Clinical correlates of atypical depression and validation of the French version of the Scale for Atypical Symptoms (SAS).
The 8-item "Scale for Atypical Symptoms" (SAS) and its structured interview, the SIGH-SAD, have been developed to assess atypical symptoms of depression in winter depression. Although they are commonly used, no validation study has yet been conducted. 270 consecutive depressed inpatients were assessed prospectively. Pearson's correlation coefficients between fulfilment of Liebowitz criteria for atypical depression and both the SAS score and the atypical balance [ratio of the AS score to the total score on the Hamilton Depression Rating Scale 29-item (HDRS-29)] were calculated. The SAS was evaluated against Liebowitz criteria using binary logistic regression. A ROC curve was performed with the atypical balance against the fulfilment of Liebowitz criteria. 18.5% of patients met the criteria for atypical depression. The presence of an atypical depression was significantly correlated with both the atypical score (r=0.42) and the atypical balance (r=0.51). The logistic regression showed that a higher score on the SAS, the absence of a somatic syndrome (ICD-10) and a lower HDRS-21 score were independent predictors of an atypical depression while age, gender and bipolarity were not. The ROC curve showed that an atypical balance of 29% was the optimal threshold for the diagnosis of atypical depression (sensitivity=0.86, specificity=0.79). Patients with bipolar I and II were not distinguished. Atypical depression is relatively frequent in hospitalised patients. The concurrent validity of the French version of the SAS and its structured interview, the SIGH-SAD is satisfactory.


Robust behavioural effects in response to acute, but not repeated, terpene administration in Zebrafish (Danio rerio).
Terpenes are fragrant aromatic compounds produced by a variety of plants, most notably cannabis and hops. With increasing legalization of cannabis there is a need to better understand the behavioural effects of terpenes and ultimately their therapeutic value. Our study investigated the dose-dependent impact of three terpenes (limonene 0.25, 0.5, 0.75%; β-myrcene 0.001, 0.01, 0.1%; and 0.0001, 0.001, 0.00125% linalool) on zebrafish (Danio rerio) behaviour when exposed both acutely and repeatedly over a 7-day period. Anxiety-like behaviour, boldness, and locomotion were assessed using the open field test and the novel object approach test. In the acute dosing experiment, limonene and β-myrcene exposed groups demonstrated a significant decrease in locomotion, a decrease in anxiety-like behaviour, and an increase in boldness, while linalool treatment groups demonstrated only minor alterations in locomotion. Moreover, repeated exposure to limonene (0.39%) or β-myrcene (0.0083%) for a seven day period did not result in any significant behavioural effects. In conclusion, our study provides support for an anxiolytic and sedative effect in zebrafish in response to acute limonene and β-myrcene exposure that is no longer present after one week of repeated exposure.


Quantitative analysis of the relationship of derivatization reagents and detection sensitivity of electrospray ionization-triple quadrupole tandem mass spectrometry: Hydrazines as prototypes.
Chemical derivatization-assisted electrospray ionization-triple quadrupole mass spectrometry (ESI-QqQ-MS) has become an efficient tool for the quantification of low-molecular-weight molecules. Many studies found that the derivatives of the same analytes derivatized by different derivatization reagents with the same reaction group had different detection sensitivity, even under the same conditions of electrospray ionization-mass spectrometry (ESI-MS). This phenomenon was suggested to be caused by the different modifying groups in the derivatization reagents. However, there is still a lack of systematic study on how modifying groups in the derivatization reagents affect the detection sensitivity of their corresponding derivatives of analytes, especially theoretical investigations. In this study, we employed a quantitative structure-activity relationship (QSAR) modeling approach to explore the relationship between modifying group structures and the detection sensitivity of derivatization reagents and their derivatives during ESI-MS detection. A total of 110 derivatization reagents of the hydrazine family and their hexanal derivatives (substituted hydrazones) were selected as the prototypes to construct QSAR models. The established models suggested that several molecular descriptors, related to hydrophobicity, electronegativity, and molecular shape, were related to the detection sensitivity of hexanal derivatives induced by different modifying groups in the derivatization reagents. Besides, we found that the detection sensitivity of compounds detected in selected ion mode (SIM) showed a positive correlation with that obtained in multiple reaction monitoring mode (MRM), and the ionization efficiency was the key factor on the detection sensitivity in both modes.


Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors.
Opioid agonists (ethylketocyclazocine, etorphine, [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Ala2, N-Me-Phe4-Gly-ol]enkephalin (DAGO), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET) and morphine were found to inhibit the proliferation of human prostate cancer cell lines (LNCaP, DU145, and PC3), in a dose-dependent manner. The 50% inhibitory concentrations (IC50) were in the picomolar range. In many cases, this effect was antagonized by the general opioid antagonist, diprenorphine, indicating the existence of specific opioid binding sites. Saturation binding experiments with selective ligands and effectors showed no opioid sites on the LNCaP cell line, kappa1 and mu sites on the PC3 cell line, and kappa1, kappa3 and mu sites on the DU145 cell line. In other cases, the opioid effect was not antagonized by diprenorphine, indicating that the action of opioids might be mediated through other membrane receptors. Furthermore, casomorphin peptides, issued from bovine alpha- (alpha-casein-90-95 and alpha-casein-90-96) and beta-caseins (beta-casomorphin and beta-casomorphin-1-5), and human alphaS1-casein (alphas -casomorphin and alphaS1-casomorphin amide) inhibited cell proliferation of human prostate cell lines, also by a mechanism partly involving opioid receptors. As opioid neurons can be found in the prostate gland, and casomorphin peptides might reach the gland through the general circulation, the above findings indicate a putative role of opioids in prostate cancer cell growth.


Acute Multi-modal Neuroimaging in a Porcine Model of Endothelin-1-Induced Cerebral Ischemia: Defining the Acute Infarct Core.
In a porcine ischemic stroke model, we sought to compare the acute predicted infarct core volume (PIV) defined by CT perfusion (CTP)-hemodynamic parameters and MR-diffusion-weighted imaging (MR-DWI)/apparent diffusion coefficient (ADC), with the true infarct core volume (TIV) as defined by histology. Ten Duroc-cross pigs had a CTP scan prior to injection of endothelin-1 (ET-1) into the left striatum. CTP scans were used to monitor ischemic progression. A second dose of ET-1 was injected 2 h from the first injection. The animal was moved to a 3-T MRI scanner where DWI was performed. CTP imaging was acquired immediately after the MR imaging. Next, the brain was removed and stained with tetrazolium chloride (TTC). Linear regression and Bland-Altman plots were used to correlate the PIV measured by each imaging modality to that of the TIV from the histological gold standard. The CTP-cerebral blood flow (CBF) parameter had the highest R (2) value and slope closest to unity, while the CTP-cerebral blood volume (CBV) had the lowest R(2) value and slope furthest away from unity. The CTP-CBF • CBV product parameter had a higher R(2) value but lower slope than both MR parameers. The best Bland-Altman agreement was observed with the CTP-CBF parameter. PIV from MR-DWI, ADC, and CTP-CBF overestimated the TIV defined with histology. We show that the PIV defined with absolute gray and white matter CT-CBF thresholds correlates best with the TIV and is similar to both MR-DWI and ADC-defined PIVs. Further, the acute CBF • CBV mismatch may not indicate penumbral tissue in the acute stroke setting.


Changes in Material Hardship During the First Year of the COVID-19 Pandemic.
This article discusses the public's spending of the stimulus checks issued by the US government during 2020 and 2021.


Histiocytosis X of lungs and kidneys.
Report on a case of histiocytosis X of the lungs and kidneys. The pulmonary changes occured mainly during the fibrotic phase of the illness. In the kidneys, the process had a distinct granulomatous character with direct transition into a scarring final stage. Unusual was the considerable vascularisation of the pulmonary foci. Because of the large amount of plasma cells, particularly in the renal cortex, an allergic-hyperergic pathogenesis of the illness had to be discussed.


A kinesin 1-protrudin complex mediates AMPA receptor synaptic removal during long-term depression.
The synaptic removal of AMPA-type glutamate receptors (AMPARs) is a core mechanism for hippocampal long-term depression (LTD). In this study, we address the role of microtubule-dependent transport of AMPARs as a driver for vesicular trafficking and sorting during LTD. Here, we show that the kinesin-1 motor KIF5A/C is strictly required for LTD expression in CA3-to-CA1 hippocampal synapses. Specifically, we find that KIF5 is required for an efficient internalization of AMPARs after NMDA receptor activation. We show that the KIF5/AMPAR complex is assembled in an activity-dependent manner and associates with microsomal membranes upon LTD induction. This interaction is facilitated by the vesicular adaptor protrudin, which is also required for LTD expression. We propose that protrudin links KIF5-dependent transport to endosomal sorting, preventing AMPAR recycling to synapses after LTD induction. Therefore, this work identifies an activity-dependent molecular motor and the vesicular adaptor protein that executes AMPAR synaptic removal during LTD.


Deep multilayer brain omics identifies the potential involvement of menopause molecular networks in Gliomas' disease progression.
The risk of high-grade gliomas is lower in young females, however, its incidence enhances after menopause, suggesting potential protective roles of female sex hormones. Hormone oscillations after menopause have received attention as a possible risk factor. Little is known about risk factors for adult gliomas. We examined the association of the aging brain after menopause, determining the risk of gliomas with proteomics and the MALDI-MSI experiment. Menopause caused low neurotransmitter levels such as GABA and ACH, high inflammatory factor levels like il-1β, and increased lipid metabolism-related levels like triglycerides in the brain. Upregulated and downregulated proteins after menopause were correlated with differentially expressed glioma genes, such as ACTA2, CAMK2D, FNBPIL, ARL1, HEBP1, CAST, CLIC1, LPCAT4, MAST3, and DOCK9. Furthermore, differential gene expression analysis of monocytes showed that the downregulated gene LPCAT4 could be used as a marker to prevent menopausal gliomas in women. Our findings regarding the association of menopause with the risk of gliomas are consistent with several extensive cohort studies. In view of the available evidence, postmenopausal status is likely to represent a significant risk factor for gliomas.


Assessing bone quality--animal models in preclinical osteoporosis research.
As new agents are developed for osteoporosis prevention and intervention, the need for reliable animal models becomes more pressing. At the same time, the necessity of not focusing on bone mass as the sole efficacy parameter has become apparent. Before accepting any agent for clinical osteoporosis trials, FDA now requires that it has proven its efficacy in a small animal model and also in a larger animal model with known intracortical bone remodeling. This efficacy should be proven both concerning bone mass and bone biomechanical competence. In this paper, methods for testing bone quality in small and large animal models are presented, and the necessity of testing several skeletal sites: vertebrae, long bones, and femoral necks is discussed.


An alternative to group homes.
This paper describes a supported lodgings scheme as an alternative to group homes. It is pointed out that the County Council has a statutory duty to finance supported lodgings and that schizophrenics are ideally suited to such a scheme. Some short-stay, the majority of the 'new' non-demented long-stay, and a large number of the 'old' long-stay patients have been discharged by this means. After-care facilities were important, as nearly half attended the day centre and over one third were regularly visited in their lodgings by the community psychiatric nurses and social workers.


Outcomes associated with antibiotic administration for isolated maternal fever in labor.
The American College of Obstetricians and Gynecologists currently recommends that antibiotic treatment should be considered for women with isolated maternal fevers during labor. However, there is little known about the maternal and neonatal impact of antibiotic treatment in this scenario. We sought to assess the outcomes in women with a nonsustained, isolated maternal fever treated with antibiotics and compare it with expectant management. This was a retrospective cohort study of laboring women with a singleton gestation at term and a single temperature of between 38.0°C and 38.9°C without other evidence of infection (leukocytosis >15,000/mm3, fetal tachycardia, malodorous amniotic fluid, suspected alternate source of infection) at a tertiary teaching hospital. A contemporaneously maintained, validated obstetrical database was used to identify women for our cohort. Women with rheumatologic or renal disease, nongestational diabetes, preterm labor, placental abruption, vaginal bleeding, HIV, malpresentation, and fetal anomalies were excluded. The primary outcome was a postpartum fever above 38.0°C. Secondary maternal outcomes were treatment for postpartum endometritis, uterine atony, postpartum hemorrhage, admission to the intensive care unit, and postpartum length of stay. Secondary neonatal outcomes were neonatal intensive care unit admission, 5-minute Apgar score of <7, 5-minute Apgar score of <4, neonatal intensive care unit length of stay, and neonatal antibiotic administration. The results were compared using univariable and multivariable analyses. From January 1, 2015, to December 31, 2018, 359 women were identified; 85 received antibiotics and 274 did not. The baseline characteristics were similar between the groups, except for gestational age at the time of delivery (39.2 weeks vs 39.5 weeks for the antibiotic and no antibiotic groups, respectively; P=.02). The incidence in postpartum fever showed a downward trend in the antibiotic group (10.59% for the antibiotic group vs 18.98% for the no antibiotic group; P=.07). Significantly fewer women in the antibiotic group were treated for postpartum endometritis (3.53% vs 11.31%; P=.03). Neonatal intensive care unit admission and neonatal antibiotic administration rates were higher in the antibiotic group (41.18% vs 17.88%; P<.001 and 36.47% vs 12.41%; P<.001, respectively). The incidence of 5-minute Apgar score of <7 was higher in the antibiotic group (8.25% vs 2.19%; P=.016). After controlling for age, gestational age, body mass index, group B streptococci status, delivery method, parity, administration of epidural, and receipt of acetaminophen, the odds for postpartum fever were reduced by a factor of 0.42 (95% confidence interval, 0.18-0.99) among women who received antibiotics when compared with those who did not receive antibiotics. Outcome results are presented in Table 2. Although there was a lower rate of treatment for endometritis among women who received antibiotics for a single isolated maternal fever, there was a higher rate of neonatal intensive care unit admissions and 5-minute Apgar score of <7. This indicates that there likely is maternal benefit associated with antibiotic use, however, there are concerns about the neonatal risk.


Hybrid Prepectoral Direct-to-Implant and Autologous Fat Graft Simultaneously in Immediate Breast Reconstruction: A Single Surgeon's Experience with 25 Breasts in 15 Consecutive Cases.
The direct-to-implant method depends on the quality of the mastectomy flaps and can be used only when the flaps are adequately perfused. Even though the method was designed to be a definitive reconstruction procedure, it has been associated with an increased likelihood that additional operative revision will be required in order to achieve the expected final cosmetic outcome. The authors describe a hybrid prepectoral direct-to-implant method that combines autologous fat grafting in the superior medial pole with immediate reconstruction. In this prospective study, 15 patients (25 reconstructed breasts) underwent simultaneous hybrid prepectoral direct-to-implant reconstruction together with autologous fat grafting performed by a single senior plastic surgeon (Y.G). The mean quantity of autologous fat grafted in the superior medial aspect of the breast was 59.4 ± 12.8 cc. The mean total volume of the hybrid reconstructed breast, including implant and autologous fat graft, was 497.2 ± 89.1 cc. Satisfying final outcomes were achieved in all cases. There were no major complications, although minor complications were observed. The authors' hybrid approach allows the surgeon to achieve a more satisfying outcome with regard to the cleavage area. It results in a better natural appearance, an improved contour, and reduced upper pole rippling and deflation, with a lower likelihood that an additional operative revision will be required to achieve the desired final aesthetic outcome. The authors believe that their hybrid approach should be implemented as an integral part of the direct-to-implant prepectoral reconstruction procedure. Therapeutic, IV.


The relationship between limited MRI section analyses and volumetric assessment of synovitis in knee osteoarthritis.
To assess whether simple, limited section analysis can replace detailed volumetric assessment of synovitis in patients with osteoarthritis (OA) of the knee using contrast-enhanced magnetic resonance imaging (MRI). Thirty-five patients with clinical and radiographic OA of the knee were assessed for synovitis using gadolinium-enhanced MRI. The volume of enhancing synovium was quantitatively assessed in four anatomical sites (the medial and lateral parapatellar recesses, the intercondylar notch and the suprapatellar pouch) by summing the volumes of synovitis in consecutive sections. Four different combinations of section analysis were evaluated for their ability to predict total synovial volume. A total of 114 intra-articular sites were assessed. Simple linear regression demonstrated that the best predictor of total synovial volume was the analysis containing the inferior, mid and superior sections of each of the intra-articular sites, which predicted between 40-80% (r(2) = 0.396, p < 0.001 for notch; r(2) = 0.818, p < 0.001 for medial parapatellar recess) of the total volume assessment. The results suggest that a three-section analysis on axial post-gadolinium sequences provides a simple surrogate measure of synovial volume in OA knees.


Altered control strategy between leading and trailing leg increases knee adduction moment in the elderly while descending stairs.
The aim of the study was to examine the external knee adduction moments in a group of older and younger adults while descending stairs and thus the possibility of an increased risk of knee osteoarthritis due to altered knee joint loading in the elderly. Twenty-seven older and 16 younger adults descended a purpose-built staircase. A motion capture system and a force plate were used to determine the subjects' 3D kinematics and ground reaction forces (GRF) during locomotion. Calculation of the leg kinematics and kinetics was done by means of a rigid, three-segment, 3D leg model. In the initial portion of the support phase, older adults showed a more medio-posterior GRF vector relative to the ankle joint, leading to lower ankle joint moments (P<0.05). At the knee, the older adults demonstrated a more medio-posterior directed GRF vector, increasing in knee flexion and adduction in the second part of the single support phase (P<0.05). Further, GRF magnitude was lower in the initial and higher in the mid-portions of the support phase for the elderly (P<0.05). The results show that older adults descend stairs by using the trailing leg before the initiation of the double support phase more compared to the younger ones. The consequence of this altered control strategy while stepping down is a more medially directed GRF vector increasing the magnitude of external knee adduction moment in the elderly. The observed changes between leading and trailing leg in the elderly may cause a redistribution of the mechanical load at the tibiofemoral joint, affecting the initiation and progression of knee osteoarthritis in the elderly.


Varietal identification in pasta through an SSR-based approach: a case study.
Pasta is a worldwide popular Italian food made exclusively of durum wheat. The choice of variety to be used to produce pasta is at the discretion of the producer based on the peculiar characteristics of each cultivar. The availability of analytical approaches for the tracking of specific varieties along the productive chain is becoming increasingly important to authenticate the pasta products and distinguish between fraudulent activities and cross-contaminations during the production process. Among the different methods, molecular approaches based on DNA markers are the most used for these purposes because of their ease of use and high reproducibility. In the present study, we used an easy simple sequence repeats-based method to identify the durum wheat varieties used to produce 25 samples of semolina and commercial pasta comparing their molecular profile with those of the four varieties declared by the producer and other 10 durum wheat cultivars commonly used in pasta production. All of the samples showed the expected molecular profile; however, most of them present also a foreign allele indicating a possible cross-contamination. Moreover, we evaluated the accuracy of the proposed approach through the analysis of 27 hand-made mixtures with increasing amounts of a specific contaminant variety, allowing the estimation of the limit of detection of 5% (w/w). We demonstrated the feasibility of the proposed method and its effectiveness in the detection of not declared varieties when these are present in a percentage equal to or higher than 5%. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1 in Oxidative Metabolism-Driven Inflammation.
Metabolic reprogramming is one of the most frequent stress-adaptive response of cancer cells to survive environmental changes and meet increasing nutrient requirements during their growth. These modifications involve cellular bioenergetics and cross talk with surrounding microenvironment, in a dynamic network that connect different molecular processes, such as energy production, inflammatory response, and drug resistance. Even though the Warburg effect has long been considered the main metabolic feature of cancer cells, recent reports identify mitochondrial oxidative metabolism as a driving force for tumor growth in an increasing number of cellular contexts. In recent years, oxidative phosphorylation has been linked to a remodeling of inflammatory response due to autocrine or paracrine secretion of interleukines that, in turn, induces a regulation of gene expression involving, among others, molecules responsible for the onset of drug resistance. This process is especially relevant in ovarian cancer, characterized by low survival, high frequency of disease relapse and chemoresistance. Recently, the molecular chaperone TRAP1 (tumor necrosis factor-associated protein 1) has been identified as a key junction molecule in these processes in ovarian cancer: in fact, TRAP1 mediates a metabolic switch toward oxidative phosphorylation that, in turn, triggers cytokines secretion, with consequent gene expression remodeling, finally leading to cisplatin resistance and epithelial-to-mesenchymal transition in ovarian cancer models. This review summarizes how metabolism, chemoresistance, inflammation, and epithelial-to-mesenchymal transition are strictly interconnected, and how TRAP1 stays at the crossroads of these processes, thus shedding new lights on molecular networks at the basis of ovarian cancer.


Disparities in utilization of outpatient surgical care among children.
The purpose of this study was to quantify disparities in the utilization of outpatient pediatric surgical care and to examine the extent to which neighborhood-level socioeconomic disadvantage is associated with access to care among children. Clinic "no-shows" were examined among children scheduled from 2017 to 2019 at seven pediatric surgery clinics associated with a tertiary care children's hospital. The association between Area Deprivation Index, a neighborhood-level measure of socioeconomic disadvantage, and other patient factors with clinic no-shows was examined using multivariable logistic regression models. Difficulties in accessing postoperative care in particular were explored in a subgroup analysis of postoperative (within 90 days) clinic visits after appendectomy or inguinal/umbilical hernia repairs. Among 10,162 patients, 16% had at least 1 no-show for a clinic appointment. Area Deprivation Index (most deprived decile adjusted odds ratio 3.17, 95% confidence interval 2.20-4.58, P < .001), Black race (adjusted odds ratio 3.30, 95% confidence interval 2.70-4.00, P < .001), and public insurance (adjusted odds ratio 2.75, 95% confidence interval 2.38-3.31, P < .001) were associated with having at least 1 no-show. Similar associations were identified among 2,399 children scheduled for postoperative clinic visits after undergoing appendectomy or inguinal/umbilical hernia repair, among whom 20% were a no-show. Race, insurance type, and neighborhood-level socioeconomic disadvantage are associated with disparities in utilization of outpatient pediatric surgical care. Challenges accessing routine outpatient care among disadvantaged children may be one mechanism through which disparate outcomes result among children requiring surgical care.


Parental same-sex relationships, family instability, and subsequent life outcomes for adult children: Answering critics of the new family structures study with additional analyses.
The July 2012 publication of my study on the outcomes of young adults who report parental same-sex relationship behavior raised a variety of questions about the New Family Structures Study and my analyses and interpretations of it. This follow-up article seeks to address a variety of the more common criticisms that have been raised, to offer new commentary and analyses, and to pose questions for future analysts of the NFSS and other datasets that are poised to consider how household dynamics are associated with youth and young-adult outcomes. The new analyses I present here still reveal numerous differences between adult children who report maternal same-sex behavior (and residence with her partner) and those with still-married (heterosexual) biological parents. Far fewer differences appear between the former and several other groups, most notably never-married single mothers.


Selenium prevented renal tissue damage in lipopolysaccharide-treated Rats.
Kidney diseases are one of the common diseases, which are one of the main causes of death in society and impose costs on the health system of the society. A growing body of evidence has well documented that inflammatory responses and oxidative damage play a significant role in the progress of various kidney diseases. This study examined whether selenium (Sel) could prevent the detrimental influences of lipopolysaccharide (LPS) in rats. Four groups of Wistar rats were considered: control, LPS (1 mg/kg, i.p., for 14 days), LPS-Sel 1 (0.1 mg/kg, i.p., for 14 days), and LPS-Sel 2 (0.2 mg/kg, i.p., for 14 days). Sel treatment markedly attenuated oxidative stress damage in the kidney tissue in LPS-induced renal toxicity. Generally, the administration of Sel resulted in improved antioxidant indicators such as catalase (CAT) and superoxide dismutase (SOD) activities, or total thiol content, and decreased malondialdehyde (MDA) in the kidney tissue. It also decreased interleukin-6 in kidney homogenates. Furthermore, Se treatment significantly inhibited the elevation of serum biochemical markers of kidney function including serum, BUN, and creatinine. Based on the findings of the current study, it seems that the administration of Sel to LPS-treated rats improves renal function by reducing oxidative damage and inflammation in kidney tissue. However, more research is needed to reveal the accurate mechanisms for the effect of Sel on renal outcomes of LPS in human subjects.


Proceedings of the 2016 annual meeting of the Fetal Alcohol Spectrum Disorders Study Group.
The 2016 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was titled "Rehabilitation in FASD: Potential Interventions and Challenges". During the previous decades, studies with human subjects and animal models have improved much of our understanding of the mechanisms underlying FASD, putting the scientific community in a good position to test hypotheses that can lead to potential therapeutic interventions. During the conference, two keynote speakers addressed potential interventions used in different fields and their applicability to FASD research. The conference also included updates from several government agencies, short presentations by junior and senior investigators that showcased the latest in FASD research, and award presentations. The conference was closed by a talk by Dr. Charles Goodlett, the recipient of the 2016 Henry Rosett award.


SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping.
Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK-positive NSCLC. The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK-positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied. Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction. Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response.


Modulatory action of arachidonic acid on GABAA/chloride channel receptor function in adult and aged brain cortex membranes.
Effect of arachidonic acid on binding parameters of two binding sites on the GABAA receptor and on GABA activated Cl- uptake was investigated in synaptic plasma membrane and in synaptoneurosomes from brain cortex of adult (4-months old) and aged (27-months old) rats. The ligands used were [3H]muscimol, a GABA agonist and [35S]-t-butylbicyclophosphorothionate ([35S]TBPS), a convulsant that binds to the site near the chloride channel. Arachidonic acid increases significantly GABAA agonist binding and concomitantly decreases [35S]TBPS binding in a concentration dependent manner. The analysis of binding parameters in adult brain showed a significant decrease by AA of KD value for low but not for high affinity of [3H]muscimol binding. Concomitantly, AA enhances Bmax values for high affinity binding and has no effect on Bmax value for low affinity binding in synaptic plasma membrane (SPM) from adult brain. In synaptic plasma membrane from aged brain AA increases low and high affinity binding of agonist to GABAA receptor, modified significantly KD value by about 30 and 66%, respectively. On the other hand, AA significantly decreases of [35S]TBPS binding to chloride channel recognition site. Scatchard's analysis indicates that this inhibition results from a decrease of total number of binding sites. Moreover, the affinity of [35S]TBPS binding was increased (KD = 37.0 nM for AA-treated membrane, as compared to 69.3 nM KD in control membrane). GABA-dependent chloride uptake into synaptoneurosomes is also inhibited by AA in a concentration dependent manner in adult brain. In aged brain synaptoneurosomes AA has similar inhibitory effect on GABA-activated chloride uptake.(ABSTRACT TRUNCATED AT 250 WORDS)


2-Pyrenyl-DNA: synthesis, pairing, and fluorescence properties.
Multiple 2-pyrenyl-C-nucleosides were incorporated into the center of a DNA duplex resulting in stable pyrene self-recognition and excimer formation. This helical pyrene array may find use in DNA-mediated charge transfer and in the creation of DNA-based sensors.


Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells.
CD8+ T cells play an important role in controlling Flavivirus infection, including Zika virus (ZIKV). Here, we have identified 25 HLA-B*0702-restricted epitopes and 1 HLA-A*0101-restricted epitope using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) in ZIKV-infected IFN-α/β receptor-deficient HLA transgenic mice. The cross-reactivity of ZIKV epitopes to dengue virus (DENV) was tested using IFN-γ-ELISPOT and IFN-γ-ICS on CD8+ T cells from DENV-infected mice, and five cross-reactive HLA-B*0702-binding peptides were identified by both assays. ZIKV/DENV cross-reactive CD8+ T cells in DENV-immune mice expanded post ZIKV challenge and dominated in the subsequent CD8+ T cell response. ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8+ T cell responses that reduced infectious ZIKV levels, and CD8+ T cell depletions confirmed that CD8+ T cells mediated this protection. These results identify ZIKV-specific and ZIKV/DENV cross-reactive epitopes and demonstrate both an altered immunodominance pattern in the DENV-immune setting relative to naive, as well as a protective role for epitope-specific CD8+ T cells against ZIKV. These results have important implications for ZIKV vaccine development and provide a mouse model for evaluating anti-ZIKV CD8+ T cell responses of human relevance.


Substituted triazoles as anti-inflammatory agents.
Newly synthesized triazoles were evaluated for their anti-inflammatory and antiproteolytic activities. These derivatives possessed potent anti-inflammatory and antiproteolytic activities. In addition, these compounds were relatively less toxic.


Comparison of the 5'-flanking sequences of the human and bovine von Willebrand factor-encoding genes reveals alternation of highly homologous domains with species-specific Alu-type repeats.
von Willebrand factor (vWF), a multimeric glycoprotein important for hemostasis, is specifically synthesized in endothelial cells and in platelet precursors (megakaryocytes). Recent studies from two laboratories, including ours, were published regarding the cell-specific transcription of reporter genes controlled by the human (hu) vWF promoter in transfected bovine (bo) endothelial cells and cells of non-endothelial origins. In order to verify that the regulatory domains previously characterized in the 5' region of hu vWF are also present in bo vWF, we have sequenced 1.9 kb upstream from the cap site, plus five exons. The comparison of human and bovine exons two to five shows homology of 83% at the nucleotide (nt) level and 78% at the deduced amino-acid sequence level. The bovine and human exons one, which are non-coding and span 233 and 250 bp, respectively, are only 64% homologous. In the first exon, potentially involved in endothelial-cell-specific transcription, the binding site for factor Sp1 is present in bo vWF, whereas the GATA sequence is replaced by a GACA sequence. The sequence corresponding to the human basal promoter, located between nt -89 and +19, is well conserved with 82% homology. However, the human TAATTA sequence (at nt -32) considered to be a TATA box, is replaced by TCATTA, and the CCAAT element at nt -18 is replaced by CCTGT. Among domains involved in transcription, the negative regulatory domain located 5' from the core promoter is highly conserved. The bovine sequence upstream from the first intron can be aligned with the human sequence up to nt -656 which is located in a polymorphic poly(GT)18-26 sequence. At this site, the bovine DNA contains an insertion of 523 bp which corresponds to a bovine Alu-type art2 repeat of 331 bp flanked by bovine microsatellites. The art2 sequence is an Alu-type repeat in artiodactyls with at least 100,000 copies in the bovine genome. Upstream from this insertion, 368 bp of the bovine sequence can be aligned with the human counterpart up to a 9-bp element which flanks an human Alu repeat which is absent from the bovine DNA. Upstream of the human Alu insertion and a duplicate of the 9-bp element, the two sequences are again homologous.


Assessing child and adolescent anxiety in psychiatric samples with the Child Behavior Checklist.
The Child Behavior Checklist's (CBCL) is often used as a screening instrument at first contact in standard child and adolescent psychiatric settings adding valuable information to the diagnostic process. However, its correspondence to clinical, in particular anxiety, diagnoses has not always been clear. Using parent reports from 2763 outpatients and 888 inpatients referred for psychiatric services, CBCL-anxiety scales were examined regarding their predictive validity and potential use as screening devices for anxiety disorders. Symptom scores across four diagnostic groups (anxiety disorder, emotional disorder, other psychiatric disorder and no psychiatric disorder) were calculated and compared; in addition ROC-analyses for the anxiety-disordered group were performed. Support for the validity of the "Anxiety Problems" scale (Achenbach et al., 2003) was found. However, AUC-values were only in the medium range (.71-.72) with substantial misclassification numbers proposing a limited utility of the scale as a screening instrument in our samples. Adding valuable information to the diagnostic process, the CBCL's associations with clinical anxiety diagnoses seem only moderate suggesting the additional use of other anxiety-specific instruments in clinical routine.


Doxorubicin Delivered via ApoE-Directed Reduction-Sensitive Polymersomes Potently Inhibit Orthotopic Human Glioblastoma Xenografts in Nude Mice.
Glioblastoma multiforme (GBM) poorly responds to chemotherapy owing to the existence of blood-brain barriers (BBB). It has been a long desire to develop BBB-permeable vehicles to facilitate drug targeting to GBM. Here, we report that doxorubicin hydrochloride loaded in ApoE peptide-functionalized reduction-sensitive polymersomes (ApoE-PS-DOX) induces potent therapy of orthotopic U-87 MG model in nude mice. ApoE-PS-DOX with varying amount of ApoE (10~30 mol%) all had stable DOX loading and small sizes (< 90 nm). As revealed by flow cytometry, confocal microscopy, apoptosis and MTT assays, ApoE-PS-DOX with 20 mol.% ApoE induced the best cellular uptake and inhibitory effect to U-87 MG cells, which were much better than the non-targeted PS-DOX and liposomal doxorubicin (Lipo-DOX) used in the clinic. ApoE-PS-DOX revealed a pharmacokinetic profile comparable to PS-DOX but induced considerably better growth inhibition of orthotopically xenografted U-87 MG tumors in nude mice than PS-DOX and Lipo-DOX, leading to significant survival benefits with a median survival time of 44 days, which was almost doubled relative to the phosphate-buffered saline (PBS) group. Moreover, in contrast to mice treated with Lipo-DOX and PS-DOX, ApoE-PS-DOX group exhibited little body weight loss, signifying that ApoE-PS-DOX not only has low side effects but also can effectively inhibit glioblastoma invasion. This ApoE-docked multifunctional polymersomal doxorubicin induces potent and safe chemotherapy of orthotopic U-87 MG model in nude mice offering an alternative treatment modality for GBM.


Valorization strategies for hazardous proteinaceous waste from rendering production - Recent advances in specified risk materials (SRMs) conversion.
Strict bans on specific risk materials (SRMs) are in place to prevent the spread of bovine spongiform encephalopathy (BSE). SRMs are characterized as tissues in cattle where misfolded proteins, the potential source of BSE infection, are concentrated. As a result of these bans, SRMs must be strictly isolated and disposed of, resulting in great costs for rendering companies. The increasing yield and the landfill of SRMs also exacerbated the burden on the environment. To cope with the emergence of SRMs, novel disposal methods and feasible value-added conversion routes are needed. The focus of this review is on the valorization progress achieved in the conversion of peptides derived from SRMs via an alternative disposal method, thermal hydrolysis. Promising value-added conversion of SRM-derived peptides into tackifiers, wood adhesives, flocculants, and bioplastics, is introduced. The potential conjugation strategies that can be adapted to SRM-derived peptides for desired properties are also critically reviewed. The purpose of this review is to discover a technical platform through which other hazardous proteinaceous waste, SRMs, can be treated as a high-demand feedstock for the production of renewable materials.


Cyclosporin A inhibits phorbol ester-induced cellular proliferation and tumor promotion as well as phosphorylation of a 100-kd protein in mouse epidermis.
Mouse epidermis and HEL30 keratinocytes contain cellular binding sites for the immunosuppressive agent cyclosporin A (CsA). Phorbol ester-induced DNA synthesis and tumor promotion in mouse skin is strongly suppressed by CsA. The anti-tumor effect of CsA is not the consequence of destruction of initiated cells. CsA selectively inhibits the phosphorylation in vitro of a protein with the relative molecular mass of 100 kd in mouse epidermis and HEL30 cytosol. The CsA-suppressible phosphorylation in vitro does not depend on the addition of Ca2+, phospholipid and the phorbol ester TPA.


[Third cranial nerve palsy and Purtscher retinopathy in a child with multiple injuries].
A 4 year-old girl was referred to our hospital after have suffered a severe accident. The patient was diagnosed with complete third nerve palsy in her right eye and Purtscher retinopathy in her left eye. Purtscher retinopathy is a rare condition. The diagnosis is made on clinical ground and its treatment is not well defined although it is believed that systemic steroids could improve the visual outcome. Traumatic third nerve palsy has a poor spontaneous recovery. The use of botulinum toxin might be useful in children to improve the recovery rate, maintaining binocularity, and avoiding amblyopia in other cases.


Tetracotyle wayanadensis (Trematoda: Digenea) metacercaria - A potential parasitic castrator of the freshwater fish Aplocheilus lineatus (Valenciennes, 1846): A histopathological and temporal variation study in the South Western Ghats, India.
Parasitic castration is a phenomenon where the parasite blocks or reduces the host reproductive output. This study explored the impact of Tetracotyle wayanadensis infection on the reproductive performance of the freshwater fish Aplocheilus lineatus. Heavily infected A. lineatus showed slow and sluggish movements with reduced food intake and feeding activities. Histopathological observations of the ovary revealed severe necrosis and degeneration of previtellogenic and vitellogenic oocytes and follicular atresia. The oogonial nests were absent; chromatin nucleolar oocytes irregularly shaped and vacuolated. Perinucleolar oocytes have a vacuolated appearance with the hypertrophied highly columnar follicular cells invading them. Vitellogenic oocytes had a shrunken appearance with folded zona radiata; yolk globules broken down into smaller granules together with vacuolar degeneration of the ooplasm. The hypertrophied highly columnar follicular cells invaded the early vitellogenic oocytes to phagocytize the degenerating material. Zona radiata was found broken and liquefaction of yolk globules was evident with advancement in follicular atresia. Seasonal variation of parasitic infection has also been studied. Metacercaria infecting the vital organs showed seasonal variation with the highest values for prevalence and abundance during monsoon and mean intensity during winter. The lowest values for these descriptors were documented during the post-monsoon period.


Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro.
Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-fibrotic drug with additional anti-inflammatory properties. However, the influence of PFD on OA is unknown. Proliferation of human fibroblast-like synoviocytes (FLSs) after treatment with TGF-β1 or PFD was evaluated using a Cell Counting Kit-8 assay and their migration using a Transwell assay. The expression of fibrosis-related genes (COL1A1, TIMP-1, and ACTA-2) and those related to inflammation (IL-6 and TNF-α) was quantified by real-time quantitative PCR. The protein expression levels of COL1A1, α-SMA (coded by ACTA-2), IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay. A rabbit model of OA was established and then PFD was administered by gavage. The expression of genes related to fibrosis (COL1A1, TIMP-1, and ADAM-12) and inflammation (IL-6 and TNF-α) was measured using RNA extracted from the synovium. Synovial tissue was examined histologically after staining with H&E, Masson's trichrome, and immunofluorescence. Synovitis scores, the volume fraction of collagen, and mean fluorescence intensity were calculated. Degeneration of articular cartilage was analyzed using a Safranin O-fast green stain and OARSI grading. The proliferation of FLSs was greatest when induced with 2.5 ng/ml TGF-β1 although it did not promote their migration. Therefore, 2.5 ng/ml TGF-β1 was used to stimulate the FLSs and evaluate the effects of PFD, which inhibited the migration of FLSs at concentrations as low as 1.0 mg/ml. PFD decreased the expression of COL1A1 while TGF-β1 increased both mRNA and protein expression levels of IL-6 but had no effect on α-SMA or TNF-α expression. PFD decreased mRNA expression levels of COL1A1, IL-6, and TNF-α in vivo. H&E staining and synovitis scores indicated that PFD reduced synovial inflammation, while Masson's trichrome and immunofluorescence staining suggested that PFD decreased synovial fibrosis. Safranin O-Fast Green staining and the OARSI scores demonstrated that PFD delayed the progression of OA. PFD attenuated synovial fibrosis and inflammation, and postponed the progression of osteoarthritis in a modified Hulth model of OA in rabbits, which was related to its anti-fibrotic and anti-inflammatory properties.


Decay constant of Doppler flow waveform as a possible indicator of ovarian malignancy.
The objectives of this study were to analyze the decay constant (tau) of the Doppler flow waveform in ovarian tumors; to determine if differences in this constant can discriminate between malignant and benign ovarian tumors; and to compare the decay constant to the known resistive index (RI), in order to determine its potential prognostic application. Patients with ovarian masses (46) were evaluated in a retrospective study; 13 had malignant tumors, 7 showed tumors with low malignant potential (LMP), 11 had benign masses, 4 had secondary ovarian metastases and 11 had functional ovarian masses. Doppler flow waves measured in the ovary before operation were analyzed from archival videotapes. The RI was calculated preoperatively, and the decay constant of the flow waveform was analyzed retrospectively. We approximated the decaying portion of the flow waveform from the systolic peak to the diastolic level to an exponential curve. Then, the decay constant associated with the flow signal was compared for different types of ovarian pathology. Ovaries with malignancies showed significantly higher mean values for the decay constant (89.7; 95% confidence interval 60.0-119.3) than those with benign tumors (41.8; 25.7-57.9) (p < 0.007), where tau is provided in pixels (in this study each pixel equals approximately 11.4 ms). The mean RI value for malignant tumors was 0.44 +/- 0.12 whereas, in benign tumors, it was 0.622 +/- 0.11. For the benign tumors, both tau and RI did not differ significantly from the measured indices in LMP tumors, metastases and functional ovarian findings. In addition, when the cutoff value of tau was set at 48, 92.3% of all malignancies were identifiable using only tau. This preliminary study indicates that the decay constant of the Doppler flow waveform is able to discriminate between malignant and benign masses and may, thus, provide substantial assistance as an additional parameter in the diagnosis of malignant ovarian tumors in postmenopausal patients.


Open repair of pectus excavatum and carinatum deformities with minimal cartilage resection.
Numerous modifications of the Ravitch open repair of pectus excavatum (PE) and carinatum (PC) have been used by surgeons with inconsistent results. During a 3-year period, 275 consecutive patients underwent open repair of PE and PC using a new less invasive technique. A small chip of costal cartilage was resected medially and laterally from each deformed cartilage, allowing it to barely touch the sternum and rib (laterally) after the sternum had been elevated or depressed, and twisted to the desired position. A support strut used for all patients was routinely removed within 6 months. With mean follow-up of 17 months, all but 5 patients regarded the results as very good or excellent. There were no major complications or deaths. Open repair using minimal cartilage resection is effective for all variations of PE and PC in patients of all ages, causes only mild pain, and produces good physiologic and cosmetic results.


Evaluation of Benzamide-Chalcone Derivatives as EGFR/CDK2 Inhibitor: Synthesis, In-Vitro Inhibition, and Molecular Modeling Studies.
EGFR (Epidermal Growth Factor Receptor) and CDK2 (Cyclin Dependent Kinase 2) are important targets in the treatment of many solid tumors and different ligands of these receptors share many common structural features. The study involved the synthesis of benzamide-substituted chalcones and determination of their antiproliferative activity as well as a preliminary evaluation of EGFR and CDK2 inhibitory potential using both receptor binding and computational methods. We synthesized 13 benzamide-substituted chalcone derivatives and tested their antiproliferative activity against MCF-7, HT-29 and U373MG cell lines using Sulforhodamine B Assay. Four compounds were examined for activity against EGFR and CDK2 kinase. The compounds were docked into both EGFR and CDK2 using Glide software. The stability of the interactions for the most active compound was evaluated by Molecular Dynamics Simulation using Desmond software. Molecular docking studies on mutant EGFR (T790M, T790M/L858R, and T790M/C797S) were also carried out. From the SRB assay, we concluded that compounds 1g, and 1k were effective in inhibiting the growth of the MCF-7 cell line whereas the other compounds were moderately active. Most compounds were either moderately active or inactive on U373 MG and HT-29 cell lines. Compounds 1g and 1k showed good inhibitory activity against CDK2 kinase while 1d and 1f were moderately active. Compounds 1d, 1f, 1g, and 1k were moderately active against EGFR kinase. Molecular docking reveals the involvement of one hydrogen bond with Met793 in binding with EGFR; however, it was not stable during the simulation and these compounds bind to the receptor mainly via hydrophobic contacts. This fact also points towards a different orientation of the inhibitor within the active site of EGFR kinase. Binding mode analysis for CDK2 inhibition studies indicates that hydrogen bonding interactions with Lys 33 and Leu83 are important for the activity. These interactions were found to be stable throughout the simulation. Considering the results for wild-type EGFR inhibition, the docking studies on mutants were performed and which indicate that the compounds bind to the mutant EGFR but the amino acid residues involved are similar to the wild-type EGFR, and therefore, the selectivity seems to be limited. These benzamide-substituted chalcone derivatives will be useful as lead molecules for the further development of newer inhibitors of EGFR and/or CDK2 kinases.


Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer's disease.
Matrix metalloproteinases (MMPs) are a multigene family of proteinases regulating the functions of a large number of signaling and scaffolding molecules that are involved in neuro-inflammation, synaptic dysfunction and neuronal death. MMPs have been associated with neurological conditions, such as Alzheimer's disease (AD), through a sudden and massive upregulation of particular members of the MMP family. Evidence for this hypothesis can be found in the clinical observation of increased MMP1 and MMP3 expression levels in plasma of AD patients compared to control individuals and in the pro-amyloidogenic effects that have been described for additional MMP family members like MMP13, MT1-MMP, and MT5-MMP. Consequently, we investigated the role of MMP1, 3, 13, MT1-MMP, and MT5-MMP in the genetic etiology of AD. We performed full exonic resequencing of these 5 MMPs in 1278 AD patients (mean age at onset [AAO]: 74.88 ± 9.10, range: 29-96) and 797 age-matched control individuals (mean age at inclusion [AAI]: 74.92 ± 6.48, range: 65-100) from Flanders-Belgium and identified MMP13 as most promising candidate gene. We identified 6 ultra-rare (≤0.01%) MMP13 missense mutations in 6 patients that were absent from the control cohort. We observed in one control individual a frameshift mutation (p.G269Qfs*2) leading to a premature termination codon. Based on previously described functional evidence, suggesting that MMP13 regulates BACE1 processing, and our genetic findings, we hypothesize a gain-of-function disease mechanism for the missense mutations found in patients. Functional experimental studies remain essential to assess the effect of these mutations on disease related processes and genetic replication studies are needed to corroborate our findings.


Laryngofissure and cordectomy for glottic carcinoma limited to the mid third of the mobile true vocal cord.
The objective of this study was to analyze the long-term results of laryngofissure with cordectomy for invasive glottic squamous cell carcinoma limited to the mid third of the mobile true vocal cord. The authors conducted a retrospective review of the medical charts and operative files of 33 patients with invasive glottic carcinoma limited to the mid third of the mobile true vocal cord managed with laryngofissure and cordectomy. A 10-year follow-up was achieved in 30 patients (90.9%). Kaplan-Meier actuarial analysis of survival, local control, nodal recurrence, distant metastasis, and second primary metachronous tumor was performed. The 5-year actuarial survival, local control, nodal recurrence, and distant metastasis estimates were 97%, 100%, 0%, and 0%, respectively. Tracheotomy was never performed. The overall laryngeal preservation rate was 100%. The 5- and 10-year actuarial metachronous second primary tumor estimates were 3% and 11.5%, respectively. The authors' experience suggested that laryngofissure and cordectomy should still be considered a valuable oncologic option for the management of invasive glottic carcinoma limited to the mid third of the mobile true vocal cord.


Knee extensor power predicts six-minute walk test performance in people with transfemoral amputations.
Lower-limb amputees have increased metabolic costs during walking that may be mitigated by maintaining quadriceps strength and power following amputation. However, there are no current studies investigating the relationship between thigh strength and walking performance in individuals with transfemoral amputation. To quantify the relationship between intact limb quadriceps strength in transfemoral amputees and six-minute walk test (6MWT) performance. Descriptive laboratory study. Laboratory. Eleven participants with unilateral transfemoral amputations from trauma or osteosarcoma (4 women/7 men, 46.21 ± 12.68 years old, 28.24 ± 20.57 years following amputation). Strength and power testing on the intact limb followed by 6MWT with a flowmeter to measure oxygen uptake (VO2 ). Strength included mass-normalized peak torque, average torque, and average power. 6MWT measures included total distance traveled and VO2 normalized to distance and mass. Significant correlations (P ≤ .05) were retained for a regression analysis. Peak isokinetic knee extensor torque was correlated with total VO2 (r = -.60, P = .05) and distance traveled (r = .84, P = .001). Average isokinetic knee extensor torque was correlated with total VO2 (r = -.61, P = .046) and distance traveled (r = .85, P = .001). Average knee extensor power was correlated with total VO2 (r = -.67, P = .026) and distance traveled (r = .88, P < .001). Peak isometric knee extensor torque was correlated with distance traveled (r = .69, P = .019). Average power explained 77.2% of the variance in distance traveled during the 6MWT (P < .001) and average power explained 44.2% of the variance in total VO2 during the 6MWT (P = .026). Knee extensor strength was correlated with performance on the 6MWT in individuals with unilateral transfemoral amputation. The strongest relationship was between isokinetic quadriceps power and distance traveled, which suggests that developing quadriceps power in the intact limb following amputation may be an important factor to reduce metabolic cost of walking and support a return to an active lifestyle.


To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides.
γ-Secretase activating protein (GSAP) is known to play an important role in the β-amyloid pathway. It acts as a modulator and accentuates the truncation of the amyloid precursor protein C-99 fragment through the γ-secretase complex. GSAP has four isoforms, out of which canonical isoform 1, a 16 kDa C-terminal portion, has been extensively studied, whereas the function of other three isoforms remains unknown. Here, we explore the GSAP isoform 4 (GSAP_I4) expression and purification from inclusion bodies followed by the refolding of the protein. The secondary structure of GSAP_I4 is predicted using circular dichroism. The protein is further characterized by western blotting and mass spectroscopy analysis. Additionally, biochemical assays and in silico molecular docking and molecular simulation are performed to investigate the binding of GSAP_I4 and APP-C99 peptide fragments. The results reflect that although GSAP_I1 and GSAP_I4 share high sequence similarity, the isoform 4 does not show any affinity toward APP-C99 peptide fragments. This hints toward the fact that GSAP_I4 might have a different role in the living system that is yet unexplored.


'Moffett's' solution: a review of the evidence and scientific basis for the topical preparation of the nose.
General anaesthesia, often causes a widespread vasodilation, producing a hyperaemic nasal mucosa, hence the need for a topical application to decongest the nose and reduce the nasal blood flow to optimize the operative field. The use of a combination of cocaine, sodium bicarbonate and adrenaline given the eponymous title of 'Moffett's Solution' is standard practice in many rhinological procedures to provide local anaesthesia, vasoconstriction and decongestion. We discuss each component of 'Moffett's' reviewing the science and evidence behind its usage and the huge variation in the techniques of its application.


Molecular expression of acute phase mediators is attenuated by machine preservation in human liver transplantation: preliminary analysis of effluent, serum, and liver biopsies.
Hypothermic machine perfusion (HMP) mitigates the effects of ischemia/reperfusion injury (IRI) in renal transplantation and preclinical work with livers. In liver transplantation, IRI increases the likelihood of primary graft dysfunction and is associated with significant morbidity. We recently completely the first phase 1 clinical trial of liver HMP at our center, and demonstrated improved clinical parameters and shorter duration of stay for patients who received grafts stored by HMP than patients who received grafts preserved in cold storage. Biomarker analysis of venous effluent collected from the hepatic veins during HMP may yield predictive information reflecting the condition of the donor liver, such as graft injury sustained during brain death and graft preservation. The aim of this study was to characterize biomarkers released into the effluent during HMP. Effluent was collected every 30 minutes during liver HMP during our phase 1 clinical trial. Serum was extracted from blood samples obtained at incision, before explantation, and at 1, 2, and 3 hours after reperfusion. The effluent and serum samples were assayed in multiplex to determine the concentration of inflammatory cytokines and growth factors. Tissue obtained from liver biopsies was processed for either downstream reverse transcription-polymerase chain reaction or immunofluorescence. Statistical significance was determined by a two-tailed t-test. Growth factors and most cytokines were not readily detectable in levels above baseline with this technique; however, interleukin-1 (IL-1) receptor antagonist and monocyte chemotactic protein-1 were present in significant concentrations in the effluent at all time points. This finding was confirmed with serum samples and mRNA expression obtained from liver biopsies. The concentrations of these proteins decreased from their initial values over the course of HMP, and mRNA expression levels were decreased by the use of HMP. IL-1β and tumor necrosis factor (TNF)-α are key mediators of inflammation in IRI. Although difficult to measure because of short half-lives, their downstream effectors indicate their levels of activity. IL-1 receptor antagonist is secreted in response to IL-1β, and monocyte chemotactic protein in response to TNF-α. Their decreased production over the course of HMP suggests that interruption of acute-phase inflammation in the graft may attenuate reperfusion-related graft injury. Further cDNA studies and effluent analyses are required to confirm this hypothesis.


[Rapidly evolving diabetic mononeuritis multiplex. Favorable outcome after immunosuppressive treatment].
A 61 year-old man with type 2 diabetes mellitus presented with an extremely rapid and aggressive mononeuritis multiplex. Four months after onset, he had severe postural hypotension and at least 6 cranial nerves and 4 somatic nerves were involved. Extensive work-up failed to discover any etiology for the neuropathy apart from diabetes. Treatment with corticosteroids, i.v. immunoglobulins and cyclosporin was followed by progressive but sustained improvement. This case and few other published ones suggest that some particularly aggressive forms of diabetic neuropathy have an immune mechanism and may be treated favorably with immunosuppressor drugs.


New York City injection drug users' memories of syringe-sharing patterns and changes during the peak of the HIV/AIDS epidemic.
In this oral history, 23 injection drug users (IDUs) were interviewed about the mid-1970s to mid-1980s when they could not legally purchase or possess syringes, and the threat of AIDS began to loom large. Several themes emerged, including: abrupt changes in syringe-sharing patterns; the effects of illnesses or deaths of others on their understanding of AIDS; and, racial/ethnic differences in responses to the threat of AIDS. Settings, such as "shooting galleries," helped HIV spread rapidly in the earliest stages of the city's AIDS epidemic. HIV entered the drug scene in the mid-1970s, just when IDUs were shifting from sharing homemade "works" (consisting of steel needles and syringes devised from rubber baby pacifiers and similar sources) among many IDUs to mass produced and distributed plastic, disposable needle and syringe sets. IDUs remember when they first became aware of AIDS and began to adjust their behaviors and social assumptions.


Incidence and number of fragility fractures of the hip in South Africa: estimated projections from 2020 to 2050.
Sub-Saharan Africa is undergoing rapid population ageing and better understanding of the burden of musculoskeletal conditions is needed. We have estimated a large increase in the burden of hip fractures for South Africa over the coming decades. These findings should support preparation of hip fracture services to meet this demand. A better understanding of the burden of fragility fractures in sub-Saharan Africa is needed to inform healthcare planning. We aimed to use recent hip fracture incidence data from South Africa (SA) to estimate the future burden of hip fracture for the country over the next three decades. Hip fracture incidence data within the Gauteng, KwaZulu-Natal and Western Cape provinces of SA were obtained from patients aged ≥ 40 years with a radiograph-confirmed hip fracture in one of 94 included hospitals. Age-, sex- and ethnicity-specific incidence rates were generated using the 2011 SA census population for the study areas. Incidence rates were standardised to United Nations (UN) population projections, for the years 2020, 2030, 2040 and 2050, and absolute numbers of hip fractures derived. The 2767 hip fracture patients studied had mean (SD) age 73.7 (12.7) years; 69% were female. Estimated age- and ethnicity-standardised incidence rates (per 100,000 person-years) for the overall SA population in 2020 were 81.2 for females and 43.1 for males. Overall projected incidence rates were discernibly higher by the year 2040 and increased further by the year 2050 (109.0 and 54.1 for females and males, respectively). Estimates of the overall annual number of hip fractures for SA increased from approximately 11,000 in 2020 to approximately 26,400 by 2050. The hip fracture burden for SA is expected to more than double over the next 30 years. Significant investment in fracture prevention services and inpatient fracture care is likely to be needed to meet this demand.


Removal of Mycobacterium avium subspecies hominissuis (MAH) from drinking water by coagulation, flocculation and sedimentation processes.
There has been a growing concern over human exposure to Mycobacterium avium subspecies hominissuis (MAH) through drinking water due to its ubiquitous presence in natural waters and remarkable resistance to both chemical and physical disinfectants in drinking water treatment processes. However, little is known about the effectiveness of physico-chemical water treatment processes to remove MAH. Therefore, we determined the removal of MAH by alum coagulation, flocculation and sedimentation processes in optimized drinking water treatment conditions using standard jar test equipment. Contrary to the prevailing hypothesis, the results of this study show that removal of MAH by coagulation, flocculation and sedimentation processes was only moderate (approx. 0.65 log10) under low turbidity treatment conditions and the removal of MAH was actually lower than that of Escherichia coli (reference bacterium) in all the waters tested. Overall, the results of this study suggested that coagulation, flocculation and sedimentation processes may not be a reliable treatment option for removing MAH, and more efforts to find an effective control measures against MAH should be made to reduce the risk of MAH infection from drinking water. Despite a growing concern over human exposure to Mycobacterium avium subspecies hominissuis (MAH) through drinking water and its remarkable resistance to water disinfectants, little is known about the effectiveness of physico-chemical water treatment processes to remove MAH. Contrary to the prevailing hypothesis, the results of this study suggest that coagulation, flocculation and sedimentation processes may not be a reliable treatment option for MAH removal. As these processes have been the last remaining conventional drinking water treatment processes that might be effective against MAH, more efforts should be urgently made to find an effective control measures against this important waterborne pathogen.


Improvement of sonochemical degradation of Brilliant blue R in water using periodate ions: Implication of iodine radicals in the oxidation process.
In this paper, the effect of periodate (IO4-) on the ultrasonic degradation at 300kHz of Brilliant Blue R (BBR), an organic dye pollutant, was investigated. The experiments were realized in the absence and presence of periodate for various operating conditions including initial solution pH (2-8) and delivered ultrasonic power (20-80W). It was found that periodate greatly enhanced the sonochemical degradation of BBR. The degradation rate increased significantly with increasing IO4- concentration up to 10mM and decreased afterward. With 10mM of periodate, the degradation rate was 2.4-fold higher than that with ultrasound alone. The chemical probes experiments showed that periodate activation into free radicals (IO3, IO4 and OH) takes place by sonolysis and iodine radicals contribute significantly in the oxidation process. It was found that the periodate-enhanced effect was strongly experimental parameters dependent. The advantageous effect of periodate increased significantly with decreasing power and the best enhancing effect was obtained for the lowest power. Correspondingly, the periodate-enhanced effect increased with pH increase in the range 2-8 and it was more remarkable at near alkaline condition (pH 8). A reaction scheme for periodate sonolysis was proposed, for the first time, discussed and then used for interpreting the obtained results.


Inactivation of ventral midline thalamus produces selective spatial delayed conditional discrimination impairment in the rat.
The reuniens (Re) and rhomboid (Rh) nuclei are organized to influence activity in distributed limbic networks involving hippocampus and medial prefrontal cortex (mPFC). To elucidate the role of these nuclei in spatial memory we inactivated Re and Rh in rats with the GABA(A) agonist muscimol and compared effects on two spatial delayed conditional discriminations: delayed nonmatching to position (DNMTP) and varying choice radial maze delayed nonmatching (VC-DNM). DNMTP is trained in operant chambers and requires rats to choose between the same two levers on all trials. VC-DNM is trained in automated radial mazes and requires rats to choose between two arms, randomly selected from eight alternatives on each trial. DNMTP is affected by hippocampal and mPFC lesions while VC-DNM is affected by hippocampal, but not mPFC lesions (Porter et al. (2000) Behav Brain Res 109:69-81). We found evidence of a localized (low dose) effect of ReRh inactivation on DNMTP but not VC-DNM. This was confirmed by comparison with muscimol injections in an anatomical control site. These results are consistent with evidence that Re and Rh affect measures of spatial working memory that depend on interactions between hippocampus and mPFC, but not measures that depend on hippocampus alone.


Apolipoprotein E promoter polymorphisms do not have a major influence on the risk of developing primary open angle glaucoma.
Primary open angle glaucoma (POAG) is a major cause of late onset visual failure of unknown etiology. Recent genetic association studies have implicated the apolipoprotein E (APOE) gene in the pathophysiology of primary open angle glaucoma, but there have been conflicting findings. To resolve this issue we studied 140 cases and 73 controls that were carefully phenotyped, and used a logistic regression model to simultaneously analyze the effect of apolipoprotein E genotype and functional polymorphisms in the apolipoprotein E gene promoter while controlling for potentially confounding variables. We found no evidence of an association between the apolipoprotein E promoter region polymorphisms and primary open angle glaucoma. Apolipoprotein E promoter polymorphisms are unlikely to have a major impact on the pathophysiology of primary open angle glaucoma.


A meta-analysis of randomized, double-blind, placebo-controlled studies of the effect of buflomedil on intermittent claudication.
A meta-analysis was performed on the results of clinical trials of buflomedil in intermittent claudication. The analysis used results from 744 patients enrolled in ten studies, conducted at 42 centers in seven countries. All studies were randomized, double-blind, placebo-controlled trials which measured improvement in "pain-free" walking distance by treadmill ergometry as the primary measure of efficacy. The meta-analysis results were based on "effect size", a standardized difference in mean response between buflomedil and placebo. Results demonstrated a statistically superior response to buflomedil compared with placebo, indicating that the average buflomedil treated patient was likely to have a greater improvement in walking distance than at least 60% of the placebo treated patients. Results were corroborated using various weighting schemes proportional to study quality ratings and sample sizes.


Applying team-based learning in a transnational post registration bachelor of nursing program in Singapore.
Team-Based Learning (TBL) is growing in popularity as a method to create active learning within larger group lectures. It is facilitated through phases of individual work, teamwork with immediate feedback and an application exercise, to develop students' understanding and assessment of conceptual knowledge. A single facilitator can manage many groups within larger lectures. The study aim was to evaluate the impact of TBL on the engagement, learning and satisfaction of students enrolled in a transnational post registration Bachelor of Nursing (BN) program in Singapore. A cross-sectional design was employed. The TBL approach was delivered during lecture sessions within a post registration BN program delivered in a Higher Education Institution in Singapore. A sample of BN students was drawn from 305 students undertaking the program. An online anonymous university-delivered student evaluation of course (SEC) survey and an online anonymous survey using the Student Assessment Instrument, were used to collect quantitative and qualitative data. Survey participation was voluntary with informed consent protocols followed. Student performance in the course was also reviewed. Eighty-two students (27%) completed the SEC scoring a median of 4/5 for satisfaction, and 68 (22%) completed the online survey. As 93 was the neutral score for the survey, there was a moderately positive evaluation with an overall score of 108.5/155 for TBL in accountability for learning, TBL preference and satisfaction with TBL compared to traditional lecture approaches. Implementation of TBL with this cohort demonstrated evidence of moderately positive engagement, learning and satisfaction when compared to traditional didactic lectures.


Effortful control moderates the relation between negative emotionality and socially appropriate behavior.
The current study investigated the relation between negative emotionality and socially appropriate behavior in a diverse sample of preschool and kindergarten children (N = 74). More specifically, we tested whether effortful control would moderate this relation. A computerized task measured children's effortful control by assessing their accuracy in shifting attention between different emotionally valenced faces (happy and angry) while inhibiting their responses to neutral faces. Teachers completed the Affect Intensity Scale-Child Version to assess child negative emotionality as well as the Preschool and Kindergarten Behavior Scales to assess two aspects of socially appropriate behavior (social cooperation and inhibition of externalizing behavior). Regression analyses indicated that children with high negative emotionality and strong effortful control had fewer externalizing problems and greater social cooperation compared with their counterparts with weaker effortful control. These findings support and extend previous research suggesting that effortful control may protect children, particularly those with high negative emotionality, from poor social outcomes. A novel contribution of this study is its use of an attention shifting task that incorporates emotionally salient stimuli. These findings have important implications for educators working with young children who encounter increased expectations for regulating their behavior during preschool and kindergarten.


Inhibitory effects of 6-(3-hydroxyphenyl)-2-naphthol on tyrosinase activity and melanin synthesis.
As a part of an ongoing project searching for new skin-lightening agents, the inhibitory property of 6-(3-Hydroxyphenyl)-2-naphthol (HPN) on melanogenesis was investigated. The inhibitory action of HPN (IC(50)=15.2 muM) on mushroom tyrosinase was revealed. To further explore the action of HPN on melanogenesis, the inhibition of tyrosinase and melanin levels were measured in B16 melanoma cells (B16 cells). Results show that HPN inhibited tyrosinase activity and reduced melanin in B16 cells. Therefore, our data indicate HPN as a new candidate for depigmentation reagents.


Artificial disc prosthesis: design concepts and criteria.
Clinical and biomechanical objectives of disc arthroplasty are reviewed in this paper. The available literature relative to these criteria for nucleus and total disc replacement where relevant is also reviewed. Clinical criteria include: pain relief, functional recovery, lower morbidity than spinal fusion, shorter recuperation, and ease of implantation and revision. Biomechanical criteria include: preservation of motion in compression-bending and compression-torsion, shock absorption, relief of abnormal stresses within and adjacent to the motion segment, stability, and alignment. A review of devices with these criteria in mind is reported.


Microcystin accumulation and antioxidant responses in the freshwater clam Diplodon chilensis patagonicus upon subchronic exposure to toxic Microcystis aeruginosa.
We investigated the accumulation and toxicity of microcystin-LR (MCLR) in the digestive gland of the freshwater clam Diplodon chilensis patagonicus. Treated clams were fed with a toxic strain of Microcystis aeruginosa (NPJB1) during 6 weeks and control clams received the non-toxic strain NPDC1. Filtration rate was estimated for both groups. Toxic effects were evaluated through the hepatosomatic index (HSI) and different oxidative stress biomarkers, lipid peroxidation (content of thiobarbituric reactive substances-TBARS), protein oxidation (carbonyl groups) and reduced glutathione (GSH) levels, and enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST). The extractable MCLR measured by ELISA in digestive gland extracts showed little or no change during the first 3 weeks and increased significantly at weeks 5 and 6. HSI was reduced by 30% in treated clams at weeks 5 and 6. No significant oxidative damage to lipids or proteins was. All the antioxidant defense parameters analyzed were significantly increased at week 5 or 6. GSH increased in treated clams at week 5, reaching 62% increase at week 6. SOD, CAT and GST activities were significantly increased in treated clams by 50%, 66% and 60%, respectively, at the end of the experiment. D. chilensis patagonicus can be exposed to prolonged cyanobacterial blooms accumulating significant quantities of MCLR, which could be a risk for mammals and birds, which feed on this species and, in a lesser extent, to humans.


Improvement and validation of a female finite element model of the cervical spine.
Although the cervical spine supports and controls the kinematics of the head, it is vulnerable to injuries during mechanical loading. Severe injuries often result in damage to the spinal cord, leading to significant ramifications. The role of gender in determining the outcome of such injuries has been established as significant. In order to better understand the essential mechanics and develop treatments or preventative measures, various forms of research have been conducted. Computational modelling is one of the most useful and extensively utilised methods, as it provides information that would otherwise be difficult to obtain. As such, the primary goal of this research is to create a new finite element of the female cervical spine that will more accurately represent the group most affected by such injuries. This work is a continuation of a previous study where a model was created from the computer tomography scans of a 46-year-old female. A functioning spinal unit consisting of the C6-C7 segment was simulated as a validation procedure. The experimental data obtained from cadaveric specimens, that assessed the range of motion of different cervical segments in flexion-extension, axial rotation, and lateral bending, was used to validate the reduced model.


Stability-indicating RP-HPLC method development and validation for determination of nine impurities in apixaban tablet dosage forms. Robustness study by quality by design approach.
A quality by design (QbD) based high-resolution HPLC method is described for determination of impurities in apixaban (APX) in the tablet dosage form. Employing a simple and stability-indicating HPLC method, nine known impurities were quantified with good peak resolution. Mobile phase A (MP-A) was prepared with buffer and acetonitrile 90:10 v/v, while mobile phase B (MP-B) contained water and acetonitrile 10:90 v/v. The gradient program was 0 min, MP-A 75%, B 25%; 20 min, MP-A 65%, B 35%; 30 min, MP-A 40%, B 60%; 40min, MP-A 40%, B 60%; 42 min, MP-A 75%, B 25%; and 50 min, MP-A 75%, B 25%. The chromatographic separation was achieved using a Zorbax RX C18 250 × 4.6 mm column, 5 μm (1.0 ml min-1 , 280 nm, 50 μl) and a column temperature of 40°C. Several separation studies were carried out using design of experiments to optimize the method. Validation results confirm the applicability of the developed method for quality analysis and stability studies of the regular product on the manufacturing stream.


Comparative transcriptomic analysis of candidate effectors to explore the infection and survival strategy of Bursaphelenchus xylophilus during different interaction stages with pine trees.
The pine wood nematode (PWN), Bursaphelenchus xylophilus, is a devastating pathogen of many Pinus species in China. The aim of this study was to understand the interactive molecular mechanism of PWN and its host by comparing differentially expressed genes and candidate effectors from three transcriptomes of B. xylophilus at different infection stages. In total, 62, 69 and 46 candidate effectors were identified in three transcriptomes (2.5 h postinfection, 6, 12 and 24 h postinoculation and 6 and 15 d postinfection, respectively). In addition to uncharacterized pioneers, other candidate effectors were involved in the degradation of host tissues, suppression of host defenses, targeting plant signaling pathways, feeding and detoxification, which helped B. xylophilus survive successfully in the host. Seven candidate effectors were identified in both our study and the B. xylophilus transcriptome at 2.5 h postinfection, and one candidate effector was identified in all three transcriptomes. These common candidate effectors were upregulated at infection stages, and one of them suppressed pathogen-associated molecular pattern (PAMP) PsXEG1-triggered cell death in Nicotiana benthamiana. The results indicated that B. xylophilus secreted various candidate effectors, and some of them continued to function throughout all infection stages. These various candidate effectors were important to B. xylophilus infection and survival, and they functioned in different ways (such as breaking down host cell walls, suppressing host defenses, promoting feeding efficiency, promoting detoxification and playing virulence functions). The present results provide valuable resources for in-depth research on the pathogenesis of B. xylophilus from the perspective of effectors.


Vein grafts: an historical perspective.
The use of autogenous vein for vascular grafting has been traced historically. Although vein remains the graft of chocie for smaller vessels, the results are imperfect and the need to identify an "ideal" graft is becoming critical.


Ronda S. Henry-Tillman, MD, FACS.
Dr Henry-Tillman was recently appointed as a member of the Advisory Committee on Research on Women's Health at the National Institutes of Health (NIH). This committee assists the Office of Research on Women's Health (ORWH) and the NIH in addressing scientific, legal, and ethical issues affecting the health of the nation's women through biomedical and behavioral research and related career opportunities. The ORWH was established in 1990 by the NIH and statutorily mandated by Congress in 1993 as a mechanism for eliciting advice and recommendations on priority issues affecting women's health research. Advisory committee members are expected to provide guidance in such areas as refinement of the NIH's women's health research agenda, exploration of questions regarding gender difference in clinical drug trials, development of methodologies that enhance research on health needs of women, and monitoring the inclusion of women in clinical trials funded by the NIH. The director of the Office of Research on Women's Health is Dr Vivian W. Pinn, former president of the National Medical Association.


Change of membrane fluidity of rat neutrophils accompanying Escherichia coli inoculation.
Membrane fluidity of rat neutrophils was studied following Escherichia coli inoculation, and characteristic changes were observed. Membrane fluidity was assessed by the excimer-forming lipid technique using pyrenedecanoic acid and flow cytometry and expressed as the fluorescence intensity ratios of excimer and monomer pyrenedecanoic acid (IE/IM ratio). High IE/IM ratios indicated high membrane fluidity. The IE/IM ratio of rat neutrophils (0.50 +/- 0.048) increased after E. coli inoculation, reaching a maximum of almost 1.00 after 10-20 min and then returning to its starting value. Intravenous injection of heat-killed E. coli or E. coli-conditioned culture supernatants into rats induced a rapid increase of IE/IM ratios, which returned to initial levels after 20 min. The effect on membrane fluidity of in vitro neutrophil incubation with E. coli, heat-killed E. coli, or E. coli-conditioned culture supernatants was similar to that observed in vivo. Addition of 5 mM ethylenediaminetetraacetic acid (EDTA) did not affect neutrophil membrane fluidity. Addition of either 5 micrograms/ml cytochalasin B or 10(-5) M colchicine did not directly affect neutrophil membrane fluidity but did block the change observed following incubation with bacteria.


Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.
Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.


Suitability of Banana and Plantain Fruits in Modulating Neurodegenerative Diseases: Implicating the In Vitro and In Vivo Evidence from Neuroactive Narratives of Constituent Biomolecules.
Active principles in plant-based foods, especially staple fruits, such as bananas and plantains, possess inter-related anti-inflammatory, anti-apoptotic, antioxidative, and neuromodulatory activities. Neurodegenerative diseases affect the functionality of the central and peripheral nervous system, with attendant cognitive deficits being hallmarks of these conditions. The dietary constitution of a wide range of bioactive compounds identified in this review further iterates the significance of the banana and plantain in compromising, halting, or preventing the pathological mechanisms of neurological disorders. The neuroprotective mechanisms of these biomolecules have been identified by using protein expression regulation and specific gene/pathway targeting, such as the nuclear and tumor necrosis factors, extracellular signal-regulated and mitogen-activated protein kinases, activator protein-1, and the glial fibrillary acidic protein. This review establishes the potential double-edged neuro-pharmacological fingerprints of banana and plantain fruits in their traditionally consumed pulp and less utilized peel component for human nutrition.


The influence of haemodialysis and haemofiltration on the clearance of torasemide in renal failure.
The concentration of Torasemide in plasma, dialysate and ultrafiltrate were determined during one haemofiltration and three dialyses. Results show that Torasemide is not significantly eliminated from the blood by these technics.


Charge transfer complex studies between some non-steroidal anti-inflammatory drugs and pi-electron acceptors.
Charge transfer (CT) complexes of some non-steroidal anti-inflammatory drugs, naproxen and etodolac which are electron donors with some pi-acceptors, such as tetracyanoethylene (TCNE), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), p-chloranil (p-CHL), have been investigated spectrophotometrically in chloroform at 21 degrees C. The coloured products are measured spectrophotometrically at different wavelength depending on the electronic transition between donors and acceptors. Beer's law is obeyed and colours were produced in non-aqueous media. All complexes were stable at least 2 h except for etodolac with DDQ stable for 5 min. The equilibrium constants of the CT complexes were determined by the Benesi-Hildebrand equation. The thermodynamic parameters DeltaH, DeltaS, DeltaG degrees were calculated by Van't Hoff equation. Stochiometries of the complexes formed between donors and acceptors were defined by the Job's method of the continuous variation and found in 1:1 complexation with donor and acceptor at the maximum absorption bands in all cases.


Hypoxia stimulates vesicular ATP release from rat osteoblasts.
Many neuronal and non-neuronal cell types release ATP in a controlled manner. After release, extracellular ATP (or, following hydrolysis, ADP) acts on cells in a paracrine manner via P2 receptors. Extracellular nucleotides are now thought to play an important role in the regulation of bone cell function. ATP (and ADP), acting via the P2Y(1) receptor, stimulate osteoclast formation and activity, whilst P2Y(2) receptor stimulation by ATP (or UTP) inhibits bone mineralization by osteoblasts. We found that rat calvarial osteoblasts released ATP constitutively, in a differentiation-dependent manner, with mature, bone-forming osteoblasts releasing up to sevenfold more ATP than undifferentiated, proliferating cells. The inhibitors of vesicular exocytosis, monensin, and N-ethylmaleimide (1-1,000 microM) inhibited basal ATP release by up to 99%. The presence of granular ATP-filled vesicles within the osteoblast cytoplasm was demonstrated by quinacrine staining. Exposure to hypoxia (2% O(2)) for up to 3 min increased ATP release from osteoblasts up to 2.5-fold without affecting cell viability. Peak concentrations of ATP released into culture medium were >1 microM, which equates with concentrations known to exert significant effects on osteoblast and osteoclast function. Monensin and N-ethylmaleimide (100 microM) attenuated the hypoxia-induced ATP release by up to 80%. Depletion of quinacrine-stained vesicles was also apparent after hypoxic stimulation, indicating that ATP release had taken place. These data suggest that vesicular exocytosis is a key mediator of ATP release from osteoblasts, in biologically significant amounts. Moreover, increased extracellular ATP levels following acute exposure to low O(2) could influence local purinergic signaling and affect the balance between bone formation and bone resorption.


Does the potential safety risk affect whether particular construction hazards are recognized or not?
Evidence from the global construction industry suggests that an unacceptable number of safety hazards remain unrecognized in construction workplaces. Unfortunately, there isn't a sufficient understanding of why particular safety hazards remain unrecognized. Such an understanding is important to address the issue of poor hazard recognition and develop remedial interventions. A recent exploratory effort provided anecdotal evidence that workers often fail to recognize safety hazards that are expected to impose relatively lower levels of safety risk. In other words, the research demonstrated that the underlying risk imposed by a safety hazard can affect whether a hazard will be recognized or not. The presented research focused on empirically testing this preliminary finding. More specifically, the study tested the proposition that Construction workers are more likely to recognize safety hazards that impose higher levels of safety risk than those that impose relatively lower levels of safety risk. The research goals were accomplished through a number of steps. First, a set of 16 construction case images depicting a variety of construction operations that included a number of known safety hazards was presented to a panel of four construction safety experts. The experts were tasked with examining each of the known safety hazards and providing a rating of the relative safety risk that the individual hazards impose. Having obtained an estimate of the underlying safety risk, a hazard recognition activity was administered to 287 workers recruited from 57 construction workplaces in the United States. The hazard recognition activity involved the examination of a random sample of two construction case images that were previously examined by the expert panel and reporting relevant safety hazards. The results of the study provided support for the proposition that workers are more likely to recognize hazards that impose relatively higher levels of safety risk. Practical Applications: The findings of the study can be leveraged to improve existing hazard recognition methods and develop more robust interventions to address the issue of poor hazard recognition levels.