects of the ideomotor mechanism that have not yet been addressed empirically. The present article is a tribute to this classical work-more precisely to the article "Der apparat des willens" [The apparatus of will], published by Emil Harleß 150 years ago. At a closer look, Harleß does not only present a concise description of the ideomotor mechanism; he also presents a wealth of intriguing ideas that deserve empirical investigation.


The molecular basis of carbon-starvation-induced general resistance in Escherichia coli.
At the onset of starvation Escherichia coli undergoes a temporally ordered program of starvation gene expression involving 40-80 genes which some four hours later yields cells possessing an enhanced general resistance. Two classes of genes are induced upon carbon starvation: the cst genes, requiring cyclic AMP, and the pex genes, not requiring this nucleotide for induction. The cst genes are not involved in the development of the resistant state and are concerned with escape from starvation, while the pex gene induction appears to be associated with resistance. Many of the latter are induced in response to a variety of starvation conditions. They include heat shock and oxidation resistance genes, and some utilize minor, stationary-phase-specific sigma factors for induction during starvation. The protective role of stress proteins may be due to their ability to rescue misfolded macromolecules. The starvation promoters can be potentially useful for selective expression of desired genes in metabolically sluggish populations, e.g. in high-density industrial fermentations and in situ bioremediation.


Transmission electron microscopy of biliary mixed lipid micelles.
One potential artifact problem in election microscopy of micellar systems is that structural changes and aggregation could be induced by high vacuum dehydration in sample preparation prior to viewing and photomicrography. This could account for an earlier report on "macroassemblies" of biliary lipid, a finding which has been discrepant with the predominance of other evidence on the size, configuration and behavior of biliary micelles. In the present work, this possibility was explored and no evidence for such macroassemblies demonstrated when freeze-drying sample preparation was used; whereas, with conventional technique, the "macroassemblies" were again observed. It is concluded that freeze-drying or freeze-etching sample preparation is required to avoid this form of artifact in electron microscopy of micellar systems. The present findings are compatible with a spherical-equivalent or oblate ellipsoid configuration for biliary mixed micelles.


PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides.
To examine the effects of global lack of proprotein convertase subtilisin/kexin 2 (PCSK2) in mouse on intestinal motility, post-fast refeeding response and levels of several PCSK-generated peptides known to regulate food intake and processing. Using male and female PCSK2 knockout (KO) and wild-type (WT) mice, intestinal motility was assessed by determining the percent of intestinal length travelled by a charcoal-dyed meal following an oral gavage; the refeeding response by measuring the amount of meal consumed following an overnight fast; the levels of the regulatory peptides by enzyme immunoassays or immunoblotting. Relative to same-gender WT mice, KO mice exhibited delayed intestinal transit (P<0.001 in females; P<0.05 in males). Their post-fast feeding response was reduced in females during the first hour of refeeding (P<0.05). The circulating level of substance P (SP) was lower (P<0.001 in females; P<0.05 in males); it was higher for somatostatin (SS) (P<0.001 in females; P<0.05 in males) and GLP-1 (P<0.001 in females; P<0.01 in males) and GLP-2 (P<0.001 in both genders); it was higher for peptide YY (PYY) in female mice only (P<0.01). Processing of brain proneuropeptide Y was impaired in both genders. The alterations in intestinal motility and post-fast refeeding response observed in PCSK2-KO mice correlate with changes in the circulating and tissue levels of the regulatory peptides tested, suggesting that PCSK2 is needed for normal food intake and processing.


pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum.
The emergence and spread of multidrug resistant Plasmodium falciparum has severely limited the therapeutic options for the treatment of malaria. With ever-increasing failure rates associated with chloroquine or sulphadoxine-pyrimethamine treatment, attention has turned to the few alternatives, which include quinine and mefloquine. Here, we have investigated the role of pfmdr1 3' coding region point mutations in antimalarial drug susceptibility by allelic exchange in the GC03 and 3BA6 parasite lines. Results with pfmdr1-recombinant clones indicate a significant role for the N1042D mutation in contributing to resistance to quinine and its diastereomer quinidine. The triple mutations S1034C/N1042D/D1246Y, highly prevalent in South America, were also found to enhance parasite susceptibility to mefloquine, halofantrine and artemisinin. pfmdr1 3' mutations showed minimal effect on P. falciparum resistance to chloroquine or its metabolite mono-desethylchloroquine in these parasite lines, in contrast to previously published results obtained with 7G8 parasites. This study supports the hypothesis that pfmdr1 3' point mutations can significantly affect parasite susceptibility to a wide range of antimalarials in a strain-specific manner that depends on the parasite genetic background.


Decoupling of Behavioral Trait Correlation Across Life Stages in Two Holometabolous Insects.
Many animal behaviors have a genetic base, and behavioral traits often correlate with one another. In this study, we tested for a behavioral correlation between tonic immobility and walking distance in the larval and adult stages independently of two holometabolous insects. We confirmed a negative correlation of traits between strains in adults of both the species; however, we did not find it in larvae of either species. This suggests that the negative correlation between tonic immobility and walking is decoupled across life stages from larva to adult. In contrast, previous studies have reported that phenotypic correlations between behavioral traits are maintained from larvae to adults in hemimetabolous insects. In addition, our present results differ from previous results with holometabolous insects. Therefore, our results suggest that metamorphosis can change trade-offs between behavioral traits.


Masseteric to buccal branch nerve transfer.
To review recent literature pertaining to the use of masseteric-facial nerve neurorrhaphy (MFNN) for facial reanimation in patients with facial paralysis. First, MFNN effectively restores some midface tone and function, including the ability to smile. Second, use of the masseteric nerve minimizes synkinesis, dysarthria, and dysphagia that frequently occur after hypoglossal-facial nerve neurorrhaphy. Third, concurrent cable grafting to the zygomatic branch from an intact proximal facial nerve remnant - when available - can restore dynamic eye closure. Masseteric nerve transfer is an alternative to hypoglossal nerve transfer that improves midface appearance and function for properly selected patients with facial paralysis.


Experimental infection of young broiler chicks with Treponema hyodysenteriae.
In young broiler chicks which were inoculated with 10(8) cells of Treponema hyodysenteriae within 24 hr after hatching, numerous treponemes were observed by scanning electron microscopy on the surface of the cecal mucosa 7 and 14 days after the inoculation. However, in the groups inoculated with 10(7) cells, treponemes were not observed on the cecal mucosa 14 days after the inoculation, and the isolation rate from the cecal contents was lower than that from cecal contents of chicks inoculated with 10(8) cells. While the cecal mucosa of noninfected chicks had a smooth surface, that of the chicks infected with treponemes was generally roughened and the epithelium was eroded. Numerous treponemes were also observed within the eroded epithelium.


Cell surface-anchored serine proteases in cancer progression and metastasis.
Over the last two decades, a novel subgroup of serine proteases, the cell surface-anchored serine proteases, has emerged as an important component of the human degradome, and several members have garnered significant attention for their roles in cancer progression and metastasis. A large body of literature describes that cell surface-anchored serine proteases are deregulated in cancer and that they contribute to both tumor formation and metastasis through diverse molecular mechanisms. The loss of precise regulation of cell surface-anchored serine protease expression and/or catalytic activity may be contributing to the etiology of several cancer types. There is therefore a strong impetus to understand the events that lead to deregulation at the gene and protein levels, how these precipitate in various stages of tumorigenesis, and whether targeting of selected proteases can lead to novel cancer intervention strategies. This review summarizes current knowledge about cell surface-anchored serine proteases and their role in cancer based on biochemical characterization, cell culture-based studies, expression studies, and in vivo experiments. Efforts to develop inhibitors to target cell surface-anchored serine proteases in cancer therapy will also be summarized.


Regulation of human airway mesenchymal cell proliferation by glucocorticoids and beta2-adrenoceptor agonists.
Altered rates of cell proliferation play important roles in the pathogenesis of a variety of conditions, including cancer, inflammation and several airway and cardiovascular diseases. One of the most consistently observed changes in asthmatic airways is an increased volume of airway smooth muscle (ASM), that has been explained by proliferation, hypertrophy, extracellular matrix deposition within the smooth muscle bundles, and more recently, the migration of mesenchymal precursor cells to the airways. The best characterised of these is proliferation of ASM cells. In vitro studies suggest that the proliferation is driven by various mitogens, and ECM proteins found in asthma, such as collagen type I. Therefore, we compared the anti-mitogenic actions of two classes of anti-asthma agents, the glucocorticoids and the beta2-adrenoceptor agonists, in ASM cells grown on collagen type I. Culture on collagen type I prevented the anti-mitogenic actions of glucocorticoids, but not beta2-adrenoceptor agonists. In contrast, glucocorticoids are efficacious in regulating ASM production of GM-CSF, whereas beta2-adrenoceptor agonists are without effect. Therefore, combination therapy may have increased efficacy over glucocorticoids alone in controlling remodelling events due to complementary actions of the two classes of compounds.


Mechanisms of the adjuvant effect of nystatin on in vitro antibody response of mouse spleen cells: indication of nystatin as a B-cell mitogen and as a stimulant for polyclonal antibody synthesis in B cells.
Adjuvanticity of nystatin, one of the polyenic antifungal antibiotics having as its primary target the membrane sterol of eukaryotic cells, was investigated by examining its effect on several functions of mouse spleen cells relevant to immunological phenomena in vitro. Nystatin was found to stimulate significantly DNA synthesis in thymus-independent (B) cells but not in thymus-dependent (T) cells. Like the other B-cell mitogens such as bacterial lipopolysaccharide (LPS), nystatin elicited nonspecifically polyclonal antibody synthesis in mouse spleen cell cultures, and also restored antibody response of T cell-deficient spleen cells of congenitally athymic nude mice to heterologous erythrocytes (RBC; thymus-dependent antigen). Thus, nystatin and LPS appeared to cause similar changes in the functions of spleen cells relevant to immunological events. However, antagonism but no additive effect in the adjuvanticity was revealed between the two adjuvants. As an interesting finding, the polyclonal generation of anti-RBC antibody-forming cells (AFC) in the spleen cell cultures by stimulation with B-cell mitogen, i.e., either nystatin or LPS, was not inhibited at all by inclusion of any anti-RBC antiserum, whereas, as is well known, the generation of AFC by stimulation with the antigen was specifically suppressed by the corresponding antiserum, indicating a difference in the genesis between the mitogen-induced AFC and the antigen-induced AFC.


Pharmacokinetics, pharmacodynamics, and prediction of developmental abnormalities.
The purpose of this article is to review the application of pharmacokinetics and pharmacodynamics to risk assessment for developmental toxicants and to the development of predictive models of developmental toxicity. Physiologically based pharmacokinetic models require knowledge of the anatomic and physiological changes taking place during pregnancy and of how the potential developmental toxicant is distributed into differentiating and developing fetal tissues. Physiologically based pharmacokinetic models of varying levels of complexity have been proposed for rodent and human gestation. Models of pharmacodynamic behavior are less well developed, although structure-activity relationships have led to useful insights for certain specific classes of developmental toxicants. Development of biologically based dose-response models, which integrate pharmacokinetics and pharmacodynamics, is in its early phases. Although their development has proven to be complex, biologically based dose-response models have the potential to form the basis for a broader understanding of mechanisms of developmental toxicity and for broad predictive utility in developmental toxicity.


The absence of hepatitis B virus DNA in hepatitis B e antigen positive sera from chronic hepatitis B surface antigen carriers in China.
Sera from 20 Chinese patients with chronic hepatitis B were examined for hepatitis B e antigen and hepatitis B virus (HBV) DNA. There was considerable discordance with HBV DNA not being detectable in 10 out of 13 (77%) patients who were hepatitis B e antigen positive. Further testing for anti-HBe and HBV-DNA polymerase activity confirmed the results. Possible reasons for this discordance are discussed but neither hepatitis D (delta) infection nor the acquired immunodeficiency syndrome (AIDS) could be implicated.


Reliability of the toxic screen in drug overdose.
To determine the reliability of the laboratory in detecting drugs taken by overdosed patients, we evaluated laboratory performance on an unbiased sample of actual clinical specimens. Replicate serum and urine samples from a series of 20 consecutive clinically overdosed patients were sent to three commercial laboratories and one academic research laboratory for identification and quantification of intoxicating agents. All laboratories used the advance analytical techniques of gas chromatography-mass spectrometry. The results suggest that laboratories do not reliably identify drugs in the serum of overdosed patients, partly because of technical limitation, partly because of laboratory error, and possibly because of inadequate specimens. Drugs judged responsible for the overdose were identified in only 50% to 70% of the cases, depending on the laboratory. Reported concentrations sometimes varied over a 10-fold range.