Novel human and mouse genes encoding an acid phosphatase family member and its downregulation in W/W(V) mouse jejunum.
Interstitial cells of Cajal (ICC) are pacemakers and mediators of motor neurotransmission in gastrointestinal smooth muscles. ICC require cellular signalling via Kit, a receptor tyrosine kinase, for development and maintenance of phenotype. Much of the evidence demonstrating the functions of ICC comes from studies of W/W(V) mice, which have reduced Kit function and reductions in specific populations of ICC. The aim of the present study was to differentially examine gene expression in the small intestines of wild-type and W/W(V) mutant mice. RNA from the jejunums of wild-type and W/W(V) mutants was analysed using a differential gene display method. Eighteen queries were identified as novel genes that were differentially displayed in wild-type and W/W(V) mice. One candidate gene, encoding a novel acid phosphatase-like protein, was significantly suppressed in fed and starved W/W(V) mice. The full length clone of the murine gene and its human counterpart were designated acid phosphatase-like protein 1 (ACPL1). Human ACPL1 cDNA encodes a protein of 428 amino acids with homology to human prostatic acid phosphatase protein. This gene is located at 1q21. ACPL1 was abundantly expressed in the human small intestine and colon. Gene products were found to be cytoplasmic in transfected COS-7 cells. Reverse transcription-polymerase chain reaction analysis revealed expression of ACPL1 mRNA within single isolated ICCs. Gene analysis showed that ACPL1 was differentially expressed in the small intestines of normal and W/W(V) mice. ICC within the small intestine expressed mRNA for ACPL1. Specific downregulation of ACPL1 in the jejunums of W/W(V) mice and high expression in human intestinal tissue suggest that the ACPL1 gene could be associated with ICC function in mice and humans.


Observation of phase variation within stationary light pulses inside a cold atomic medium.
The successful formation of stationary light pulses in a cold atomic medium was demonstrated recently. However, unlike in hot media, a detuning between the counterpropagating fields had to be applied. Here we demonstrate that a significant nonuniform phase variation can be induced during a period of stationary light owing to off-resonantly driven transitions. The experimental results are in good agreement with theoretical predictions for media of low optical depth. For media of high optical depth the numerical simulations indicate that such phase variation becomes negligible. Thus stationary light based on this coupling scheme could be used for possible future applications in quantum information processing.


Nursing Students' Perceptions of Participatory Action Research.
This article evaluates the experience of students engaged in a participatory action research project. Nursing students were assigned to research activities addressing poverty and social inclusion in the lives of individuals with mental health issues. Focus group interviews were held with 25 students, representing 58.1% of eligible students. Themes and subthemes were categorized from the transcripts, with two overarching themes emerging: (a) aspects that worked well, and (b) aspects that could be improved. The range of activities students engaged in while assigned to the project and students' perceptions, both positive and negative, about their overall exposure to participatory action research are identified and discussed. Findings in the literature with regard to perceived benefits and limitations of participatory action research projects involving students are supported by those found in this study. Based on the findings of this study, curriculum development for an interdisciplinary graduate-level course is in process. [J Nurs Educ. 2018;57(5):282-286.].


Non-Linear Frequency Dependence of Neurovascular Coupling in the Cerebellar Cortex Implies Vasodilation-Vasoconstriction Competition.
Neurovascular coupling (NVC) is the process associating local cerebral blood flow (CBF) to neuronal activity (NA). Although NVC provides the basis for the blood oxygen level dependent (BOLD) effect used in functional MRI (fMRI), the relationship between NVC and NA is still unclear. Since recent studies reported cerebellar non-linearities in BOLD signals during motor tasks execution, we investigated the NVC/NA relationship using a range of input frequencies in acute mouse cerebellar slices of vermis and hemisphere. The capillary diameter increased in response to mossy fiber activation in the 6-300 Hz range, with a marked inflection around 50 Hz (vermis) and 100 Hz (hemisphere). The corresponding NA was recorded using high-density multi-electrode arrays and correlated to capillary dynamics through a computational model dissecting the main components of granular layer activity. Here, NVC is known to involve a balance between the NMDAR-NO pathway driving vasodilation and the mGluRs-20HETE pathway driving vasoconstriction. Simulations showed that the NMDAR-mediated component of NA was sufficient to explain the time course of the capillary dilation but not its non-linear frequency dependence, suggesting that the mGluRs-20HETE pathway plays a role at intermediate frequencies. These parallel control pathways imply a vasodilation-vasoconstriction competition hypothesis that could adapt local hemodynamics at the microscale bearing implications for fMRI signals interpretation.


[Assessment of nutritional status of patients candidates for lung resection by 2 methods].
It is important to determine the nutritional status of an individual that may be submitted to a surgical intervention since it has been shown a relationship between nutritional status impairments and the incidence of complications. We present the data from a study comparing two nutritional assessment methods. To study the rate of hyponutrition in patients candidates to lung resection in southern Galicia, and to determine if there were significant differences in the use of 2 different nutritional assessment methods. 200 patients participated in this study: 144 males (aged 29-83 years) and 56 females (aged 20-80 years). All of them were assessed for their nutritional status according to Chang's method and we also performed a patient-generated global subjective assessment (PG-GSA) according to the SENBA working group protocol. There is agreement between the 2 methods in assessing 122 patients as having "good nutritional status". There are two cases with agreement between both methods in the diagnosis of "moderate hyponutrition or risk for hyponutrition". No case of "severe hyponutrition" is diagnosed by the Chang's method. We found statistically significant differences between the observations obtained with the two methods. The Chang's method performed more accurately than the PG-GSA, so that we believe it should be the first choice method for the preoperative nutritional assessment of patients candidate to a lung resection.


Characterization of Mycobacterium tuberculosis LexA: recognition of a Cheo (Bacillus-type SOS) box.
The gene coding for the Mycobacterium tuberculosis homologue of LexA has been cloned and sequenced. Amino acids required for autocatalytic cleavage are conserved, whereas those important for specific DNA binding are not, when compared with Escherichia coli LexA. The transcriptional start site was mapped and a DNA sequence motif was identified which resembled the consensus Cheo box sequence involved in the regulation of DNA-damage-inducible genes in Bacillus subtilis. The M. tuberculosis-LexA protein was overexpressed in E. coli and purified by means of a His tag. The purified LexA was shown to bind to the Cheo box sequence found upstream of its own gene.


Interactions between immunogenic peptides and MHC proteins.
The MHC class-I and class-II molecules are highly polymorphic membrane proteins, which bind and transport to the surface of cells peptide fragments of intact proteins. The peptide-MHC complexes are recognized by the antigen-specific receptor of T lymphocytes and are the basis by which the cellular immune system distinguishes self from nonself. In order to perform this function, MHC proteins simultaneously display a large spectrum of structurally divergent peptides for a sufficiently long period of time for the T cell repertoire to scan the cell effectively. Consistent with the protein's biological role, the rates of association and dissociation at physiological pH are very slow relative to other known receptor-ligand interactions. The mechanism by which the proteins do this is still poorly understood, but recent experimental results indicate that the rate determining step may be a conformational change that results in the entrapment of the peptide. A variety of binding assays have been developed that allow study of the detailed kinetics and specificity of the interaction. The optimal peptide length for binding is between 8 and 12 amino acids with the central 5-7 residues contributing the majority of the specific contacts. Determining the conformation of bound peptides has been hampered by the inherent ability of the receptor to bind manifold sequences. Consequently, strategies employing monosubstituted analogs have had only limited success. Approaches using biotinylated amino acids and other bulky substituents or multiple substitutions have generated more information. Recent experiments demonstrating that peptides with polyalanine, polyproline, or polyglycine bind well to MHC proteins have proven that the structural requirements for binding are quite minimal. In fact, a significant factor of the selectivity for binding appears to be the avoidance of deleterious contacts, rather than the need for a large number of critical interactions. Binding experiments also have shown that several peptides can bind a large number of MHC class-I and class-II alleles. The degenerate binding indicated that the binding site of MHC proteins must have a significant number of conserved features. Solution of the crystal structures of the MHC class-I alleles A2 and Aw68 has identified a putative antigen-combining site whose overall dimensions were quite similar between the two structures. The detailed surface topology of the site varied between the two alleles due to the size and chemical properties of the side chains of the polymorphic amino acids composing the cleft.(ABSTRACT TRUNCATED AT 400 WORDS)


Caprine arthritis-encephalitis virus isolated from Michigan goats.
A syncytium-forming agent with reverse transcriptase activity was isolated in cell culture from materials collected from 19 Michigan goats and 1 goat recently imported from California. Syncytia formation could be maintained by subpassaging cells or filtered supernate from infected cultures with caprine fetal synovial membrane indicator cells. Electron microscopy by negative staining with ammonium molybdate revealed 100-nm retrovirus-like particles morphologically identified as caprine arthritis-encephalitis virus. The agent was recovered from synovial membrane explants, synovial fluid, colostrum cells, and peripheral blood mononuclear cells of clinically arthritic goats. Samples were collected from 9 Michigan goat herds, and virus was isolated from 7 of these herds.


Solitary fibrous tumor presenting as a symptomatic intraspinal mass: case report.
Mesenchymal, nonmeningeal tumors of the central and peripheral nervous systems are rare. Specifically, the solitary fibrous tumor, which occurs in both benign and malignant forms, was first described in the pleura and more recently in a number of sites, including the mediastinum, abdomen, upper respiratory tract, nasopharynx, and orbit. It has not, however, previously been known to involve the spine or to induce cord compression. We describe the case of a 33-year-old man who presented with back pain, progressive myelopathy, and lower extremity dysesthesias. Imaging studies demonstrated an intradural extramedullary mass at T7-T8. At surgery, the lesion was found to be firm, fibrous, intimately apposed to the T8 sensory nerve root but emanating from neither root nor dura. Histologically, the tumor was composed of spindle cells in a storiform pattern with extensive collagen deposition in the intercellular matrix. Immunohistochemistry showed diffuse positive staining of tumor cells for CD34 antigen but negative staining for S100 and EMA, a profile that is consistent with a histopathological diagnosis of solitary fibrous tumor and that effectively rules out meningioma and nerve sheath tumor. This is the first report of an intraspinal solitary fibrous tumor, a rare entity that should be included in the differential diagnosis of intradural extramedullary spinal neoplasms.


Evidence-based clinical decision making for the management of patients with periodontal osseous defect after impacted third molar extraction: A systematic review and meta-analysis.
Extraction of impacted mandibular third molar (MTM) is one of the most common procedures in clinical dental treatment; building a decision tree to perform MTM extraction can be prudent in alleviating periodontal diseases. This study is to review the latest research on the management of periodontal osseous defect (POD) after MTM extraction and rebuild a new clinical decision tree. Current study was conducted according to PRISMA statement. Medline, Embase, Scopus, and Google Scholar were searched concerning treatment of MTM extraction up to Oct.2019. Three focused questions revolving around asymptomatic versus disease site, age, and necessity of ridge preservation after >6 months follow up will be answered. A total of 7 studies were included for meta-analysis. Evidences were inadequate in regards to asymptomatic vs disease site of MTM extraction in the long-term follow-up. For patients with age <25 years, postoperative probing depth (PD) always remained at < 4 mm. However, for patients with age >25 years with initial PD > 7 mm, residual pockets still remained at 5 mm. For ridge preservation, significant positive effect in reduction of second molar distal site PD was observed, regardless of different biomaterials being placed (z = 4.69, p < 0.00001). Age is of utmost importance in preoperative evaluation during impacted MTM extraction. The timing for ridge preservation is essential determinant for achieving optimal treatment outcome. The clinical decision tree as proposed could serve as guidance when dealing with POD after impacted MTM extraction.


Clinical, clinicopathologic, radiographic, and ultrasonographic characteristics of intestinal lymphangiectasia in dogs: 17 cases (1996-1998).
To characterize the clinical, clinicopathologic, and imaging findings in dogs with intestinal lymphangiectasia and to compare the histologic grade of lymphangiectasia with clinicopathologic and imaging abnormalities. Retrospective study. 17 dogs with a histologic diagnosis of intestinal lymphangiectasia. Medical records of dogs with a histologic diagnosis of intestinal lymphangiectasia were reviewed for signalment, history, clinical signs, results of exploratory laparotomy, and clinicopathologic, radiographic, ultrasonographic, and histologic findings. Mean age of dogs was 8.3 years; the most common clinical signs were diarrhea, anorexia, lethargy, vomiting, and weight loss. Abnormal physical examination findings included dehydration, ascites, and signs of pain on palpation of the abdomen. The most notable clinicopathologic findings were low serum ionized calcium concentration and hypoalbuminemia. Abdominal ultrasonography was performed in 12 dogs and revealed intestinal abnormalities in 8 dogs and peritoneal effusion in 7 dogs. Exploratory laparotomy revealed abnormalities in 9 of 16 dogs including thickened small intestine, dilated lacteals, lymphadenopathy, and adhesions. On histologic examination of the small intestine, concurrent inflammation was observed in 15 of 17 dogs, crypt ectasia in 5 of 17, and lipogranulomas in 2 of 17. Intestinal lymphangiectasia in dogs appears to be a heterogeneous disorder characterized by various degrees of panhypoproteinemia, hypocholesterolemia, lymphocytopenia, and imaging abnormalities. In most dogs, the severity of hypoalbuminemia appears to offer the best correlation with severity of histologic lesions of lymphangiectasia. Imaging abnormalities are common in dogs with intestinal lymphangiectasia but are not specific enough to differentiate this disorder from other gastrointestinal disorders, nor are they predictive of histologic severity.


Freedom from local and regional failure of contralateral neck with ipsilateral neck radiotherapy for node-positive tonsil cancer: updated results of an institutional clinical management approach.
To update the outcomes of an institutional clinical management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion. Between August 2003 and April 2014, 61 consecutive patients with ipsilateral node-positive squamous cell carcinoma of the tonsil without involvement of the base of the tongue or midline soft palate were treated at a community hospital-based cancer center with radiotherapy to the primary site and ipsilateral neck. Overall survival, disease-free survival and freedom from contralateral failure were calculated. Median follow up was 37.2months (range 4-121months). Freedom from contralateral nodal failure at 5years was 98% with one contralateral nodal failure noted. The patient underwent a salvage neck dissection and was treated with post-operative radiotherapy with no evidence of disease to date. 5-year overall survival (OS) was 92.4% and 5year disease-free survival (DFS) was 86.7%. This represents the single largest series reported from a community hospital-based cancer center in which lateralized tonsil cancers with N+ disease were treated with ipsilateral neck radiotherapy. In this carefully selected cohort of patients with well-lateralized tonsil cancers, the risk of contralateral nodal failure appears to be <5%, suggesting that prophylactic radiation of the contralateral neck may not be necessary. Future planned studies will focus on prospectively selecting subgroups of patients eligible for treatment de-intensification as survivorship issues in excellent prognosis HPV positive patients are increasingly becoming relevant.


A risk stratification scheme for synchronous oligometastatic non-small cell lung cancer developed by a multicentre analysis.
Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan - Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29-53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00-1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45-1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 - 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21-3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease.


Leptin improves osteoblast differentiation of human bone marrow stroma stem cells.
To study the effects of leptin (LEP) on the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and to explore the mechanism controlling the process. Respectively cultivated the third-generation hBMSCs with 100 ng/ml bone morphogenetic protein (BMP) culture media containing 320, 160, 80 and 40 ng/mL LEP, and regular medium. We administered alkaline phosphatase (ALP) dye (on the 7th day) and mineralized nodules alizarin red (on the 21st day) and tested the ALP activity as well as osteocalcin (OCN) level on 7th, 14th, 21st day in each group to establish the best inducing concentration of LEP. 7 days later, we tested bone differentiation related genes expression in the control, 160 ng/mL LEP and 100 ng/mL BMP groups using RT-PCR. The activity of ALP and OCN in the 160 ng/mL LEP group after 7, 14 and 21 days was lower than that of the BMP group but higher than that of other groups. However, LEP significantly promoted the expression of bone differentiation related genes, namely, Cbfal, ALP, COL-I and OCN. LEP promoted the bone differentiation in hBMSCs by promoting the expression of genes related to bone differentiation.


Cyclodextrin Inclusion Complexes with Antibiotics and Antibacterial Agents as Drug-Delivery Systems-A Pharmaceutical Perspective.
Cyclodextrins (CDs) are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits linked by α-1,4 glycosidic bonds. The shape of CD molecules is similar to a truncated cone with a hydrophobic inner cavity and a hydrophilic surface, which allows the formation of inclusion complexes with various molecules. This review article summarises over 200 reports published by the end of 2021 that discuss the complexation of CDs with antibiotics and antibacterial agents, including beta-lactams, tetracyclines, quinolones, macrolides, aminoglycosides, glycopeptides, polypeptides, nitroimidazoles, and oxazolidinones. The review focuses on drug-delivery applications such as improving solubility, modifying the drug-release profile, slowing down the degradation of the drug, improving biological membrane permeability, and enhancing antimicrobial activity. In addition to simple drug/CD combinations, ternary systems with additional auxiliary substances have been described, as well as more sophisticated drug-delivery systems including nanosponges, nanofibres, nanoparticles, microparticles, liposomes, hydrogels, and macromolecules. Depending on the desired properties of the drug product, an accelerated or prolonged dissolution profile can be achieved when combining CD with antibiotics or antimicrobial agents.


Persistent High Percentage of HLA-DR+CD38high CD8+ T Cells Associated With Immune Disorder and Disease Severity of COVID-19.
The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection. A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. We revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. Our findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.


Tissue-specific accumulation of latency-associated transcripts in herpes virus-infected rabbits.
Herpes simplex virus (HSV) DNA persists in the corneas of patients and animals with a history of herpetic keratitis. The purpose of this study was to detect viral transcripts in the corneas of latently infected rabbits with a history of herpetic keratitis to determine whether the viral DNA represents latent virus, characterized by the restricted transcription of HSV genes and accumulation of the stable latency-associated transcripts (LATs), as occurs in neurons. Rabbits were injected in the subalveolar mucosa with HSV strain RE. After 30 days, corneas were infected by intrastromal injection of HSV. Corneal disease was evaluated, and 7 to 378 days after infection, the rabbits were killed. DNA and RNA were isolated from corneas and trigeminal ganglia and amplified by PCR using gene-specific primers. Herpetic keratitis developed in all rabbits. All corneas of these immune rabbits contained viral DNA as many as 120 days after infection and then the frequency decreased over the next 260 days. Overall, viral DNA was detected in all ganglia and in 57% of corneas. All latently infected ganglia but no corneas contained LATs. Transcripts of the early viral gene for thymidine kinase were detected in 23 of 30 ganglia and 10 of 17 corneas. Transcripts for the late viral glycoprotein C were not detected in either tissue. These data document that after HSV keratitis, viral DNA persists in corneas in the absence of stable LATs and with restricted expression of other viral genes.


All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases.
Mucin-type linkages (GalNAcalpha1-O-Ser/Thr) are initiated by a family of glycosyltransferases known as the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferases (ppGaNTases, EC 220.127.116.11). These enzymes transfer GalNAc from the sugar donor UDP-GalNAc to serine and threonine residues, forming an alpha anomeric linkage. Despite the seeming simplicity of ppGaNTase catalytic function, it is estimated on the basis of in silico analysis that there are 24 unique ppGaNTase human genes. ppGaNTase isoforms display tissue-specific expression in adult mammals as well as unique spatial and temporal patterns of expression during murine development. In vitro assays suggest that a subset of the ppGaNTases have overlapping substrate specificities, but at least two ppGaNTases (ppGaNTase-T7 and -T9 [now designated -T10]) appear to require the prior addition of GalNAc to a synthetic peptide before they can catalyze sugar transfer to this substrate. Site-specific O-glycosylation by several ppGaNTases is influenced by the position and structure of previously added O-glycans. Collectively, these observations argue in favor of a hierarchical addition of core GalNAc residues to the apomucin. Various forms of O-glycan pathobiology may be reexamined in light of the existence of an extensive ppGaNTase family of enzymes. Recent work has demonstrated that at least one ppGaNTase isoform is required for normal development in Drosophila melanogaster. Structural insights will no doubt lead to the development of isoform-specific inhibitors. Such tools will prove valuable to furthering our understanding of the functional roles played by O-glycans.


Optical model analyses of heavy ion fragmentation in hydrogen targets.
Quantum-mechanical optical-model methods for calculating cross sections for the fragmentation of high-energy heavy ions by hydrogen targets are presented. The cross sections are calculated with a knockout-ablation collision formalism which has no arbitrary fitting parameters. Predictions of elemental production cross sections from the fragmentation of 1.2A GeV 139La nuclei and of isotope production cross sections from the fragmentation of 400A MeV 32S nuclei are in good agreement with recently reported experimental measurements.


Measurement of flecainide acetate in human plasma by an extraction spectrophotofluorometric method.
A fluorometric method for the quantitation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (R-818, flecainide acetate) in human plasma has been developed. The minimum quantifiable concentration of flecainide acetate by this method is 25 ng/ml with a 2 ml plasma sample; a slightly modified procedure which also requires the use of a microcell in the spectrophotofluorometer further increases the maximum sensitivity to 12.5 ng/ml. The precision, expressed as relative standard deviation is 2.9, 0.7, 5.6, 3.5, and 4.3% for 75, 150, 250, 500, and 700 ng flecainide acetate/ml, respectively. The accuracy, expressed as relative error, is -6.7, -3.3, -0.4, +4.4, and -0.4%, respectively, for the corresponding concentrations specified above. The relative standard deviations for the inter-day variation are 19, 7, 9, 9, 8, 10, 13, 12, and 9% for the 25, 50, 100, 200, 300, 400, 600, 800, and 1000 ng/ml standards, respectively. Preliminary data indicate that propranolol and quinidine interfere with this method while procainamide, disopyramide, hydralazine, methyldopa, diazepam, hydrochlorothiazide, and sulfinpyrazone exhibit little or no interference. The results of the analyses of clinical samples by the fluorometric method agree well with an established GLC method. Thus, the quality of the fluorometric method is considered adequate for estimating plasma flecainide acetate levels during drug therapy in most non-research settings, if careful consideration is given to possible interference by other drugs.


Nuclear localization of phosphatidylinositol 4-kinase beta.
Whereas most phosphatidylinositol 4-kinase (PtdIns 4-kinase) activity is localized in the cytoplasm, PtdIns 4-kinase activity has also been detected in membrane-depleted nuclei of rat liver and mouse NIH 3T3 cells. Here we have characterized the PtdIns 4-kinase that is present in nuclei from NIH 3T3 cells. Both type II and type III PtdIns 4-kinase activity were observed in the detergent-insoluble fraction of NIH 3T3 cells. Dissection of this fraction into cytoplasmic actin filaments and nuclear lamina-pore complexes revealed that the actin filament fraction contains solely type II PtdIns 4-kinase, whereas lamina-pore complexes contain type III PtdIns 4-kinase activity. Using specific antibodies, the nuclear PtdIns 4-kinase was identified as PtdIns 4-kinase beta. Inhibition of nuclear export by leptomycin B resulted in an accumulation of PtdIns 4-kinase beta in the nucleus. These data demonstrate that PtdIns 4-kinase beta is present in the nuclei of NIH 3T3 fibroblasts, suggesting a specific function for this kinase in nuclear processes.


Detection of disulfide bonds in bovine brain tubulin and their role in protein folding and microtubule assembly in vitro: a novel disulfide detection approach.
Cysteine residues in tubulin are actively involved in regulating ligand interactions and microtubule formation both in vivo and in vitro. These cysteine residues are sensitive reporters in determining the conformation of tubulin. Although some of the cysteines are critical in modulating drug binding and microtubule assembly, it is not clear how many of these normally exist as disulfides. The controversy regarding the disulfide bonds led us to develop a disulfide detection assay to reexamine the presence of the disulfide linkages in purified alphabeta tubulin and explore their possible biological functions in vitro. The accessible cysteine residues in alphabeta tubulin were alkylated with an excess of iodoacetamide to prevent artifactual generation of disulfide linkages in tubulin. After removal of excess iodoacetamide, tubulin was unfolded in 8 M urea. Half of the unfolded tubulin was treated with dithiothreitol to reduce any disulfide bonds present. The aliquots were then treated with iodo[(14)C]acetamide and the incorporation of radioactivity was measured. We also used the same approach to detect the disulfide linkages in the tubulin in a whole-cell extract. We found in both cases that the samples which were not treated with dithiothreitol had little or no incorporation of iodo[(14)C]acetamide, while the others that were treated with dithiothreitol had significant amounts of (14)C incorporation into tubulin. Moreover, the reduction of the disulfide linkages in tubulin resulted in inhibition of microtubule assembly (29-54%) and markedly affected refolding of the tubulin from both an intermediate and a completely unfolded state. All these data therefore suggest that tubulin has intrachain disulfide bonds in the alpha- and beta-subunits and that these disulfides assist in correct refolding of tubulin from the intermediate unfolded state or help to recover the hydrophobic domains from the completely unfolded state. These disulfides also regulate microtubule assembly and the stability of tubulin in vitro. Our results suggest that tubulin disulfides may play a role in tubulin folding and that thiol-disulfide exchange in tubulin could be a key regulator in microtubule assembly and dynamics of tubulin in vivo.


A Delightful Trip Along the Pathway of Cannabinoid and Endocannabinoid Chemistry and Pharmacology.
After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Two plant cannabinoids, Δ9-tetrahydrocannabinol and cannabidiol, are approved drugs. However, the endogenous cannabinoids and the anandamide-like constituents have not yet been well investigated in humans. For me, intellectual freedom-the ability to do research based on my own scientific interests-has been the most satisfying part of my working life. Looking back over the 91 years of my long life, I conclude that I have been lucky, very lucky, both personally and scientifically.


Mortality rates among early-stage hormone receptor-positive breast cancer patients: a population-based cohort study in Denmark.
Indications for adjuvant endocrine treatment of breast cancer have gradually increased over the past several years. We aimed to define subgroups of patients who may or may not benefit from adjuvant endocrine therapy. A population-based cohort of systemically untreated breast cancer patients (N = 3197) were identified within the registry of the Danish Breast Cancer Cooperative Group (DBCG). The patients were node negative and had estrogen receptor-positive and/or progesterone receptor-positive tumors (except medullary tumors) and were further characterized by the following risk factors: aged 35-74 years (grouped into 5-year categories) at surgery, tumor size (≤20 mm), and histopathology (grade 1 ductal carcinoma, grade 1 or 2 invasive lobular carcinoma, other or unknown histopathology). Standardized mortality ratios (SMRs) were calculated based on the mortality rate (observed number of deaths per 100,000 person-years) among patients relative to the mortality rate in the general population of women (expected number of deaths per 100,000 person-years). The association between standardized mortality ratio and risk factors were analyzed in univariate and multivariable Poisson regression models. All findings were validated in a subsequent DBCG cohort of breast cancer patients (N = 2710). The median follow-up after surgery was 14.8 years. In the study population there were 970 deaths compared with expected death of 737 women, which was an excess mortality of 233 deaths (SMR = 1.32, 95% CI = 1.24 to 1.40). Mortality rates were 2356 per 100,000 person-years in the study population and 1790 per 100,000 person-years in the general population of women. The mortality rate was associated with larger tumor size (11-20 mm tumors vs 1-10 mm tumors, SMR = 1.42, 95% confidence interval [CI] = 1.31 to 1.53 vs. SMR = 1.12, 95% CI = 1.00 to 1.26). The mortality rate was also associated with age (35-59 years, SMR > 1) compared with that in the general population of age-matched women, except for a small subgroup of patients (aged 60-74 years, tumors ≤10 mm, grade 1 ductal carcinoma, and grade 1 or 2 lobular carcinoma: adjusted relative risk = 1.02, 95% CI = 0.89 to 1.16.). A small subgroup of breast cancer patients who were 60 years or older and had hormone-responsive early-stage tumors up to 10 mm, and received no systemic adjuvant therapy, were not at increased risk of mortality compared with women in this age-group in the general population.


Staphylococcal phosphoenolpyruvate-dependent phosphotransferase system. Purification and protein sequencing of the Staphylococcus carnosus histidine-containing protein, and cloning and DNA sequencing of the ptsH gene.
The histidine-containing protein (HPr) of the bacterial phosphoenolpyruvate-dependent phosphotransferase system (PTS) was isolated from Staphylococcus carnosus and purified to homogeneity. The protein sequence was determined by Edman degradation of peptides obtained by proteolytic digestion with proteases V8, trypsin and chemical cleavage with BrCN. Furthermore, immunological screening of a chromosomal S. carnosus DNA gene library in pUC19 vector enabled us to isolate S. carnosus HPr-expressing colonies. The nucleotide sequence of this ptsH gene and its flanking regions was determined by the dideoxy-chain-termination technique. Upstream, the 264-bp open reading frame of the ptsH gene is flanked by a putative S. carnosus promoter structure and a putative ptsI gene downstream suggesting that ptsH gene is the first gene in the PTS operon of S. carnosus. Comparison of the amino acid sequence of S. carnosus HPr with the HPr sequence of Staphylococcus aureus (derived from peptide sequencing) showed a high degree of similarity.


The geriatric assessment.
The geriatric assessment is a multidimensional, multidisciplinary assessment designed to evaluate an older person's functional ability, physical health, cognition and mental health, and socioenvironmental circumstances. It is usually initiated when the physician identifies a potential problem. Specific elements of physical health that are evaluated include nutrition, vision, hearing, fecal and urinary continence, and balance. The geriatric assessment aids in the diagnosis of medical conditions; development of treatment and follow-up plans; coordination of management of care; and evaluation of long-term care needs and optimal placement. The geriatric assessment differs from a standard medical evaluation by including nonmedical domains; by emphasizing functional capacity and quality of life; and, often, by incorporating a multidisciplinary team. It usually yields a more complete and relevant list of medical problems, functional problems, and psychosocial issues. Well-validated tools and survey instruments for evaluating activities of daily living, hearing, fecal and urinary continence, balance, and cognition are an important part of the geriatric assessment. Because of the demands of a busy clinical practice, most geriatric assessments tend to be less comprehensive and more problem-directed. When multiple concerns are presented, the use of a "rolling" assessment over several visits should be considered. Academy of Family Physicians.


Changing difficulty level in a one-dimensional tracking task and corresponding heart rate changes.
Subjects were required to track a target consisting of two vertical bars moving with either a constant or a sinusoidally modulated speed across an oscilloscope screen with a joystick-controlled light-spot. Either target size (distance between bars-size guided tasks) or velocity of the target movement (velocity guided tasks), varied throughout different tasks determined by subject's performance. The target's initial movement period was either 2 or 3 seconds. The following parameters were studied: time on-target intervals, time off-target intervals, number of tracking errors, heart rate and tracking error incidence over the cardiac cycle. Time on-target intervals were longer for the velocity guided tasks than for the size guided ones. The same was true for time off-target intervals. Values for both types of intervals decreased gradually over the fixed sequence of tasks for velocity but not for size guided tasks. Heart rate was higher in the size guided task. Tracking error incidence did not depend on the phase of cardiac cycle.


Digital holographic microscopy: a noninvasive contrast imaging technique allowing quantitative visualization of living cells with subwavelength axial accuracy.
We have developed a digital holographic microscope (DHM), in a transmission mode, especially dedicated to the quantitative visualization of phase objects such as living cells. The method is based on an original numerical algorithm presented in detail elsewhere [Cuche et al., Appl. Opt. 38, 6994 (1999)]. DHM images of living cells in culture are shown for what is to our knowledge the first time. They represent the distribution of the optical path length over the cell, which has been measured with subwavelength accuracy. These DHM images are compared with those obtained by use of the widely used phase contrast and Nomarski differential interference contrast techniques.


[Regulation of the cycle of phospholipid turnover in hamster fibroblasts transformed by v-src and N-ras oncogenes].
The phospholipid turnover has been studied in two lines of golden hamster cells: in cells transformed by the Rous sarcoma virus (line HET-SR) and in cells additionally transfected with the activated oncogene N-ras (line HET-SR-N-ras, clone 6). It has been found that HET-SR cells are distinguished by a high level of phosphatidylcholine turnover and a relatively low level of phosphoinositide turnover. Transfection of cells with the activated N-ras (line HET-SR-N-ras) leads to the inhibition of phosphatidylcholine synthesis and activation of phosphoinositide metabolism. Both cell lines preserve their sensitivity to serum growth factors stimulating the rate of phospholipid turnover. In both cell lines dexamethasone decreases the rate of DNA synthesis and inhibits the phosphatidylcholine and phosphoinositide turnover. At the same time, dexamethasone does not influence the predominant activation of phosphatidylcholine synthesis in HET-SR cells or the activation of phosphoinositide synthesis characteristic of HET-SR-N-ras cells. The data obtained suggest that the transmission of the mitogenic signal from growth factor in HET-SR and HET-SR-N-ras cells occurs via the activation of the phospholipid turnover and is controlled by steroid hormones. The role of v-src and N-ras oncogens in the transmission of the mitogenic signal seems to be insignificant; their activity is not controlled by dexamethasone.


Comprehensive Characterization of Polymeric Composites Reinforced with Silica Microparticles Using Leftover Materials of Fused Filament Fabrication 3D Printing.
Silica exhibits properties such that its addition into polymeric materials can result in an enhanced overall quality and improved characteristics and as a result silica has been widely used as a filler material for improving the rheological properties of polymeric materials. The usage of polymers in three-dimensional printing technology has grown exponentially, which has increased the amount of waste produced during this process. Several polymers, such as polypropylene (PP), polyvinyl alcohol (PVA), polylactic acid (PLA), and nylon, are applied in this emerging technology. In this study, the effect of the addition of silica as a filler on the mechanical, thermal, and bulk density properties of the composites prepared from the aforementioned polymeric waste was studied. In addition, the morphology of the composite materials was characterized via scanning electron microscopy. The composite samples were prepared with various silica concentrations using a twin extruder followed by hot compression. Generally, the addition of silica increased the tensile strength of the polymers. For instance, the tensile strength of PVA with 5 wt% filler increased by 76 MPa, whereas those of PP and PLA with 10 wt% filler increased by 7.15 and 121.03 MPa, respectively. The crystallinity of the prepared composite samples ranged from 14% to 35%, which is expected in a composite system. Morphological analysis revealed the random dispersion of silica particles and agglomerate formation at high silica concentrations. The bulk density of the samples decreased with increased amount of filler addition. The addition of silica influenced the changes in the characteristics of the polymeric materials. Furthermore, the properties presented in this study can be used to further study the engineering design, transportation, and production processes, promoting the recycling and reuse of such waste in the same technology with the desired properties.


Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immunoregulation combined with Reg protein treatment.
Oral linomide, (quinoline-3-carboxamide), has been shown to prevent autoimmune insulitis, islet destruction, and diabetes in NOD mice treated at an early stage of the disease, but confers only partial protection in animals with advanced disease. Reg protein, the gene product of a complementary DNA isolated from a regenerating rat islet library, has been previously shown to induce expansion of beta-cell mass in pancreatectomized rats. To determine the effect of treatment combining immunomodulation and Reg protein on advanced autoimmune diabetes, we treated female NOD mice with oral linomide and i.p. Reg protein injections. In 14-week-old animals with less severe disease (glucose tolerant), treatment with each agent alone resulted in amelioration of diabetes, as did treatment with Reg alone in 5-week-old prediabetic mice. In 14-week-old animals with more severe disease (glucose intolerant), only treatment with the combination of both agents, but not that with each separately, resulted in amelioration of diabetes. Our study suggests that treatment aimed at abrogation of autoimmunity combined with expansion of beta-cell mass constitutes a potential therapeutic approach for treatment of insulin-dependent diabetes mellitus.


Effects of acute cytomegalovirus infection on rat islet allograft survival.
Transplantation of pancreatic islets is a promising therapy for the treatment of type 1 diabetes mellitus. However, long-term islet graft survival rates are still unsatisfactory low. In this study we investigated the role of cytomegalovirus (CMV) in islet allograft failure. STZ-diabetic rats received an allogenic islet graft in combination with either an acute CMV infection or control infection. A third group received ganciclovir treatment in addition to the CMV infection. Graft function was assessed by measuring basal blood glucose levels. After sacrifice, the islet grafts were retrieved for analysis of infection and leukocyte infiltration. CMV-infected recipients demonstrated accelerated islet graft failure compared to noninfected controls. CMV infection of the graft was only observed prior to complete graft failure. Quantification of the leukocyte infiltration demonstrated increased CD8(+) T-cell and NK cell infiltration in the CMV-infected grafts compared to the controls. This suggests that CMV infection accelerates immune-mediated graft destruction. Antiviral ganciclovir treatment did not prevent accelerated graft failure, despite effectively decreasing the grade of infection. Our data confirm the recently published CITR data, which state that CMV is an independent risk factor for failure of islet grafts. Also, our data demonstrate that new approaches for preventing virus-induced islet allograft failure may be required.


The attitudes, knowledge and beliefs of Arab parents in Kuwait about stuttering.
An Arabic version of the Public Opinion Survey of Human Attributes Inventory [POSHA-E; St Louis, K. O. (2005), a global instrument to measure public attitudes about stuttering. (The ASHA Leader, 22, 2-13)] was administered to 424 Arab parents of preschool and school age children in 18 government schools across all six governorates in Kuwait. The survey questions pertained to and investigated attitudes, knowledge and beliefs towards stuttering as well as comparative attitudes toward several other conditions. The aim was to identify whether potential barriers existed that might hinder the establishment and conduct of treatment programs for stuttering within Kuwait. These potential barriers might be negative stereotypes, misconceptions about stuttering, cultural beliefs as well as lack of awareness of the disorder within Kuwaiti society. The instrument successfully sampled a variety of beliefs, reactions and emotions that identified cultural beliefs, societal ignorance and confusion about the disorder. It was found that although stuttering appears to be a disorder that most people in Kuwait are aware of and familiar with, their level of knowledge about stuttering in general and about some specific aspects of the disorder was limited. This indicates a need to disseminate scientific information about stuttering in Kuwait and possibly other Arabic speaking countries. Readers will be able: (1) to evaluate the status of speech-language pathology in Kuwait and the Middle East and compare it to that in other countries, such as Australia and the United States; (2) to list similarities in the stereotypes and attitudes towards stuttering cross-culturally. Readers will also be able to: (3) discuss the differences in knowledge and attitudes according to age, gender and educational level in Kuwait; (4) discuss public awareness and knowledge of stuttering among Arabs in Kuwait specifically.


Classical MHC class I genes composed of highly divergent sequence lineages share a single locus in rainbow trout (Oncorhynchus mykiss).
The classical MHC class I genes have been known to be highly polymorphic in various vertebrates. To date, putative allelic sequences of the classical MHC class I genes in teleost fish have been reported in several studies. However, the establishment of their allelic status has been hampered in most cases by the lack of appropriate genomic information. In the present study, using heterozygous and homozygous fish, we obtained classical-type MHC class I sequences of rainbow trout (Oncorhynchus mykiss) and investigated their allelic relationship by gene amplification and Southern and Northern hybridization analyses. The results indicated that all MHC class I sequences we obtained were derived from a single locus. Based on this, a unique polymorphic nature of the MHC class I locus of rainbow trout has been revealed. The mosaic combination of highly divergent ancient sequences in the peptide-binding domains is notable, and the variable nature around the boundary between the alpha3 and transmembrane domains is unprecedented.


Towards an evolutionary theory of the origin of life based on kinetics and thermodynamics.
A sudden transition in a system from an inanimate state to the living state-defined on the basis of present day living organisms-would constitute a highly unlikely event hardly predictable from physical laws. From this uncontroversial idea, a self-consistent representation of the origin of life process is built up, which is based on the possibility of a series of intermediate stages. This approach requires a particular kind of stability for these stages-dynamic kinetic stability (DKS)-which is not usually observed in regular chemistry, and which is reflected in the persistence of entities capable of self-reproduction. The necessary connection of this kinetic behaviour with far-from-equilibrium thermodynamic conditions is emphasized and this leads to an evolutionary view for the origin of life in which multiplying entities must be associated with the dissipation of free energy. Any kind of entity involved in this process has to pay the energetic cost of irreversibility, but, by doing so, the contingent emergence of new functions is made feasible. The consequences of these views on the studies of processes by which life can emerge are inferred.


Evening electronic device use and sleep patterns in athletes.
The present study aimed to investigate pre-sleep behaviours (including evening electronic device use) and sleep quantity in well-trained athletes. Seventy well-trained athletes (44 females, 26 males) aged 21 ± 4 y from a range of team and individual sports were asked to complete an online sleep diary for 7 days. The sleep diary included questions about pre-sleep behaviours (e.g. napping, caffeine intake), electronic device use in the 2 h prior to bedtime (e.g. type of device and duration of use) and sleep (e.g. time in bed, sleep onset latency). On average, athletes spent 8:20 ± 1:21 h in bed each night. Associations between age, time in bed and sleepiness suggested that younger athletes spent more time in bed (B = -0.05, p = 0.001) but felt sleepier (r = -0.32, p < 0.01) than older athletes. On average, athletes mostly used electronic devices for 0-30 min prior to sleep. The use of multiple devices in the evening was associated with more perceived difficulty in falling asleep (B = 0.22, p = 0.03), but no associations existed with other sleep variables. In summary, younger athletes may require later start times or improved sleep quality to resolve excessive sleepiness.


Expression of a Xenopus counterpart of mammalian syndecan 2 during embryogenesis.
We have identified a Xenopus cDNA, XS-2, by screening a Xenopus embryonic stage-22-24 cDNA library with a DNA probe encoding the transmembrane and cytoplasmic domains of mouse syndecan 1. The 1.4 kb cDNA consists of an open reading frame of 642 nucleotides encoding a protein of 191 amino acids. The predicted protein of 20869 Da contains a 25-amino acid putative transmembrane domain and a 32-amino acid putative cytoplasmic domain, both of which are highly similar to the corresponding regions of rat syndecan 2 (92% identity) and to a lesser degree those of rat syndecans 1, 3 and 4 (62, 64 and 78% respectively). The putative N-terminal ectodomain contains a possible attachment site for heparan sulphate, identical with the comparable glycosaminoglycan-attachment sequence of rat syndecan 2. Polyclonal antisera raised against recombinant ectodomain of XS-2, expressed as a fusion protein, recognized a heparan sulphate proteoglycan in XTC cell-culture medium. This proteoglycan bound to DEAE-Sephacel and was eluted with 1 M NaCl; digestion with heparitinase but not chondroitinase ABC resulted in the identification of a 46 kDa protein by these antisera. Northern-blot analysis indicated that XS-2 identifies two Xenopus mRNA species approx. 4 and 2 kb in size in embryos ranging in maturation from the 64-cell stage to stage 54. These results demonstrate that a heparan sulphate proteoglycan, similar to syndecan 2, is expressed during Xenopus embryogenesis.


Lower Trapezius Flap for Reconstruction of Posterior Scalp and Neck Defects after Complex Occipital-Cervical Surgeries.
Objectives To review the indications, techniques, and outcomes for a series of patients in whom the lower trapezius flaps was used for repair of complex posterior scalp and neck defects after posterior occipital-cervical surgeries. Design Retrospective case series. Setting Tertiary academic hospital. Participants A retrospective review of cases that required complex occipital-cervical repair was performed to identify patients who underwent reconstruction using the lower trapezius flap. Data collected included demographics, clinical presentations, surgical anatomy, operative techniques, and outcomes with review of the pertinent literature. Outcomes Nine patients who underwent reconstruction using the lower trapezius flap were identified. Prior surgical interventions included five complex tumor resections, two patients with multiple instrumented cervical spine surgeries, one patient with a craniotomy for attempted extracranial to intracranial arterial bypass for a basilar aneurysm repair, and a posterior occipital-cervical decompression after trauma. During the median follow-up period of 7 months, all nine single-stage reconstructions resulted in successful healing without major surgical complications. Conclusion Lower trapezius island flaps provide a reliable option for the reconstruction of complex scalp and neck defects that develop after complex occipital-cervical surgeries.


Psychometric properties of the Pre-Sleep Arousal Scale in a large community sample.
The purpose was to examine the psychometric properties of the Pre-Sleep Arousal Scale. From a randomly selected sample of the general population (N=5000), 2327 participants completed a survey on nighttime symptoms, daytime symptoms, health outcomes, and psychological processes. The study sample consisted of 1890 participants who did not fulfill criteria for a sleep disorder other than insomnia. Findings indicated that the PSAS did not produce an adequate factorial solution. When three problematic items were removed, the solution, accounting for 48.5% of the variance, improved (PSAS-13). One subscale, cognitive arousal (α=.88), consisted of five items (37.1%), and one subscale, somatic arousal (α=.72), of eight items (11.4%). The two factors were significantly inter-correlated (ρ=.51) and associated with the PSAS-13 (ρ=.91, ρ=.80). Among those with insomnia, a shortened PSAS (PSAS-14) was established, which consisted of a cognitive and a somatic subscale (48.6% of the variance). The PSAS-13 and the two subscales showed discriminant validity between three sleep groups (normal sleep, poor sleep, and insomnia disorder) (R(2)=.24-.34). The PSAS-13 and the subscales demonstrated convergent validity with measures on sleep-related worry, sleep-related beliefs, anxiety, and depression. The PSAS-13 and the two subscales were significantly correlated with sleep parameters and daytime impairment. Though acceptable psychometric properties were established for the PSAS, the cognitive subscale's focus upon general pre-sleep arousal and the relatively low variance accounted for calls for further work on and a possible re-conceptualization of the PSAS.


Ultrasound diagnosis of the small intestinal adenomyoma in children.
Adenomyoma is an exceptionally rare hamartoma in the small intestine. Few data have been reported on the features of this rare disease. The aim of this study was to describe the ultrasound (US) characteristics of small intestinal adenomyomas. Material and methods: This retrospective study analyzed the clinical features and US data of 15 pediatric patients diagnosed as small intestinal adenomyomas in the age range between 1 day to 12 years in our hospital during 2014-2021. The clinical manifestations of all the small intestinal adenomyomas were abdominal pain, vomiting or/and hemafecia. The small intestinal adenomyoma usually acted as the lead point of secondary intussusception. They were identified in the ileum (n=11), jejunum (n=2), and Meckel's diverticulum (n=2). The diagnostic accuracy (the concordance rate between US diagnosis and pathological diagnosis) of small intestinal adenomyoma was 73.3%. The small intestinal adenomyoma had approximately 1.0-3.0 cm, were typically located in the submucosal region, had the basal part wide and without a pedicle, and its boundaries were clear. The mass protruded into the intestinal cavity, and showed oval hypoechoic polycystic echo nodules, containing multiple small quasi-circular or irregular cysts of different sizes surrounded by solid hypoechoic mosaic areas. The color Doppler US showed in the solid hypoechoic areas of the mass abundant or sparse blood flow signals.Conclusions The US findings of small intestinal adenomyomas in children are characteristic, and US is valuable in the identification of intestinal adenomyomas in children.


Coping trajectories in emerging adulthood: The influence of temperament and gender.
The study of coping has far-reaching implications for understanding psychopathology and resilience, as well as for the treatment of psychological disorders. Developmental work has examined how the ability to cope changes across time in children and adolescents; however, work in emerging adulthood is still lacking. Coping is thought to emerge from basic biological and psychological processes, such as temperament and gender, which may influence the trajectory of coping use over time. Using a sample of college students (N = 1,000), our 4-year longitudinal study with yearly assessments sought to (a) examine the trajectory of coping styles in emerging adulthood and to (b) examine the influence of temperament and gender on these coping trajectories. Our findings suggest that young adults' use of avoidance strategies decreased slightly over college, whereas the use of approach strategies and social support seeking remained stable. Temperament (BIS/BAS) and gender were related to certain coping styles at baseline and appeared to have an influence on some of these trajectories over time, though these associations were complex. This work may inform intervention research attempting to promote adaptive coping because it may help identify young adults most in need of such interventions.


Utility of pulse oximetry in the detection of arterial hypoxemia in liver transplant candidates.
Hepatopulmonary syndrome, arterial hypoxemia caused by intrapulmonary vasodilatation, occurs in approximately 10% of patients with cirrhosis. The severity of hypoxemia affects liver transplant candidacy and is associated with increased morbidity and mortality posttransplantation. Screening guidelines for detecting the presence of arterial hypoxemia do not exist. The aim of this study is to investigate the accuracy and utility of pulse oximetry in the detection of hypoxemia (PaO(2) < 70 mm Hg) in patients with cirrhosis. Two hundred prospective liver transplant candidates were compared with 94 controls. Arterial oxyhemoglobin saturation was obtained by pulse oximetry (SpO(2)) and compared with simultaneous arterial blood gas (ABG) oxyhemoglobin values (SaO(2); bias = the difference). PaO(2), carboxyhemoglobin, methemoglobin, and routine clinical and biochemical parameters were investigated to account for the bias. SpO(2) overestimated SaO(2) in 98% of patients with cirrhosis (mean bias, 3.37%; range, -1% to 10%). Forty-four percent of patients with cirrhosis and controls had a bias of 4% or greater. No clinical or biochemical parameters of cirrhosis accounted for the overestimation of pulse oximetry. Twenty-five subjects with cirrhosis were hypoxemic, and an SpO(2) of 97% or less showed a sensitivity of 96% and a positive likelihood ratio of 3.9 for detecting hypoxemia. An SpO(2) of 94% or less detected all subjects with an arterial PaO(2) less than 60 mm Hg. Pulse oximetry significantly overestimates arterial oxygenation, and the inaccuracy is not influenced by liver disease. Nevertheless, pulse oximetry can be a useful screening tool to detect arterial hypoxemia in patients with cirrhosis, but a higher threshold for obtaining an ABG must be used.


Trauma History Predicts Decoupling of C-Reactive Protein and Somatic Symptoms: Results From a Cohort Study of Sexual and Gender Minority Youth.
Systemic inflammation can induce somatic symptoms (e.g., pain, nausea, fatigue) through neuroimmune signaling pathways. Previous research suggests that early-life adversity amplifies signaling between peripheral inflammation and the brain. We therefore hypothesized that greater lifetime trauma exposure at baseline would predict stronger associations between systemic inflammation and somatic symptoms at 2.5-year follow-up in a cohort study of sexual and gender minority youth assigned male at birth ( n = 694). We measured prior trauma exposure (lifetime count of traumatic event types reported at baseline), somatic symptoms (Brief Symptom Inventory somatization score), and systemic inflammation (C-reactive protein, interleukin 6, interleukin 1β, and tumor necrosis factor α). All models included age, gender, education, recent trauma exposure, substance use, body mass index, and HIV status as covariates. Higher C-reactive protein concentrations were associated with greater somatic symptoms in the main effects model ( β = 0.019, 95% confidence interval [CI] = 0.006 to 0.031). Contrary to our hypothesis, we observed a negative interaction between prior trauma exposure and C-reactive protein levels in predicting somatic symptoms ( β = -0.017, 95% CI = -0.030 to -0.004). Higher C-reactive protein was associated with greater somatic symptoms only in participants without prior trauma exposure at baseline ( β = 0.044, 95% CI = 0.026 to 0.062). Specificity analyses revealed similar patterns when nonsomatic depressive symptoms were used as the outcome variable. These results suggest that sexual and gender minority youth assigned male at birth who have a history of prior trauma exposure may experience decoupling of systemic inflammation and somatic symptoms. The absence of inflammation-related symptoms may prevent individuals from seeking necessary medical care by reducing interoceptive awareness of pathological states.


Postischemic, systemic administration of polyamine-modified superoxide dismutase reduces hippocampal CA1 neurodegeneration in rat global cerebral ischemia.
Antioxidant enzymes such as superoxide dismutase (SOD) have shown neuroprotective effects in animal models of cerebral ischemia, but only at very high doses. Modifications to increase the plasma half-life or blood-brain barrier (BBB) permeability of SOD have resulted in limited neuroprotective effects. No one has demonstrated neuroprotection with postischemic administration. The specific aim of the present study was to administer systemically a polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, following global cerebral ischemia in rats and analyze the effects on the selective vulnerability of CA1 hippocampal neurons. Following 12 min of four-vessel occlusion, global cerebral ischemia, male Wistar rats were dosed (i.v.) with either saline, native SOD (5000 U/kg), polyamine-modified SOD (5000 U/kg), or enzymatically inactive, polyamine-modified SOD (2.1 mg/kg) twice daily for 3 days. Neuroprotective effects on hippocampal CA1 neurons were assessed using standard histological methods. Saline-treated animals had very few remaining CA1 neurons (1.44 +/- 0.60 neurons/reticle; x +/- S.E.M.) compared to sham rats (58.57 +/- 0.69). Native (10.38 +/- 2.96) or inactive, polyamine-modified SOD (7.32 +/- 2.68) did not show significant neuroprotective effects. Polyamine-modified SOD, however, resulted in the survival of significantly more CA1 neurons (24.61 +/- 5.90; P < 0.01). Postischemic, systemic administration of polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, significantly reduced hippocampal CA1 neuron loss following global cerebral ischemia. Similar modification of other antioxidant enzymes and neurotrophic factors with polyamines may provide a useful technique for the systemic delivery of therapeutic proteins across the BBB for the treatment of stroke and other neurodegenerative disorders.


Polarized release of hepatic microRNAs into bile and serum in response to cellular injury and impaired liver function.
Extracellular microRNAs (miRNAs) in serum and bile are currently under intense investigation for biomarker purposes in liver disease. However, the directions and pathways by which miRNAs are released from hepatic cells remains largely unknown. Here, we investigated the release of hepatocyte and cholangiocyte-derived miRNAs (HDmiRs and CDmiRs) into blood and bile during various (patho)physiological hepatic conditions. MiRNA release was analysed using longitudinally collected tissue and paired bile and serum samples (n = 124) that were obtained from liver transplant recipients during follow-up. Cell-type specificity of HDmiRs and CDmiRs was confirmed in liver and common bile duct biopsies (P < 0.001). Analysis of paired bile and serum samples showed up to 20-times higher miRNA-levels in bile compared to serum (P < 0.0001). Fractionation of bile showed the majority of miRNAs being present in the unpelletable supernatant, where protein conjunctions protect miRNAs against degradation (P < 0.0001). During episodes of liver injury and histologically proven rejection in liver transplant recipients, relative HDmiR-levels in bile decreased while its levels in serum increased (P ≤ 0.015). Simultaneously, relative CDmiR-levels in bile significantly increased, while their levels in serum decreased. Related to liver excretory function, a strong positive correlation was observed between HDmiR-122 levels and bilirubin excretion into bile (R = 0.694, P < 0.0001), whereas CDmiRs showed an inverse correlation (P < 0.05). During impaired excretory function and injury, the liver shows polarized release of extracellular HDmiRs and CDmiRs. This sheds new light on the biology of hepatic miRNA release which is relevant for the interpretation of hepatic miRNAs as biomarkers.


Abortion and psychiatric practice.
The subject of abortion is fraught with politics, emotions, and misinformation. A widespread practice reaching far back in history, abortion is again in the news. Psychiatry sits at the intersection of the religious, ethical, psychological, sociological, medical, and legal facets of the abortion issue. Although the religions that forbid abortion are more prominent in the media, many religions have more liberal approaches. While the basic right to abortion has been upheld by the U.S. Supreme Court, several limitations have been permitted, including parental notification or consent (with the possibility of judicial bypass) for minors, waiting periods, and mandatory provision of certain, sometimes biased, information. Before the Roe v. Wade decision legalizing abortion in 1973, many women were maimed or killed by illegal abortions, and psychiatrists were sometimes asked to certify that abortions were justified on psychiatric grounds. Currently, there are active attempts to convince the public and women considering abortion that abortion frequently has negative psychiatric consequences. This assertion is not borne out by the literature: the vast majority of women tolerate abortion without psychiatric sequelae. The psychiatric outcome of abortion is best when patients are able to make autonomous, supported decisions. Psychiatrists need to know the medical and psychiatric facts about abortion. Psychiatrists can then help patients prevent unwanted pregnancies, make informed decisions consonant with their own values and circumstances when they become pregnant, and find appropriate social and medical resources whatever their decisions may be.


Optical coherence tomography provides an optical biopsy of burn wounds in children-a pilot study.
Thermic injuries are among the most severe injuries in childhood. Burn depth is the most relevant prognostic factor, and still its assessment is both difficult and controversial. This diagnostic uncertainty results in repeated wound assessments over a 10-day period and carries a relevant risk for over- and undertreatment. Precise wound assessment would thus be a significant step toward improved care. Optical coherence tomography (OCT) is a noninvasive laser-based technique with a penetration depth of ∼2 mm. It provides structural images of the skin while dynamic OCT (D-OCT) shows blood vessels. In this study, we investigated burns and scalds in 130 children with OCT and D-OCT to identify patterns of injury related to the depth of the burn wound. OCT and D-OCT images from burned skin differed consistently from normal skin. We observed several not formerly described morphologic patterns associated with burn injuries. Superficial wounds are characterized by a loss of the epidermal layer and a smooth surface. With deeper wounds, surface irregularity, loss of the dermal papillary pattern, disappearance of skin lines, and characteristic changes in the microvascular architecture were observed. This is the first systematic study of D-OCT in the assessment of burn wounds in children. A number of burn-associated patterns of injury were identified. Thus, D-OCT provided an "optical biopsy" of burn wounds that adds significant information about the severity of a burn wound.


Slide-free virtual histochemistry (Part I): development via nonlinear optics.
Histochemistry is a microscopy-based technology widely used to visualize the molecular distribution in biological tissue. Recent developments in label-free optical imaging has demonstrated the potential to replace the conventional histochemical labels/markers (fluorescent antibodies, organic dyes, nucleic acid probes, and other contrast agents) with diverse optical interactions to generate histochemical contrasts, allowing "virtual" histochemistry in three spatial dimensions without preparing a microscope slide (i.e. labor-intensive sample preparation). However, the histochemical information in a label-free optical image has often been rather limited due to the difficulty in simultaneously generating multiple histochemical contrasts with strict spatial co-registration. Here, in the first part (Part I) of this two-part series study, we develop a technique of slide-free virtual histochemistry based on label-free multimodal multiphoton microscopy, and simultaneously generate up to four histochemical contrasts from in vivo animal and ex vivo human tissue. To enable this functionality, we construct and demonstrate a robust fiber-based laser source for clinical translation and phenotype a wide variety of vital cells in unperturbed mammary tissue.


Validity and reliability of an intuitive conscious sedation scoring tool: the nursing instrument for the communication of sedation.
To develop a symmetrical 7-level scale (+3, "dangerously agitated" to -3, "deeply sedated") that is both intuitive and easy to use, the Nursing Instrument for the Communication of Sedation (NICS). Prospective cohort study. University medical center. Mixed surgical, medical intensive care unit (ICU) population. Patient assessment. Criterion, construct, face validity, and interrater reliability of NICS over time and comparison of ease of use and nursing preference between NICS and four common intensive care unit sedation scales. A total of 395 observations were performed in 104 patients (20 intubated [INT], 84 non intubated) by 59 intensive care unit providers. Criterion validity was tested comparing NICS WITH the 8-point level of arousal scale, demonstrating excellent correlation (rs = .96 overall, .95 non intubated, 0.85 intubated, all p < .001). Construct validity was confirmed by comparing NICS with the Richmond Agitation-Sedation Scale, demonstrating excellent correlation (rs = .98, p < .001). Face validity was determined in a blinded survey of 53 intensive care unit nurses evaluating NICS and four other sedation scales. NICS was highly rated as easy to score, intuitive, and a clinically relevant measure of sedation, and agitation and was preferred overall (74% NICS, 17% Richmond Agitation-Sedation Scale, 11% Other, p < .001 NICS vs. Richmond Agitation-Sedation Scale). Interrater reliability was assessed, using the five scales at three timed intervals, during which 37% of patients received sedative medication. The mean NICS score consistently correlated with each of the other scales over time with an rs of >.9. Using the intraclass correlation coefficient as a measure of Interrater reliability, NICS scored as high, or higher than Richmond Agitation-Sedation Scale, Riker Sedation-Agitation Scale, Motor Activity Assessment Scale, or Ramsay over the three time periods. NICS is a valid and reliable sedation scale for use in a mixed population of intensive care unit patients. NICS ranked highest in nursing preference and ease of communication and may thus permit more effective and interactive management of sedation.


Acute Myeloid Leukemia Treatment in the Elderly: A Comprehensive Review of the Present and Future.
Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology in the past decade. It is also an affliction of the elderly that predominantly affects patients above 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate. Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug, and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low intense therapy remains a challenge and it requires careful assessment of individual patient's fitness and disease characteristics. This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.


A cell-targeted photodynamic nanomedicine strategy for head and neck cancers.
Photodynamic therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intratumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise toward a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas.


Application of Oil-in-Water Cannabidiol Emulsion for the Treatment of Rheumatoid Arthritis.
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.


Age-associated changes in ammoniagenesis in isolated rat renal tubule segments.
We investigated renal ammoniagenesis in isolated nephron segments from control and acidotic senescent and young adult rats. When young (6 mo) and senescent (24 mo) control groups were compared, there was no significant difference in glutamine-dependent ammonia production in any nephron tubule segments. However, ammonia production rates in glomeruli from old rats were significantly greater than the rate from young rats and were correlated with the serum creatinine and blood urea nitrogen (BUN) levels. After giving young and old rats an equivalent acid load (by gavage) of ammonia chloride solutions (6 mo, blood pH 7.34; 24 mo, blood pH 7.07), we measured a significant increase in ammoniagenesis on the S1 and S2 segments of proximal tubules and the distal convoluted tubules from old rats, and no increase in any segment from young rats. When we increased the acid load in young rats to an equivalent severity of acidosis (blood pH 7.07), we found significant increases in ammonia production in the S1, S2, S3, and distal convoluted tubule. With comparable blood pH values, ammoniagenesis in S1, S2, and S3 segments from young rats was about double the values measured in segments from senescent rats. The severity of the acidosis in the 24-mo-old rats was related to serum creatinine and BUN. Our findings show that ammoniagenesis in isolated segments from senescent rats is qualitatively similar to their younger counterparts but that this maximum capacity to generate ammonia is reduced. The change in nephron capacity to synthesize ammonia may be the result of age-associated physiological changes and/or the chronic renal failure exhibited in old rats.


Reversible cerebral vasoconstriction syndrome during caesarean section.
We describe the case of a 25-year-old parturient who presented sudden onset and short-lived severe headache caused by reversible cerebral vasoconstriction syndrome (RCVS) during an emergency caesarean section. The syndrome was triggered by phenylephrine administered intravenously to correct arterial hypotension following spinal anaesthesia. RCVS is a clinical and radiological syndrome attributed to transient disturbance in the control of cerebral arterial tone resulting in vasospasms. The syndrome can be precipitated by several triggers, including vasoactive drugs, often used during spinal anaesthesia, illicit drugs, pregnancy and postpartum state. Diagnosis and management can be challenging during pregnancy, peripartum or post partum, since many medications commonly used during these periods must be avoided to prevent triggering RCVS. The aim of this report is to raise the awareness, particularly for anaesthesiologists and obstetricians, of this rare and potentially serious syndrome. We discuss diagnosis, triggers, pathogenesis, clinical course and complications, as well as coordinated multidisciplinary management plans.


Inhibitory effects of insulin-like growth factor (IGF)-binding proteins-1 and -3 on IGF-activated glucose consumption in mouse BALB/c 3T3 fibroblasts.
We have examined the biological effects of insulin-like growth factor-binding proteins (IGFBPs) on insulin-like growth factor (IGF)-activated glucose consumption in a BALB/c 3T3 subline. The method employed was a colorimetric measurement of glucose consumption, allowing the detection of changes from the initial glucose concentration in conditioned medium, following the addition of IGFs and IGFBPs. Human IGFBP-1, purified from amniotic fluid, inhibited IGF-activated glucose consumption, although it had no effect on insulin-activated glucose consumption. The median effective dose (ED50) of IGFBP-1 to cause inhibitory effects on IGF-activated glucose consumption was 100-200 micrograms/l and was similar for both IGF-I and IGF-II at a concentration of 1.0 microgram IGF/l. Therefore, at IGF concentrations of comparable activity, the inhibitory effects of IGFBP-1 were greater for IGF-I than for IGF-II, because of the higher activity of IGF-I in this assay. Recombinant human IGFBP-3 also inhibited IGF-activated glucose consumption, without affecting insulin-stimulated glucose consumption. The inhibitory effects of IGFBP-3 were greater for IGF-II than for IGF-I when IGFBP-3 was coincubated with either of the IGFs, at both IGF concentrations of comparable activity and equivalent molar concentrations. Thus, it became clear that the inhibitory effects of these IGFBPs on IGF biological action depended primarily upon their affinity for the specific IGF ligand and molar ratio of IGFBP/IGF peptide. Interestingly, when cells were pretreated with IGFBP-3, prior to the simultaneous addition of IGFs and IGFBP-3, the inhibitory effect was higher for IGF-I than for IGF-II. Either no effect or a minor inhibitory effect on IGF-activated glucose consumption was detected with IGFBP pretreatment alone. When the ED50 for inhibition of IGF action by IGFBPs in this in-vitro assay was compared with the physiological concentrations of IGFs and IGFBPs in normal human serum and in amniotic fluid, it was estimated that the IGFBP-1 concentration present in serum was not sufficient to modulate IGF action effectively while the concentration in amniotic fluid was enough for effective suppression. IGFBP-3 exhibited an ED50 low enough to suppress IGF-II and possibly IGF-I action when cells were pretreated with IGFBP-3. Thus, our data suggested that IGFBP-1 in amniotic fluid and IGFBP-3 in serum could be a potent inhibitor for IGF action. IGFBP-1 in serum, however, may not be able to function as a direct inhibitor under physiological conditions but, rather, may modulate IGF action together with other IGFBPs.


Intermodulation spectroscopy as an alternative to pump-probe for the measurement of fast dynamics at the nanometer scale.
We present an alternative approach to pump-probe spectroscopy for measuring fast charge dynamics with an atomic force microscope (AFM). Our approach is based on coherent multifrequency lock-in measurement of the intermodulation between a mechanical drive and an optical or electrical excitation. In response to the excitation, the charge dynamics of the sample is reconstructed by fitting a theoretical model to the measured frequency spectrum of the electrostatic force near resonance of the AFM cantilever. We discuss the time resolution, which in theory is limited only by the measurement time, but in practice is of order 1 ns for standard cantilevers and imaging speeds. We verify the method with simulations and demonstrate it with a control experiment, achieving a time resolution of 30 ns in ambient conditions, limited by thermal noise.


Hepcidin expression and iron transport in alveolar macrophages.
Alveolar macrophages express many proteins important in iron homeostasis, including the iron importer divalent metal transport 1 (DMT1) and the iron exporter ferroportin 1 (FPN1) that likely participate in lung defense. We found the iron regulatory hormone hepcidin (HAMP) is also produced by alveolar macrophages. In mouse alveolar macrophages, HAMP mRNA was detected at a low level when not stimulated but at a high level when exposed to lipopolysaccharide (LPS). LPS also affected the mRNA levels of the iron transporters, with DMT1 being upregulated and FPN1 downregulated. However, iron had no effect on HAMP expression but was able to upregulate both DMT1 and FPN1 in alveolar macrophages. IL-1 and IL-6, which are important in HAMP augmentation in hepatocytes, also did not affect HAMP expression in alveolar macrophages. In fact, the LPS-induced alterations in the expression of HAMP as well as DMT1 and FPN1 were preserved in the alveolar macrophages isolated from IL-1 receptor or IL-6-deficient mice. When alveolar macrophages were loaded with transferrin-bound (55)Fe, the subsequent release of (55)Fe was inhibited significantly by LPS. In addition, treatment of these cells with either LPS or HAMP caused the diminishment of the surface FPN1. These findings are consistent with the current model that HAMP production leads to a decreased iron efflux. Our studies suggest that iron mobilization by alveolar macrophages can be affected by iron and LPS via several pathways, including HAMP-mediated degradation of FPN1, and that these cells may use unique regulatory mechanisms to cope with iron imbalance in the lung.


Economic evaluation of childhood 7-valent pneumococcal conjugate vaccination in Korea.
Streptococcus pneumoniae (sp) is a leading cause of invasive and noninvasive bacterial disease in children. 7-valent pneumococcal conjugate vaccine (PCV-7) has been shown to significantly reduce the incidence of pneumococcal diseases, such as meningitis, bacteremia, pneumonia, and otitis media. Although PCV-7 was introduced in Korea in 2003, it is not yet included in the universal immunization program. To evaluate the health outcomes, costs, and cost-effectiveness of universal vaccination with PCV-7 in Korean infants and to estimate the break-even price for PCV-7 from a societal perspective. A decision analytic model was used to evaluate the cost-effectiveness of immunization with PCV-7 in a birth cohort of Korean infants born in 2006. A universal vaccination strategy was compared with no vaccination in terms of costs and life years gained (LYG) over a 5-year time horizon. The birth cohort size, incidence of disease, resource utilization, and associated costs were obtained from the Korea National Statistical Office, the Korean Centers for Disease Control and Prevention, the Korean National Health and Nutrition Examination Survey, and the Korean Ministry of Health and Welfare. Inputs on the probabilities of clinical treatment pathways (e.g., tympanostomy) were derived from international literature if data specific to Korea did not exist. To estimate the benefits of universal immunization, the serotype-specific efficacy of PCV-7 was derived from studies conducted by Northern California Kaiser Permanente and by the Finnish Otitis Media Vaccine Study and applied to the serotypes isolated in Korean children with sp infections. The effects of vaccination on quality of life, herd immunity, benefits after the first 5 years of life, and patient copayments were not considered. A 4-dose schedule was used in the base-case analysis. A 3-dose schedule was also evaluated. The assumed price per dose was Korean won (KW) 70,000 (approximately US$54; 2009 exchange rate US$1 = KW1,300). Univariate and probabilistic sensitivity analyses were performed. Implementing a 4-dose universal PCV-7 vaccination strategy in a birth cohort of 451,514 infants in Korea would prevent 96,728 cases of pneumococcal-related infections (591 meningitis, 1,379 bacteremia, 43,950 pneumonia, and 50,808 otitis media cases) and 218 deaths (199 discounted deaths averted, 575 discounted LYG over 5 years). The medical and nonmedical cost burden of pneumococcal diseases offset with vaccination was KW44,033 million (US$33.87 million). The incremental discounted cost of universal vaccination was estimated to be KW86,384 million (US$66.45 million). The incremental cost per LYG was KW150.2 million (US$115,549) for the 4-dose schedule and KW103.91 million (US$79,955) for the 3-dose schedule. The break-even costs were KW22,100 and KW28,100 per dose for the 4- and 3-dose schedules, respectively. Universal PCV-7 vaccination of infants in Korea could substantially reduce pneumococcal disease morbidity, mortality, and related costs by preventing pneumococcal infections. However, at current market prices for the vaccine, a universal vaccination strategy is not cost-effective. The literature suggests that factors not considered in this analysis, including vaccine price reduction and indirect effects on public health (e.g., herd immunity), have the potential to make the public health impact and cost-effectiveness of universal PCV-7 vaccination in Korea more favorable.


[Percutaneous intervention therapy for vascular erectile dysfunction].
Erectile dysfunction (ED) is defined as the inability to get and maintain a sufficient erection to ensure an acceptable sexual activity for the subject and the partner. Although ED does not represent per se a serious disease, it carries a notable and severe influence on quality of life, with significant implications on familiar and social relationship; DE may cause depression, shame, impairment of personal esteem and relational problems. Among many possible etiologies of ED, atherosclerotic disease of penile arteries represents one of the most frequent causes, so it should always be looked for in patients with multiple risk factors for cardiovascular disease or an established coronary or peripheral artery disease. Up to 75% of patients with ED have a stenosis of the iliac-pudendus-penile artery system, deputy to perfusion of male genital organ. Recently the potential treatment of this pathologic condition by percutaneous approach has emerged with valid angiographic results and with a significant improvement in symptoms and quality of life. This review focuses on the normal anatomy and physiology of erection, the pathophysiology of ED, the common points between ED and ischemic cardiomyopathy and, lastly, the new chance of endovascular intervention for ED, to give our cardiologist colleagues the opportunity to screen and adequately treat patients with vascular ED.


Impact of the COVID-19 pandemic on army families: Household finances, familial experiences, and soldiers' behavioral health.
The Coronavirus Disease 2019 (COVID-19) pandemic has significantly impacted employment and finances, childcare, and behavioral health across the United States. The Behavioral Health Advisory Team assessed the pandemic's impact on the behavioral health of U.S. Army soldiers and their families. Over 20,000 soldiers at three large installation groups headquartered in the northwestern continental U.S., Republic of Korea, and Germany participated in the cross-sectional survey. Multivariable logistic regression models indicated that key demographics (gender, rank), severity of household financial impact, changes in work situation due to childcare issues, and family members' difficulty coping (both self and spouse/partner and/or child) were independently and consistently associated with greater odds of screening positive for probable clinical depression and generalized anxiety, respectively. These findings highlight how Army families were impacted similarly by the pandemic as their civilian counterparts. Army leadership may action these findings with targeted support for soldiers and their families to ensure they are utilizing supportive services available to them, and that military services continually evolve to meet soldier and family needs during times of crisis and beyond.