[Pregnancy and labor after spontaneous and induced abortion].
The course of pregnancy, delivery and puerperium has been analysed in 91 women after spontaneous abortion in the past, 170 women after artificial abortion and in 91 women during the first pregnancy. The women after abortion were characterized by the advanced age the more frequent hemorrhage during the pregnancy, the renal failures, the preterm deliveries and the gestoses. After the artificial abortions the deliveries were longer and the blood loss greater. If compare women with the first pregnancy the women after abortion were characterized by more frequent complications during the puerperium. The clinical state of neonates from the group compared showed no significant differences.


Infection prevention for all facilities.
In many states, the same regulations that apply to hospitals don't apply to clinics and ambulatory centers. But regardless of whether the government demands it, health care workers at these facilities should be just as meticulous about infection prevention practices as health care workers in hospitals. As with any other organization, a good place to start is hand hygiene and proper education about what infection prevention entails.


Home Oxygen in Chronic Obstructive Pulmonary Disease.
Two landmark trials conducted more than 35 years ago provided scientific evidence that, under very specific circumstances, long-term oxygen therapy (LTOT) may prolong life. These two trials enrolled 290 patients with chronic obstructive pulmonary disease and severe daytime hypoxemia documented by direct arterial blood gas measurement. From that time, LTOT became a standard of care, and the indications for oxygen therapy expanded to include nocturnal oxygen therapy for isolated nocturnal oxygen desaturation, ambulatory oxygen to correct exercise-induced desaturation, and short-burst oxygen to relieve dyspnea. In most cases, the rationale for broadening the indications for oxygen therapy is that, if hypoxemia exists, correcting it by increasing the FiO2 should help. However, with the exception of LTOT in severely hypoxemic patients with chronic obstructive pulmonary disease, randomized controlled trials of oxygen therapy have failed to demonstrate clinically significant benefits. Also, adherence to LTOT is usually suboptimal. Important areas for future research include improving understanding of the mechanisms of action of supplemental oxygen, the clinical and biochemical predictors of responsiveness to LTOT, the methods for measuring and enhancing adherence to LTOT, and the cost-effectiveness of oxygen therapy. A standardization of terminology to describe the use of supplemental oxygen at home is provided.


Burring technique in modern podiatric palliative care.
A review of the literature reveals sparse references regarding the application of burs in the conservative treatment of soft tissues and nails. The most recent publications were in 1946. The authors present an update on the technology and practical application of burs in podiatric medicine, their metallurgy, types, and recommended bur selection for reduction, remodeling, and burnishing of hyperkeratotic tissue and thickened nails.


Design of selective thrombin inhibitors based on the (R)-Phe-Pro-Arg sequence.
Potent and selective inhibitors of thrombin were sought based on the (R)-Phe-Pro-Arg sequence. The objective was to generate similar binding interactions to those achieved by potent competitive inhibitors of the argatroban type, so eliminating the need for covalent interaction with the catalytic serine function, as utilized by aldehyde and boronic acid type inhibitors. Improving the S(1) subsite interaction by substitution of arginine with a 4-alkoxybenzamidine residue provided potent lead 2 (K(i) = 0.37 nM). Though an amide bond, which H-bonds to the active site, is lost, modeling indicated that a new H-bond is generated between the alkoxy oxygen atom and the catalytic Ser-195 hydroxyl group. Substitution of the benzamidine system by 1-amidinopiperidine then gave compound 4, which provided a further gain in selectivity over trypsin. However, previous work had shown that these compounds were likely to be too lipophilic (Log D +0.4 and +0.2, respectively) and to suffer rapid hepatic extraction, presumably via biliary elimination. Accordingly, both proved short-acting when administered intravenously to rats and showed poor activity when given intraduodenally. The aim was then to reduce lipophilicity below a log D of -1.2, which in a previously reported series had been effective in preventing rapid clearance. It was anticipated that compounds of this type would rely on the cation selective paracellular route of absorption from the gastrointestinal tract. Potent polar analogues with selectivity >1000 over trypsin were obtained. The best in vivo activity was shown by compound 12. However, in the final analysis, its oral bioavilability proved poor, relative to analogues with similar physicochemical properties derived from argatroban, consistent with the hypothesis that molecular shape is an additional important determinant of paracellular absorption.


Autophosphorylation of the 16 kDa and 70 kDa antigens (Hsp 16.3 and Hsp 70) of Mycobacterium tuberculosis.
Several antigens of Mycobacterium tuberculosis, identified by monoclonal antibodies, have been previously cloned and are being exploited in the development of improved vaccines and diagnostic reagents. In this study, the molecular characteristics of two of these antigens, the immunodominant proteins Hsp 16.3 and Hsp 70, were analysed in further detail by assessing their capacity to undergo protein phosphorylation, a chemical modification frequently used by organisms to adjust to environmental variations. Hsp 16.3 was overproduced in an Escherichia coli expression system and purified to homogeneity. Upon incubation in the presence of radioactive ATP, it was shown to possess autophosphorylation activity. Two-dimensional analysis of its phosphoamino acid content revealed that it was modified exclusively at serine residues. In addition, cross-linking experiments demonstrated that it could tightly bind to ATP. Purified Hsp 70 was also shown to autophosphorylate but phosphorylation occurred exclusively at threonine residues. This reaction was found to be strongly stimulated by calcium ions. These data indicate that both structural and functional similarities exist between Hsp 16.3 (Acr) and alpha-crystallin, a eukaryotic protein which plays an important role in maintaining the transparency of the vertebrate eye, and that the functional properties of Hsp 70 from M. tuberculosis are similar to those of other bacterial members of the Hsp 70 family, particularly the E. coli homologue DnaK.


Hyoid chondroma presenting as an external neck mass.
Chondromas of the larynx are rare neoplasms; only a few examples of cartilaginous tumors affecting hyoid bone have been reported. A 33-year-old woman presented with a neck mass on the left carotid triangle. The patient's computed tomography and magnetic resonance imaging revealed a heterogenous mass, which seemed to originate from the left greater cornu of hyoid. The mass was excised using a transcervical approach with left greater cornu of hyoid bone. The pathologic diagnosis was chondroma of hyoid. Expert radiologic and pathologic review is mandatory in cartilaginous neoplasms of the larynx. Cartilaginous neoplasms of the hyoid should be included in the differential diagnosis of neck masses at the carotid triangle.


Repression of the aroF promoter by the TyrR repressor in Escherichia coli K-12: role of the 'upstream' operator site.
Three sequences are required for complete repression of the aroF promoter by the TyrR repressor protein. Two of these operator sites lie adjacent to each other and overlap the -35 region of the aroF promoter while the third lies about 70 base pairs upstream of the promoter. An aroF-cat (chloramphenicol acetyltransferase) gene fusion has been used to assay the effect of DNA insertions that alter the distance between the two promoter-proximal and the third, distal, operator sites on the repression of the aroF promoter in vivo. The distal site contributes to the repression of the promoter up to a distance of about 400 base pairs and its effect is not dependent on its separation from the first and second sites by an integral number of turns of the DNA helix.


Circumferential fusion by posterior approach in lumbosacral instability with or without pedicle screw fixation: a comparison of methods.
Lumbosacral circumferential fusion, a method which is widely adopted for the treatment of the different causes of lumbar pain, may be carried out in a single stage by posterior approach, associating interbody fusion with cages with posterolateral fusion. During the same operation, pedicle screw fixation may also be performed. In order to evaluate the need for this final surgical stage represented by pedicle screws, a comparison was conducted in 2 groups of patients affected with lumbosacral instability, treated at the Division of Vertebral Surgery at the Rizzoli Orthopaedic Institute between May 1995 and May 1997. The best clinical results were obtained in the first group (where pedicle fixation was associated). Because of the persistance of pain symptoms, successive pedicle fixation was instead required in a high percentage of patients (45%) in the second group (without pedicle fixation).


Sports-Related Pediatric Facial Trauma: Analysis of Facial Fracture Pattern and Concomitant Injuries.
Objective Sports-related injuries, such as facial fractures, are potentially debilitating and may lead to long-term functional and aesthetic deficits in a pediatric patient. In this study, we analyze sports-related facial fractures in the urban pediatric population in an effort to characterize patterns of injury and improve management strategies and outcomes. Methods Retrospective chart review was performed for all facial fractures resulting from sports injuries in the pediatric population at a level-1 trauma center (University Hospital, Newark, NJ). Results Seventeen pediatric patients were identified as having sustained a fracture of the facial skeleton due to sports injury. Mean age was 13.9 years old. A total of 29 fractures were identified. Most common fracture sites included the orbit ( n = 12), mandible ( n = 5), nasal bone ( n = 5), and zygomaticomaxillary complex ( n = 3). The most common concomitant injuries included skull fracture ( n = 3), intracranial hemorrhage ( n = 4), and traumatic brain injury ( n = 4). One patient was intubated upon arrival to the emergency department. Hospital admission was required in 13 patients, 4 of which were admitted to an intensive care setting. Nine patients required operative intervention. Mean length of hospital stay was 2.4 days. No patients were expired. Conclusions Sports-related facial fractures are potentially debilitating injuries in the pediatric population. Analysis of fracture pattern and concomitant injuries is imperative to develop effective management strategies and prevention techniques.


Standardised comparison of limonene-derived monoterpenes identifies structural determinants of anti-inflammatory activity.
Mint species are widely used in traditional and conventional medicine as topical analgesics for osteoarthritic pain and for disorders of the gastrointestinal and respiratory tracts which are all associated with chronic inflammation. To identify the structural determinants of anti-inflammatory activity and potency which are required for chemical optimization towards development of new anti-inflammatory drugs, a selected group of monoterpenes especially abundant in mint species was screened by measuring bacterial lipopolysacharide (LPS)-induced nitric oxide (NO) production in murine macrophages. Nine compounds significantly decreased LPS-induced NO production by more than 30%. IC50 values were calculated showing that the order of potency is: (S)-(+)-carvone > (R)-(-)-carvone > (+)-dihydrocarveol > (S)-8-hydroxycarvotanacetone > (R)-8-hydroxycarvotanacetone > (+)-dihydrocarvone > (-)-carveol > (-)-dihydrocarveol > (S)-(-)-pulegone. Considering the carbon numbering relative to the common precursor, limonene, the presence of an oxygenated group at C6 conjugated to a double bond at C1 and an isopropenyl group and S configuration at C4 are the major chemical features relevant for activity and potency. The most potent compound, (S)-(+)-carvone, significantly decreased the expression of NOS2 and IL-1β in macrophages and in a cell model of osteoarthritis using primary human chondrocytes. (S)-(+)-carvone may be efficient in halting inflammation-related diseases, like osteoarthritis.


From Russian Refugee to Iowa's First Neurosurgeon and Pioneer of Cranial Hemostasis: The Legacy of Anatole Kolodny (1892-1948).
After immigrating to the United States from Russia in the wake of the First World War, Anatole Kolodny became the first surgeon in Iowa to specialize in neurological surgery. Kolodny was vital to the initial practice of neurosurgery in the state of Iowa and to the specific development of academic neurosurgery at the University of Iowa. In an effort to improve his surgical outcomes, Kolodny invented a hemostat that bears his name and is still used for cranial hemostasis. He also provided early outcomes of myelomenigocele repair and wrote extensively on bone sarcoma. Kolodny's achievements brought favorable attention to the university and altered the course of neurosurgery at the University of Iowa. Of significant importance, Kolodny influenced and trained Iowa's second neurosurgeon, Olan Hyndman, and this action led the way to the eventual recruitment of the university's first division head of neurosurgery. The purpose of this manuscript is to shed light on Kolodny's important contributions to the development of neurosurgery not only at Iowa, but also in the profession as a whole.


Pain and Cognitive Function Among Older Adults Living in the Community.
Pain related to many age-related chronic conditions is a burdensome problem in elderly adults and may also interfere with cognitive functioning. The purpose of this study was to examine the cross-sectional relationship between measures of pain severity and pain interference and cognitive performance in community-living older adults. We studied 765 participants in the Maintenance of Balance Independent Living Intellect and Zest (MOBILIZE) Boston Study, a population-based study of persons aged 70 and older. Global pain severity and interference were measured using the Brief Pain Inventory subscales. The neuropsychological battery included measures of attentional capacity (Trail Making Test A, WORLD Test), executive function (Trail Making Test B and Delta, Clock-in-a-Box, Letter Fluency), memory (Hopkins Verbal Learning Test), and a global composite measure of cognitive function. Multivariable linear regression models were used to analyze the relationship between pain and cognitive functioning. Elderly adults with more severe pain or more pain interference had poorer performance on memory tests and executive functioning compared to elders with none or less pain. Pain interference was also associated with impaired attentional capacity. Additional adjustment for chronic conditions, behaviors, and psychiatric medication resulted in attenuation of many of the observed associations. However, the association between pain interference and general cognitive function persisted. Our findings point to the need for further research to understand how chronic pain may contribute to decline in cognitive function and to determine strategies that may help in preventing or managing these potential consequences of pain on cognitive function in older adults.


Modulation of neuromuscular synapses and contraction in Drosophila 3rd instar larvae.
Over the past four decades, Drosophila melanogaster has become an increasingly important model system for studying the modulation of chemical synapses and muscle contraction by cotransmitters and neurohormones. This review describes how advantages provided by Drosophila have been utilized to investigate synaptic modulation, and it discusses key findings from investigations of cotransmitters and neurohormones that act on body wall muscles of 3rd instar Drosophila larvae. These studies have contributed much to our understanding of how neuromuscular systems are modulated by neuropeptides and biogenic amines, but there are still gaps in relating these peripheral modulatory effects to behavior.


Long-term results of pulmonary valve annular enlargement with valve repair in tetralogy of Fallot.
We adopted an operative technique of pulmonary valve (PV) annular enlargement with valve repair in tetralogy of Fallot (TOF) correction to reduce postoperative pulmonary regurgitation (PR) 16 years ago. Here, we have evaluated the long-term results. Between April 2000 and August 2005, 43 patients (26 men) with tetralogy of Fallot with pulmonary stenosis underwent PV annular enlargement with valve repair. The median age and body weight at the time of surgery were 14 months and 10.2 kg, respectively. There was no operative mortality. Mean postoperative PR grade at discharge was 0.93 ± 0.40 (none or trivial in 10 patients, mild in 27 patients, mild to moderate in 5 patients and moderate in 1 patient), and the mean postoperative pressure gradient across PV was 13.0 ± 10.9 mmHg. The mean follow-up duration was 131.9 ± 42.9 months. During follow-up, 1 reoperation was performed for residual ventricular septal defect. The mean PR grade at the last follow-up echocardiography was 1.59 ± 0.60 (mild in 17 patients, mild to moderate in 8 patients, moderate in 14 patients, moderate to severe in 1 patient and severe in 3 patients), and the mean pressure gradient was 22.7 ± 9.9 mmHg. We have compared the incidence of moderate or more PR with the incidence of patients who underwent simple transannular patch enlargement through propensity score matching. The PV repair group had a lower incidence of moderate or more PR compared with the simple transannular patch group (40% vs 68%, P = 0.04). PV annular enlargement with valve repair has reasonable long-term results and yields a lower long-term incidence of significant PR compared with the simple transannular patch enlargement technique.


A weight-based formula for the estimation of gastric tube insertion length in newborns.
Safe and effective functioning of nasogastric and orogastric tubes in the neonatal intensive care unit (NICU) is achieved by ensuring their correct placement within the stomach. Insertion length has traditionally been estimated using morphological measures, but studies have indicated that these are frequently inaccurate. This study aimed to evaluate the frequency of correct tube placement and to determine a weight-based formula for estimation of insertion length. A prospective study was performed over a 6-month period in a tertiary NICU. Infants with gastric tubes who required radiography for clinical reasons were included. The infant's weight and the type and length of tube were documented. A radiologist assessed the tube position to be high, borderline, correct, or long. A total of 218 radiographs of infants weighing 397 to 4131 g were included. Correct tube position was achieved on 74% of occasions. By analyzing data for correct tube positions, formulas were derived to predict tube insertion length in centimeters: orogastric = [3 × weight (kg) + 12] and nasogastric = [3 × weight (kg) + 13]. The formulas correctly predicted 60% of misplaced orogastric tubes and 100% of misplaced nasogastric tubes. We propose a novel weight-based formula for estimation of gastric tube insertion length in newborn infants to improve the accuracy of this routine procedure.


Increased focal Kv4.2 channel expression at the plasma membrane is the result of actin depolymerization.
Voltage-dependent potassium channel trafficking and localization are regulated by proteins of the cytoskeleton, but the mechanisms by which these occur are still unclear. Using human embryonic kidney (HEK) cells as a heterologous expression system, we tested the role of the actin cytoskeleton in modulating the function of Kv4.2 channels. Pretreatment (>or=1 h) of HEK cells with 5 microM cytochalasin D to disrupt the actin microfilaments greatly augmented whole cell Kv4.2 currents at potentials positive to -20 mV. However, no changes in the voltage dependence of activation and inactivation of macroscopic currents were observed to account for this increase. Similarly, single channel recordings failed to reveal any significant changes in the single channel conductance, open probability, and kinetics. However, the mean patch current was increased from 0.9 +/- 0.2 pA in control to 6.7 +/- 3.0 pA in the presence of cytochalasin D. Imaging experiments revealed a clear increase in the surface expression of the channels and the appearance of "bright spot" features, suggesting that large numbers of channels were being grouped at specific sites. Our data provide clear evidence that increased numbers and altered distribution of Kv4.2 channels at the cell surface are primarily the result of reorganization of the actin cytoskeleton.


Simple and sensitive CO2 laser visual screen.
The present paper describes a simple and sensitive CO2 laser visual screen which is made from silica gel with cobalt chloride as indicator. The screen can directly and almost immediately display a clear mode pattern of an exposing CO2 laser beam, it can respond to laser intensities ranging from 80 mW/cm2 to 26 W/cm2. It is suitable for the observation of both high-power lasers, which are used for surgery, and very low power ones, which are used for biostimulation.


A High Frequency of Peripheral Blood IL-22(+) CD4(+) T Cells in Patients With New Onset Type 2 Diabetes Mellitus.
This study is aimed at investigating the frequency of different functional IL-22(+) CD4(+) T cells in Chinese patients with type 2 diabetes mellitus (T2DM). The frequency of circulating IFN-γ+IL-17-IL-22-CD4(+) (Th1), IFN-γ-IL-17A+IL-22-CD4(+) (Th17), and IFN-γ-IL-17A-IL-22(+) CD4(+) (Th22), and other subsets of IL-22(+) CD4(+) T cells in 31 patients with new onset T2DM and 16 healthy controls was characterized by flow cytometry. The levels of serum IL-22, IL-17, IFN-γ, insulin C-peptide, hemoglobin A1c (HbA1c), fasting plasma glucose, and insulin were examined. The frequency of Th1, Th17, Th22, IFN-γ(+) IL-17(-) IL-22(+) , and IFN-γ(-) IL-17(+) IL-22(+) CD4(+) T cells and the concentrations of IL-22, but not IL-17 and IFNγ, in the patients were significantly higher than controls. The percentages of Th22 cells were correlated positively with the frequency of IFN-γ(-) IL-17(+) IL-22(+) CD4(+) T cells, the values of body mass index (BMI) and homeostatic model assessment insulin resistance (HOMA-IR), and the levels of serum IL-22 in those patients. Our data suggest that IL-22(+) CD4(+) T cells may contribute to the early process of T2DM.


A novel Mn++-dependent ribonuclease that functions in U16 SnoRNA processing in X. laevis.
The intron-encoded U16 small nucleolar RNA (snoRNA) is a component of a new family of molecules which originate by processing of pre-mRNA in which they are contained. The mechanism of U16 snoRNA biosynthesis involves an initial step of endonucleolytic cleavage of the pre-mRNA with the release of a pre-snoRNA molecule; the subsequent step consists of exonucleolytic trimming that produces mature U16 molecules. In order to identify the molecular components involved in this peculiar biosynthetic pathway, we have undertaken the characterization of the endonucleolytic activity by biochemical fractionation of Xenopus laevis oocyte nuclear extract. In this paper we show the production of a protein fraction (BSF) which is highly enriched for a specific endonucleolytic activity that exactly reproduces the cleavage pattern of the U16-containing pre-mRNA identified in vivo in X. laevis oocytes and in unfractionated nuclear extract.


Therapy of non-Hodgkin's lymphomas in relapse.
The authors present the results of treatment of 26 patients suffering from non-Hodgkin's lymphoma in relapse. Remission which preceded the relapse was obtained in all patients with combination chemotherapy CVP (cyclophosphamide, vincristine and prednisone). For a second-choice regimen the following treatment modalities were used: 1) DTIC + prednisone; 2) VM-26 + procarbazine + prednisone; or 3) therapeutic splenectomy + combination CVP. The best results (the longest second remission) were obtained in patients who underwent therapeutic splenectomy, followed by a CVP regimen.


TYK2 as a therapeutic target in the treatment of autoimmune and inflammatory diseases.
JAKs are intracellular protein tyrosine kinases that, through activation of STATs, are responsible for signal transduction pathways that regulate cellular responses to numerous cytokines, growth factors and hormones in many different cells. JAK-STAT signaling plays a key role in regulating immune function, and cytokines - such as IL-23, IL-12 and type I interferons - are central to the pathogenesis of autoimmune diseases, including psoriasis, inflammatory bowel disease and systemic lupus erythematosus. Here the authors review the evidence for targeting TYK2 as a more specific approach to treating these conditions. TYK2 inhibitors are clinically effective in autoimmune and inflammatory diseases and may avoid some of the complications reported with nonselective JAK inhibitors.


Diversity of the US Public Health Workforce Pipeline (2016-2020): Role of Academic Institutions.
Objectives. To develop a diversity index (DI) comparing the diversity of graduates across public health schools and programs in the United States and to examine characteristics associated with institutions' graduate diversity. Methods. We analyzed longitudinal data from the Association of Schools and Programs of Public Health (ASPPH) across 5 academic years (2016-2017 to 2020-2021) for 109 ASPPH members. The outcome was the percentage of underrepresented minority (URM) students among those with bachelor's and graduate degrees in public health. The DI was constructed by dividing the percentage of URM graduates by the percentage of URM residents 20 to 35 years of age in the state where the ASPPH member was located. Results. The mean DI score increased from 0.7 in 2016 to 0.8 in 2020, but URM students remain underrepresented. A 1-percentage-point increase in the proportion of URM faculty members was associated with a 0.7-percentage-point increase in the proportion of URM graduates (P < .001). Conclusions. Although the diversity of the public health educational pipeline shows an upward trend, racial/ethnic minority students remain underrepresented in public health. We found that institutional characteristics such as faculty diversity, program degree level, and area of study were associated with student diversity. (Am J Public Health. 2023;113(9):1000-1008. https://doi.org/10.2105/AJPH.2023.307352).


Hsp90 Inhibitor; NVP-AUY922 in Combination with Doxorubicin Induces Apoptosis and Downregulates VEGF in MCF-7 Breast Cancer Cell Line.
Breast cancer is one of the most prevalent malignancies and leading causes of females' mortality worldwide. Because of resistance to various treatment options, new treatments based on molecular targeting has introduced as noticeable strategies in cancer treatment. In this regard, heat shock protein 90 (Hsp90) inhibitors are proposed as effective anticancer drugs. The goal of the study was to utilize a combination of the doxorubicin (DOX) and NVP-AUY 922 on the MCF-7 breast cancer model to investigate the possible cytotoxic mechanisms. MCF-7 breast cancer cell line was prepared and treated with various concentrations of DOX and NVP-AUY922 in single-drug treatments. We investigated the growth-inhibitory pattern by MTT assay after continuous exposure to NVP-AUY922 and DOX in order to determine dose-response. Then the combinatorial effects were evaluated in concentrations of 0.5 × IC50, 0.2 × IC50, 1 × IC50 and, 2 × IC50 of each drugs. Based on MTT results of double combinations, low effective doses were selected for Real-time PCR [caspase3 and vascular endothelial growth factor(VEGF)] and caspase 3 enzyme activity. A dose-dependent inhibitory effects were presented with increasing the doses of both drugs in single treatments. The upregulation of caspase 3 and downregulation of VEGF mRNA were observed in double combinations of NVP-AUY922 and DOX versus single treatments. Also, in these combinations in low doses of examined drugs (0.5 × IC50, 0.2 × IC50), higher caspase 3 activity were presented in comparison to single treatments (p<0.05). Our findings indicate an effective action of NVP-AUY922 in combined with DOX in this cell line. These results can predict the treatment outcome in this model.


Influence of Pressure on the Composition of Gaseous Reference Materials.
We have shown that the amount fraction of carbon dioxide in a nitrogen or synthetic air matrix stored in cylinders increases as the pressure of the gas mixture reduces, while the amount fraction of methane remains unchanged. Our measurements show the initial amount fraction of carbon dioxide to be lower than the gravimetric value after preparation, which we attribute to the adsorption of a proportion of the molecules to active sites on the internal surface of the cylinder and the valve. As the mixture is consumed, the pressure in the cylinder reduces and the amount fraction of the component is observed to increase. The effect is less pronounced in the presence of water vapor. More dramatic effects have been observed for hydrogen chloride. These findings have significant implications for the preparation of high accuracy gaseous reference materials with unprecedented uncertainties which underpin a broad range of requirements, in particular atmospheric monitoring of high impact greenhouse gases.


Functional Characterization of TaFUSCA3, a B3-Superfamily Transcription Factor Gene in the Wheat.
The end-use quality of wheat, including its unique rheology and viscoelastic properties, is predominantly determined by the composition and concentration of gluten proteins. While, the mechanism regulating expression of the seed storage protein (SSP) genes and other related genes in wheat remains unclear. In this study, we report on the cloning and functional identification of TaFUSCA3, a B3-superfamily transcription factor (TF) gene in wheat. Sequence alignment indicated that wheat and barley FUSCA3 genes are highly conserved. Quantitative reverse-transcription (qRT)-PCR analysis showed that the transcript of TaFUSCA3 was accumulated mostly in the stamens and the endosperms of immature wheat seeds. Yeast-one-hybrid results proved that the full-length TaFUSCA3 and its C-terminal region had transcriptional activities. Yeast-two-hybrid and bimolecular fluorescence complementation assays indicated that TaFUSCA3 could activate the expression of the high molecular weight glutenin subunit gene Glu-1Bx7 and interact with the seed-specific bZIP protein TaSPA. DNA-protein-interaction enzyme-linked immunosorbent assay demonstrated that TaFUSCA3 specifically recognizes the RY-box of the Glu-1Bx7 promoter region. Transient expression results showed that TaFUSCA3 could trans-activate the Glu-1Bx7 promoter, which contains eight RY-box sequences. TaFUSCA3 was unable to activate the downstream transcription when the RY-box was fully mutated. TaFUSCA3 could activate the transcription of the At2S3 gene promoter in a complementation of loss-of-function experiment using the Arabidopsis thaliana line fus3-3, which is a FUSCA3 mutant, demonstrating the evolutionary conservation of the TaFUSCA3 gene. In conclusion, the wheat B3-type TF, TaFUSCA3, is functional conserved between monocot and dicot, and could regulate SSP gene expression by interacting specifically with TaSPA.


Why do children have chronic abdominal pain, and what happens to them when they grow up? Population based cohort study.
To test the hypotheses that children with abdominal pain have anxious parents and come from families with high rates of physical illness and that they grow up to suffer from high rates of medically unexplained symptoms and psychiatric disorders. Population based birth cohort study. General population. Participants in the Medical Research Council (MRC) national survey of health and development, a population based birth cohort study established in 1946. Abdominal pain present throughout childhood in the absence of defined organic disease, and measures of physical symptoms and psychiatric disorder at age 36 years. There were high rates of complaints about physical health among the parents of children with persistent abdominal pain, and the mothers had higher neuroticism scores. Children with persistent abdominal pain were more likely to suffer from psychiatric disorders in adulthood (odds ratio 2.72 (95% confidence interval 1.65 to 4.49)) but were not especially prone to physical symptoms once psychiatric disorder was controlled for (odds ratio 1. 39 (0.83 to 2.36)). Persistent abdominal pain is associated with poor health and emotional disorder in the parents. Children with abdominal pain do not necessarily continue to experience physical symptoms into adulthood but are at increased risk of adult psychiatric disorders.


Postural Orthostatic Tachycardia in a Patient with Type 2 Diabetes with Diabetic Neuropathy.
A 24-year-old Japanese man with type 2 diabetes mellitus and diabetic neuropathy was admitted to our ward to evaluate the cause of orthostatic intolerance. During a head-up tilt test, his heart rate increased from 105 to 155 beats/minute within 3 minutes, and chest discomfort began. He was diagnosed with postural orthostatic tachycardia syndrome (POTS), and orthostatic intolerance disappeared after β-blocker treatment. Scintigraphy using 123I-metaiodobenzylguanidine showed decreased cardiac uptake. Power spectral analysis of heart rate variability for 24 hours in Holter electrocardiography demonstrated decreases in both sympathetic and parasympathetic nervous system activities, with a greater decrease in parasympathetic activity than sympathetic activity. The relative sympathetic hyperactivity in the present patient with diabetic neuropathy seemed to be related to POTS.


Multiple Fungicide Resistance in Botrytis cinerea from Greenhouse Strawberries in Hubei Province, China.
Two hundred and forty isolates of Botrytis cinerea were collected during the early summer of 2012 and 2013 from strawberry greenhouses in 10 locations in Hubei Province and examined for sensitivity to five fungicides, most of which were commonly used to control this fungus. High frequency of resistance to carbendazim (Car, 63.63%) and cyprodinil (Cyp, 42.42%) was detected. Boscalid-resistant (BosR) isolates were detected for the first time in China, whereas no fludioxonil-resistant isolates were identified. Dual resistance to carbendazim and diethofencarb (Die) was also detected. There were six phenotypes of resistance profile (i.e., CarRDieSBosSCypS, CarRDieRBosSCypS, CarRDieSBosSCypR, CarRDieSBosRCypS, CarRDieRBosSCypR, and CarRDieSBosRCypR). CarRDieSBosSCypS and CarRDieSBosSCypR were the most common phenotypes, occurring at eight and seven locations, respectively. After 10 successive transfers on fungicide-free potato dextrose agar, tested resistant isolates retained levels of resistance similar to or comparative with the initial generation, indicating the stability of these resistances. Fitness evaluations based on investigation of mycelial growth, osmotic sensitivity, sporulation in vitro and in vivo, and virulence revealed the uncompromising fitness in resistant isolates, except that decreased virulence was observed in BosR isolates. The molecular basis of carbendazim, diethofencarb, and boscalid resistance was investigated. Results showed that all 13 sequenced carbendazim-resistant isolates harbored the mutation E198V or E198A in the β-tubulin gene and the five isolates with dual resistance to carbendazim and diethofencarb showed the mutation E198K in the same gene. BosR isolates possessed the H272R mutation in succinate dehydrogenase subunit B gene. The results achieved in this study challenge the current management strategies for B. cinerea, which largely depend on applications of these fungicides.


Saturated-absorption cavity ring-down spectroscopy.
We report on a novel approach to cavity ring-down spectroscopy with the sample gas in saturated-absorption regime. This technique allows us to decouple and simultaneously retrieve the empty-cavity background and absorption signal, by means of a theoretical model that we developed and tested. The high sensitivity and frequency precision for spectroscopic applications are exploited to measure, for the first time, the hyperfine structure of an excited vibrational state of 17O12C16O in natural abundance with an accuracy of a few parts in 10{-11}.


Dysregulation of MiR-519d Affects Oral Squamous Cell Carcinoma Invasion and Metastasis by Targeting MMP3.
MicroRNA-519d (miR-519d) has been reported to play important roles in tumor development and progression in multiple cancers, either as tumor suppressor or tumor promotor. However, the expression level, biological function and molecular mechanisms of miR-519d in oral squamous cell carcinoma (OSCC) remain unclear. Therefore, the aims of this study were to investigate the functional role of miR-519d in OSCC and the possible underlying regulatory mechanism. In this study, we found that miR-519d was significantly downregulated in OSCC tissues and cell lines compared with normal oral mucosae and normal oral epithelial cells. Importantly, downregulation of miR-519d was closely correlated with the lymph node metastasis, advanced tumor stage and poor overall survival of OSCC patients. Furthermore, miR-519d significantly inhibited the migration and invasion of OSCC cells. Using bioinformatics and biological approaches, we showed that miR-519d directly targeted matrix metalloproteinase-3 (MMP3), which might account for the underlying mechanism involved in the miR-519d mediated suppression of OSCC progression. What is more, miR-519d expression was inversely correlated with MMP3 expression in OSCC tissues, and high levels of MMP3 expression in OSCC tissues were also associated with the metastasis and poor prognosis of these patients. In addition, we further identified that miR-519d acted as a regulator of epithelial-mesenchymal transition (EMT) in OSCC cells. Overall, the present study highlighted miR-519d as a tumor suppressor in OSCC by targeting MMP3 and supported biological and clinical links between miR-519d-MMP3 and OSCC, thus indicating the potential therapeutic value of miR-519d for alleviating OSCC metastasis.


Investigating the association of ApoE genotypes with blood-brain barrier dysfunction measured by cerebrospinal fluid-serum albumin ratio in a cohort of patients with different types of dementia.
Since more than a decade ApoE is known to be a strong risk factor for Alzheimer's disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimer's disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier.


Safety evaluation of perampanel as monotherapy or first adjunctive therapy in patients with epilepsy.
There is a need for anti-seizure medications (ASMs) that are well tolerated and effective as monotherapy or first adjunctive therapy to reduce the need for adjunctive ASMs to treat newly diagnosed epilepsy, and to reduce the number of concomitant ASMs in patients with refractory epilepsy. Although the pivotal trials of perampanel evaluated its adjunctive use in patients with refractory seizures, open-label/real-world studies support its use in first/second-line settings. This paper reviews the pharmacology, efficacy, and safety/tolerability of perampanel, focusing on its use as monotherapy or first adjunctive therapy. The safety of perampanel in special populations and its safety/tolerability compared with that of other ASMs is also discussed. Perampanel is a favorable candidate for initial or first adjunctive therapy due to its favorable efficacy and safety/tolerability as monotherapy and adjunctive therapy, its long half-life and ease of use, and its limited drug-drug interactions. The proposed mitigation strategies for managing the risk of serious psychiatric adverse events are appropriate patient selection, use of low doses, and slow titration. The growing body of evidence might shift current treatment strategies toward the early use of perampanel and its use at a low dose (4 mg/day).


Synthesis of Leucas Aspera Extract Loaded Gold-PLA-PEG-PLA Amphiphilic Copolymer Nanoconjugates: In Vitro Cytotoxicity and Anti-Inflammatory Activity Studies.
Gold nanoparticles (GNPs) are synthesized using the medicinal plant Leucas Aspera extract (LAE) and poly lactic acid-co-poly ethylene glycol-co-poly lactic acid (PLA-PEG-PLA) copolymer by water-in-oil (W/O) emulsion method. The proposed method of W/O emulsion technique involves synthesis of GNPs and loading of Leucas Aspera extract on to the PLA-PEG-PLA copolymer matrix simultaneously. The synthesized GNPs are characterized by Fourier transform infra-red (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffractometry (XRD) and transmission electron microscopy (TEM). The GNPs-LAE loaded polymer NPs are examined for the in vitro cytotoxicity on South African green monkey's kidney cells. The GNPs-LAE loaded polymer nanoconjugates exhibit maximum up to 95% of cell viability with 100 μg concentration of GNPs in the sample. The GNPs-LAE loaded polymer NPs exhibit better anti-inflammatory activity when compared to the pure LAE.


Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside.
Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.


Bottom-up or top-down: unit cost estimation of tuberculosis diagnostic tests in India.
Of 18 sites that participated in an implementation study of the Xpert® MTB/RIF assay in India, we selected five microscopy centres and two reference laboratories. To obtain unit costs of diagnostic tests for tuberculosis (TB) and drug-resistant TB. Laboratories were purposely selected to capture regional variations and different laboratory types. Both bottom-up and the top-down methods were used to estimate unit costs. At the microscopy centres, mean bottom-up unit costs were respectively US$0.83 (range US$0.60-US$1.10) and US$12.29 (US$11.61-US$12.89) for sputum smear microscopy and Xpert. At the reference laboratories, mean unit costs were US$1.69 for the decontamination procedure, US$9.83 for a solid culture, US$11.06 for a liquid culture, US$29.88 for a drug susceptibility test, and US$18.18 for a line-probe assay. Top-down mean unit cost estimates were higher for all tests, and for sputum smear microscopy and Xpert these increased to respectively US$1.51 and US$13.58. The difference between bottom-up and top-down estimates was greatest for tests performed at the reference laboratories. These unit costs for TB diagnostics can be used to estimate resource requirements and cost-effectiveness in India, taking into account geographical location, laboratory type and capacity utilisation.


In vitro and in vivo evaluation of colon cancer targeted epichlorohydrin crosslinked Portulaca-alginate beads.
The aim of this study was to formulate a novel dual crosslinked hydrogel bead using Portulaca mucilage for colon-targeted delivery of 5-fluorouracil (5-FU) and evaluate its safety, specificity and efficacy. The ionotropic gelation technique was employed to prepare the hydrogel beads of Portulaca mucilage. For this, the mucilage was initially crosslinked with alginate and calcium ions. Epichlorohydrin was employed as a crosslinker in the second crosslinking step. The formulation was subjected to in vitro and in vivo studies to evaluate morphology, size, cytotoxicity, and organ distribution. Human HT-29 colon cancer cell-line was used for in vitro assays and in vivo studies were performed in Wistar rats to assess the usefulness and effectiveness of the formulation for colon cancer therapy. Microsphere sizes ranged from 930 to 977μm and possessed a high level of drug encapsulation efficiency (ca. 78% w/w). Compared with 5-FU solution (Tmax = 1.2 h, mean resident time: MRT = 3.3h) the dual crosslinked Portulaca microspheres exhibited sustained drug release after oral administration to rats (Tmax = 16h, MRT = 14h). The relative bioavailability of 5-FU solution and the microspheres were 100 and 93.6% respectively. Tissue distribution studies indicated high concentration of 5-FU in colon. In-vitro anticancer assay demonstrated IC50 value of 11.50 μg/ml against HT-29 colon cancer cell line. The epichlorohydrin cross-linked Portulaca microspheres prepared in this study provided sustained release of 5-FU up to 16h in the colonic region and enhanced the antitumor activity of the neoplastic drug. The formulation is hence an ideal carrier system for colon-targeted drug delivery.


Intestinal malrotation in adult seen on hepatobiliary scintigraphy.
Hepatobiliary scintigraphy is primarily used to diagnose acute and chronic biliary tract disorders. However, its potential role in diagnosing unsuspected extrahepatic pathology is not well described. We present 2 adult patients with chronic abdominal pain who underwent hepatobiliary scintigraphy for evaluation of cystic duct patency. In both cases, the proximal small bowel was located on the right side of the abdomen, which suggested the diagnosis of malrotation. Retrospective review of abdominal CT scan, upper gastrointestinal series, and subsequent laparotomy confirmed malrotation. The diagnosis of malrotation in both these patients was first suggested on hepatobiliary scintigraphy, which significantly impacted their subsequent management.


Corneal infections after implantation of intracorneal ring segments.
To report risk factors, clinical course, and outcome in patients with infectious keratitis following implantation of intracorneal ring segments (ICRS). The records of 8 patients with culture-proven infectious keratitis after ICRS (Ferrara or Intacs) implantation were retrospectively reviewed. Age, gender, corneal findings, ocular abnormalities, the condition that led to ICRS implantation, immediate prior use of a contact lens, elapsed time between implantation and the onset of symptoms, previous medications, and systemic disorders were noted. Culture-positive infectious keratitis developed in 7 eyes of 7 patients (2 men and 5 women) with a mean age of 35 years who underwent Ferrara implantation for the treatment of keratoconus and in a 29-year-old man who underwent Intacs implantation for correction of low myopia. Contact lens use, diabetes, and trauma were factors possibly associated with the risk of infection in three cases. Microorganisms, identified in all cases, included Staphylococcus aureus, Streptococcus viridans, Streptococcus pneumoniae, Pseudomonas sp, Nocardia sp, Klebsiella sp, and Paecylomices sp. Onset of symptoms of infection varied from less than 1 week to 22 months postoperatively, depending on the infecting organism. Infectious keratitis following ICRS implantation is a sight-threatening complication for which early recognition and rapid institution of appropriate treatment may result in a better visual outcome.


Global functional impairment in head and neck cancer survivors after completing radiotherapy treatment.
Improvements in diagnosis and treatment of head and neck cancer (HNC) patients have resulted in improved long-term survival rates. However, a variety of symptoms and comorbidities, often secondary to the cancer and its treatments, are experienced by a relevant number of survivors. So, the aim of this study was to determine the global functional impairment in HNC survivors 1 year after radiotherapy treatment. A descriptive case-control study was performed. HNC survivors were recruited from San Cecilio Clinical University Hospital in Granada. The main variables included were functionality and quality of life. 30 HNC survivors were included in our study. Significant differences were found in the WHO-DAS 2.0 test, with a worse score in the HNC group in most subscales (p < 0.05), and poorer scores in the COMP test, performance (p < 0.001) and satisfaction (p < 0.001). Significant differences were also found in most QLQ-30 subscales (p < 0.05) and the QLQ-H&N35. In regard to the EQ-5D, significant differences were found between groups, with worse results in the HNC group (p < 0.05). HNC survivors presented a poorer global function and a worse quality of life and health status 1 year after the radiotherapy treatment. Moreover, a good correlation was found between functionality and quality of life outcomes.IMPLICATIONS FOR REHABILITATIONA worse quality of life and health status are shown in head and neck survivors 1 year after radiotherapy.Global functionality is related to quality of life outcomes in head and neck cancer survivors.There is a need to recognise the need for and to provide longer term rehabilitation.


Utility of intraoperative flexible endoscopy in frontal sinus surgery.
Surgical management of the frontal sinus can be challenging. Extensive frontal sinus pneumatization may form a far lateral or supraorbital recess that can be difficult to reach by conventional endoscopic surgical techniques, requiring extended approaches such as the Draf III (or endoscopic modified Lothrop) procedure. Rigid endoscopes may not allow visualization of these lateral limits to ensure full evacuation of the disease process. Here we describe the utility of intraoperative flexible endoscopy in two patients with far lateral frontal sinus disease. In both cases, flexible endoscopy allowed confirmation of complete evacuation of pathologic material, thereby obviating more extensive surgical dissection. In cases where visualization of the far lateral frontal sinus is inadequate with rigid endoscopes, flexible endoscopy can be used to determine the need for more extensive dissection.


Preventive effect of L-carnitine on the disorder of lipid metabolism and circadian clock of mice subjected to chronic jet-lag.
Circadian clock plays an essential role in orchestrating daily physiology, and its disruption can evoke metabolic diseases such as obesity. L-Carnitine can reduce blood lipid levels, and ameliorate fatty liver through regulating lipid metabolism. However, whether L-Carnitine administration may affect the disturbance of lipid metabolism and circadian rhythm of mice induced by prolonged circadian disruption is still unknown. Herein, we investigated the effects of L-Carnitine on conditions of circadian clock and lipid metabolism through a chronic jet-lag mice model which was developed by reversing 12 h light/12 h dark cycle every 4 days for a continuous 12 weeks. Results showed that L-Carnitine administration significantly decreased levels of serum glutamic-oxaloacetic transaminase (GOT) and triglycerides (TG), which were remarkably elevated by chronic jet-lag. More importantly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that L-Carnitine supplementation would effectively counteract the negative alterations in gene expression which related to lipid metabolism (Srebp1, Acaca, Fasn, and Scd1), metabolic regulator (mTOR) and circadian rhythm (Bmal1, Per1, Cry1 and Dec1) in the liver of mice subjected to the chronic jet-lag. As a conclusion, L-Carnitine was partly effective in preventing the disruption of circadian clock and lipid metabolic disorders induced by the chronic jet-lag.


Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration.
Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool. Following myelosuppressive irradiation, PTN expression is increased in bone marrow endothelial cells (BMECs), and PTN+ ECs are more frequent in the niche. Moreover, deleting Ptn from ECs impairs HSC regeneration whereas Ptn deletion from BM stromal cells does not. These findings reveal dichotomous and complementary regulation of HSC maintenance and regeneration by BM stromal cells and ECs.


Effects of adrenalectomy on the incorporation of 3H-cytidine in neurophysin and vasopressin-containing neurons of the rat hypothalamus.
Using radioautography and immunocytochemistry, we investigated differences in 3H-cytidine incorporation into RNA in vasopressin or neurophysin-positive neurons in the rat hypothalamus following adrenalectomy. Control animals and those that had been bilaterally adrenalectomized for 2 weeks received 0.3 mCi 3H-cytidine subcutaneously and were decapitated 1 h following injection. Brains were prepared for combined radioautography and immunocytochemistry. Incorporation was estimated by counting silver grains over immunoreactive neurons. The neurons of the paraventricular nucleus (PVN) showed a consistent and significant increase in the amount of incorporation of label 2 weeks after bilateral adrenalectomy. There was no change in incorporation in neurons of either the supraoptic or suprachiasmatic nuclei. These findings suggest that the vasopressin PVN neurons, some of which project to the zona externa of the median eminence, are activated under conditions of adrenalectomy.


Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study.
The aim of this work was to study the effect of oxidative stress on the structural changes of the secondary peptide structure of amyloid beta 1-42 (Aβ 1-42), in the dentate gyrus of hippocampus of rats exposed to low doses of ozone. The animals were exposed to ozone-free air (control group) and 0.25 ppm ozone during 7, 15, 30, 60, and 90 days, respectively. The samples were studied by: (1) Raman spectroscopy to detect the global conformational changes in peptides with α-helix and β-sheet secondary structure, following the deconvolution profile of the amide I band; and (2) immunohistochemistry against Aβ 1-42. The results of the deconvolutions of the amide I band indicate that, ozone exposure causes a progressively decrease in the abundance percentage of α-helix secondary structure. Furthermore, the β-sheet secondary structure increases its abundance percentage. After 60 days of ozone exposure, the β-sheet band is identified in a similar wavenumber of the Aβ 1-42 peptide standard. Immunohistochemistry assays show an increase of Aβ 1-42 immunoreactivity, coinciding with the conformational changes observed in the Raman spectroscopy of Aβ 1-42 at 60 and 90 days. In conclusion, oxidative stress produces changes in the folding process of amyloid beta peptide structure in the dentate gyrus, leading to its conformational change in a final β-sheet structure. This is associated to an increase in Aβ 1-42 expression, similar to the one that happens in the brain of Alzheimer's Disease (AD) patients.


A highly selective G-quadruplex-based luminescent switch-on probe for the detection of gene deletion.
A G-quadruplex-based switch-on luminescence assay has been developed for the detection of gene deletion using a cyclometallated iridium(III) complex as a G-quadruplex-selective probe. Upon hybridization with the target DNA, the two split G-quadruplex-forming sequences assemble into a split G-quadruplex, which greatly enhances the luminescence emission of the iridium(III) probe. The assay is simple and highly selective.


Does Pasteurized Donor Human Milk Efficiently Protect Preterm Infants Against Oxidative Stress?
Pasteurized donor human milk (DHM) is the preferred alternative for infant nutrition when own mother's milk (OMM) is unavailable. Whether DHM is an efficient means for protecting preterm infants from oxidative stress remains unknown. We quantified a panel of oxidative stress biomarkers in urine samples from preterm infants (≤32 weeks of gestation and a birth weight ≤1500 g) receiving ≥80% of feeding volume as either DHM or OMM. The noninvasive in vivo assessment of oxidative stress showed no statistically significant difference between both groups at the time when full enteral nutrition (150 mL/kg body weight) was achieved and until hospital discharge. In addition, the changes of urinary biomarker levels with time were assessed. This is the first longitudinal study on oxidative stress levels in preterm infants fed with DHM in comparison with OMM. There is no statistically significant difference in urinary oxidative stress levels of preterm infants from both groups indicating that despite the effects of pasteurization, DHM is a valid alternative when OMM is not available. Based on the results, we raise the hypothesis that pasteurized DHM protects preterm infants from oxidative stress as good as OMM, and consequently, its use could prevent oxidative stress-related diseases. Antioxid. Redox Signal. 31, 791-799.


Inverted battery design as ion generator for interfacing with biosystems.
In a lithium-ion battery, electrons are released from the anode and go through an external electronic circuit to power devices, while ions simultaneously transfer through internal ionic media to meet with electrons at the cathode. Inspired by the fundamental electrochemistry of the lithium-ion battery, we envision a cell that can generate a current of ions instead of electrons, so that ions can be used for potential applications in biosystems. Based on this concept, we report an 'electron battery' configuration in which ions travel through an external circuit to interact with the intended biosystem whereas electrons are transported internally. As a proof-of-concept, we demonstrate the application of the electron battery by stimulating a monolayer of cultured cells, which fluoresces a calcium ion wave at a controlled ionic current. Electron batteries with the capability to generate a tunable ionic current could pave the way towards precise ion-system control in a broad range of biological applications.


Policy responses to COVID-19: lessons for the global trade and investment regime.
During the past two years, the COVID-19 pandemic has cost millions of lives around the globe, caused major morbidity and provoked widespread economic and social disruption. In response, governments have enacted policies to mitigate the impacts of the pandemic. This research focuses in on policies aimed at increasing access to essential health products and services by comparing them to the global rules governing trade, investment and intellectual property. We have assessed whether these rules have or could have constrained countries in responding to this and future crises. The study identifies the nature and scope of the trade-related health sector policies implemented by our sample group of countries, selected because of their systemic significance: the United States, Germany, France, China, South Africa and India. Each policy is placed into one of five broad categories covered by trade and investment rules so that we could assess their consistency with those rules. We found, among other things, that the types of trade-related health measures were quite diverse. The high-income countries in our study were the most active in the policy space and tended to rely on subsidies-based measures while the middle-income countries relied more heavily on export and import measures. Policies directly relevant to intellectual property protection were virtually non-existent. When evaluating the implemented policies against the global trade and investment rules, we found potential constraints under five different types of rules: those governing subsidies, import and export trade barriers, investment measures, government procurement and trade-related intellectual property. Given the tension between the global rules and the practices of policymaking during the pandemic, we conclude that the tension must be resolved in favor of governments making policy rather than relying on existing exceptions or pushing national governments to comply more exactly with the rules. Although the pandemic itself does not respect national borders, governance still generally occurs at the national level because national governments are often the only entities with both the legal authority and the practical ability to respond.


Analysis of a commercial dimethyl-sulfoxide-stabilized frozen canine platelet concentrate by turbidimetric aggregometry.
To assess platelet function of a commercial dimethyl-sulfoxide (DMSO)-stabilized frozen platelet concentrate (PC) using turbidimetric aggregometry. In vitro analysis. Research laboratory in a school of veterinary medicine. Five units of frozen PC in 6% DMSO were studied. Fresh platelet-rich plasma (PRP), with and without 6% DMSO, from 6 healthy dogs were used as controls. Turbidimetric platelet aggregation was measured after initiation of platelet aggregation by addition of adenosine diphosphate (ADP), collagen, or thrombin at concentrations of 30 μM, 20μg/mL, and 0.5U/mL, respectively. Measures were performed at thaw and repeated 2 hours after thaw for the frozen PC. Compared with PRP, the frozen PC showed decreased aggregation in response to thrombin (amplitude of 84% versus 25%, P=0.01), and collagen (amplitude of 13% versus 3%, P=0.05) but not ADP (6.5% versus 18%, P=0.2). Compared with frozen PC at thaw, the frozen PC at 2 hours after thaw showed decreased aggregation in response to thrombin, collagen, and ADP (P<0.05). There was no difference in aggregation between PRP in 6% DMSO and frozen PC. These in vitro data suggest there is a decrease in platelet response to agonists associated with the freeze-thaw process in the commercially available 6% DMSO canine frozen PC.


Endogenous lentivirus in Malayan colugo (Galeopterus variegatus), a close relative of primates.
A significant fraction of mammalian genomes is composed of endogenous retroviral (ERV) sequences that are formed by germline infiltration of various retroviruses. In contrast to other retroviral genera, lentiviruses only rarely form ERV copies. We performed a computational search aimed at identification of novel endogenous lentiviruses in vertebrate genomes. Using the in silico strategy, we have screened 104 publicly available vertebrate genomes for the presence of endogenous lentivirus sequences. In addition to the previously described cases, the search revealed the presence of endogenous lentivirus in the genome of Malayan colugo (Galeopterus variegatus). At least three complete copies of this virus, denoted ELVgv, were detected in the colugo genome, and approximately one hundred solo LTR sequences. The assembled consensus sequence of ELVgv had typical lentivirus genome organization including three predicted accessory genes. Phylogenetic analysis placed this virus as a distinct subgroup within the lentivirus genus. The time of insertion into the dermopteran lineage was estimated to be more than thirteen million years ago. We report the discovery of the first endogenous lentivirus in the mammalian order Dermoptera, which is a taxon close to the Primates. Lentiviruses have infiltrated the mammalian germline several times across millions of years. The colugo virus described here represents possibly the oldest documented endogenization event and its discovery can lead to new insights into lentivirus evolution. This is also the first report of an endogenous lentivirus in an Asian mammal, indicating a long-term presence of this retrovirus family in Asian continent.


Autoimmunity in demyelinating diseases.
Demyelinative diseases of the CNS and peripheral nervous system can be distinguished on the basis of primary mediation by antibody or T lymphocytes (or failure of the T-cell-mediated response) and on the basis of chronicity. The principal mechanisms are autoimmunization to myelin antigens after actual immunization with tissue or infection with cross-reactive viruses or, alternatively, persistent infection of the nervous system (viral or spirochetal) with an associated immune response to the pathogen.


CCL23/myeloid progenitor inhibitory factor-1 inhibits production and release of polymorphonuclear leukocytes and monocytes from the bone marrow.
CCL23/Myeloid progenitor inhibitory factor-1 is a human CC chemokine with potent in vitro suppressor effects on both human and murine myeloid progenitor cells. This study concerns in vivo inhibitory effect of CCL23 on production of polymorphonuclear leukocytes (PMNs) and monocytes in the bone marrow and their release into the circulation. 5'-Bromo-2'-deoxyuridine (BrdU; 100 mg/kg) was used to label dividing PMNs and monocytes in the bone marrow, and BrdU-labeled cells were followed for 10 days in the circulation and identified using immunocytochemistry. Rabbits were given CCL23 (100 mug/kg, n = 5) or saline (control: n = 5) intravenously daily for 3 days before labeling with BrdU. Turnover of PMNs and monocytes in the bone marrow and their transit times through the bone marrow were calculated. CCL23 treatment tended to prolong transit time of PMN (98.4 +/- 4.3 hours vs 111.2 +/- 3.8 hours, control vs CCL23, p = 0.06) through the bone marrow and decreased the size of the bone marrow mitotic pool of PMN (p < 0.01). CCL23 treatment also prolonged the transit time of monocyte (43.4 +/- 3.1 hours vs 54.2 +/- 1.3 hours, control vs CCL23, p < 0.05) through the bone marrow and decreased turnover and pool size of monocytes in the bone marrow (p < 0.05). We conclude that CCL23 suppresses PMN and monocyte progenitors, decreases the pool size and slows their turnover in the bone marrow.


A Systematic Critical Appraisal of Clinical Practice Guidelines in Heart Failure Using the AGREE II Tool.
Multiple clinical practice guidelines (CPGs) for heart failure management have been published to provide the best practices regarding the use of foundational therapies to reduce morbidity and mortality in this patient population. However, a critical appraisal of these heart failure guidelines has not been performed. This systematic review aimed to assess the methodological quality of current CPGs in the management of patients with heart failure. A comprehensive search of EMBASE and PubMed was conducted to identify CPGs published between January 1, 2021 and September 8, 2022. Any CPGs published in the last 2 years addressing the management of heart failure were eligible for inclusion. The methodological quality of the CPGs was assessed using the AGREE II (Appraisal of Guidelines for Research & Evaluate II) instrument. The initial search yielded 3,269 citations, of which, 6 CPGs were included. A total of 2 CPGs were each published by the cardiology associations in North America and Asia and 1 each in Europe and South America. The overall median score for the AGREE II domains were 100% for scope and purpose, 71% for stakeholder involvement, 71% for the rigor of development, 100% for clarity of presentation, 43% for applicability, 100% for editorial independence, and 64% for overall assessment. CPG developers would benefit from the use of a standardized approach to the development of CPGs and use the contents of the AGREE II tool to improve the methodological rigor, reporting, and applicability of CPGs.


PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency.
Mutations of the PROP1 gene lead to combined pituitary hormone deficiency (CPHD), which is characterized by a deficiency of GH, TSH, LH/FSH, PRL and, less frequently, ACTH. This study was undertaken to investigate the molecular defect in a cohort of patients with CPHD. A multicentric study involving 46 cases of CPHD (17 familial cases belonging to seven kindreds and 29 sporadic cases) selected on the basis of clinical and hormonal evidence of GH deficiency, central hypothyroidism and hypogonadotrophic hypogonadism, in the absence of an identified cause of hypopituitarism. Mutations of PROP1 were investigated by DNA sequencing. Clinical, hormonal and neuroradiological data were collected at each centre. PROP1 mutations were identified in all familial cases: five kindreds presented a c. 301-302delAG mutation, one kindred presented a c. 358C --> T (R120C) mutation and one presented a previously unreported initiation codon mutation, c. 2T --> C. Of the 29 sporadic cases, only two (6.9%) presented PROP1 germline mutations (c. 301-302delAG, in both). Phenotypic variability was observed among patients with the same mutations, particularly the presence and age of onset of hypocortisolism, the levels of PRL and the results of pituitary imaging. One patient presented a sellar mass that persisted into adulthood. This is the first report of a mutation in the initiation codon of the PROP1 gene and this further expands the spectrum of known mutations responsible for CPHD. The low mutation frequency observed in sporadic cases may be due to the involvement of other unidentified acquired or genetic causes.


Synthetic antiprotozoal thiazolide drug induced apoptosis in colorectal cancer cells: implications of IL-6/JAK2/STAT3 and p53/caspases-dependent signaling pathways based on molecular docking and in vitro study.
Colorectal cancer (CRC) is a global pressing healthcare priority. Dysregulation of the IL6/JAK2/STAT3 and p53/caspase downstreaming pathways are significantly involved in the progression of CRC, and mainly affecting apoptosis. Discovery of new anti-cancer agents is laborious, time consuming, and costly with obvious socioeconomic burden. In the present study, we are proposing new molecular insights on the anti-proliferative and apoptotic therapeutic effects of nitazoxanide (NTZ) on CRC. NTZ is FDA-approved thiazolide antiparasitic agent, which has excellent safety and pharmacokinetic profiles. The molecular docking study revealed that NTZ has better binding affinity and docking score against JAK2 and BCL2 proteins compared to 5-Fluorouracil, which is the standard drug for treatment of CRC. The current in vitro work on a human HCT116 cell line displayed that NTZ had lower IC50 value (11.20 µM) than 5-flurouracil (23.78 µM), and NTZ induced a statistically significant down-regulation of IL6/JAK2/STAT3. NTZ also modulated significantly the p53/caspases-dependent signaling pathways, leading to enhancement of apoptosis and an increase of DNA fragmentation. Moreover, NTZ regulated the Bcl-2 gene family and promoted the loss of mitochondrial function which was depicted by release of cytochrome c (Cyt c), and caspase activation in apoptotic HCT116 cells. Additionally, NTZ was able to reduce the expression of VEGF in CRC cell line, which needs future thorough molecular investigations. In conclusion, our findings provided a novel evidence that NTZ could be a dual potential IL6/JAK2/STAT3 signaling inhibitor and p53/caspases-dependent pathway activator in CRC cell line. These potentials support further exploratory molecular researches targeting the therapeutic roles of NTZ in CRC; individually and simultaneously with current approved chemotherapeutic regimens.


Effect of gamma-radiation and microwave heating on endosperm microstructure in relation to some technological properties of wheat grain.
Grains of the Polish winter wheat variety Begra were subject to gamma-radiation (60Co) within the dose range of 0.05-10 kGy and microwave treatment from 15 to 180 s, the latter resulting in a bulk grain temperature ranging from 28 to 98 degrees C. Both processes were responsible for marked structural changes of wheat kernel endosperm and were pronounced with increasing dose of ionizing radiation or with prolonged time of microwave treatment. Endosperm microstructures of wheat kernels treated with gamma-radiation ranging from 0.05 to 0.5 kGy did not differ from that of untreated ones. Only some changes in the structure of starch granules and proteins were observed at doses of 1, 5 and 10 kGy. Simultaneously at the doses of 5 and 10 kGy a statistically significant decrease of falling number, sodium dodecyl sulfate (SDS) sedimentation values, dough stability and energy were observed, while dough weakening progressed. Microwave treatment longer than 90 s caused marked changes in kernel endosperm structure. Some changes of proteins caused by denaturation created visible fibrils as well as high swelling and deformation of starch granules. This was followed by an increase in the falling number value, decrease in the estimated results of SDS sedimentation test, lowering of the percent of gluten washed out and of the dough energy, respectively. Also a significant decrease in bread quality expressed by volume and score was observed with increasing time of exposure to microwave.


Targeting Adenosine Receptors for the Treatment of Cardiac Fibrosis.
Adenosine is a ubiquitous molecule with key regulatory and cytoprotective mechanisms at times of metabolic imbalance in the body. Among a plethora of physiological actions, adenosine has an important role in attenuating ischaemia-reperfusion injury and modulating the ensuing fibrosis and tissue remodeling following myocardial damage. Adenosine exerts these actions through interaction with four adenosine G protein-coupled receptors expressed in the heart. The adenosine A2B receptor (A2BAR) is the most abundant adenosine receptor (AR) in cardiac fibroblasts and is largely responsible for the influence of adenosine on cardiac fibrosis. In vitro and in vivo studies demonstrate that acute A2BAR stimulation can decrease fibrosis through the inhibition of fibroblast proliferation and reduction in collagen synthesis. However, in contrast, there is also evidence that chronic A2BAR antagonism reduces tissue fibrosis. This review explores the opposing pro- and anti-fibrotic activity attributed to the activation of cardiac ARs and investigates the therapeutic potential of targeting ARs for the treatment of cardiac fibrosis.


Isolation and properties of an elastase-like proteinase from horse blood leucocytes.
The rapid, two steps method of purification of an elastase-like proteinase from cytoplasmic granules of horse leucocytes is described. This enzyme called the proteinase 1 is released easily from isolated granules in the low ionic strength solutions in opposite to the other two molecular forms of which one differs slightly in isoelectric point from the other. The enzyme is a typical neutral proteinase of a broad substrate specificity and wide pH optimum. In a physiological conditions the enzyme is built of two polypeptide chains of molecular weight about 30000 and 20000, respectively.


Thionine-Modified Poly(glycidyl methacrylate) Nanospheres as Labels of Antibodies for Biosensing Applications.
Monodisperse poly(glycidyl methacrylate) (PGMA) nanospheres were obtained by emulsifier-free emulsion polymerization and characterized by physicochemical methods. The effects of various reaction parameters on the particle properties were investigated. The particle size was controlled in the range of 350-420 nm. To introduce carboxyl groups, the PGMA nanospheres were hydrolyzed and oxidized with KMnO4. Subsequently, the enzyme horseradish peroxidase (HRP) and the electron mediator thionine were covalently attached to the PGMA nanospheres to obtain an antibody indicator suitable for enzyme-based electrochemical immunosensors. Combined HRP and thionine binding to the nanospheres had beneficial effects for the labeling efficiency and at the same time prevented the formation of soluble electron mediators.


Simple jumping process with memory: transport equation and diffusion.
We present a stochastic jumping process, defined in terms of jump-size probability density and jumping rate, which is a generalization of the well-known kangaroo process. The definition takes into account two process values: after and before the jump. Therefore, the process is able to preserve memory about its previous values. It possesses a simple stationary limit. Its master equation is interpreted as the kinetic equation with variable collision rate. The process can be easily applied to model systems which relax to distributions other than Maxwellian. The case of a constant jumping rate corresponds to the diffusion process, either normal or ballistic.


Restoring the secretory function of irradiation-damaged salivary gland by administrating deferoxamine in mice.
One of the major side effects of radiotherapy for treatments of the head and neck cancer is the radiation-induced dysfunction of salivary glands. The aim of the present study is to investigate the efficacy of deferoxamine (DFO) to restore the secretory function of radiation-damaged salivary glands in mice. DFO (50 mg/kg/d) was administered intraperitoneally in C57BL/6 mice for 3 days before and/or after point-fixed irradiation (18 Gy) of submandibular glands. The total 55 mice were randomly divided into: (1) Normal group: mice received no treatment (n = 5); (2) Irradiation group (IR): mice only received irradiation (n = 5); (3) Pre-DFO group (D+IR) (n = 10); (4) Pre+Post DFO group (D+IR+D) (n = 10); (5) Post-DFO group (IR+D) (n = 10); (6) For each DFO-treated group, the mice were intraperitoneally injected with 0.1 ml sterilized water alone (by which DFO was dissolved) for 3 days before and/or after irradiation, and served as control. Sham1: Pre-sterilized water group (n = 5); sham2: Pre+Post sterilized water group (n = 5); sham3: Post-sterilized water group (n = 5). The salivary flow rate (SFR) was assessed at 30th, 60th and 90th day after irradiation, respectively. After 90 days, all mice were sacrificed and their submandibular glands were removed for further examinations. The salivary glands showed remarkable dysfunction and tissue damage after irradiation. DFO restored SFR in the irradiated glands to a level comparable to that in normal glands and angiogenesis in damaged tissue was greatly increased. DFO also increased the expression levels of HIF-1α and VEGF while reduced apoptotic cells. Furthermore, Sca-1+cells were preserved in the salivary glands treated with DFO before IR. Our results indicate DFO could prevent the radiation-induced dysfunction of salivary glands in mice. The mechanism of this protective effect may involve increased angiogenesis, reduced apoptosis of acinar cells and more preserved stem cells.


[Thumb and finger reconstruction by anastomosing the digital arteries of the toe to finger transplant].
In a series of 295 cases of toe-to-finger reconstruction, 30 cases with 40 digits were reconstructed by arterial anastomosis between digital arteries of the toe transplant and the recipient thumb or fingertoe. Among them 5 thumbs were reconstructed by the distal segment of the big toe. 11 thumbs (10 cases), 15 fingers (8 cases) and 1 case with concomitant thumb and 3 fingers were reconstructed by toe transfer. Six cases of thumb pulp defect were also reconstructed by the big toe pulp transfer. The anastomosis of digital arteries instead of dorsalis pedis artery and radial artery and saphenous vein with cephali vein to re-establish circulation is an innovation and has the advantages of simplifying the operative procedure, minimizing operative trauma, reducing operation time, attenuating patients suffering, and obtaining good appearance and function after reconstruction. Besides the operation would not be hindered by anatomical variations of the artery and would reduce blood supply disturbance of the donor foot.


Predominance of three NF-kappaB binding sites in the long terminal repeat region of HIV Type 1 subtype C isolates from Zambia.
Human immunodeficiency virus type-1 (HIV-1) is a leading cause of mortality and morbidity in the world, with almost 46 million people infected globally. HIV-1 subtype C accounts for 55% of these infections. In Zambia, the majority of HIV-1 infections are subtype C. However, to its north most countries have non-subtype C as the most predominant HIV-1 subtype while to its south most of them are predominantly subtype C. The aim of this study was to determine the subtype distribution and to analyze the long terminal repeat (LTR) region of HIV-1 isolates from the northern part of Zambia. We amplified as well as directly sequenced the LTR, gag, and env regions of 78 HIV-1 peripheral blood samples from adult Zambians. Our results show 95% (74/78) of our isolates were HIV-1 subtype C. Furthermore, of the subtype C samples analyzed across the LTR, 61% (25/41) carried 3 NF-kappaB signature binding site sequences.


APOE genotype and cognitive functioning in a large age-stratified population sample.
There is evidence that the cognitive effects of Alzheimer's disease can be seen decades before disease diagnosis. If this is the case, then the apolipoprotein E (APOE) *E4 allele might be expected to have effects on cognitive functioning earlier in the life span. To assess such effects, the authors examined data on the *E4 allele and cognitive functioning from a population sample of 6,560 Caucasians covering the age groups of 20-24, 40-44, and 60-64 years. Participants were assessed on tests of episodic memory, working memory, mental speed, reaction time, and reading vocabulary. Although performance on all tests except reading vocabulary declined across age groups, there was no effect of the APOE *E4 allele at any age. These results indicate that APOE *E4 does not have preclinical effects early in the life span on these cognitive functions. Cognitive aging effects between the ages of 20 and 64 years must not be due to preclinical Alzheimer's disease.


Nursing care of the patient with non-Hodgkin's lymphoma. A case study.
A patient's significant life events, such as the diagnosis of cancer, coupled with critical developmental milestones provide particular challenges to nurses caring for young adults. A case study format is used to identify nursing care priorities throughout the diagnosis and treatment of a young adult male with non-Hodgkin's lymphoma. Diagnosis and treatment protocols are discussed to provide a background for nursing assessment and interventions. Nursing implications related to the treatment protocol are incorporated as are implications based on the physical and psychological impact of the disease and necessary life-style changes. Stressors created by the disease and treatments are identified, and the support of patient coping strategies and continued achievement of developmental tasks are addressed.


Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway.
Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinase-dependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.


Fitness Advantage in Heterozygous Ladybird Beetle Eriopis connexa (Germar) Resistant to Lambda-Cyhalothrin.
The pyrethroid lambda-cyhalothrin is widely recommended for use against defoliators in crop ecosystems, but this broad-spectrum insecticide lacks efficacy against aphids; thus, key aphid predators such as the ladybird beetle Eriopis connexa (Germar) (Coleoptera: Coccinellidae) must be preserved. Given that populations of E. connexa recently identified as resistant to lambda-cyhalothrin show potential of integrating chemical and biological control in crop ecosystems, a historical goal of integrated pest management. In the present study, the resistance maintenance over F1, F2, and F3 progenies from crossing resistant (R) and susceptible (S) E. connexa populations that might be expected after releasing R predator in the crop field and the F1 offspring performance when the R population is crossed with the S population are evaluated. The offspring performance is determined for F1 progenies from crossing the R population at F40- and F45-reared generations in the laboratory with the S population at F38- and F1-reared generations in the laboratory. The mortality rate in the heterozygous F1 progeny is low and similar to the rate for the R population (<5%), but it is about 75% in F2 and F3 progenies from crossing R and S populations. Fecundity and longevity of the heterozygous F1 progeny are significantly greater compared to the R population. These results suggest that when R population beetles are released and mating with S population residents, their field offspring retains the resistance phenotype with the advantages of greater egg production and longer survival compared to the parental R population.


Does Atmospheric Corrosion Alter the Sound Quality of the Bronze Used for Manufacturing Bells?
Bells are made of bronze, an alloy of copper and tin. Art objects and musical instruments belong to tangible and intangible heritage. The effect of atmospheric alteration on their sound is not well documented. To address this question, alteration cycles of bronze specimens are performed in a chamber reproducing a realistic polluted coastal atmosphere. The corrosion layers are characterized by X-ray diffraction, electron microscopy and X-ray photoelectron spectrometry. The buried interface of the film (alloy-layer interface) is formed by a thin, adherent and micro-cracked layer, mainly composed of sulfates, copper oxide and chloride, on top of tin corrosion products. Near the atmosphere-film interface, less adherent irregular clusters of soot, calcite, gypsum and halite developed. Through these observations, an alteration scenario is proposed. To correlate the bronze corrosion effect on the bell sound, linear and nonlinear resonance experiments are performed on the corroded bronze specimens, where resonance parameters are monitored as a function of increasing driving force using a shaker. Results show that the corrosion effect on the acoustic properties can be monitored through the evolution of the acoustic nonlinear parameters (damping and resonance). These well-calibrated original experiments confirm the effect of corrosion on the acoustic properties of bronze.


Differential effect of high pressure on NMDA receptor currents in Xenopus laevis oocytes.
Hyperbaric environments over 1.1 MPa induce in mammals and humans the high pressure neurological syndrome (HPNS). HPNS is characterized by cognitive and motor decrements associated with sleep disorders, EEG changes, tremor, and convulsions. Previously, it was proposed that augmented responses of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) may be involved. Recently, we have reported that, in rat hippocampus brain slices, isolated NMDAR synaptic responses were augmented at high pressure. We now test how high pressure affects NMDAR ionic currents. Mammalian (rat) cRNA of the most common hippocampal NMDAR compositions NR1-1a / NR2A and NR1-1b / NR2A were injected into Xenopus laevis oocytes, and NMDAR ionic currents were recorded, applying the two-electrode voltage clamp technique, at normobaric and at hyperbaric pressure (10.1 MPa). Statistical analysis revealed that high pressure increased NR1-1a / NR2A current amplitudes. By contrast, high pressure decreased NR1-1b / NR2A current amplitudes. These preliminary results demonstrate a differential high pressure effect on two types of NMDAR subunits. Moreover, augmentation of the NR1-1a / NR2A composition further supports the recently reported increase of NMDAR synaptic response in rat hippocampus brain slices. These results support the notion that increased NMDAR response, in addition to other mechanisms, plays an important role in HPNS.


Lewis Acid Catalyzed Asymmetric Three-Component Coupling Reaction: Facile Synthesis of α-Fluoromethylated Tertiary Alcohols.
A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of α-fluoromethyl-substituted tertiary alcohols using a three-component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom-economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields.


De novo refolding and aggregation of insulin in a nonaqueous environment: an inside out protein remake.
While thermodynamic penalties associated with protein-water interactions are the key driving force of folding, perturbed hydration of destabilized protein molecules may trigger aggregation, which in vivo often causes cellular and histological damage. Here we show, that the denatured state of an alpha-helical protein, insulin, converts to a non-native beta-sheet-rich structure upon de novo "refolding" in an anhydrous environment. The beta-pleated conformer precipitates from solutions of DMSO-denatured insulin upon dilution with chloroform. DMSO destroys hydrogen bond network of the native protein acting as a strong acceptor of main chain hydrogen bonds. Upon the addition of chloroform, which is a weak hydrogen bond donor per se, competitive hydrogen bonds between DMSO and chloroform are formed. This leads to the release of unfolded insulin molecules. In the absence of water, the imminent saturation of polypeptide's dandling hydrogen bonds does not produce the native and predominantly alpha-helical state but a beta-sheet-rich structure, which is morphologically and spectrally distinct from insulin amyloid fibrils. Unlike insulin fibrils, the beta-sheet conformer is metastable and refolds spontaneously to the native form in an aqueous environment. This implies that "folding" in the absence of water results in inefficient burial of hydrophobic side-chains, and thermodynamic frustration at the water-protein interface.


Lack of association between E148Q MEFV variant and Kawasaki disease.
We investigated a possible association between Kawasaki disease (KD), a systemic vasculitis of unknown etiology, or its coronary artery lesions (CAL) and MEFV gene variants including E148Q, the most common and mild mutation in the MEFV gene for familial Mediterranean fever or vasculitis-related disorders. The study population comprised a total of 138 Japanese patients with KD, including 45 patients with CAL and 93 patients without CAL and 170 normal controls. Sequence variations for the MEFV gene were detected by direct sequencing, followed by the TaqMan SNP genotyping assay. The genotype and allele frequencies of MEFV gene variants (E148Q, L110P, R202Q, P369S, R408Q) were compared between KD patients with and without CAL or between KD patients with CAL and controls. E148Q heterozygotes and homozygotes were observed in 37.1 and 5.5% of healthy controls, 33.3 and 5.1% of KD patients, and 37.8 and 4.4% of KD patients with CAL. No significant differences were observed in the genotype and allele frequencies of other MEFV gene variants (L110P, R202Q, P369S, R408Q) between KD patients with and without CAL or between KD patients with CAL and controls. No associations were detected between the MEFV gene variants and the development of KD or CAL formation in KD.


A quantitative framework for the analysis of multimodal optical microscopy images.
Multimodal optical microscopy, a set of imaging techniques based on unique, yet complementary contrast mechanisms and spatially and temporally co-registered data acquisition, has emerged as a powerful biomedical tool. However, the analysis of the dense, high-dimensional datasets acquired by these instruments remains mostly qualitative and restricted to analysis of each modality individually. Using a custom-built multimodal nonlinear optical microscope, high dimensional datasets were acquired for automated classification of functional cell states as well as identification of histopathological features in tissues slices. Supervised classification of cell death modes was performed through support vector machines (SVM) and semi-supervised classification of tissue slices was performed through the use of the expectation maximization (EM) algorithm. Applications of these techniques to the automated classification of cell death modes as well as to the identification of tissue components in fixed ex vivo tissue slices are presented. The analysis techniques developed provide a direct link between multimodal image contrast and biological structure and function, resulting in highly accurate classification in both settings. Quantification of multimodal optical microscopy images through statistical modeling of the high dimensional data acquired gives a strong correlation between biological structure and function and image contrast. These methods are sensitive to the identification of diagnostic, cellular-level features important in a variety of clinical settings.


Allogeneic and autologous stem cell transplantation in myelodysplastic syndromes.
Allogeneic bone marrow transplantation is the only currently available curative treatment for myelodysplastic syndromes (MDSs) but can be used only in the minority of patients (10%) who are younger than 55 years or so and for whom an HLA-identical donor is available. Each year in Europe, about 100 patients with MDSs receive an autologous bone marrow transplant. This procedure is usually indicated as first-line treatment, except in patients without excess of blasts or complex cytogenetic abnormalities. In forms with excess of blasts, chemotherapy prior to bone marrow transplantation deserves discussion. Autologous bone marrow transplants or the more recent technique involving transplantation of autologous peripheral stem cells can be considered in patients who have achieved a complete remission under aggressive chemotherapy. This method has been followed by higher recurrence rates in patients with MDSs than in those with de novo acute myeloblastic leukemia, and randomized studies are under way to compare it with aggressive maintenance chemotherapy.


Proactive vs. reactive psoriasis therapy: a long-term evaluation with dermoscopic and confocal microscopy assessment.
The PSO-LONG trial demonstrated that proactive management of psoriasis based on the regular application of the fixed-dose combination calcipotriol and betamethasone dipropionate (Cal/BD) foam twice a week for 52 weeks prolonged the time to first relapse and reduced the number of relapses, compared with the reactive management. Nevertheless, data about proactive management in clinical practice are still poor. This observational study compares the Cal/BD foam proactive management of psoriasis with the reactive scheme in consecutive patients with localized mild-to-moderate psoriasis. The degree of the skin atrophy was also assessed with dermoscopic and confocal microscopy analyses. This retrospective observational study was conducted at the Federico II University Dermatological Clinic of Naples in adult patients treated with the fixed-dose combination Cal/BD foam (Enstilar®, Leo Pharma, Ballerup, Denmark) according to either a proactive or a reactive scheme (on-demand treatment). The observation time was 52 weeks. 149 patients were involved. The effectiveness of the proactive therapy was sustained by the significant reduction of the mean number of relapses (p=0.004) and by the significant increase of the median time to relapse (p=0.014) compared to the reactive regimen. Compared to the baseline values, significant improvements in the Psoriasis Area and Severity Index (PASI) score, Investigator Global Assessment (IGA) score, and Skindex-16 index were reported. Dermoscopy and confocal microscopy analyses showed the absence of cutaneous atrophy during the proactive treatment and improved the lesion's appearance. The proactive regimen represents a valuable therapeutic novelty in treating mild-to-moderate psoriasis.