Lead Intoxication in Free-Ranging Bald Eagles ( Haliaeetus leucocephalus).
Lead toxicity due to ingestion of spent ammunition is an ongoing cause of mortality in bald eagles. While gross and histologic lesions of lead intoxication have been described in a few individuals of this species, the prevalence of lesions is underreported. A retrospective study of 93 bald eagles with severe lead intoxication was performed to describe the associated lesions and their prevalence and to compare the lesions with blood, liver, kidney, and/or bone lead concentrations. Gross lesions associated with lead toxicity were most frequent within the heart (51/93 birds) and consisted of multifocal myocardial pallor and rounding of the apex. Within the brain, gross lesions included petechiae or hemorrhagic necrosis (13/93 birds). Histologic lesions compatible with lead toxicity occurred within the heart (76/93 birds), brain (59/93 birds), and eyes (24/87 birds). Lead toxicity in bald eagles is characterized by fibrinoid necrosis of small- to medium-caliber arteries, most commonly affecting the heart, brain, and eyes. Gross and histologic lesions are consistent with ischemia caused by a primary vascular injury. A blood lead concentration of greater than 4 ppm and markedly elevated liver lead concentrations were associated with a greater likelihood of lesions in the heart. Severe lead intoxication is frequently associated with lesions that are histologically detectable in bald eagles. The presence of fibrinoid arterial necrosis and parenchymal degeneration, necrosis, and/or hemorrhage within the heart, brain, and/or eyes is suggestive of lead toxicity in bald eagles and warrants evaluation of liver or bone lead concentrations.


Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group.
Alveolar rhabdomyosarcoma (RMS) is an aggressive pediatric cancer of the myogenic lineage with frequent chromosomal translocations involving the PAX3 or PAX7 and FOXO1 genes. Based on previous studies indicating that the fusion genes are amplified in a subset of these cancers, we conducted a comprehensive molecular and clinical investigation of these amplification events. Using oligonucleotide arrays to localize amplicons, we found that the minimal 1p36 amplicon measured 0.13 Mb and only contained PAX7 whereas the minimal 13q14 amplicon measured 0.53 Mb and contained FOXO1 and the poorly characterized LOC646982 gene. Application of a fluorescence in situ hybridization assay to over 100 fusion-positive cases revealed that the fusion gene is amplified in 93% of PAX7-FOXO1-positive and 9% of PAX3-FOXO1-positive cases. While most cells in amplified PAX7-FOXO1-positive cases contained the amplicon, only a fraction of cells in the amplified PAX3-FOXO1-positive cases contained the amplicon. Expression studies demonstrated that the fusion transcripts were generally expressed at higher levels in amplified cases, and that the PAX7-FOXO1 fusion transcript was expressed at higher levels than the PAX3-FOXO1 fusion transcript. Finally, fusion gene amplification and PAX7-FOXO1 fusion status were each associated with significantly improved outcome; a multivariate analysis demonstrated that this predictive value was independent of other standard prognostic parameters. These findings therefore provide further evidence for a novel good prognosis subset of fusion-positive RMS.


Calorie restriction and cancer prevention: metabolic and molecular mechanisms.
An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the antitumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that might be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.


Anticancer effects of FL34 through the inhibition of GLI1 in glioblastoma.
The hedgehog (HH) signaling pathway is abnormally activated in glioblastoma (GBM); thus, its downstream effector GLI1 may be a suitable target for the treatment of GBM. The aim of the present study was to evaluate the antitumor activities of a novel compound, FL34, in GBM through the inhibition of GLI1. The effect of FL34 on suppressing the proliferation, angiogenesis, and invasion of GBM cells was investigated in vitro using proliferation, invasion, tube formation, flow cytometry, GLI1 dual luciferase, reverse transcription-quantitative polymerase chain reaction, and western blot assays. A subcutaneously transplanted and orthotopic U-87 MG GBM cell xenograft model was used to study the effect of FL34 on tumor growth in vivo. The results of the present study demonstrated that FL34 markedly inhibited the proliferation, invasion, and angiogenesis of GBM, in addition to decreasing the transcriptional activity and expression of GLI1, resulting in the downregulation of GLI1 target genes, including B-cell lymphoma-2, vascular endothelial growth factor, and matrix metalloproteinases. Furthermore, FL34 inhibited the activation of GLI1 without influencing upstream canonical HH/Smoothened signaling or through crosstalk with other oncogenic pathways, including Ras/ERK and AKT signaling. At a dose of 30.0 mg/kg, FL34 suppressed tumor growth by 78.74% in tumor weight in subcutaneously transplanted U-87 MG xenograft models and by 64.24% in volume in orthotopic U-87 MG GBM xenograft models. These data suggested that FL34 exerted antitumor activity mediated by the inhibition of GLI1 and that FL34 may be a potential antitumor candidate compound that could be used to develop new antitumor drugs for the treatment of GBM.


Modulation of alpha5beta1 integrin functions by the phospholipid and cholesterol contents of cell membranes.
Several modifications of the alpha5beta1 integrin, which alter its intracellular and extracellular interaction with fibronectin and other proteins, have been reported. However, the significance of the lateral mobility of integrin molecules in the plasma membrane, as a regulator of their distribution and function, is poorly understood. We examined this problem by increasing the cholesterol content of plasma membranes, and consequently modifying the fluidity of membrane phospholipids, in rat fibroblasts. Under these conditions, the clustering of alpha5beta1 integrin molecules in focal adhesions, their adhesion to the cell-binding domain of fibronectin, and their association with the cytoskeletal protein talin were significantly enhanced as compared to control cells. However, the activation of MAP-kinase pathways by the association of fibronectin with alpha5beta1 integrin, and its association with integrin-linked kinase (ilk), were suppressed. The treated cells also showed distinct changes in shape, and their actin stress fiber network was more dense and thick as compared to control cells. The changes in fluidity of phospholipids occurred differentially and fluidity of phosphatidyl-ethanolamine increased, while that of phosphatidyl-choline was reduced. Our results suggest that proteins in focal adhesions could be partitioned in specific lipid domains, which regulate specific aspects of alpha5beta1 integrin functions.


Matrix metalloproteinase-2, caveolins, focal adhesion kinase and c-Kit in cells of the mouse myocardium.
Matrix metalloproteinase-2 (MMP-2) may play roles at intracellular and extracellular sites of the heart in ischaemia/reperfusion injury. Caveolins (Cav-1, -2 and -3) are lipid raft proteins which play roles in cell sig-nalling. This study examined, using immunohistochemistry and two photon confocal microscopy, if MMP-2 and caveolins co-localize at the plasma membrane of cardiac cells: cardiomyocytes (CM), fibroblasts (FB) and capillary endothelial cells (CEC) in the left ventricle (LV) of the Cav-1(+/+) and Cav-1(-/-) mouse heart. In Cav-1(+/+) mouse LV MMP-2 and Cav-1 co-localized at CM plasma membranes, and at multiple locations in FB and CEC. MMP-2 co-localized with Cav-2 only at CEC. MMP-2 co-localized with Cav-3 at CM plasma membranes and Z-lines, and partially at FB and CEC. In Cav-1(-/-) LV Cav-1 and MMP-2 were absent or reduced everywhere. Cav-2 appeared at CEC despite the absence of Cav-1. Cav-3 appeared at CM plasma membranes and Z-lines, FB and CEC. Also, FAK in FB and c-Kit in interstitial Cajal-like cells (ICLC) were completely absent. By transmission electron microscopy in Cav-1(+/+), regular size caveolae (Cav) were at CEC, irregular size Cav were at CM and a few were at FB. In Cav-1(-/-) there were few Cav at CM and FB and some at CEC. To conclude, MMP-2 is closely associated with caveolins at FB and CEC as well as at CM. Also, MMP-2 is closely associated with FAK at FB and c-Kit at ICLC. Thus, Cav-1 expression is not necessary for Cav-2 expression. Cav-3 or Cav-3 with Cav-2 has the capability to make Cav.


Research on regimens for early medical abortion.
Until recently the medical abortion regimen of mifepristone followed by a suitable prostaglandin analogue two days later has been available in only a few countries. Limited access to the drug has hampered research and forced investigators without access to seek alternatives. Where mifepristone has not been available, investigators have tested repeated doses of the prostaglandin misoprostol alone or in combination with methotrexate. However, these regimens cannot compete in efficacy, safety, and convenience with the mifepristone-prostaglandin regimen. The development of the mifepristone-prostaglandin regimen has continued since approval, and a more effective and better tolerated medical method than was available ten years ago can now be offered to women. Several randomized double-blind studies have demonstrated that the dose of mifepristone can be lowered to 200 mg, one-third of the original dose, without compromising efficacy. Misoprostol has now largely replaced other prostaglandin analogues in the regimen, and this has made medical abortion simpler and more cost effective. Although women prefer oral administration of drugs, recent evidence suggests that to achieve sufficient efficacy, misoprostol has to be administered vaginally in women beyond 49 days' gestation. This medical abortion regimen has proved to be acceptable to women and safe when provided under proper conditions.


Codelivery of temozolomide and siRNA with polymeric nanocarrier for effective glioma treatment.
The treatment of glioma remains a challenge because conventional chemotherapy is often ineffective by drug resistance. Combinative therapy using chemotherapeutic agents and siRNA has demonstrated potential to improve anticancer outcome through a synergistic effect in various cancers. The current study aims to achieve better glioma treatment through a combinative therapy based on a folate-targeted nanocarrier carrying both temozolomide (TMZ) and anti-BCL-2 siRNA. A polymeric micelle (TMZ-FaPEC@siRNA) incorporating TMZ and anti-BCL-2 siRNA was prepared based on folate-conjugated triblock copolymer (Fa-PEG-PEI-PCL, Fa-PEC) of poly(ε-caprolactone) (PCL), poly(ethylenimine) (PEI) and poly(ethylene glycol) (PEG). The physicochemical properties and drug release profile of TMZ-FaPEC@siRNA were tested. The Fa-targeted drug delivery and joint effect of siRNA and TMZ to induce glioma apoptosis and tumor growth inhibition were evaluated both in vitro and in vivo. In vitro cell study demonstrated that the nanocarrier effectively facilitates codelivery of siRNA and TMZ into C6 cells, resulting in a strong apoptotic response of cancer cells by silencing the antiapoptosis BCL-2 gene and activating the proapoptotic Bax gene simultaneously. In vivo study in rat bearing orthotropic glioma showed that tumor growth was inhibited and meanwhile animal survival was prolonged remarkably through intracranial injection of TMZ-FaPEC@siRNA. Our results evidence the strong efficacy of the folate-targeted nanomedicine carrying TMZ and BCL-2 siRNA in treating glioma.


Reliability and validity of manual palpation for the assessment of patients with low back pain: a systematic and critical review.
Static or motion manual palpation of the low back is commonly used to assess pain location and reproduction in low back pain (LBP) patients. The purpose of this study is to review the reliability and validity of manual palpation used for the assessment of LBP in adults. We systematically searched five databases from 2000 to 2019. We critically appraised internal validity of studies using QAREL and QUADAS-2 instruments. We stratified results using best-evidence synthesis. Validity studies were classified according to Sackett and Haynes. We identified 2023 eligible articles, of which 14 were low risk of bias. Evidence suggests that reliability of soft tissue structures palpation is inconsistent, and reliability of bony structures and joint mobility palpation is poor. We found preliminary evidence that gluteal muscle palpation for tenderness may be valid in differentiating LBP patients with and without radiculopathy. Reliability of manual palpation tests in the assessment of LBP patients varies greatly. This is problematic because these tests are commonly used by manual therapists and clinicians. Little is known about the validity of these tests; therefore, their clinical utility is uncertain. High quality validity studies are needed to inform the clinical use of manual palpation tests.


Incidence of iron deficiency anemia in patients with large diaphragmatic hernia. A controlled study.
The incidence of anemia in 259 patients with a diaphragmatic hernia large enough to be seen on a routine chest roentgenogram was compared with that in 259 age- and sex-matched controls. Eighteen patients with diaphragmatic hernia were anemic, compared to one control subject (P less than 0.001). In thirteen patients with diaphragmatic hernia and in one control the anemia was proven to be caused by iron deficiency. The findings provide additional evidence that a large diaphragmatic hernia can cause anemia secondary to chronic gastrointestinal blood loss, which is usually not the result of reflux esophagitis.


Evolution of consanguinity in the Archbishopric of Santiago de Compostela (Spain) during 1900-1979.
We present a study of the frequencies of the different types of consanguineous marriages, up to the level of second cousins, using as a source the ecclesiastical dispensations given from 1900 to 1979 in the Archbishopric of Santiago de Compostela (Galicia, Spain). We also report the rate of consanguinity, the average coefficient of inbreeding, and its evolution. From 1900 to 1979, 15,739 consanguineous marriages were registered, corresponding to 25 different categories of relationship. The rate of consanguinity of the total number of consanguineous marriages is 5.13% and the average coefficient of inbreeding is 1.94 x 10(-3), values that are within the wide range of variability found in other Spanish populations. Spain is characterized, with regard to the rest of Western Europe, by a high level of inbreeding with a late and rapid decrease in this factor. The most relevant aspect of the structure of consanguinity lies in the high frequency of marriages between close relatives: 0.16% uncle-niece or aunt-nephew marriages and 1.62% marriages between first cousins, both values with respect to the total number of marriages. This phenomenon appears to be generalized throughout northern Spain. The evolution of the total consanguinity lends itself to a polynomial curve model. The fitted curve of the evolution of the average coefficient of inbreeding has an ascending branch and a descending branch, with the inflection point situated in the year 1918; the regression lines, for both the ascending and the descending branches, have regression coefficients significantly different from 0 (p < 0.001).


DNA methylation profiling identifies the HOXA11 gene as an early diagnostic and prognostic molecular marker in human lung adenocarcinoma.
DNA hypermethylation plays important roles in carcinogenesis by silencing key genes. The goal of our study was to identify pivotal genes using MethyLight and assessed their diagnostic and prognostic values in lung adenocarcinoma (AD). In the present study, we detected DNA methylation at sixteen loci promoter regions in twenty one pairs of primary human lung AD tissues and adjacent non-tumor lung (AdjNL) tissues using the real-time PCR (RT-PCR)-based method MethyLight. By comparing the sixteen analyzed loci in lung AD tissues and AdjNL and non-tumor (NL) tissues, we found that, among the six genes identified with hypermethylation, the HOXA11, CDKN2A-EX2 and EYA4 genes showed highly promising DNA hypermethylation diagnostic markers in the lung AD tissues. Moreover, comparing lung AD tissues (> 2 cm in diameter) to the AdjNL or AD in situ (AIS) tissues by RT-qPCR and immunohistochemistry revealed that HOXA11 expression was significantly increased. A further study showed that HOXA11 expression was controlled by methylation in the promoter region in human lung tumor cell lines. Aberrant hypermethylation and the methylation-induced down-regulation of HOXA11 may promote tumor progression. Our results suggested that HOXA11 might be a diagnostic and prognostic marker in patients with lung AD.


Clustering of adolescent dating violence, peer violence, and suicidal behavior.
To understand the co-occurrence of multiple types of violence, the authors developed a behavioral typology based on self-reports of suicidal behaviors, physical violence, and psychological abuse. Using a sample of dating adolescents from a high-risk school district, they identified five clusters of behaviors among the 1,653 students who reported being abusive or violent in the past year. Victimization and perpetration with same-sex peers and dating partners clustered together among the students who reported the highest levels of abusive (n = 357) or violent behavior (n = 146). These students also reported high levels of suicidal behavior. There were few significant demographic differences across clusters. The implications of the results for the need to design and evaluate efforts to prevent multiple types of violence are discussed.


Rigorous coupled wave analysis applied to transmission efficiency of diffractive beam array relays for free-space optical interconnects.
Parallel high-density free-space optical interconnects typically relay multiple channels in an array configuration; thus, they require good uniformity across their aperture for optimum performance. Rigorous coupled wave analysis is used to determine the throughput off-axis diffraction efficiency for Fresnel lenses within a diffractive imaging relay. The rigorous results are compared with scalar theory and show a significant nonuniformity not predicted by scalar theory. However, the polarization sensitivity is found to be negligible for the f-numbers considered (f/2.9 to f/10.2). These results are supported by experiment.


Flow dependence of proximal tubular bicarbonate absorption.
Rat proximal convoluted tubules were microperfused in vivo to examine the effect of flow rate on bicarbonate absorption. When tubules were perfused with 25 mM bicarbonate, increases in perfusion rate from 15 to 33 to 49 nl/min caused bicarbonate absorption to increase from 105 +/- 4 to 176 +/- 8 to 209 +/- 7 pmol X mm-1 X min-1, respectively. Only 15% of this stimulation could be attributed to a flow-induced increase in the measured axial luminal bicarbonate concentration profile. In addition, effects of flow on passive bicarbonate diffusion or convection could not account for the observed stimulation. When tubules were perfused with 58 mM bicarbonate (a concentration previously shown to achieve maximal rates of proton secretion), increasing flow rate from 15 to 49 nl/min did not stimulate bicarbonate absorption. Thus, when examined as a function of mean luminal bicarbonate concentration, increases in flow increased the rate of proton secretion without affecting the maximal rate. The data are most consistent with flow-dependent stimulation of bicarbonate absorption, secondary to flow-dependent changes in luminal bicarbonate concentration, occurring by two mechanisms: 1) flow-dependent increases in the measured axial luminal bicarbonate concentration profile and 2) flow-dependent decreases in radial luminal bicarbonate concentration gradients.


Melanoma segmentation based on deep learning.
Malignant melanoma is one of the most deadly forms of skin cancer, which is one of the world's fastest-growing cancers. Early diagnosis and treatment is critical. In this study, a neural network structure is utilized to construct a broad and accurate basis for the diagnosis of skin cancer, thereby reducing screening errors. The technique is able to improve the efficacy for identification of normally indistinguishable lesions (such as pigment spots) versus clinically unknown lesions, and to ultimately improve the diagnostic accuracy. In the field of medical imaging, in general, using neural networks for image segmentation is relatively rare. The existing traditional machine-learning neural network algorithms still cannot completely solve the problem of information loss, nor detect the precise division of the boundary area. We use an improved neural network framework, described herein, to achieve efficacious feature learning, and satisfactory segmentation of melanoma images. The architecture of the network includes multiple convolution layers, dropout layers, softmax layers, multiple filters, and activation functions. The number of data sets can be increased via rotation of the training set. A non-linear activation function (such as ReLU and ELU) is employed to alleviate the problem of gradient disappearance, and RMSprop/Adam are incorporated to optimize the loss algorithm. A batch normalization layer is added between the convolution layer and the activation layer to solve the problem of gradient disappearance and explosion. Experiments, described herein, show that our improved neural network architecture achieves higher accuracy for segmentation of melanoma images as compared with existing processes.


[Chromosome instability syndromes].
Chromosome instability syndromes are defined by either an increase of chromosomal breakage or by an increase of sister chromatid exchange number, or by an increase of the two. Bloom's syndrome, Ataxia telangiectasia, Fanconi's Anemia are the main components of this group. The incidence of cancers or malignant blood diseases is high. The finding of DNA repair abnormalities in some of them and their high sensitivity to particular mutagenic agents make these syndromes an interesting model for oncogenesis.


An investigation of female adolescent twins with both major depression and conduct disorder.
Conduct disorder (CD) and major depression (MDD) frequently co-occur in adolescents, but little is known about the characteristics and functioning of youths, especially females, with both disorders. This study describes the functioning of female adolescents with histories of both CD and MDD. Subjects were selected from an epidemiological sample of 17-year-old female twins based on having a lifetime DSM-III-R diagnosis of MDD and/or CD; control subjects had no history of either disorder. In nearly all domains examined, including measures of academic success (including academic achievement and school adjustment), personality, quality of peer relationships, and high-risk behavior (including substance dependence and early sexual experience), main effects of one or both disorders were found and related to impaired functioning. In addition, interaction effects were found in the areas of substance dependence symptoms (for all classes of substances), negative school-related events, and a personality-based predisposition not to experience positive emotions, indicating that those with both diagnoses were especially impaired. In some domains, histories of MDD and CD interact and relate to particularly severe problems. The implications of these findings for research and treatment, including the high likelihood of substance and school adjustment problems in these youths, are discussed.


Mental Health in Residential Healthcare Workers During the COVID-19 Pandemic: The Moderating Role of Selfobject Needs.
The COVID-19 outbreak has affected healthcare across all levels. Older adults and those with chronic illness are at greatest risk for infection complications and mortality, which presents significant psychological distress for residential healthcare workers. The concept of selfobject needs, consisting of Mirroring, Idealizing, and Twinship, may be relevant in explaining psychological distress. This study seeks to enhance our understanding of the needs of healthcare workers responsible for elderly patients and evaluate the role of psychosocial support through selfobject needs to mitigate the effects of trauma during the pandemic. Participants (N = 103) employed in residential healthcare facilities in the metropolitan Detroit, MI (USA) region completed an online survey during the peak initial infection. Assessments included standardized measures of trauma-related symptoms, depression, anxiety, and general distress symptoms, as well as a validated measure of selfobject needs. Residential healthcare workers reported mental health symptoms across domains, including clinical elevations in symptoms of trauma, depression, and anxiety. Selfobject needs and mental health outcomes were positively correlated, indicating that greater unmet relational need was associated with greater severity of symptoms. Greater trauma symptom severity as a proxy index of current experience during the pandemic predicted high depressive symptoms, and greater Mirroring need worsened the effect. These results suggest that interventions targeting selfobject needs, specifically Mirroring, may be effective at mitigating acute mental health symptoms among healthcare workers during a distressing event.


Non-Gaussian heart rate as an independent predictor of mortality in patients with chronic heart failure.
Morbidity and mortality due to chronic heart failure remain unacceptably high despite effective drug therapies, and the search for a better risk predictor is ongoing. Statistics derived from beat-to-beat fluctuations in heart rate or heart rate variability (HRV) have been used for this purpose, but the current predictability level is low or moderate at best. The purpose of this study was to evaluate whether a recently proposed non-Gaussian index of HRV is a significant and independent mortality predictor in patients with congestive heart failure (CHF). Twenty-four-hour Holter ECGs from 108 CHF patients were evaluated. Thirty-nine (36.1%) of the patients died during the follow-up period of 33 +/- 17 months. Cox proportional hazards regression analysis was performed to determine factors related to all-cause mortality. The factors evaluated derived from clinical information, including plasma brain natriuretic peptide, conventional time- and frequency-domain and fractal HRV measures, and a recently proposed non-Gaussian index lambda of HRV. The short-term (<40 beats) non-Gaussian index lambda(40) (hazard ratio per increment of unit standard deviation 1.64, 95% confidence interval [1.23, 2.18], P <.001) and the long-term (<1,000 beats) index lambda(1000) (hazard ratio 1.42, 95% confidence interval [1.07, 2.18], P <.02), together with brain natriuretic peptide (hazard ratio 2.26, 95% confidence interval [1.45, 3.53], P <.001), are significant univariate risk predictors of mortality. In a multivariate model, lambda(40) (1.49, [1.13, 1.96], P <.005) and brain natriuretic peptide (2.39, [1.53, 3.75], P <.001) are independent predictors of the survival statistics of patients. None of the conventional HRV measures have predicted the mortality of patients in a significant and independent manner. The results of this study indicate the usefulness of the short-term non-Gaussian index of HRV for risk prediction in patients with CHF.


Multivariate genome-wide analysis of stress-related quantitative phenotypes.
Exposure to traumatic stress increases the odds of developing a broad range of psychiatric conditions. Genetic studies targeting multiple stress-related quantitative phenotypes may shed light on mechanisms underlying vulnerability to psychopathology in the aftermath of stressful events. We applied a multivariate genome-wide association study (GWAS) to a unique military cohort (N = 583) in which we measured biochemical and behavioral phenotypes. The availability of pre- and post-deployment measurements allowed to capture changes in these phenotypes in response to stress. For genome-wide significant loci, we performed functional annotation, phenome-wide analysis and quasi-replication in PTSD case-control GWASs. We discovered one genetic variant reaching genome-wide significant association, surviving permutation and sensitivity analyses (rs10100651, p = 9.9 × 10-9). Functional annotation prioritized the genes INTS8 and TP53INP1. A phenome-wide scan revealed a significant association of these same genes with sleeping problems, hypertension and subjective well-being. Finally, a targeted lookup revealed nominally significant association of rs10100651 in a PTSD case-control GWAS in the UK Biobank (p = 0.02). We provide comprehensive evidence from multiple resources hinting at a role of the highlighted genetic variant in the human stress response, marking the power of multivariate genome-wide analysis of quantitative measures in stress research. Future genetic and functional studies can target this locus to further assess its effects on stress mediation and its possible role in psychopathology or resilience.


Investigation of crocin's protective effect on cyclophosphamide-induced hypothalamic-pituitary-gonadal axis defects in adult female rats.
Cyclophosphamide is a drug used in chemotherapy. However, it has side effects, including changes in reproductive system functioning. Some herbal compounds can reduce the harmful effects of cyclophosphamide. This study aims to investigate the protective role of crocin against changes caused by Cyclophosphamide in ovarian tissue through changes in the expression of genes involved in the hypothalamic-pituitary-gonadal axis. This experimental study was performed on 24 adult female Wistar rats. Mice were divided into four groups (normal saline, 30 mg/kg cyclophosphamide, 100 mg/kg crocin and 30 mg/kg cyclophosphamide, and 200 mg/kg crocin and 30 mg/kg cyclophosphamide). At the end of the treatment period, the hypothalamus and ovaries were also removed to evaluate ob-Rb, ob-Ra, and NPY genes expression using real-time PCR and histological changes in the ovaries. Data were analyzed by SPSS statistical software. The expression of genes, number of follicles, and follicle diameter significantly decreased in the cyclophosphamide-treated groups compared with the control group. In the crocin and cyclophosphamide-treated groups, drug-induced reproductive complications were mitigated. The current findings indicate that by increasing the expression of genes ob-Rb, ob-Ra, and NPY, crocin could modulate the harmful effects of cyclophosphamide.


Before you call renal: Acute kidney injury for hospitalists.
Acute kidney injury is a clinical problem of growing incidence in hospitalized patients. It increases the risk of poor outcomes, length of stay and the cost of hospitalization. Successful management of acute kidney injury requires early recognition and diagnosis through detailed medical history, careful physical exam, judicious use of laboratory and radiologic tests and timely renal consultation. Subsequent management is tailored to the likely mechanism of injury with emphasis on limiting both further injury and systemic consequences. A common sense approach to acute kidney injury is essential for hospitalists aiming to limit further injury, prevent acute complications and lessen the risk of chronic morbidity.


Angiotensin I-Converting Enzyme (ACE) Inhibitory Activity, Antioxidant Properties, Phenolic Content and Amino Acid Profiles of Fucus spiralis L. Protein Hydrolysate Fractions.
Food protein-derived hydrolysates with multi-bioactivities such as antihypertensive and antioxidant properties have recently received special attention since both activities can play significant roles in preventing cardiovascular diseases. This study reports, for the first time, the angiotensin I-converting enzyme (ACE)-inhibition and antioxidant properties of ultrafiltrate fractions (UF) with different molecular weight ranges (<1, 1-3 and ≥3 kDa) obtained from Fucus spiralis protein hydrolysate (FSPH) digested with cellulase-bromelain. The amino acids profile, recovery yield, protein, peptide and total phenolic contents of these FSPH-UF, and the in vitro digestibility of F. spiralis crude protein were also investigated. FSPH-UF ≥3 kDa presented remarkably higher ACE-inhibition, yield, peptide and polyphenolic (phlorotannins) contents. Antioxidant analysis showed that FSPH-UF <1 kDa and ≥3 kDa exhibited significantly higher scavenging of 2,2-diphenyl-1-picrylhydrazyl radical and ferrous ion-chelating (FIC) activity. FSPH-UF ≥3 kDa had also notably higher ferric reducing antioxidant power (FRAP). Strong correlations were observed between ACE-inhibition and antioxidant activities (FIC and FRAP). The results suggest that ACE-inhibition and antioxidant properties of FSPH-UF may be due to the bioactive peptides and polyphenols released during the enzymatic hydrolysis. In conclusion, this study shows the potential use of defined size FSPH-UF for the prevention/treatment of hypertension and/or oxidative stress-related diseases.


Kinematic and EMG Responses to Pelvis and Leg Assistance Force during Treadmill Walking in Children with Cerebral Palsy.
Treadmill training has been used for improving locomotor function in children with cerebral palsy (CP), but the functional gains are relatively small, suggesting a need to improve current paradigms. The understanding of the kinematic and EMG responses to forces applied to the body of subjects during treadmill walking is crucial for improving current paradigms. The objective of this study was to determine the kinematics and EMG responses to the pelvis and/or leg assistance force. Ten children with spastic CP were recruited to participate in this study. A controlled assistance force was applied to the pelvis and/or legs during stance and swing phase of gait through a custom designed robotic system during walking. Muscle activities and spatial-temporal gait parameters were measured at different loading conditions during walking. In addition, the spatial-temporal gait parameters during overground walking before and after treadmill training were also collected. Applying pelvis assistance improved step height and applying leg assistance improved step length during walking, but applying leg assistance also reduced muscle activation of ankle flexor during the swing phase of gait. In addition, step length and self-selected walking speed significantly improved after one session of treadmill training with combined pelvis and leg assistance.


Detoxifying SARS-CoV-2 antiviral drugs from model and real wastewaters by industrial waste-derived multiphase photocatalysts.
The use of antiviral drugs has surged as a result of the COVID-19 pandemic, resulting in higher concentrations of these pharmaceuticals in wastewater. The degradation efficiency of antiviral drugs in wastewater treatment plants has been reported to be too low due to their hydrophilic nature, and an additional procedure is usually necessary to degrade them completely. Photocatalysis is regarded as one of the most effective processes to degrade antiviral drugs. The present study aims at synthesizing multiphase photocatalysts by a simple calcination of industrial waste from ammonium molybdate production (WU photocatalysts) and its combination with WO3 (WW photocatalysts). The X-ray diffraction (XRD) results confirm that the presence of multiple crystalline phases in the synthesized photocatalysts. UV-Vis diffuse reflectance spectra reveal that the synthesized multiphase photocatalysts absorb visible light up to 620 nm. Effects of calcination temperature of industrial waste (550-950 °C) and WO3 content (0-100%) on photocatalytic activity of multiphase photocatalysts (WU and WW) for efficient removal of SARS-CoV-2 antiviral drugs (lopinavir and ritonavir) in model and real wastewaters are studied. The highest k1 value is observed for the photocatalytic removal of ritonavir from model wastewater using WW4 (35.64 ×10-2 min-1). The multiphase photocatalysts exhibit 95% efficiency in the photocatalytic removal of ritonavir within 15 of visible light irradiation. In contrast, 60 min of visible light irradiation is necessary to achieve 95% efficiency in the photocatalytic removal of lopinavir. The ecotoxicity test using zebrafish (Danio rerio) embryos shows no toxicity for photocatalytically treated ritonavir-containing wastewater, and the contrary trend is observed for photocatalytically treated lopinavir-containing wastewater. The synthesized multiphase photocatalysts can be tested and applied for efficient degradation of other SARS-CoV-2 antiviral drugs in wastewater in the future.


Childhood asthma and fruit consumption.
The present authors investigated whether wheezing is less common in children who consume more apples and other fruits. A population-based survey of 2,640 primary school children aged 5-10 yrs was carried out in Greenwich (South London, UK). Information about asthma symptoms and fruit consumption was obtained by means of a questionnaire. After controlling for potential confounding variables, eating bananas at least once a day (compared with less than once a month) was negatively associated with current wheeze (odds ratio 0.66; 95% confidence interval 0.44-1.00) and ever wheeze (0.69 (0.50-0.95)), but not with ever asthma (0.80 (0.56-1.14)). Drinking apple juice from concentrate at least once a day (compared with less than once a month) was also negatively associated with current wheeze (0.53 (0.34-0.83)), weakly associated with ever wheeze (0.74 (-0.54-1.02)), but not associated with ever asthma. Consumption of apples, other fruits and orange juice was not significantly associated with asthma symptoms. No association was found between eating fresh apples and asthma symptoms in the study population, but some evidence was found to suggest that a higher consumption of apple juice from concentrate and bananas may protect against wheezing in children.


Temporal trends and current practice patterns for intraoperative ventilation at U.S. academic medical centers: a retrospective study.
Lung protective ventilation strategies utilizing lower tidal volumes per predicted body weight (PBW) and positive end-expiratory pressure (PEEP) have been suggested to be beneficial in a variety of surgical populations. Recent clinical studies have used control groups ventilated with high tidal volumes without PEEP based on the assumption that this reflects current clinical practice. We hypothesized that ventilation strategies have changed over time, that most anesthetics in U.S. academic medical centers are currently performed with lower tidal volumes, and that most receive PEEP. Intraoperative data were pooled for adults undergoing general anesthesia with tracheal intubation. Median tidal volumes per kilogram of PBW were categorized as > 10, 8-10 and < 8 mL per kg of PBW. The percentages of cases in 2013 that were performed with median tidal volumes < 8 mL per kg of PBW and PEEP were determined. As a secondary analysis, a proportional odds model using institution, year, height, weight and gender determined the relative associations of these factors using categorical and interquartile odds ratios. 295,540 cases were analyzed from 5 institutions over a period of 10 years. In 2013, 59.3% of cases used median tidal volumes < 8 mL per kg of PBW, 83.3% used PEEP, and 51.0% used both. Of those cases with PEEP, 60.9% used a median pressure of ≥ 5 cmH2O. Predictors of lower categories of tidal volumes included height (odds ratio (OR) 10.83, 95% confidence interval [10.50, 11.16]), institution (lowest OR 0.98 [0.96, 1.00], highest OR 9.63 [9.41, 9.86]), year (lowest OR 1.32 [1.21, 1.44], highest OR 6.31 [5.84, 6.82]), male gender (OR 1.10 [1.07, 1.12]), and weight (OR 0.30 [0.29, 0.31]). Most general anesthetics with tracheal intubation at the institutions surveyed are currently performed with a median tidal volume < 8 mL per kg of PBW, most are managed with PEEP of ≥ 5 cmH2O and approximately half utilize both. Given the diversity of the institutions included, this is likely reflective of practice in U.S. academic medical centers. The utilization of higher tidal volumes without PEEP in control groups for clinical research studies should be reconsidered.


Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease.
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Canada and elsewhere. It affects 5% of all adult Canadians and is the fourth leading cause of death. Interestingly, the leading causes of hospitalizations and mortality among COPD patients are cardiovascular events. In the Lung Health Study, over 5 800 patients with mild to moderate COPD were studied. Forty-two to 48% of all hospitalizations that occurred over the study's 5-year follow-up period were related to cardiovascular complications. Various population-based studies suggest that independent of smoking, age, and gender, COPD increases the risk of cardiovascular morbidity and mortality twofold. Alarmingly, some bronchodilators, which are commonly used to treat symptoms in COPD, may increase the risk of cardiovascular morbidity and even mortality among COPD patients. In this paper, we discuss the epidemiologic evidence linking COPD and cardiovascular events as well as the potential mechanism(s) which may be responsible for this association.


MUTATIONS IN LIVER X RECEPTOR ALPHA THAT IMPAIR DIMERIZATION AND LIGAND DEPENDENT TRANSACTIVATION.
Liver X receptor alpha (LXRα) is crucial for the maintenance of lipid and cholesterol homeostasis. Ligand binding and dimerization with retinoid X receptor (RXR) or peroxisome proliferator-activated receptor (PPAR) is required for forming active DNA binding complexes leading to gene regulation. Structure based prediction and solvent accessibility of LXRα LBD shows that residues H383, E387, H390, L414, and R415 which are located in helices 9 and 10 may be critical for mediating protein-protein interactions. In this study, LXRα interface residues were individually mutated to determine their effects on ligand binding, protein-protein association, subcellular localization, and transactivation activity. LXRα L414R and R415A lacked binding to T-0901317, but retained binding to 25-Hydroxycholesterol. In vitro assay and a cell based assay demonstrated that LXRα L414R was specifically impaired for interactions with RXRα but not PPARα suggesting that charge reversal at the interface provides selectivity to LXRα dimerization. Furthermore, binding of LXRα L414R or R415A with PPARα exhibited minimal conformational changes in the dimer secondary structure. Interestingly, all LXRα mutants exhibited lower levels of ligand dependent luciferase activity driven by the SREBP-1c or ApoA1 promoter. Taken together, our data demonstrates that intact hydrophobic interactions and salt bridges at the interface mediate efficient ligand-dependent transactivation activities.


Risk pathways among traumatic stress, posttraumatic stress disorder symptoms, and alcohol and drug problems: a test of four hypotheses.
The present study utilized longitudinal data from a community sample (n = 377; 166 trauma-exposed; 54% males; 73% non-Hispanic Caucasian; 22% Hispanic; 5% other ethnicity) to test whether pretrauma substance use problems increase risk for trauma exposure (high-risk hypothesis) or posttraumatic stress disorder (PTSD) symptoms (susceptibility hypothesis), whether PTSD symptoms increase risk for later alcohol/drug problems (self-medication hypothesis), and whether the association between PTSD symptoms and alcohol/drug problems is attributable to shared risk factors (shared vulnerability hypothesis). Logistic and negative binomial regressions were performed in a path analysis framework. Results provided the strongest support for the self-medication hypothesis, such that PTSD symptoms predicted higher levels of later alcohol and drug problems, over and above the influences of pretrauma family risk factors, pretrauma substance use problems, trauma exposure, and demographic variables. Results partially supported the high-risk hypothesis, such that adolescent substance use problems increased risk for assaultive violence exposure but did not influence overall risk for trauma exposure. There was no support for the susceptibility hypothesis. Finally, there was little support for the shared vulnerability hypothesis. Neither trauma exposure nor preexisting family adversity accounted for the link between PTSD symptoms and later substance use problems. Rather, PTSD symptoms mediated the effect of pretrauma family adversity on later alcohol and drug problems, thereby supporting the self-medication hypothesis. These findings make important contributions to better understanding the directions of influence among traumatic stress, PTSD symptoms, and substance use problems.


Long-term follow-up and outcome of extremely-low-birth-weight (ELBW) infants.
Modern day obstetric and neonatal care has dramatically increased the survival of the extremely-low-birth-weight (ELBW) neonates. As the limits of viability decrease, it is of paramount importance to have reliable data on long-term morbidity. Long-term follow-up of these high-risk survivors is thus becoming an integral part of neonatal intensive care units. Detailed Medline search and review of leading journal articles were done to assess the current data on long-term outcome of ELBW infants. The developmental outcome of the ELBW infant is determined by a complex interaction of medical and environmental factors acting on a developmentally vulnerable premature brain. In early childhood, 13% to 37% of ELBW survivors have a significant delay in cognitive function while 7% to 17% have neurosensory impairment viz. cerebral palsy. Advances have been made in measuring functional outcome to assess the impact of ELBW births on long-term quality of life and skills for independent living. Measuring school age outcome is an important landmark in the longitudinal follow-up of ELBW infants and most reports show high rates of cognitive impairment as well as increased incidence of learning disability and school difficulties as well as behavioural problems. The ELBW adolescent and young adult continue to lag behind in academic achievement and cognitive score. However, more than half of the ELBW survivors function within the normal range of variability and their self-reported quality of life in adolescence continues to be comparable to that of their peers. In managing ELBW infants, a holistic, systematic approach is needed to assess the degree and impact of impairment on their daily function and issues related to quality of life.


Beyond intention to treat: what is the right question?
Most methodologists recommend intention-to-treat (ITT) analysis in order to minimize bias. Although ITT analysis provides an unbiased estimate for the effect of treatment assignment on the outcome, the estimate is biased for the actual effect of receiving treatment (active treatment) compared to some comparison group (control). Other common analyses include measuring effects in (1) participants who follow their assigned treatment (Per Protocol), (2) participants according to treatment received (As Treated), and (3) those who would comply with recommended treatment (Complier Average Causal Effect (CACE) as estimated by Principal Stratification or Instrumental Variable Analyses). As each of these analyses compares different study subpopulations, they address different research questions. For each type of analysis, we review and explain (1) the terminology being used, (2) the main underlying concepts, (3) the questions that are answered and whether the method provides valid causal estimates, and (4) the situations when the analysis should be conducted. We first review the major concepts in relation to four nuances of the clinical question, 'Does treatment improve health?' After reviewing these concepts, we compare the results of the different analyses using data from two published randomized controlled trials (RCTs). Each analysis has particular underlying assumptions and all require dichotomizing adherence into Yes or No. We apply sensitivity analyses so that intermediate adherence is considered (1) as adherence and (2) as non-adherence. The ITT approach provides an unbiased estimate for how active treatment will improve (1) health in the population if a policy or program is enacted or (2) health of patients if a clinician changes treatment practice. The CACE approach generally provides an unbiased estimate of the effect of active treatment on health of patients who would follow the clinician's advice to take active treatment. Unfortunately, there is no current analysis for clinicians and patients who want to know whether active treatment will improve the patient's health if taken, which is different from the effect in patients who would follow the clinician's advice to take active treatment. Sensitivity analysis for the CACE using two published data sets suggests that the underlying assumptions appeared to be violated. There are several methods within each analytical approach we describe. Our analyses are based on a subset of these approaches. Although adherence-based analyses may provide meaningful information, the analytical method should match the clinical question, and investigators should clearly outline why they believe assumptions hold and should provide empirical tests of the assumptions where possible.


Type 2 diabetes susceptibility gene expression in normal or diabetic sorted human alpha and beta cells: correlations with age or BMI of islet donors.
Genome-wide association studies have identified susceptibility genes for development of type 2 diabetes. We aimed to examine whether a subset of these (comprising FTO, IDE, KCNJ11, PPARG and TCF7L2) were transcriptionally restricted to or enriched in human beta cells by sorting islet cells into alpha and beta - specific fractions. We also aimed to correlate expression of these transcripts in both alpha and beta cell types with phenotypic traits of the islet donors and to compare diabetic and non-diabetic cells. Islet cells were sorted using a previously published method and RNA was extracted, reverse transcribed and used as the template for quantitative PCR. Sorted cells were also analysed for insulin and glucagon immunostaining and insulin secretion from the beta cells as well as insulin, glucagon and GLP-1 content. All five genes were expressed in both alpha and beta cells, with significant enrichment of KCNJ11 in the beta cells and of TCF7L2 in the alpha cells. The ratio of KCNJ11 in beta to alpha cells was negatively correlated with BMI, while KCNJ11 expression in alpha cells was negatively correlated with age but not associated with BMI. Beta cell expression of glucagon, TCF7L2 and IDE was increased in cells from islets that had spent more time in culture prior to cell sorting. In beta cells, KCNJ11, FTO and insulin were positively correlated with each other. Diabetic alpha and beta cells had decreased expression of insulin, glucagon and FTO. This study has identified novel patterns of expression of type 2 diabetes susceptibility genes within sorted islet cells and suggested interactions of gene expression with age or BMI of the islet donors. However, expression of these genes in islets is less associated with BMI than has been found for other tissues.


Women's occupational exposure to polycyclic aromatic hydrocarbons and risk of breast cancer.
To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer. Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections. Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01). Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.


Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells.
Liver transplantation is the primary treatment for various end-stage hepatic diseases but is hindered by the lack of donor organs and by complications associated with rejection and immunosuppression. There is increasing evidence to suggest the bone marrow is a transplantable source of hepatic progenitors. We previously reported that multipotent bone marrow-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells with almost 100% induction frequency under defined conditions, suggesting the potential for clinical applications. The aim of this study was to critically analyze the various parameters governing the success of bone marrow-derived mesenchymal stem cell-based therapy for treatment of liver diseases. Lethal fulminant hepatic failure in nonobese diabetic severe combined immunodeficient mice was induced by carbon tetrachloride gavage. Mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells were then intrasplenically or intravenously transplanted at different doses. Both mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells, transplanted by either intrasplenic or intravenous route, engrafted recipient liver, differentiated into functional hepatocytes, and rescued liver failure. Intravenous transplantation was more effective in rescuing liver failure than intrasplenic transplantation. Moreover, mesenchymal stem cells were more resistant to reactive oxygen species in vitro, reduced oxidative stress in recipient mice, and accelerated repopulation of hepatocytes after liver damage, suggesting a possible role for paracrine effects. Bone marrow-derived mesenchymal stem cells can effectively rescue experimental liver failure and contribute to liver regeneration and offer a potentially alternative therapy to organ transplantation for treatment of liver diseases.


Superior parietal cortex is critical for the manipulation of information in working memory.
In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n = 19), lesions not involving superior parietal cortex (n = 146), and no brain lesions (n = 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory.


Social network constellation and sexuality of sexually abused and comparison girls in childhood and adolescence.
This longitudinal study examines how childhood and early adolescent (age 6 to 15) peer and nonpeer social networks relate to sexual attitudes and behaviors in adolescence and young adulthood (age 12 to 25) for sexually abused and comparison girls. A large number of male peers in childhood is related to heightened sexual activity, sexual preoccupation, increased sexual pressure, and risky sexual behavior in adolescence. High-quality, female, nonpeer relationships have a positive effect on attitudes toward casual sex. Multiple group models illuminate several cross-lag group moderators: (a) Abused girls who are happier with male nonpeers are less preoccupied with sex; (b) abused girls who are happier with male peers are more likely to use birth control; and (c) abused girls who have early physical relationships are more likely to engage in risky sexual behavior. Treatment implications include monitoring the effects of low-status peer groups, encouraging contact with female role models, and encouraging the formation of high-quality relationships with male peers and nonpeers.


Daily physical education in primary school and physical activity in midlife: the Trois-Rivières study.
Although a commonly stated purpose of physical education (PE) classes is to foster life-long participation in physicalactivity (PA), few longitudinal studies have assessed the impact of childhood PE interventions on PA as an adult. The Trois-Rivières Growth and Development Study provided a unique opportunity to address this question. In 2008, 86 participants in the original 1970-1977 Trois-Rivières Study (44 women and 42 men aged 44.0 ± 1.2 years) completed a questionnaire examining their current PA level and different correlates of PA (i.e. individual's intention to engage in PA, perceived enjoyment, usefulness and ease in engaging in PA, perceived social support and social norms). Participants had initially been assigned to either an experimental program (5 h/week of specialist-taught PE) or a control group (40 min/week of home-room teacher-taught PE) from grades 1 to 6. There were no current differences between the experimental and control groups neither in the frequency, duration nor volume of PA undertaken at the current follow-up. Furthermore, no differences between groups were found for any of the PA correlates examined. Providing daily PE throughout primary school seems insufficient to ensure that individuals will remain active in midlife. The development of a life-course approach to PA promotion is thus warranted.


Safe Patient Handling and Pressure Injury Prevention for Patients With Delayed Sternal Closure.
Pressure injuries are associated with increased morbidity, mortality, and cost. Patients with delayed sternal closure after cardiac surgery are at increased risk of developing pressure injury because of their reduced mobility and inability to undergo complete skin assessment. Safe patient handling of patients with delayed sternal closure is challenging because of mobility restrictions, leading to increased risk for patient and staff harm. An interprofessional team composed of bedside nurses, ergonomic specialists, a wound ostomy continence nurse, and cardiothoracic surgeons developed a patient mobility protocol for patients with delayed sternal closure consisting of levitating the patient for thorough skin assessment and care. A multimodal educational strategy was used to disseminate the new protocol. Patient information was collected on the type of surgery, results of the levitation, completion of the skin assessment, and subsequent interventions. Staff injury related to this work was monitored. After implementation of the protocol, 84 levitations were performed including 50 patients. No staff injuries were reported. Comprehensive skin assessments and care were completed for 98% of patients. Five patients were identified with pressure injury development, and appropriate interventions were applied. A standardized patient mobility protocol for patients with delayed sternal closure that leveraged available equipment was successful in reducing the risk for injury among staff and patients. The protocol allowed assessment and care and thus also reduced the risk for pressure injury development in these patients. Development of an innovative protocol to safely mobilize patients with delayed sternal closure resulted in improved patient care and increased staff safety.


Reversible cerebral vasoconstriction syndromes: analysis of 139 cases.
To compare the clinical, laboratory, and imaging features of patients with reversible cerebral vasoconstriction syndromes evaluated at 2 academic centers, compare subgroups, and investigate treatment effects. Retrospective analysis. Massachusetts General Hospital (n = 84) or Cleveland Clinic (n = 55). One hundred thirty-nine patients with reversible cerebral vasoconstriction syndromes. Clinical, laboratory, and imaging features; treatment; and outcomes. The mean age was 42.5 years, and 81% were women. Onset with thunderclap headache was documented in 85% and 43% developed neurological deficits. Prior migraine was documented in 40%, vasoconstrictive drug exposure in 42%, and recent pregnancy in 9%. Admission computed tomography or magnetic resonance imaging was normal in 55%; however, 81% ultimately developed brain lesions including infarcts (39%), convexity subarachnoid hemorrhage (34%), lobar hemorrhage (20%), and brain edema (38%). Cerebral angiographic abnormalities typically normalized within 2 months. Nearly 90% had good clinical outcome; 9% developed severe deficits; and 2% died. In the combined cohort, calcium channel blocker therapy and symptomatic therapy alone showed no significant effect on outcome; however, glucocorticoid therapy showed a trend for poor outcome (P = .08). Subgroup comparisons based on prior headache status and identified triggers (vasoconstrictive drugs, pregnancy, other) showed no major differences. Patients with reversible cerebral vasoconstriction syndromes have a unique set of clinical imaging features, with no significant differences between subgroups. Prospective studies are warranted to determine the effects of empirical treatment with calcium channel blockers and glucocorticoids.


Long-term prevalence of NIRF-labeled magnetic nanoparticles for the diagnostic and intraoperative imaging of inflammation.
Inflammation is a very common disease worldwide. In severe cases, surgery is often the method of choice. Today, there is a general need for the implementation of image-based guidance methodologies for reliable target resection. We investigated new near infrared fluorescence (NIRF)-nanoparticles (NPs) as a simple but effective bimodal magnetic resonance imaging (MRI) and optical contrast agent for diagnosis and intraoperative imaging of inflammation. Physicochemical analysis revealed that these NPs were highly fluorescent with similar characteristics like unlabeled NPs (hydrodynamic diameter about 130 nm and zeta potential about -10 mV). NP-uptake and NIR-dye labeling was biocompatible to macrophages (no impact on cellular ATP and reactive oxygen species production). These cells could successfully be tracked with MRI and NIRF-optical imaging. I.v. injection of fluorescent NPs into mice led to highly specific T2-weighted signal of edema due to uptake by phagocytic cells and subsequent migration to the site of inflammation. NIRF signals of the edema region were well detectable for up to 4 weeks, underlining the potential of the NPs for systematic planning and flexible time scheduling in intraoperative applications. NPs were degraded over a time period of 12 weeks, which was not altered due to inflammation. Redistribution of iron might be primarily due to inflammation and not to the presence of NPs per se in a concentration suitable for imaging. Our findings highlight the potential of the NPs to be used as a suitable tool for pre- and intraoperative imaging of inflammation.


Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice.
In this study, we investigated the involvement of the blood-brain barrier (BBB) in the brain of the dystrophin-deficient mdx mouse, an experimental model of Duchenne muscular dystrophy (DMD). To this purpose, we used two tight junction markers, the Zonula occludens (ZO-1) and claudin-1 proteins, and a glial marker, the aquaporin-4 (AQP4) protein, whose expression is correlated with BBB differentiation and integrity. Results showed that most of the brain microvessels in mdx mice were lined by altered endothelial cells that showed open tight junctions and were surrounded by swollen glial processes. Moreover, 18% of the perivascular glial endfeet contained electron-dense cellular debris and were enveloped by degenerating microvessels. Western blot showed a 60% reduction in the ZO-1 protein content in mdx mice and a similar reduction in AQP4 content compared with the control brain. ZO-1 immunocytochemistry and claudin-1 immunofluorescence in mdx mice revealed a diffuse staining of microvessels as compared with the control ones, which displayed a banded staining pattern. ZO-1 immunogold electron microscopy showed unlabeled tight junctions and the presence of gold particles scattered in the endothelial cytoplasm in the mdx mice, whereas ZO-1 gold particles were exclusively located at the endothelial tight junctions in the controls. Dual immunofluorescence staining of alpha-actin and ZO-1 revealed colocalization of these proteins. As in ZO-1 staining, the pattern of immunolabeling with anti-alpha-actin antibody was diffuse in the mdx vessels and pointed or banded in the controls. alpha-actin immunogold electron microscopy showed gold particles in the cytoplasms of endothelial cells and pericytes in the mdx mice, whereas alpha-actin gold particles were revealed on the endothelial tight junctions and the cytoskeletal microfilaments of pericytes in the controls. Perivascular glial processes of the mdx mice appeared faintly stained by anti-AQP4 antibody, while in the controls a strong AQP4 labeling of glial processes was detected at light and electron microscope level. The vascular permeability of the mdx brain microvessels was investigated by means of the horseradish peroxidase (HRP). After HRP injection, extensive perivascular areas of marker escape were observed in mdx mice, whereas HRP was exclusively intravascularly localized in the controls. Inflammatory cells, CD4-, CD8-, CD20-, and CD68-positive cells, were not revealed in the perivascular stroma of the mdx brain. These findings indicate that dystrophin deficiency in the mdx brain leads to severe injury of the endothelial and glial cells with disturbance in alpha-actin cytoskeleton, ZO-1, claudin-1, and AQP4 assembly, as well as BBB breakdown. The BBB alterations suggest that changes in vascular permeability are involved in the pathogenesis of the neurological dysfunction associated with DMD.


PR-1 protein inhibits the differentiation of rust infection hyphae in leaves of acquired resistant broad bean.
Treatment of broad bean leaves with salicylic acid (SA) or 2, 6-dichloro-isonicotinic acid (DCINA) induces resistance against the rust fungus Uromyces fabae resulting in reduced rust pustule density. Light-microscopy studies showed that in induced resistant plants the rust fungus is inhibited immediately after penetration through the stomatal pore. The differentiation of infection structures growing within the intercellular space of the leaf, i.e. infection hyphae and haustorial mother cells, is inhibited. Furthermore, low-temperature scanning electron microscopy studies of freeze fractures revealed protrusions at the tips of infection hyphae growing in induced resistant broad bean leaves. Treatment of in vitro-differentiating rust infection structures with intercellular fluids (IFs) from induced resistant plants confirmed that the fungus is sensitive towards an apoplastic anti-fungal activity only after having formed appressoria. Other legume rusts such as U. vignae and U. appendiculatus were likewise inhibited in the presence of IF from SA-treated broad bean leaves. Heterologous antibodies were used to study changes in the extracellular pathogenesis-related (PR) protein pattern after resistance induction. Western blots indicated that chitinases and beta-1,3-glucanases were present in both induced and control plants. In contrast, PR-1 proteins were newly synthesized in response to SA or DCINA application. The major induced PR-1 protein was purified and exhibited strong differentiation-inhibiting activity towards U. fabae infection structures. We conclude that the inhibition of rust infection hyphae in acquired resistant broad bean plants is mainly due to the anti-fungal activity of this induced basic PR-1 protein.


Virtual versus in-person physiotherapy following total knee arthroplasty: a comparative analysis.
At our centre, we developed and implemented a video-based post-operative physiotherapy program for patients undergoing total knee arthroplasty (TKA). Our aims were to analyse and compare the outcomes of this program to in-person physiotherapy. We reviewed the outcomes of 112 patients and captured range-of-motion (ROM) measurements and pain scores (P4 questionnaire). We compared the outcomes to a cohort of 175 patients undergoing in-person therapy. Comparative analysis was performed using a two-tailed Student's t-test. There was no significant difference between the two groups in age, sex, or initial post-operative knee ROM. On discharge from virtual physiotherapy, mean flexion was 122.6° (SD 7.6). There was no significant difference in improvement in knee flexion between the virtual and in-person groups (mean 30.6° vs 34.0°, p = 0.07). There was no significant difference in the proportion of patients achieving ≥ 120° of flexion (85.0% virtual vs 91.3% in-person, p = 0.11) or those achieving an extension deficit of ≤ 5° (96.0% vs 98.3%, p = 0.25). There was no difference in the number of PT visits to discharge (10.5 vs 11.1, p = 0.14) or final pain scores (12.4 vs 11.9, p = 0.61). Improvements in knee ROM measures are comparable between virtual and in-person physiotherapy with both groups achieving a good functional range. These findings have implications for the virtual delivery of healthcare, especially among remote populations and patients with mobility limitations.


Splenic T1ρ as a noninvasive biomarker for portal hypertension.
There is a need for noninvasive methods for the diagnosis and monitoring of portal hypertension (PH). To 1) assess the correlation of liver and spleen T1 and T1ρ measurements with portal pressures in patients with chronic liver disease, and 2) to compare the diagnostic performance of the relaxation parameters with radiological assessment of PH. Prospective. Twenty-five patients (M/F 16/9, mean age 56 years, range 21-78 years) undergoing portal pressure (hepatic venous pressure gradient [HVPG]) measurements. 1.5T abdominal MRI scan, including T1ρ and T1 mapping. Liver and spleen T1ρ and T1 , radiological PH score, and (normalized) spleen length were evaluated. Spearman correlation of all MRI parameters with HVPG was assessed. The diagnostic performance of the assessed parameters for prediction of PH (HVPG ≥5 mmHg) and clinically significant PH (CSPH, HVPG ≥10 mmHg) was determined by receiver operating characteristic (ROC) analysis. The mean HVPG measurement was 7.8 ± 5.3 mmHg (PH, n = 18 [72%] including CSPH, n = 9 [36%]). PH score, (normalized) spleen length and spleen T1ρ significantly correlated with HVPG, with the strongest correlation found for spleen T1ρ (r = 0.613, P = 0.001). Spleen T1ρ was the only parameter that showed significant diagnostic performance for assessment of PH (area under the curve [AUC] 0.817, P = 0.015) and CSPH (AUC = 0.778, P = 0.024). Normalized spleen length also showed significant diagnostic performance for prediction of CSPH, with a slightly lower AUC (= 0.764, P = 0.031). The radiological PH score, T1ρ and T1 of the liver and T1 of the spleen, did not show significant diagnostic performance for assessment of CSPH (P > 0.075). Spleen T1ρ showed a significant correlation with portal pressure and showed improved diagnostic performance for prediction of CSPH compared to radiological assessment. These initial results need confirmation in a larger cohort. 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;52:787-794.


Meta analysis: effects of interventions on premature infants feeding.
Nipple feeding of premature infants presents a challenge to neonatal nurses who are trying to prepare the infants for eventual discharge from the hospital. To determine what empirical evidence there was to support interventions that positively influence feeding performance and feeding efficiency a meta-analysis is presented. The effects of NPO, nasogastric tubes, different nipples, breast versus bottle feeding, gestational age, oral support, oral stimulation, and nonnutritive sucking on volume intake are evaluated. The results suggest that nursing care should: (a) consider the infant's gestational age; (b) maturational ability and development; (c) keep track of and attempt to minimize the length of time an infant is NPO; and (d) provide prefeeding oral stimulation and oral support.


Prevalence of Lower Urinary Tract Symptoms and Affecting Factors in Female University Students in Türkiye.
Lower urinary tract symptoms (LUTS) are common in women, and negatively affect their lives. The aim of this study is to determine the frequency of LUTS and its affecting factors in female graduate students in Turkey. This descriptive, cross-sectional study consisted of 815 women attending education at Canakkale Onsekiz Mart University. Data were; provided sociodemographic characteristics, a questionnaire, and the Bristol Female LUTS Scale. Linear regression analysis was used to identify the risk factors associated with LUTS. According to the data obtained, the prevalence of at least one of the LUTS was determined as 71.8% (515/815). It was determined that the prevalence of storage symptoms was higher than that of voiding and urinary incontinence. According to the results of the linear regression analysis, the risk factors for LUTS in female student were hold urine at school, complaints of urinary incontinence in family, bedwetting in children, constipation, regular drug use, obesity. Consequently, LUTS is a common condition in female students. It is recommended to organize well-attended and repeated training programs for university students on healthy living behaviors, urinary habits, and hygiene.


MRI in children with mental retardation.
In mental retardation (MR) an aetiological diagnosis is not always obtained despite a detailed history, physical examination and metabolic or genetic investigations. In some of these patients, MRI is recommended and may identify subtle abnormal brain findings. We reviewed the cerebral MRI of children with non-specific mental retardation in an attempt to establish a neuroanatomical picture of this disorder. Thirty children with non-specific MR were selected to undergo cerebral MRI. The examination included supratentorial axial slices, mid-sagittal images and posterior fossa coronal images. Brain malformations, midline and cerebellar abnormalities were studied. In 27 of 30 patients, the neuroimaging evaluation revealed a relatively high incidence of cerebral and posterior fossa abnormalities. The most frequent were: dysplasia of the corpus callosum (46%; hypoplasia, short corpus callosum and vertical splenium), partially opened septum pellucidum and/or cavum vergae (33%), ventriculomegaly (33%), cerebral cortical dysplasia (23%), subarachnoid space enlargement (16.6%), vermian hypoplasia (33%), cerebellar and/or vermian disorganised folia (20%), and subarachnoid spaces enlargement in the posterior fossa (20%). Other anomalies were: enlarged Virchow-Robin spaces (10%), white matter anomalies (10%) and cerebellar or vermian atrophy. MRI has shown a high incidence of subtle cerebral abnormalities and unexpected minor forms of cerebellar cortical dysplasia. Even if most of these abnormalities are considered as subtle markers of brain dysgenesis, their role in the pathogenesis of mental retardation needs further investigation.


Live Birth Rate of Frozen-Thawed Single Blastocyst Transfer After 6 or 7 Days of Progesterone Administration in Hormone Replacement Therapy Cycles: A Propensity Score-Matched Cohort Study.
Progesterone administration before transfer in hormone replacement treatment (HRT) is crucial to pregnancy outcomes in frozen-thawed blastocyst transfer (FET), but the optimal progesterone duration is inconsistent. The objective of this study was to investigate live birth rate (LBR) of different progesterone duration before blastocyst transfer in HRT-FET cycles. In this retrospective cohort study, patients underwent first HRT-FET (including suppression HRT) from January 2016 to December 2019 were included. Logit-transformed propensity score matching (PSM) was performed to assess covariates. The primary outcome was live birth rate after 28 weeks' gestation. Basing on different duration of progesterone before transfer, patients were classified into P6-protocol (blastocyst transfer performed on the sixth day), or P7-protocol (blastocyst transfer performed on the seventh day). Subgroup analyses were conducted as follows: age stratification (-35, 35-38, 38-), development days of blastocyst (D5 or D6), blastocyst quality (high-quality or poor-quality), and endometrial preparation protocols (HRT or suppression HRT). After case matching with propensity score methods, a total of 1,400 patients were included finally: 700 with P6-protocol and 700 with P7-protocol. Significantly higher live birth rate (38.43% versus 31.57%, respectively, P = 0.01) and clinical pregnant rate (50.43% versus 44.14%, respectively, P = 0.02) were observed in P6-protocol than those of P7-protocol. First-trimester abortion rates (18.13% versus 20.71%, P = 0.40) and ectopic pregnancy rates (2.27% versus 1.94%, P = 0.77) were similar between P6- and P7-groups. Preterm birth rate, low birth weight rate, newborn sex proportion, neonatal malformation rate were comparable between groups. Significantly higher LBRs were observed in patients with: age under 35, D5 blastocyst transfer, high-quality blastocyst transfer, and undergoing HRT cycles combined P6-protocol. Frozen-thawed blastocyst transfer on the sixth day of progesterone administration in first HRT cycle is related to higher live birth rate compared with transfer on the seventh day, especially among patients aged under 35, D5 blastocyst and/or high-quality blastocyst transfer.


Regional cerebral blood flow in focal cortical epilepsy.
Regional cerebral blood flow (rCBF) was studied in ten patients with focal cortical epilepsy. The blood flow was measured by the intra-arterial injection of xenon 133 (133Xe), and the isotope clearance was recorded by a multidetector scintillation camera with 254 detectors. Three patients were studied both during a seizure and (in the same setting) in the interictal period; six patients were studied only in the interictal period, and one patient was studied only during a seizure. Studies during seizures all showed marked flow increases in areas presumed to participate in the seizure activity. This finding accords with earlier studies. All nine patients studied in the interictal phase showed, either spontaneously or during activation by intermittent light, focal flow increases in areas presumed to comprise the epileptic focus. These interictal hyperemic foci probably reflect subictal neuronal hyperactivity in epileptogenic nervous tissue. Only two of the patients had distinct epileptic electroencephalographic foci. It appears that rCBF studies can be a valuable diagnostic tool in the investigation of cortical epileptogenic lesions.


Recent Advances in Nanostructured Thermoelectric Half-Heusler Compounds.
Half-Heusler (HH) alloys have attracted considerable interest as promising thermoelectric (TE) materials in the temperature range around 700 K and above, which is close to the temperature range of most industrial waste heat sources. The past few years have seen nanostructuing play an important role in significantly enhancing the TE performance of several HH alloys. In this article, we briefly review the recent progress and advances in these HH nanocomposites. We begin by presenting the structure of HH alloys and the different strategies that have been utilized for improving the TE properties of HH alloys. Next, we review the details of HH nanocomposites as obtained by different techniques. Finally, the review closes by highlighting several promising strategies for further research directions in these very promising TE materials.


Survival of Escherichia coli in two sewage treatment plants using UV irradiation and chlorination for disinfection.
We investigated the survival of Escherichia coli in two STPs utilising UV irradiation (STP-A) or chlorination (STP-B) for disinfection. In all, 370 E. coli strains isolated from raw influent sewage (IS), secondary treated effluent (STE) and effluent after the disinfection processes of both STPs were typed using a high resolution biochemical fingerprinting method and were grouped into common (C-) and single (S-) biochemical phenotypes (BPTs). In STP-A, 83 BPTs comprising 123 isolates were found in IS and STE, of which 7 BPTs survived UV irradiation. Isolates tested from the same sites of STP-B (n = 220) comprised 122 BPTs, however, only two BPTs were found post-chlorination. A representative isolate from each BPT from both STPs was tested for the presence of 11 virulence genes (VGs) associated with uropathogenic (UPEC) or intestinal pathogenic (IPEC) E. coli strains. Strains surviving UV irradiation were distributed among seven phylogenetic groups with five BPTs carrying VGs associated with either UPEC (4 BPTs) or IPEC (1 BPT). In contrast, E. coli strains found in STP-B carried no VGs. Strains from both STPs were resistant to up to 12 out of the 21 antibiotics tested but there was no significant difference between the numbers of antibiotics to which surviving strains were resistant to in these STPs. Our data suggests that some E. coli strains have a better ability to survive STPs utilising chlorination and UV irradiation for disinfection. However, strains that survive UV irradiation are more diverse and may carry more VGs than those surviving SPTs using chlorination.


Prostaglandins, renin, aldosterone, and catecholamines in preeclampsia.
Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.


Calcium channels in isolated cells and strips of longitudinal muscle of rat myometrium.
The properties of Ca2+ channels in strips and single muscle cells of longitudinal muscle of estrogen-dominated rat myometrium were studied under the effects of elevation of K+ concentration, the partial channel agonist Bay K 8644, and nitrendipine. In isolated strips in 0.5 mM Ca2+, Bay K 8644 (pD2 = 7.8-8.0) lowered the threshold for and enhanced the contractions in response to an elevation of K+ concentration, including the maximum response to K+ elevation alone. Bay K 8644 alone in concentrations up through 10(-6) M did not initiate contractions in 0.5 mM Ca2+ solutions. At higher concentrations (10(-5) M), Bay K 8644 behaved as an antagonist to contractions induced by elevation of K+. In isolated cells 10(-7) M Bay K 8644 enhanced the shortenings to elevated K+ and lowered the threshold K+ concentration required. Also no significant contraction occurred with 10(-7) M Bay K 8644 at normal K+ concentration. In contrast with its effect in isolated strips, no significant increase in maximum shortening (to 60 mM K+) was observed, possibly because cells without a mechanical load were maximally shortened by K+ alone. From these studies, we conclude that Ca2+ channels of isolated strips and cells of rat myometrium behave similarly and have similar properties to those of other smooth muscles in their interactions with elevation of K+, nitrendipine, and Bay K 8644.


Test technique for arbitrary length high dielectric sheet materials based on perturbation method.
In this article, a very effective method is proposed to measure the permittivity of sheet materials with a high dielectric constant and loss. To meet the constraints of the perturbation method, controlling the magnitude of the perturbation by reducing the sample size is necessary. However, this will cause significant changes in the polarization field within the sample and, consequently, affects the accuracy of the calculations. To solve the problem, the effects of the polarized electric field and the non-uniformity of the electric field in the resonant cavity have been considered and an empirical model is developed based on this using curve fitting techniques. Taking the optimized depolarization factor into the resonant perturbation equation, the dielectric properties of arbitrary length of the sample can be accurately calculated when the frequency shift and the quality factor variation are known. Then, the method is validated and analyzed by numerical simulations. Finally, practical tests are carried out on a variety of materials at different sizes, and the results are stable and in excellent agreement with the simulated ones. Therefore, we can conclude that the method can accurately measure the complex permittivity of high dielectric sheet materials.


The effect of intra-hippocampal injection of growth hormone on spatial learning and memory in animal model of Alzheimer's disease.
The aim of this study was to evaluate the effect of intra-hippocampal injection of Growth Hormone (GH) on impaired spatial cognition in rats with Alzheimer's Disease (AD). Growth hormone replacement therapy leading to improved cognition and well-being has mainly been carried in GH-deficient patients. Nevertheless, relatively only a few studies have investigated the function of GH in the brain. Aged Wistar male rats (350-400 g, 18-20 months old) were randomly divided into 6 groups (7 in each): Control (healthy aged); L; L + Veh; L + GH10; L + GH20 and L + GH40. Rats with AD-like cognitive deficiency was induced by injection of ibotenic acid into Nucleus Basalis of Meynert (NBM) bilaterally (5 microg 0.5 microL(-1), each side). A guide cannula was implanted in the right hippocampus under stereotaxic surgery for injection of human recombinant GH (10, 20 and 40 microg 2 microL(-1), during 5 min, twice daily, 9:00 am and 3:00 pm, for 7 days). All rats were trained in Morris water maze to evaluate the spatial learning and memory. Escape latency, traveled distance to find hidden platform and percent time spent in gaol qudrant did not differ between L and L + Veh groups, while latency and distance were reduced significantly. But percent time spent in gaol quadrant (without hidden platform) was increased significantly in NBM-lesioned rats treated with GH (L + GH groups) dose dependently to compare with vehicle treated group. These results suggest that intra-hippocampal injection of GH to aged rats with dementia type of AD (with NBM lesioned) could improve spatial cognition.


Sanctioned social violence: a psychoanalytic view. Part II.
This paper is the second in a series of two papers. In Part I, the first paper, the author reviewed the influence on the development of socially sanctioned violence of psychodynamics of group psychology and mass psychology, the regressive pull of ideologies, personality features of social and political leadership, and historical trauma and social crises. In this Part II, the author explores, from a psychoanalytic perspective, the dehumanization processes related to fundamentalist ideologies and terrorism.


[Regenerative medicine of the pancreas].
Insulin has been used generally in treatment of diabetic patients with absolute insulin deficiency since its discovery. However, while normal pancreatic beta-cells continually adjust insulin secretion in response to varying blood glucose levels, insulin administration cannot maintain blood glucose levels within a physiological range that protects from the development of various diabetic complications. It is possible to achieve normoglycemia in absolute insulin insufficiency by transplantation of pancreas or pancreatic islets, but the approach is impractical especially because of the shortage of transplantable pancreases and islets. For this reason, the transplantation of pancreatic beta-cells or islets generated from stem cells has become the more promising therapeutic approach to normoglycemia. In this article, recent progress of regenerative medicine of the pancreas is reviewed.


α-Pyrrolidinopentiophenone ("Flakka") Catalyzing Catatonia: A Case Report and Literature Review.
: Synthetic cathinones are a class of novel psychoactive substances. α-Pyrrolidinopentiophenone (α-PVP), or "Flakka", is one of these substances. Users often present acutely psychotic or agitated. We present the case of a 20-year-old male without prior psychiatric history who was brought to the hospital by his family because of increasingly bizarre and erratic behavior after reported ingestion of Flakka. What ensued was a prolonged course of psychosis and severe catatonia. Synthetic cathinones are thought to cause catatonia in approximately 1% of cases. Awareness of the possible presentations associated with α-PVP intoxication is increasingly important and should be further explored, as they can have important implications in setting expectations for care. Additionally, providers should have a low threshold for asking patients about bath salt ingestion.


Leptin and fractalkine: novel subcutaneous cytokines in burn injury.
Burn injury is a pathology underpinned by progressive and aberrant inflammation. It is a major clinical challenge to survival and quality of life. Although the complex local and disseminating pathological processes of a burn injury ultimately stem from local tissue damage, to date relatively few studies have attempted to characterise the local inflammatory mediator profile. Here, cytokine content and associated transcriptional changes were measured in rat skin for three hours immediately following induction of a scald-type (60°C, 2 min) burn injury model. Leptin (P=0.0002) and fractalkine (P=0.0478) concentrations were significantly elevated post-burn above pre-burn and control site values, coinciding with the development of burn site oedema and differential expression of leptin mRNA (P=0.0004). Further, gene sequencing enrichment analysis indicated cytokine-cytokine receptor interaction (P=1.45×10-6). Subsequent behavioural studies demonstrated that, following subcutaneous injection into the dorsum of the paw, both leptin and fractalkine induced mechanical allodynia, heat hyperalgesia and the recruitment of macrophages. This is the first report of leptin elevation specifically at the burn site, and the first report of fractalkine elevation in any tissue post-burn which, together with the functional findings, calls for exploration of the influence of these cytokines on pain, inflammation and burn wound progression. In addition, targeting these signalling molecules represents a therapeutic potential as early formative mediators of these pathological processes.


Validation and clinical application of an UHPLC method for simultaneous analysis of total homocysteine and cysteine in human plasma.
Several studies indicate that high levels of homocysteine (Hcy) and L-cysteine (L-Cys) are independent risk factors for cardiovascular disease. The validation and clinical application of an ultra HPLC method for analysis of Hcy and L-Cys is described. The reported method is simple, sensitive, rapid, precise, and less aggressive than other previously reported methods. The effect of the derivatization reaction time, pH, and organic solvent contents in the mobile phase are described and discussed. Optimized conditions resulted in excellent peak shapes. Results of method validation showed a good linearity (r(2) ≥ 0.993) over the investigated concentration ranges and were observed for both compounds. The LOD and LOQ were 0.05 μM and 0.15 μM for Hcy and 0.24 μM and 0.80 μM for L-Cys, respectively. Validation results proved that the method precision was good and the accuracy was satisfactory. This validated method was successfully applied in an epidemiological study to measure and compare the prevalence of Hcy and L-Cys high levels in plasma of Portuguese type 2 diabetic patients with and without angiopathy. The study results showed that prevalence of hyperhomocysteinemia and hypercysteinemia were at least two times higher in diabetic patients with angiopathy compared to diabetics without angiopathy.


Finding psychodynamic psychiatry's lost generation.
This paper describes forces that have adversely affected the place of the psychodynamic perspective within psychiatric practice and training over the last generation. One effect of these forces has been to create a lost generation of psychiatrists with little knowledge or experience with psychodynamic treatment. The article addresses opportunities to reverse some of the detrimental effects of recent changes. The Residency Review Committee's introduction of a requirement that residents achieve a measurable level of competence in five schools of psychotherapy represents a major opportunity to influence psychiatric training and practice. The past and present work of the Committee on Psychotherapy by Psychiatrists (COPP) is summarized, including efforts to integrate and revise the five existing core competencies in psychotherapy into a "Y"-shaped model in a way that secures the future of psychodynamic therapy training in residencies. One existing unusual training opportunity with a central psychodynamic focus is described.


Apoptosis by CD95 (Fas)-dependent and -independent mechanisms in Peyer's patch lymphocytes in murine retrovirus-induced immunodeficiency syndrome.
CD95 (Fas)/CD95 ligand (CD95 L)-mediated apoptosis is thought to be involved in the delayed progression of murine AIDS (MAIDS) induced by LP-BM5 murine leukemia virus (MuLV). We show evidence of apoptosis in lymphocytes of Peyer's patches (PP) at the early stage of MAIDS. Both T and B cells in PP expressed CD95 at the early stage of MAIDS and decreased in number thereafter. The decrease in T cells was not evident in CD95-mutated lpr mice with MAIDS, suggesting that CD95/CD95 L interaction is involved in the apoptosis of T cells in PP during the course of MAIDS. On the other hand, the number of B cells was also decreased in PP of lpr mice with MAIDS. The proliferative ability of B cells in PP of MAIDS mice in response to immunoglobulin M cross-linking or lipopolysaccharide was severely impaired, while the B cells normally proliferated in response to anti-CD40 monoclonal antibody. These findings imply that aberrantly activated B cells in PP undergo apoptosis independently of the CD95/CD95 L system during the course of infection with MAIDS virus.


Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients.
We describe a method to postlabel, in vivo, biotinylated monoclonal antibodies pretargeted onto tumor deposits when most of the non-tumor-bound antibodies have already been cleared as avidin-bound complexes. The application of this principle to tumor detection by immunoscintigraphy was tested in 20 patients with histologically documented cancer and increased circulating carcinoembryonic antigen levels. One mg of biotinylated anti-carcinoembryonic antigen monoclonal antibody (FO23C5) was administered i.v. (first step). After 3 days, 4-6 mg of cold avidin were injected i.v. (second step), followed 48 h later by 0.2-0.3 mg of a biotin derivative labeled with 111In (2-3 mCi) (third step). No evidence of toxicity was observed. Whole body radioactivity distribution was measured in five patients at various intervals postinjection by the conjugate counting technique. Tumors and metastases were detected in 18 of 19 patients (the remaining patient was a true negative) within 3 h after administration of 111In-biotin by planar or single photon emission tomography imaging. At the time of imaging, tumor/blood pool ratio was 5.5 +/- 3.2, and tumor/liver ratio was 6.7 +/- 3.9. Blood clearance of 111In-biotin was multiexponential, with the fast component having a t1/2 of 5 +/- 3 min. Urinary excretion of radioactivity over 3 h was 63.5 +/- 4.9% of the injected dose. Radioactivity at 3 h was 6.5 +/- 1.8% in blood, 1.6 +/- 0.3% in the kidney, and 2.4 +/- 0.6% in the liver. This approach represents an improvement in immunoscintigraphic techniques for tumor localization. The potential use for radioimmunotherapy is discussed.