Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells.
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has opened new therapeutic possibilities. However, karyotypic abnormalities detected in iPSCs compromised their utility, especially chromosomal aberrations found at early passages raised serious safety concerns. The mechanism underlying the chromosomal abnormality in early-passage iPSCs is not known. Human dermal fibroblasts (HDFs) were stimulated with KMOS (KLF4, cMYC, OCT4 and SOX2) proteins to enhance their proliferative capacity and many vigorous clones were obtained. Clonal reprogramming was carried out by KMOS mRNAs transfection to confirm the 'chromosomal mutagenicity' of reprogramming process. Subculturing was performed to examine karyotypic stability of iPSCs after the re-establishment of stemness. And antioxidant N-acetyl-cysteine (NAC) was added to the culture medium for further confirmming the mutagenicity in the first few days of reprogramming. Chromosomal aberrations were found in a small percentage of newly induced iPS clones by reprogramming transcription factors. Clonal reprogramming ruled out the aberrant chromosomes inherited from rare karyotypically abnormal parental cell subpopulation. More importantly, the antioxidant NAC effectively reduced the occurrence of chromosomal aberrations at the early stage of reprogramming. Once iPS cell lines were established, they restored karyotypic stability in subsequent subculturing. Our results provided the first line of evidence for the 'chromosomal mutagenicity' of reprogramming process.


Fluorescence and circular dichroism studies on the Streptomyces R61 DD-carboxypeptidase-transpeptidase. Penicillin binding by the enzyme.
The circular dichroism of the dd-carboxypeptidase-transpeptidase from Streptomyces R61 shows in the near u.v. a set of weak extrema at 289nm (positive) and at 282, 275 and 268nm (all negative). In the far u.v. it shows negative extrema at 217-218 and 208nm, crossover at 202nm and a positive maximum at about 194nm. The u.v. absorption of the enzyme shows it to contain tyrosine and tryptophan in approx. 3.4:1 ratio. The enzyme is fluorescent with a maximum emission at 318-320nm. The near-u.v. circular dichroism of the protein is extensively affected by binding of penicillin G, but the far u.v. is unaffected. Binding of the antibiotic also causes quenching of the fluorescence of the enzyme. The latter effect has been used to study the binding of penicillin G to the enzyme and the influence exerted upon it by salts, denaturants and peptide substrates and inhibitors. High-affinity binding of penicillin appears to be comparatively slow and reversible, and can occur under conditions in which the protein is enzymically inactive. The thermal denaturation of the enzyme in guanidinium chloride at pH7 is affected by binding of the antibiotic. The presence of even large concentrations of beta-mercaptoethanol neither impaired the activity of the enzyme nor prevented its inhibition by penicillin G or cephalosporin C. A new hypothesis for the molecular mechanism of the interaction of the enzyme with penicillin is proposed.


Does State Dissociation Mediate the Relation Between Alcohol Intoxication and Deliberate Self-Harm?
Research supports the notion that alcohol intoxication is a risk factor for deliberate self-harm (DSH). However, the underlying mechanisms for this relationship are poorly understood. We aimed to determine whether alcohol-induced dissociation mediated alcohol's effects on DSH. We used data from a dose-response study of alcohol intoxication and DSH to test the proposed model. Participants were assigned to reach target blood alcohol concentrations (BAC) ranging from 0.00% through 0.10% and then completed a behavioral measure of DSH. Dissociation was assessed using the Alcohol Dissociative Experiences Scale. BAC predicted both dissociation and DSH, but dissociation did not predict DSH. Although research on clinical populations suggests dissociation is related to DSH, our findings suggest dissociation does not mediate the effects of alcohol on self-harm.


Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.


Unmet dental care needs among children with special health care needs: implications for the medical home.
Little is known about the characteristics of children with special health care needs (CSHCN) who have unmet dental care needs. We sought to describe the magnitude of unmet needs for dental care among CSHCN and to characterize those with unmet dental care needs. We used data from the National Survey of Children with Special Health Care Needs, which used a telephone survey to identify 750 CSHCN from each of the 50 states and the District of Columbia. Families of 38,866 CSHCN were interviewed, and the data were weighted to represent 9.32 million CSHCN nationally. Our primary outcome of interest was unmet dental care need, defined as whether CSHCN were said to have needed dental care but were unable to obtain it. We also considered reasons why a child had an unmet dental care need and compared other categories of health care service needs and unmet needs with dental care. Bivariate and multivariate analyses were conducted to determine factors associated with unmet dental care needs. Overall, 78% of CSHCN were reported as needing dental care in the past 12 months, which was second only to prescription medications in the frequency of need. Of those who reported a dental care need, an estimated 755,581 or 10.4% of CSHCN did not receive all of the dental care they needed. Relative to all other health care service categories, unmet dental care needs affected the most children. Poorer children, uninsured children, children with lapses in insurance, and children with greater limitations attributable to disability had significantly greater odds of unmet dental care needs in multivariate analyses. Children with a personal doctor or nurse were significantly less likely to have unmet dental care needs. Dental care is the most prevalent unmet health care need for CSHCN, affecting substantially more children than any other health care need category. Moreover, the perceived need for dental care for CSHCN exceeds the need for either preventive or specialty medical care. Given these findings, dental care should be an integral and explicitly stated part of the comprehensive coordinated services that the medical home aims to provide for CSHCN. Greater efforts to improve access to dental care for poor and more disabled CSHCN are needed.


Functional visual field of patients with visual field loss.
To assess the capability of perceiving forms in patients with visual field loss, a concept of functional visual field was introduced based on determinations of the time required for pattern recognition. Two series of stimulus patterns were made of Japanese syllabic hiragana characters drawn with black dots in the background of open circles of various sizes: the clear stimulus had only open circles in the background and the noisy stimulus had black dots scattered in the background. The stimuli were presented for various durations to 15 normal subjects and 25 patients with narrowed visual field; a correlation of the percentages of correct pattern recognition with the stimulus durations permitted calculations of the 50% recognition time. The recognition time was longer with the noisy than with the clear stimuli. The recognition time with a given stimulus size was longer in patients than in normal subjects. In 3 normal subjects the visual field was artificially narrowed and the recognition time was determined. The recognition time could be expressed by a power function of the ratio of the effective visual field diameter to the diameter of the stimulus pattern. On this basis the functional visual field size of a patient was defined as the size of the artificially narrowed visual field of the normal subject that required the same recognition time as that of the patient. The functional visual field of patients could be correlated with the area of the perimetric field with the V/4 target of Goldmann's projection perimeter. The concept of the functional visual field was found to be useful to express the patients' capability for pattern perception.


LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine.
The objective of this study was to compare the performance of an immunoassay screening for synthetic cannabinoids with a newly developed confirmation method using liquid chromatography quadrupole time-of-flight mass spectrometry. The screening included metabolites from JWH-018, JWH-073, and AM-2201. The confirmation included metabolites from AM-2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, JWH-398, MAM-2201, RCS-4, and UR-144. The immunoassay was tested and found to have no cross-reactivity with UR-144 metabolites but considerable cross-reactivity with MAM-2201 and JWH-122 metabolites. Sensitivity and specificity for the immunoassay were evaluated with 87 authentic urine samples and found to be 87% and 82%, respectively. With a cutoff at 2 ng/ml, the confirmation showed 80 positive findings in 38 cases. The most common finding was JWH-122 5-OH-pentyl, followed by JWH-018 5-OH-pentyl. There were 9 findings of UR-144 metabolites and 3 of JWH-073 metabolites. In summary, the immunoassay performed well, presenting both high sensitivity and specificity for the synthetic cannabinoids present in the urine samples tested. The rapid exchange of one cannabinoid for another may pose problems for immunoassays as well as for confirmation methods. However, we consider time-of-flight mass spectrometry to be superior since new metabolites can be quickly included and identified.


Cholangiocarcinoma. Role of percutaneous transhepatic cholangiography in determination of resectability.
Exploratory laparotomy is frequently used to diagnose, treat, or palliate cholangiocarcinoma although surgery is rarely curative. In light of newly developed percutaneous and endoscopic approaches to diagnosis and therapy, we reviewed our experience with 35 cases of cholangiocarcinoma diagnosed and treated at the University of Michigan Medical Center from 1979 to 1984. Percutaneous transhepatic cholangiography (PTCA) was performed in 34 cases of which only four were resectable. All 22 patients who had preoperative cholangiograms suggesting unresectability had confirmation of this at surgery. Surgical palliation was accomplished with a combination of internal and percutaneous drainage in most cases. Angiographic, cytologic, and laboratory data are presented. PTCA accurately predicted unresectability of cholangiocarcinoma and is superior to angiography in this respect. In patients with cholangiocarcinoma, percutaneous and endoscopic approaches offer alternatives to surgery for diagnosis and palliation.


Obesity-associated hypertension: new insights into mechanisms.
Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.


Men's experiences of radiotherapy treatment for localized prostate cancer and its long-term treatment side effects: a longitudinal qualitative study.
To investigate men's experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.


Efficacy of desonide 0.05% cream and lotion in steroid-responsive dermatoses in Indian patients: a post-marketing surveillance study.
Desonide, a non-halogenated, low-potency topical steroid, is indicated in the treatment of steroid-responsive dermatoses. A post-marketing surveillance study was conducted to evaluate the efficacy and safety of Desowen (Desonide 0.05%) cream and lotion in Indian patients for the treatment of steroid-responsive dermatoses of mild to moderate severity. A 3-week, multicenter, open-label, non-comparative Phase IV trial involving 1789 patients from 229 centers across India was conducted between January and August 2003. Of the 1789 patients, 1483 patients completed the treatment as per protocol. At the end of the therapy, 98.5% of the patients showed an improvement in their dermatitis from baseline. More than half of the patients showed a greater than 75% improvement in their signs and symptoms. No adverse effects were noted in any of the patients. Both the lotion and cream were found to be equally effective. Desonide 0.05% is a safe and effective low-potency corticosteroid for the treatment of mild to moderate dermatoses in Indian patients. No clinically apparent side-effects were observed in infants less than 1 year of age.


[Influence of granulated bacterial preparation complex action on the growth and yield of barley].
The influence of granulated bacterial preparation of complex action on the growth and yield of barley (H. distichum L.) has been studied. The treatment of barley seeds by this preparation has been established to have a very significant effect on the mass of 1000 grains, grain natural weight and to increase the yield of plants, but to different degree. Consequently, the interaction of certain barley varieties with bacteria-components of the preparation is rather specific. It has been displayed that the treatment of grains of different barley varieties by the bacterial preparation takes a very significant influence on the function of microbial associations in the rhizosphere.


Evidence for a persistent microbial seed bank throughout the global ocean.
Do bacterial taxa demonstrate clear endemism, like macroorganisms, or can one site's bacterial community recapture the total phylogenetic diversity of the world's oceans? Here we compare a deep bacterial community characterization from one site in the English Channel (L4-DeepSeq) with 356 datasets from the International Census of Marine Microbes (ICoMM) taken from around the globe (ranging from marine pelagic and sediment samples to sponge-associated environments). At the L4-DeepSeq site, increasing sequencing depth uncovers greater phylogenetic overlap with the global ICoMM data. This site contained 31.7-66.2% of operational taxonomic units identified in a given ICoMM biome. Extrapolation of this overlap suggests that 1.93 × 10(11) sequences from the L4 site would capture all ICoMM bacterial phylogenetic diversity. Current technology trends suggest this limit may be attainable within 3 y. These results strongly suggest the marine biosphere maintains a previously undetected, persistent microbial seed bank.


Fluoroscopic-guided balloon dilatation and stenting in tracheal stenosis with metallic self-expandable stents and long-term follow-up results.
The purpose of this study was to assess the safety and long-term efficacy of self-expandable stents in the treatment of benign tracheal stenosis. Nine patients (seven men) with tracheal stenosis (including one with fistula) of varied cause were treated by fluoroscopically guided balloon dilatation and stenting with self-expandable metallic stents. The procedure was carried out under topical spray in eight patients and under general anaesthesia in one patient. The patients were followed up for a period ranging between 13 and 60 months. In eight of the nine patients, satisfactory positioning of the stent was achieved at the first instance, with immediate relief of dyspnoea. One patient with innominate artery aneurysm died 16 days after the procedure because of renal failure. At 1 month of follow up, six out of eight (75%) of our live patients were without any respiratory embarrassment. This dyspnoea-free result reached almost 90% by the end of 1 year especially so in the fibrous strictures. Four out of the eight live patients (50%) had cough for 2 months and two (25%) had mild blood-tinged sputum treated by inhalation and mucolytic agents. Secondary intervention was required in one patient at 1 month because of recurrent symptoms. The patient with tracheo-oesophageal fistula required surgical intervention because of fracture of the stent. Fluoroscopically guided balloon dilatation and stenting of the tracheal stenosis is an effective non-surgical therapy resulting in cure of fibrous strictures and palliation in cases of malignancy.


A recurrent giant cell tumor of bone treated with denosumab.
Although the giant cell tumor of bone is generally classified as a benign tumor it can rarely metastasize and has a potential risk of local recurrence. We want to report about a female patient who suffered from a recurrence of a giant cell tumor of bone after the implantation of a total endoprosthesis of the knee joint. We have treated her with denosumab, which is a receptor activator of nuclear factor kappa-B ligand inhibitor. In this case report we want to present a new option to treat this kind of neoplasm.


Early translaryngeal tracheostomy in patients with severe brain damage.
To describe the effects of early translaryngeal tracheostomy on intracranial pressure (ICP), cerebral perfusion pressure (CPP), and jugular bulb saturation (SjO2); to identify the main mechanisms affecting ICP during tracheostomy; and to evaluate the long-term effects of tracheostomy on tracheal anatomy and function. Prospective, observational, clinical study. Neurosurgical intensive care unit in a teaching hospital. 20 patients admitted to the ICU because of head injury, subarachnoid hemorrhage, or brain tumor with a Glasgow Coma Scale less than 8. Patients underwent translaryngeal tracheostomy under strict neuromonitoring. ICP rose significantly (p < 0.05) at the critical time of cannula placement while all other parameters remained stable. At this time five patients suffered intracranial hypertension (ICP > 20 mmHg). In one of them CPP dropped below 60 mmHg. Arterial CO2 tension (PaCO2) did not rise significantly. No other major complications were recorded during the procedures. Three months after tracheostomy normal findings were detected by tracheoscopy in all cases (11 patients could be examined). Translaryngeal tracheostomy, performed in selected patients when the risk of intracranial hypertension was reduced to the minimum, was well tolerated in the majority of cases and did not induce persistent intracranial disorders. However, ICP is affected by tracheostomy, and careful monitoring and patient selection is necessary. At follow-up no severe anatomical or functional damage was detected.


Nanoparticles with surface features of dendritic oligopeptides as potential oral drug delivery systems.
Surface features are key to the transcellular transport of nanoparticles (NPs) across intestinal epithelium cells. Endowing the NPs with specific surface features adapted to the physiological conditions of the gastrointestinal (GI) tract holds great potential for the oral delivery of peptide/protein drugs. Therefore, in this work, a glutamic acid conjugated amphiphilic dendrimer (Glu-APD) was synthesized to replace the widely used 1,2-distearoyl-sn-glycero-3-phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG) in the preparation of poly(lactic-co-glycolic acid) (PLGA)-based NPs. Glu-APD could provide the formed NPs (Glu-APD NPs) with specific surface features of dendritic oligopeptides. With such surface features, Glu-APD NPs exhibited a 7.78-fold increase in cellular uptake and a 2.17-fold increase in the transepithelial transport amount compared with those of the DSPE-PEG2000 modified counterparts (P NPs). Instead of a dominant clathrin-mediated endocytosis as shown by P NPs, Glu-APD can provide the NPs with optional endocytosis pathways (i.e. clathrin-mediated, caveolae-mediated and micropinocytosis pathways), with the involvement of oligopeptide transporters and amino acid transporters, subsequently leading to a broadened intracellular trafficking route via the endoplasmic reticulum (ER) and Golgi apparatus. Furthermore, l-glutamic acid (l-Glu), a natural nutrient, could specifically facilitate the exocytosis of Glu-APD NPs, indicating an amino-acid-associated intracellular trafficking. Oral administration of insulin-loaded Glu-APD NPs could also achieve a good hypoglycemic effect with a relative bioavailability of 10.04%, which is 1.89-fold higher than that of P NPs and 5.20-fold higher than insulin solution. Safety evaluations further verified the biocompatibility of Glu-APD NPs and the related materials. The results confirmed the feasibility of introducing Glu-APD to NPs for improving the oral delivery of insulin. With the surface features of dendritic peptide, Glu-APD could facilitate oligopeptide/amino-acid-associated transport of the related NPs, which might be considered as an advantage under physiological conditions. This work might also be considered as a valid reference for the construction of highly efficient oral delivery systems.


A role for inflammatory mediators in heterologous desensitization of CysLT1 receptor in human monocytes.
Cysteinyl-leukotrienes (cysteinyl-LT) are rapidly generated at sites of inflammation and, in addition to their role in asthma, rhinitis, and other immune disorders, are increasingly regarded as significant inflammatory factors in cancer, gastrointestinal, cardiovascular diseases. We recently demonstrated that in monocyte/macrophage-like U937 cells, extracellular nucleotides heterologously desensitize CysLT(1) receptor (CysLT(1)R)-induced Ca(2+) transients. Given that monocytes express a number of other inflammatory and chemoattractant receptors, this study was aimed at characterizing transregulation between these different stimuli. We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating G(i)-coupled receptor (FPR1, BLT(1)) desensitize CysLT(1)R-induced Ca(2+) response unidirectionally through activation of PKC. Conversely, PAF-R, exclusively coupled to G(q), cross-desensitizes CysLT(1)R without the apparent involvement of any kinase. Interestingly, G(s)-coupled receptors (beta(2)AR, H(1/2)R, EP(2/4)R) are also able to desensitize CysLT(1)R response through activation of PKA. Heterologous desensitization seems to affect mostly the G(i)-mediated signaling of the CysLT(1)R. The hierarchy of desensitization among agonists may be important for leukocyte signal processing at the site of inflammation. Considering that monocytes/macrophages are likely to be the major source of cysteinyl-LT in many immunological and inflammatory processes, shedding light on how their receptors are regulated will certainly help to better understand the role of these cells in orchestrating this complex network of integrated signals.


Mental health patients in emergency departments are suffering: the national failure and shame of the current system. A report on the Australasian College for Emergency Medicine's Mental Health in the Emergency Department Summit.
Inadequate capacity in Australia's mental health system means that many people turn to emergency departments (ED) in crisis for care and support, often because it is the only service available. Australian Governments have set a 4-h target for all ED care, but the data shows that people presenting to an ED in a mental health crisis are the group most likely to wait more than 24 h for care. These long waits, seemingly with no end in sight, are harmful for patients and deeply frustrating for clinicians. In response, in 2018, the Australasian College for Emergency Medicine (ACEM) organised the national Mental Health in the Emergency Department Summit. Delegates from across clinical disciplines and user groups were unified in their deep concern at the unacceptable state of mental health support available to people seeking help through EDs. The Summit identified four priorities for urgent action and urged government to take immediate steps to improve this situation.


Clinical and ultrasound approach to achalasia in a child. Case report.
Achalasia is a primary esophageal motor disorder of unknown etiology characterized by insufficient lower esophageal sphincter (LES) relaxation in response to deglution. We present the case of a child diagnosed with asthma, with no response to asthma treatment. On account of associating dysphagia, regurgitation of food and weight loss he was given an abdominal ultrasound that revealed a massive dilated and narrowing of its distal segment esophagus. Ultrasound examination proved to be a good diagnostic tool, reorienting from the initial asthma diagnosis to the correct achalasia diagnosis, confirmed through barium swallow, upper digestive endoscopy and esophageal manometry. Esocardiomiotomy with antireflux technique was performed with excellent results.


[The heme oxygenase system and its physiopathology].
The HENE-OX system (isoforms 1, 2 and 3) is the key enzyme in the oxygen dependent HEME catabolism pathway and cleavage to HEME into biliverdin IX alfa, iron and carbon-monoxide (CO). The biliverdin reductase catalyzes biliverdin into bilirubin unconjugated what is converted in bilirubin conjugated, mono and biglucuronized for the activity of hepatic Uridindifosfo-glucuronil-transferase (UDFGT). The hyperbilirubinemias unconjugated can produce kernicterus. This should be treated with metalloporphyrins (Zn-Proto IX, Zn-Mesoporphyrin, Sn-Proto-IX, Sn-Mesoporphyrin). Relations between HEM-OX/CO and NOS/NO systems. The induction of the HEME-OX system is a protective cellular mechanism against oxidative damage. Studies about the relations of the HEME-OX system with functions of various tissues (liver, kidney, cardiovascular and respiratory and hematological system, etc.).


Perturbation-reperturbation test of selection vs. hitchhiking of the two major alleles of Esterase-5 in Drosophila pseudoobscura.
A perturbation-reperturbation tests selective neutrality of 100/100/100/100/100 and 106/100/100/100/100, the two most common alleles at the highly polymorphic X-linked locus Esterase-5 in Drosophila pseudoobscura. A total of 22 replicate populations are set up in cages, 11 start at a high frequency of 76% (U) and 11 at a low frequency of 21% (N) of the 106 allele. Allele frequencies change directionally and decrease in both U and N populations as groups and reach equilibria of 60 and 14%, respectively, after 200-300 days. These changes suggest natural selection. A hypothesis of balancing selection accounts for the pattern and predicts a dynamic equilibrium. A rival neutral hypothesis accounts for the pattern equally well by postulating hitchhiking and breakup of linkage leaving the Est-5 variants to drift at neutral equilibria. A reperturbation of allele frequencies in each population, creating 22 additional reperturbed populations EN and EU, with the original populations as controls, directly addresses the question of balancing selection or hitchhiking and breakup of linkage effects. Allele frequencies do not change directionally among the reperturbed populations as a group. The hypothesis of balancing selection is rejected in favor of the hypothesis of initial hitchhiking and dissipated linkage effects. The power of the experimental design to detect selection is studied by simulation. Within the limits of power set by the design, it is concluded that the 100 and 106 are iso-fitness alleles of Est-5 under the environmental conditions of the laboratory populations. The requirements of a method of perturbation and reperturbation are discussed.


Predictors of change in mothers' and fathers' parent-child aggression risk.
Parents' cognitive schemas about parenting, personal vulnerabilities, and personal resources may affect their risk of engaging in parent-child aggression (PCA). This longitudinal study examined predictors of change in mothers' and fathers' PCA risk across the transition to parenthood, comparing trajectories of parents evidencing high versus low sociodemographic risk. Potential predictors involved parenting-relevant schemas (consistent with Social Information Processing theory, including approval of PCA, negative attributions of child behavior, and knowledge of nonphysical discipline options), personal vulnerabilities (psychopathology, intimate partner violence, substance use issues), and resources (problem-focused coping, emotion regulation, social support, and partner satisfaction). Results indicated that increases in PCA approval, negative child behavior attributions, and symptoms of psychopathology, as well as decreases in problem-focused coping skills, emotion regulation ability, and partner satisfaction, all significantly predicted changes in mothers' and fathers' PCA risk over time-regardless of risk group status. Notably, increases in intimate partner violence victimization and decreases in social support satisfaction predicted mothers' but not fathers' PCA risk change; moreover, increases in knowledge of nonphysical discipline alternatives or in substance use issues did not predict change in PCA risk for either mothers or fathers. Risk groups differed in PCA risk across all predictors with minimal evidence of differential trajectories. Overall, these findings have important implications for child abuse prevention programs involving both universal and secondary abuse prevention efforts.


Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative's Neuro-Oncology Disease Site Group.
This systematic review describes the diagnosis and management of adult patients with a suspected or confirmed diagnosis of extradural malignant spinal cord compression (MSCC). MEDLINE, CANCERLIT, and the Cochrane Library databases were searched to January 2004 using the following terms: spinal cord compression, nerve compression syndromes, spinal cord neoplasms, clinical trial, meta-analysis, and systematic review. Symptoms for MSCC include sensory changes, autonomic dysfunction, and back pain; however, back pain was not predictive of MSCC. The sensitivity and specificity for magnetic resonance imaging (MRI) range from 0.44 to 0.93 and 0.90 to 0.98, respectively, in the diagnosis of MSCC. The sensitivity and specificity for myelography range from 0.71 to 0.97 and 0.88 to 1.00, respectively. A randomized study detected higher ambulation rates in patients with MSCC who received high-dose dexamethasone before radiotherapy (RT) compared with patients who did not receive corticosteroids before RT (81% v 63% at 3 months, respectively; P = .046). There is no direct evidence that supports or refutes the type of surgery patients should have for the treatment of MSCC, whether surgical salvage should be attempted if patient is progressing on or shortly after RT, and whether patients with spinal instability should be treated with surgery. Patients with symptoms of MSCC should be managed to minimize treatment delay. MRI is the preferred imaging technique. Treatment for patients with MSCC should consider pretreatment ambulatory status, comorbidities, technical surgical factors, the presence of bony compression and spinal instability, potential surgical complications, potential RT reactions, and patient preferences.


An insight into piscidins: The discovery, modulation and bioactivity of greater amberjack, Seriola dumerili, piscidin.
Antimicrobial peptides (AMPs) play an important role in the innate immune response of vertebrates by creating a hostile environment for any invading pathogens. Piscidins are potent teleost specific AMPs, which have a broad spectrum activity. We have identified a novel piscidin active peptide, in the greater amberjack, Seriola dumerili, that consists of 25 aa, which forms an amphipathic helix with distinct hydrophobic and positively charged regions. Following homology and phylogenetic analysis the greater amberjack piscidin was deemed to belong to the group 3 family of piscidins. Piscidin was expressed constitutively at immune sites, with transcript level highest in the spleen and gut, at an intermediate level in the gills and lowest in the head kidney. Following in vivo stimulation with PAMPs (poly I:C, LPS and flagellin) piscidin transcript level increased in gills in response to flagellin, in gut and spleen in response to poly I:C, and in head kidney in response to poly I:C, LPS and flagellin. Head kidney and spleen cells were then isolated from greater amberjack and incubated with each of the PAMPs for 4, 12 and 24 h. Piscidin expression was unchanged at 4 and 12 h post PAMP stimulation in head kidney cells but at 24 h transcript level was markedly upregulated compared to control (unstimulated) cells, especially with the bacterial PAMPs. In contrast, spleen cells upregulated piscidin expression by 4 h post stimulation with poly I:C and flagellin, and remained upregulated to 24 h with flagellin exposure, but had returned to baseline levels by 12 h using poly I:C. To determine if piscidin expression could be modulated by diet, greater amberjack were fed diets supplemented with MOS and cMOS for 30 days when transcript level was determined. It was found that MOS supplemented diets increased expression in the spleen, cMOS supplemented diets upregulated transcript levels in the gills and head kidney, whilst a diet containing both MOS and cMOS upregulated transcript in the gut, when compared to fish fed the control diet. Finally, a synthetic greater amberjack piscidin was produced and showed bacteriostatic activity against a number of bacterial strains, including both Gram positive and Gram negative fish pathogens.


Esophageal Scab Mimicking a Parasite: A Case Report.
BACKGROUND Parasitic helminths in the esophagus are rare. Here, we report a case of esophageal scab mimicking a parasite. CASE REPORT A 65-year-old man was admitted to our hospital because after choking on food. Gastroscopy showed 2 foreign bodies adherent to the esophagus wall 28 and 34 cm from the incisor, which appeared to be a fluke. Two fluke-like foreign bodies (1.5 and 1.8 cm in length) were removed from the esophageal ulcer with forceps. After fixation with alcohol, the suspected fluke-like foreign bodies were noted to be brown and woody. Under a light microscope, the structure of the foreign body was not apparent, and no typical flatworm tegument structure was demonstrated on pathologic sections, but it had a blood clot-like structure. Administration of albendazole did not expel any helminths. A stool examination showed no eggs of the putative flukes. The genomic DNA of the suspected flukes was extracted and a 700 bp fragment was amplified by universal barcoding primers. The sequencing showed that the homology with human cytochrome c oxidase subunit I gene was 98.8%. CONCLUSIONS The scab formed by the esophageal ulcer was identified based on clinical manifestations, anti-helminth and stool examinations, parasite morphology, and molecular biology. Our experience with this case suggests that the universal barcoding technique can be used for identification of foreign bodies suspected to be parasites.


Evidence for an indirect effect of radiation on mammalian chromosomes. II. UV-induced isochromosome formation in cell hybrids.
Cell fusion has been used to test the hypothesis that chromosomes may be damaged indirectly by UV light, as well as by direct interaction with DNA. Hybrids were found to contain isochromosomes of mouse origin, whose frequency increased as the dose of UV delivered to the hamster cell parent was increased. This unusual type of aberration was shown to be induced also by direct UV irradiation of mouse or hybrid cells. These results suggest that UV light has a hitherto undiscovered indirect effect on chromosome integrity, mediated by some irradiated cell component.


Interaction of common bacterial blight bacteria with disease resistance quantitative trait loci in common bean.
Common bacterial blight (CBB) of common bean (Phaseolus vulgaris L.) is caused by Xanthomonas campestris pv. phaseoli and X. fuscans subsp. fuscans, and is the most important bacterial disease of this crop in many regions of the world. In 2005 and 2006, dark red kidney bean fields in a major bean-growing region in central Wisconsin were surveyed for CBB incidence and representative symptomatic leaves collected. Xanthomonad-like bacteria were isolated from these leaves and characterized based upon phenotypic (colony) characteristics, pathogenicity on common bean, polymerase chain reaction (PCR) with X. campestris pv. phaseoli- and X. fuscans subsp. fuscans-specific primers, and repetitive-element PCR (rep-PCR) and 16S-28S ribosomal RNA spacer region sequence analyses. Of 348 isolates that were characterized, 293 were identified as common blight bacteria (i.e., pathogenic on common bean and positive in PCR tests with the X. campestris pv. phaseoli- and X. fuscans subsp. fuscans-specific primers), whereas the other isolates were nonpathogenic xanthomonads. Most (98%) of the pathogenic xanthomonads were X. campestris pv. phaseoli, consistent with the association of this bacterium with CBB in large-seeded bean cultivars of the Andean gene pool. Two types of X. campestris pv. phaseoli were involved with CBB in this region: typical X. campestris pv. phaseoli (P) isolates with yellow mucoid colonies, no brown pigment production, and a typical X. campestris pv. phaseoli rep-PCR fingerprint (60% of strains); and a new phenotype and genotype (Px) with an X. campestris pv. phaseoli-type fingerprint and less mucoid colonies that produced brown pigment (40% of strains). In addition, a small number of X. fuscans subsp. fuscans strains, representing a new genotype (FH), were isolated from two fields in 2005. Representative P and Px X. campestris pv. phaseoli strains, an FH X. fuscans subsp. fuscans strain, plus five previously characterized X. campestris pv. phaseoli and X. fuscans subsp. fuscans genotypes were inoculated onto 28 common bean genotypes having various combinations of known CBB resistance quantitative trait loci (QTL) and associated sequence-characterized amplified region markers. Different levels of virulence were observed for X. campestris pv. phaseoli strains, whereas X. fuscans subsp. fuscans strains were similar in virulence. The typical X. campestris pv. phaseoli strain from Wisconsin was most virulent, whereas X. campestris pv. phaseoli genotypes from East Africa were the least virulent. Host genotypes having the SU91 marker-associated resistance and one or more other QTL (i.e., pyramided resistance), such as the VAX lines, were highly resistant to all genotypes of common blight bacteria tested. This information will help in the development of CBB resistance-breeding strategies for different common bean market classes in different geographical regions, as well as the identification of appropriate pathogen genotypes for screening for resistance.


Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans.
The recently discovered adipose cell-specific hormone called leptin decreases food intake and increases energy expenditure in rodents through a pathway involving hypothalamic leptin receptors, OB-R. In addition, leptin decreases insulin circulating levels independent of the reduction in food intake. Whether or not the hormone has a direct effect on pancreatic beta-cells is not clear, because previous in vitro studies have led to controversial results depending on the animal model used. The present study was designed to investigate the effects of leptin in islets of Langerhans isolated from normal rodents. Three isoforms of the leptin receptor, OB-Ra, b, and f, were detected by RT-PCR analysis of total RNA from rat islets. In static incubations, leptin (10 ng/ml) did not alter basal insulin secretion nor insulin secretion stimulated by glucose alone, potassium chloride, or ketoisocaproic acid. In contrast, insulin secretion stimulated by glucose + 3-isobutyl 1-methylxanthine (IBMX) was inhibited by 34 +/- 15% (n = 4, P < 0.05). This was further substantiated in perifusion experiments, in which leptin decreased by 31 +/- 3% (n = 5, P < 0.01) glucose + IBMX-stimulated insulin release. Similarly, in mouse islets a significant inhibitory effect of leptin (-31 +/- 4%, n = 6, P < 0.05) was observed only on glucose + IBMX-stimulated insulin secretion, with no effect of the hormone on basal nor glucose-stimulated secretion. Finally, leptin was totally inefficient in islets isolated from obese fa/fa rats, which bear a mutation in OB-R. These results suggest that, in normal rodent islets, leptin specifically inhibits IBMX-potentiated glucose-induced insulin secretion, through a direct effect involving at least one of the three isoforms of OB-R expressed in islets.


Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood?
In recent years, evidence is growing on the role played by gestational factors in shaping brain development and on the influence of intrauterine experiences on later development of neurodegenerative diseases including Parkinson's (PD) and Alzheimer's disease (AD). The nine months of intrauterine development and the first three years of postnatal life are appearing to be extremely critical for making connections among neurons and among neuronal and glial cells that will shape a lifetime of experience. Here, the multiple epigenetic factors acting during gestation - including maternal diet, malnutrition, stress, hypertension, maternal diabetes, fetal hypoxia, prematurity, low birth weight, prenatal infection, intrauterine growth restriction, drugs administered to the mother or to the baby - are reported, and their ability to modulate brain development, resulting in interindividual variability in the total neuronal and glial burden at birth is discussed. Data from recent literature suggest that prevention of neurodegeneration should be identified as the one method to halt the diffusion of neurodegenerative diseases. The "two hits" hypothesis, first introduced for PD and successfully applied to AD and other neurodegenerative human pathologies, should focus our attention on a peculiar period of our life: the intrauterine and perinatal periods. The first hit to our nervous system occurs early in life, determining a PD or AD imprinting to our brain that will condition our resistance or, alternatively, our susceptibility to develop a neurodegenerative disease later in life. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including PD and AD, is emerging as a new fascinating research focus. This assumption implies that research on prevention of neurodegenerative diseases should center on events taking place early in life, during gestation and in the perinatal periods, thus presenting a new challenge to perinatologists: the prevention of neurodegenerative human diseases.


Temporal dynamics of cerebro-cerebellar network recruitment during a cognitive task.
Previous investigations have demonstrated that two regions in the right cerebellum, one located superiorly in hemispheral lobule VI/Crus I and another located inferiorly in hemispheral lobule VIIB/VIIIA, are activated during verbal working memory performance. On the basis of functional neuroimaging patterns of activation, as well as known cortico-pontine and ponto-cerebellar projections, the superior region has been hypothesized to contribute to the articulatory control system of working memory whereas the inferior region has been linked to the phonological store. The present study used event-related fMRI and individual estimates of hemodynamic response for both the cerebellum and neocortex to test this model and characterize the task phase specific cerebro-cerebellar activations for a Sternberg verbal working memory task. Results demonstrated that the right superior cerebellum showed the strongest activation during the initial encoding phase of the task, and, consistent with predictions, a similar pattern was observed in left opercular inferior frontal and premotor regions. In contrast, the right inferior cerebellum exhibited the greatest activation during the maintenance phase of the task, and as predicted, corresponded with activation in the left inferior parietal lobule. The significance of the results with respect to cerebro-cerebellar models of verbal working memory and to theoretical accounts of cerebellar involvement in cognition is discussed.


Effects of acute cocaine or dopamine receptor agonists on AMPA receptor distribution in the rat nucleus accumbens.
Changes in α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) surface expression in the rodent nucleus accumbens (NAc) are produced by cocaine exposure and implicated in addiction-related behaviors. The direction of change depends on the animal's prior drug history. However, little is known about the effect of a single exposure to cocaine on AMPAR distribution in the NAc of untreated rats. This is essential information for interpreting the literature on AMPAR trafficking after repeated cocaine exposure. In this study, we used a protein crosslinking assay to determine the effect of a single cocaine injection on surface and intracellular AMPAR subunit levels in the rat NAc. We found increased AMPAR surface expression in the NAc 24 h, but not 30 min or 2 h, after cocaine injection. A major effect of cocaine is to increase extracellular dopamine (DA) levels, leading to DA receptor activation. Therefore, we also evaluated the effects of directly acting DA receptor agonists. In contrast to the effects of cocaine, AMPAR surface expression was significantly decreased 24 h after injection of the D2-class agonist quinpirole, whereas no significant effects were produced by the D1-class agonist SKF 81297 or the mixed DA agonist apomorphine. Our results show that the effects of a single cocaine exposure in drug- and injection-naïve rats are distinct from those previously reported after repeated cocaine administration. They further suggest that cocaine exerts these effects by influencing neuronal circuits rather than simply stimulating NAc DA transmission.


Insights from China: understanding the impact of community resilience and government trust in psychological resilience and anxiety during COVID-19.
COVID-19 has the potential to greatly impact an individual mental well-being. However, an individual's psychological resilience, combined with support from their community and government disaster relief efforts can aid individuals in confronting crises with a positive mindset. The purpose of this study is to investigate how individuals, across three dimensions of individual resilience perception, community resilience perception, and government trust perception, mitigate individual anxiety during COVID-19. This study employed an online survey method that was not restricted by geographical location. Data collection took place from January 2022 to June 2022, and the valid questionnaires covered all 31 provinces, autonomous regions, and municipalities in China. The assessment of community resilience was conducted employing the Conjoint Community Resilience Assessment Measure-10 (CCRAM-10). Structural Equation Modeling (SEM) was also used to examine the relationship between community resilience, government trust, individual psychological resilience, and anxiety. The SEM results reveal that individual psychological resilience is significantly negatively correlated with anxiety (b = -0.099, p < 0.001), while there is a significant positive correlation between community resilience perception (b = 0.403, p < 0.001) and government trust (b = 0.364, p < 0.001) with individual psychological resilience. Furthermore, government trust perception enhances psychological resilience, consequently reducing anxiety (b = -0.036, p < 0.001). The results also revealed that women and increasing age had a mitigating effect on individual anxiety during COVID-19. Individual's mental state is influenced on multiple dimensions during COVID-19. Not only can individual psychological resilience better cope with anxiety, but support at the community and government dimensions has a significant impact on individual psychology. These resources can enhance the resilience of both individuals and communities, helping them better cope with stress and difficulties.


The LungPath study: variation in the diagnostic and staging pathway for patients with lung cancer in England.
The LungPath project investigated differences in lung cancer diagnostic practice by following the diagnostic pathways of 1507 patients from 19 representative English lung cancer centres. We found large variation in the proportion of patients receiving positron emission tomography-CT scan (range 13%-64%) and endobronchial ultrasound (range 2%-31%). There was also wide variation in the proportion of patients with good performance status who had their tumours histologically confirmed (range 61%-100%). The variation is discussed with reference to current national guidelines and implications for patient care.


The potential of proton magnetic resonance spectroscopy ((1)H-MRS) in the diagnosis and management of patients with brain tumors.
Proton ((1)H) magnetic resonance spectroscopy (MRS) is a noninvasive method that can monitor the metabolic changes in most brain diseases. This technique is now available on current 1.5 Tesla magnetic resonance units and does not require sophisticated software or time-consuming post-processing techniques. Previous studies using single-voxel techniques showed the usefulness of MRS for the diagnosis of brain tumor despite some technical issues, including spatial resolution and volume coverage. Recent advances have been made through the use of multivoxel techniques and metabolite maps, which allow assessment of both the entire volume of the lesion and the surrounding normal-appearing brain tissue. Recent studies suggest the potential of this technique to guide biopsies, to define radiotherapy targets, and to monitor patients after treatment. Some persistent drawbacks, including measurement time and spectral resolution, will probably be overcome in the near future.


Bicycloaromaticity and Baird-type bicycloaromaticity of dithienothiophene-bridged [34]octaphyrins.
Aromatic properties of two recently synthesized dithienothiophene-bridged (DTT) [34]octaphyrins have been investigated by calculating magnetically induced current densities and vertical excitation energies. These intriguing molecules have been proposed to be the first synthesized neutral bicycloaromatic compounds. The triplet state of their dications was even suggested to be Baird-type bicycloaromatic rendering them very interesting as a new prototype of molecules possessing simultaneously the two rare types of aromaticity. Here, we investigate computationally the aromatic properties of the neutral as well as the singly and doubly charged DTT-bridged [34]octaphyrins. Our study provides unambiguous information about changes in the aromatic properties of the DTT-bridged [34]octaphyrins upon oxidation. The calculations identify two independent diatropic ring currents in the neutral DTT-bridged [34]octaphyrins, showing that they are indeed bicycloaromatic. The current-density flow of the two independent ring currents of the bicycloaromatic compounds are visualized and individual aromatic pathways are quantified by performing numerical integration. The calculations show that two independent diatropic ring currents can indeed be sustained by molecules consisting of two aromatic rings that share a common set of π electrons. The current density calculations on the singly charged DTT-bridged [34]octaphyrins show that they are weakly antiaromatic, which does not agree with the suggested aromatic character deduced from spectroscopical studies. The triplet state of the two DTT-bridged [34]octaphyrin cations with very similar molecular structures have unexpectedly different aromatic character. One of them is Baird-type bicycloaromatic, whereas the triplet state of the other dication has one aromatic and one nonaromatic ring, which could not be resolved from available spectroscopical data. Calculations of excitation energies reveal that a simple model cannot be employed for interpreting the electronic excitation spectra of the present molecules, because more than 20 excited states contribute to the spectra above 2.5 eV (500 nm) showing the importance of computations. The present work illustrates how detailed information about molecular aromaticity can nowadays be obtained by scrutinizing calculated current densities.


Constrained Dual Scaling for Detecting Response Styles in Categorical Data.
Dual scaling (DS) is a multivariate exploratory method equivalent to correspondence analysis when analysing contingency tables. However, for the analysis of rating data, different proposals appear in the DS and correspondence analysis literature. It is shown here that a peculiarity of the DS method can be exploited to detect differences in response styles. Response styles occur when respondents use rating scales differently for reasons not related to the questions, often biasing results. A spline-based constrained version of DS is devised which can detect the presence of four prominent types of response styles, and is extended to allow for multiple response styles. An alternating nonnegative least squares algorithm is devised for estimating the parameters. The new method is appraised both by simulation studies and an empirical application.


Improving Night Time Driving Safety Using Vision-Based Classification Techniques.
The risks involved in nighttime driving include drowsy drivers and dangerous vehicles. Prominent among the more dangerous vehicles around at night are the larger vehicles which are usually moving faster at night on a highway. In addition, the risk level of driving around larger vehicles rises significantly when the driver's attention becomes distracted, even for a short period of time. For the purpose of alerting the driver and elevating his or her safety, in this paper we propose two components for any modern vision-based Advanced Drivers Assistance System (ADAS). These two components work separately for the single purpose of alerting the driver in dangerous situations. The purpose of the first component is to ascertain that the driver would be in a sufficiently wakeful state to receive and process warnings; this is the driver drowsiness detection component. The driver drowsiness detection component uses infrared images of the driver to analyze his eyes' movements using a MSR plus a simple heuristic. This component issues alerts to the driver when the driver's eyes show distraction and are closed for a longer than usual duration. Experimental results show that this component can detect closed eyes with an accuracy of 94.26% on average, which is comparable to previous results using more sophisticated methods. The purpose of the second component is to alert the driver when the driver's vehicle is moving around larger vehicles at dusk or night time. The large vehicle detection component accepts images from a regular video driving recorder as input. A bi-level system of classifiers, which included a novel MSR-enhanced KAZE-base Bag-of-Features classifier, is proposed to avoid false negatives. In both components, we propose an improved version of the Multi-Scale Retinex (MSR) algorithm to augment the contrast of the input. Several experiments were performed to test the effects of the MSR and each classifier, and the results are presented in experimental results section of this paper.


Thermal behaviour of ytterbium-doped fluorite crystals under high power pumping.
We report an in situ thermal study of Yb-doped fluorite crystals Yb:CaF(2) and Yb:SrF(2) under high power pumping, with or without laser operation. The experiment combines simultaneously thermography and measurement of the thermal aberrations. This setup allows us to measure temperature gradients, thermal lens, and absorption coefficients. From these measurements, we evaluate the thermal conductivity, fractional thermal load, and thermo-optic coefficient. Great differences are observed between the lasing and non lasing regimes. Our measured thermal lenses are greater than what are expected from the thermo-optic parameters found in previous work. Based on this thermal study, we design a laser cavity operating with large output power and TEM(00), leading to better performances for Yb:CaF(2) than Yb:SrF(2).


Medication adherence, hospitalization, and healthcare resource utilization and costs in patients with pulmonary arterial hypertension treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors.
Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real-world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type-5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type-5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six-month post-index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type-5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post-discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type-5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.


Spatial features of calcium transients during early and delayed afterdepolarizations.
Although changes in intracellular Ca2+ concentration ([Ca2+]i) are spatially heterogeneous during spontaneous contraction in mammalian cardiac muscle, it has not yet been observed how [Ca2+]i changes spatially within cardiac myocytes during delayed (DADs) and early (EADs) afterdepolarizations. The aim of this study is to characterize the spatial features of the increase in [Ca2+]i during such afterdepolarizations and to understand the ionic mechanisms responsible for them. Myocytes were enzymatically isolated from guinea pig ventricles and loaded with fura 2-acetoxymethylester, the Ca2+ fluorescence indicator dye. Membrane potential was recorded with a conventional microelectrode technique, and spatiotemporal changes in fura 2 fluorescence and cell length were recorded using a digital television system. After superfusion with potassium-free Tyrode solution, DADs and EADs were induced. During DADs, fluorescence transients were heterogeneous within myocytes (n = 11). Furthermore, they often propagated within myocytes as if they were "waves." In contrast, during EADs, fluorescence transients showed no waves within myocytes but rather showed synchronous changes throughout the myocytes (n = 15). The results of this study suggest that the spatial features of the increase in [Ca2+]i differ between the DADs and EADs. We concluded from these differing features that the ionic mechanisms responsible for the two triggered activities are different.


Correlation of age and sex with urine dehydroepiandrosterone sulfate level in healthy Thai volunteers.
Dehydroepiandrosterone sulfate (DHEAs), a prohormone secreted by the adrenal gland, plays a role in the synthesis of sex hormones, namely, androgen and estrogen. It has been found that the amount of DHEAs is correlated with age, although most studies have focused on the correlation of serum DHEAs levels with age and sex. Thus, this noninvasive, cross-sectional study aimed to investigate the correlation of urine DHEAs levels with age and sex in healthy Thai volunteers aged 20-80 years. DHEAs levels were measured in 178 healthy volunteers using electrochemiluminescence immunoassay and then normalized by creatinine. Multiple regression was performed to determine the correlation of urine DHEAs levels normalized by creatinine with age and sex. The normalized DHEAs levels are correlated with age group for both sexes. Moreover, an increasing trend in DHEAs levels was found in the age group 20-29 years, and the DHEAs level peaked at the age group 30-39 years before declining with advancing age. Based on the multiple regression analyses, the significance of the interaction term (P < 0.05) indicates that both age and sex significantly contribute to the prediction of ln (DHEAs/Creatinine). Our fitted model implies the following: as age increases by 1 year, DHEAs/Creatinine is expected to decrease by 3.63% in females and by 2.18% in males. This study reports more data on clinical reference value of urine DHEAs levels in healthy volunteers. Our result demonstrates urine DHEAs levels are associated with age and sex and decline by 2-3% a year.


Exon-based phylogenomics strengthens the phylogeny of Neotropical cichlids and identifies remaining conflicting clades (Cichliformes: Cichlidae: Cichlinae).
The phenotypic, geographic, and species diversity of cichlid fishes have made them a group of great interest for studying evolutionary processes. Here we present a targeted-exon next-generation sequencing approach for investigating the evolutionary relationships of cichlid fishes (Cichlidae), with focus on the Neotropical subfamily Cichlinae using a set of 923 primarily single-copy exons designed through mining of the Nile tilapia (Oreochromis niloticus) genome. Sequence capture and assembly were robust, leading to a complete dataset of 415 exons for 139 species (147 terminals) that consisted of 128 Neotropical species, six African taxa, and five Indo-Malagasy cichlids. Gene and species trees were calculated using alternative partitioning schemes and reconstruction methods. In general, all methods yielded similar topologies to previously hypothesized relationships within the Cichlinae and clarified several relationships that were previously poorly supported or in conflict. Additional work will be needed to fully resolve all aspects of Cichlinae phylogeny. Overall, this approach yielded a well-resolved phylogeny of Neotropical cichlids that will be of utility for future assessments of the evolutionary and ecological processes within this diverse group of fishes. Furthermore, the general methodology employed here of exon targeting and capture should be applicable to any group of organisms with the availability of a reference genome.


Symposium "International Medical Students - Support Programs in Practical Application": Networking, best-practice examples and local representation.
The new project "International Medical Students" within the German Medical Students' Association (bvmd) aims at connecting local support programs for international medical students as well as the representation of their interests within the bvmd. Within the frame of this project, the first symposium "International Medical Students - Support Programs in Practical Application" took place from the 12th to the 14th of May 2017 at the Hannover Medical School (MHH). Through partaking in different workshops, 31 participants discussed the framework conditions of local work (i.e. curricula, tutorials, social offers, cooperation between faculty members and student body, legal aspects), common problems (i.e. addressing the target group, funding of support programs) and possible solutions (i.e. targeted advertisement, application for public funds). This report constitutes a summary of the results of these discussions. The feedback from the participants on the need for such a regular exchange and the format of the symposium was positive. However, there were requests for further thematic specification. Based on this feedback the next symposium is planned for 2018.


Formalistic description of multislice calculation method.
This paper presents a formalistic description of the multislice method. The effects of the number of beams, the number of Fourier components for the projected potential used for the phase grating, the number of the iterations and the slice thickness on multislice calculations are discussed qualitatively. The phenomenon of "leaking" of the wave function to higher order reflections in reciprocal space in a multislice calculation is also discussed. The relationship between the number of Fourier components of the projected potential and the number of beams used for the wave function in reciprocal space is discussed. Additionally, the difference between the eigenvalue method and the multislice method is introduced. The difference between the use of the Fourier transformation vs. the convolution in reciprocal space on multislice calculations is also discussed. Multislice computer simulations were carried out using the commercial program Cerius2 for rutile TiO2. Calculated results are compared with the results of other programs reported in the literature. The effect of slice thickness of the multislice calculation is also shown.


Carbon profile of the managed forest sector in Canada in the 20th century: sink or source?
Canada contains 10% of global forests and has been one of the world's largest harvested wood products (HWP) producers. Therefore, Canada's managed forest sector, the managed forest area and HWP, has the potential to significantly increase or reduce atmospheric greenhouse gases. Using the most comprehensive carbon balance analysis to date, this study shows Canada's managed forest area and resulting HWP were a sink of 7510 and 849 teragrams carbon (TgC), respectively, in the period 1901-2010, exceeding Canada's fossil fuel-based emissions over this period (7333 TgC). If Canadian HWP were not produced and used for residential construction, and instead more energy intensive materials were used, there would have been an additional 790 TgC fossil fuel-based emissions. Because the forest carbon increases in the 20th century were mainly due to younger growing forests that resulted from disturbances in the 19th century, and future increases in forest carbon stocks appear uncertain, in coming decades most of the mitigation contribution from Canadian forests will likely accrue from wood substitution that reduces fossil fuel-based emissions and stores carbon, so long as those forests are managed sustainably.


Appraisal of pollution scenario, sources and public health risk of harmful metals in mine water of Barapukuria coal mine industry in Bangladesh.
This study was conducted to assess the accumulation and sources of harmful metals and associated public health risk from the usage of underground mine water of Barapukuria coal mine in Bangladesh, keeping in mind the optimum reuse. Thirty underground mine water samples had been analyzed for assessing temperature, pH, EC, TC, DO, BOD, COD, Ca, K, S, Ti, Mn, V, Fe, Co, Ni, Cu, Zn, Br, Rb, Sr, and Pb. Numerous pollution evaluation and health risk assessment indices along with multivariate statistical tools were employed in this study to apprise the pollution scenario, controlling factors, and probable health risk. The chronic or persistent health risk of metals via oral and dermal exposure of adults and children was determined using the hazard quotient (HQ) and hazard index (HI). The results showed that the content of physicochemical parameters and potentially harmful elements in water samples was many folds higher than the national and international standards. The results of pollution evaluation indices indicate that coal seam-leached mine water is highly concentrated by potentially harmful metals and not suitable for drinking, agriculture, and aquatic lives. The correlation coefficients and multivariate analysis illustrate both the geological and anthropogenic factors controlling the variability of metals in mine water. Results of HQoral value suggest that V, Co, and Pb are significant health risk for adults and Mn, V, Co, Cu, and Pb are for children. Vanadium is found potential for dermal effects, and HIdermal value directs 33%, and 70% samples exceed the safe limit for adults and children, respectively. The HI value suggests that oral exposure to harmful metals creates more harm than dermal absorption, and children are more vulnerable than adults. It is anticipated that the outcomes of this study would deliver expedient insights to initiate necessary steps to minimize the public health risk by applying appropriate environmental protocols.


Numerical simulation of heat transfer performance of spiral wound heat exchanger under sloshing condition.
LNG floating production storage and offloading (FPSO) unit is a new type of floating production unit developed for offshore natural gas fields. It performs the functions of natural gas extraction, pretreatment, liquefaction, and storage. In this study, the heat transfer characteristics of a spiral-wound heat exchanger were studied using numerical simulations, which provides a basis for equipment selection and structural optimization of spiral-wound heat exchangers. The main research contents and conclusions are as follows. Under land-based simulation conditions, the heat transfer coefficient of the shell side of the spiral-wound heat exchanger decreases with an increase in the winding angle of the heat exchange tube, decreases with an increase in the spacing of the heat exchange tube, and increases with an increase in the outer diameter of the heat exchange tube. When the winding angle increased from 5° to 8°, the heat transfer coefficient decreased by 6.70%. The heat transfer coefficient of the shell side decreased by 13.21% when the heat exchange tube spacing increased from 14 to 17 mm. The heat transfer coefficient of the shell side increased by 22.89% when the outer diameter of the heat exchange tube increased from 9 to 12 mm. When the sloshing angle is constant, the heat transfer coefficient of the spiral-wound heat exchanger decreases with an increase in the winding angle and spacing of the heat exchange tubes, and increases with an increase in the outer diameter of the heat exchange tubes. When the structural parameters of the heat exchanger are constant, the heat transfer coefficient decreases as the sloshing angle increases. When the sloshing angle was less than 3°, the sloshing promoted heat transfer on the shell side. When the sloshing angle was higher than 7°, the heat transfer effect of the shell side deteriorated considerably, which weakened the heat transfer performance of the heat exchanger. When the sloshing period is constant, the heat transfer coefficient of the wound heat exchanger decreases with an increase in the winding angle and spacing of the heat exchange tubes, and increases with an increase in the outer diameter of the heat exchange tubes. When the structural parameters of the heat exchanger are constant, the heat transfer coefficient increases with sloshing period. When the sloshing period was greater than 15 s, the influence of sloshing on the heat transfer on the shell side of the heat exchanger was relatively weak.


Does Phase of the Menstrual Cycle Affect Balance and Postural Control?
The aim of the study is to examine the effects of menstrual cycle phases (MCP) on balance and postural control. The study was carried out with 63 volunteer women. Digital ovulation kits and, a Menstrual Cycle Regularity Questionnaire (MCRQ) to detect menstrual cycle regularity and duration, Premenstrual Syndrome Questionnaire (PMSQ) to question the presence of premenstrual syndrome, Menstruation Attitude Questionnaire (MAQ) to assess menstrual attitudes, International Physical Activity Questionnaire Short Form (IPAQ-SF) to question physical activity level was used. Balance and postural oscillation were evaluated with Balance Master balance and performance test device and Tekscan MatScan™ Pressure Mat System, respectively. All evaluations were repeated twice, in the preovulatory period and the postovulatory period. When the evaluations of the preovulatory period and the postovulatory period were compared, there was %3 increase in the percent weight-bearing of the non-dominant extremity (p = 0.01) and %2.5 decrease in the percent weight-bearing of the dominant limb in the postovulatory period (p = 0.01). %8 increase in functional reach distances was detected in the postovulatory period (p < 0.01). It was determined that there was %7.4 decrease in the oscillation rate of the center of gravity in the static stance with eyes open and %9 decrease in the static stance with eyes closed in the postovulatory period (p = 0.35, p = 0.18, respectively). It has been determined that the balance and postural control of young women are negatively affected in the preovulatory period and the function improved from the preovulatory period to the postovulatory period.


Developmental regulation of erythropoiesis by hematopoietic growth factors: analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver.
Fetal hematopoiesis is characterized by expanding erythropoiesis to support a continuously increasing RBC mass. To explore the basis for this anabolic, nonhomeostatic erythropoiesis, the proliferative effect of recombinant hematopoietic growth factors on highly enriched hematopoietic progenitor cells from fetal and adult tissues were compared. Fetal hepatic BFU-E, unlike adult bone marrow (BM) or peripheral blood (PB) BFU-E, were capable of proliferating in response to erythropoietin in the absence of added GM colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), and erythropoietin (Epo) directly stimulated the expansion of the fetal BFU-E pool in suspension culture. A murine monoclonal antibody (MoAb), Ep 3, was raised against enriched fetal liver progenitor cells, which detected all fetal BFU-E and which reacted with the erythropoietin-responsive, GM-CSF/IL-3-independent fraction of adult BM BFU-E and CFU-E. All adult PB BFU-E were Ep 3- but became Ep 3+ after stimulation with GM-CSF or IL-3. These data indicate that Epo plays a unique role in fetal hepatic erythropoiesis, stimulating proliferation of immature BFU-E in addition to promoting terminal differentiation of later erythroid progenitor cells. In addition, these results demonstrate a MoAb which detects all erythropoietin-responsive progenitor cells and distinguishes the BFU-E compartments in adult BM and PB.


Feasibility and efficacy of the Vojta therapy in subacromial impingement syndrome: a randomized controlled trial.
Subacromial impingement syndrome (IS) is a common disorder associated with functional impairment and disability of the shoulder. The aim of this study was to evaluate the efficacy of Vojta therapy (VT) techniques compared with standard therapy (ST) in patients with subacromial IS. A randomized controlled trial was performed, with 60 patients with IS (mean age, 61±12 years) randomized into two groups: ST (n=30) and ST plus Vojta therapy (SVT, n=30). Both received 15 treatment sessions over 4 weeks. Outcome measures included pain intensity, functionality, joint range of motion (RoM), strength, and quality of life measurements. The efficacy of both treatments was analysed, both comparatively and separately, immediately after completion of treatment and after 3 months. After the intervention, both groups showed statistically significant differences in visual analogue scale (P=0.001), RoM (P<0.01), and strength (P<0.001), which were also seen 3 months after the intervention. SVT is more efficient in both the short and medium term in reducing pain, improving functionality, increasing articular RoM and strength, and offering a better quality of life in IS patients.


Water-Soluble Nanoparticle Receptors Supramolecularly Coded for Acidic Peptides.
Sequence-specific recognition of peptides is of enormous importance to many chemical and biological applications, but has been difficult to achieve due to the minute differences in the side chains of amino acids. Acidic peptides are known to play important roles in cell growth and gene expression. In this work, we report molecularly imprinted micelles coded with molecular recognition information for the acidic and hydrophobic side chains of acidic peptides. The imprinted receptors could distinguish acidic amino acids from other polar and nonpolar amino acids, with dissociation constants of tens of nanomolar for biologically active peptides containing up to 18 amino acids.


A new insertion sequence, IS14999, from Corynebacterium glutamicum.
A new insertion sequence from Corynebacterium glutamicum ATCC 14999 was isolated and characterized. This IS element, designated IS14999, comprised a 1149 bp nucleotide sequence with 22 bp imperfect terminal inverted repeats. IS14999 carries a single open reading frame of 345 amino acids encoding a putative transposase that appears to have partial homology to IS642, an IS630/Tc1 superfamily element, at the C-terminal region in the amino acid sequence. This indicated that IS14999 belonged to the IS630/Tc1 superfamily, which was first identified in C. glutamicum. IS14999 has a unique distance of 38 amino acid residues between the second and third amino acids in the DDE motif, which is well known as the catalytic centre of transposase. This suggested that IS14999 constituted a new subfamily of the IS630/Tc1 superfamily. A phylogenetic tree constructed on the basis of amino acid sequences of transposases revealed that this new transposable element was more similar to eukaryotic Tc1/mariner family elements than to prokaryotic IS630 family elements. Added to the fact that IS14999 was present in only a few C. glutamicum strains, this implies that IS14999 was probably acquired by a recent lateral transfer event from eukaryotic cells. Analysis of the insertion site in C. glutamicum R revealed that IS14999 appeared to transpose at random and always caused a target duplication of a 5'-TA-3' dinucleotide upon insertion, like the other IS630/Tc1 family elements. These findings indicated that IS14999 could be a powerful tool for genetic manipulation of corynebacteria and related species.


Ultrasonographic evaluation in plantar fasciitis.
The heels of 23 patients who were diagnosed with unilateral/bilateral plantar fasciitis were evaluated via ultrasonography and compared with their asymptomatic feet and a control group of 23 people. Plantar fascial thickness, echogenity, and heel pad thickness were evaluated, and the results were statistically analyzed. For symptomatic feet, increased thickness of the fascia and reduced echogenity were constant ultrasonographic findings (mean, 4.79 mm for symptomatic feet; 2.17 mm for control group, P < .05). No significant difference was found between heel pads of the diseased and healthy feet (mean, 12.96 mm for symptomatic feet; 13.10 mm for control group; P > .05). Ultrasonography seems to be a valuable, noninvasive diagnostic tool for the evaluation of plantar fasciitis.


[Determination of particle size distribution of nano-particles by capillary zone electrophoresis].
A new method was established for the determination of the size distribution of nano-particles by capillary zone electrophoresis (CZE). The data processing method for acquiring size distribution from primary electropherogram was investigated. The relative standard deviation of migration time was deduced by using dimethyl sulfoxide (DMSO) as an internal standard. Scattering effect of nano-particles was studied and a correction equation was established to correct this influence. The experimental results showed that the correction method was effective. After correction, the measuring results for the mixed samples with different mass ratios of PS50 and PS125 were almost the same with their theoretical values and the relative deviation was reduced from 35% to 5%. This method for the determination of size distribution is satisfactory.


O brother, where art thou? Investment in siblings for inclusive fitness benefits, not father absence, predicts earlier age at menarche.
Numerous studies have indicated that father absence is associated with earlier age at menarche, with many evolutionary theories assuming that father absence is a causal factor that accelerates reproductive development. However, an alternative interpretation suggests that offspring may reproduce earlier in the presence of half- or step-siblings as the indirect fitness benefits to investing in them are lower, relative to delaying reproduction and investing in full siblings. From this perspective, father absence may perform no causal role in facilitating the onset of menarche. Using data from the Avon Longitudinal Study of Parents and Children, I find that individuals with only half- or step-siblings reach reproductive age earlier than those with only full siblings, with no independent effect of father absence. These results suggest that inclusive fitness benefits to investing in siblings, rather than father absence, may predict variation in age at menarche. These results provide a greater understanding of the adaptive mechanisms involved in reproductive decision-making, as well as potential implications for human life-history evolution and cooperative breeding more broadly.


Mediation Effects of Coping Styles on Fear of Progression and Reproductive Concerns in Breast Cancer Patients of Reproductive Age.
This study aimed to investigate reproductive concerns among breast cancer patients of reproductive age, analyze the influencing factors, explore the relationship between coping styles, fear of progression (FOP), and reproductive concerns, and identify the multiple effects of coping styles on the relationship between FOP and reproductive concerns among Chinese breast cancer patients. A cross-sectional, descriptive study was conducted among breast cancer patients in four tertiary grade A hospitals in Fujian, China, from January 2022 to September 2022. A total of 210 patients were recruited to complete paper-based questionnaires, which included the general data questionnaires, the Reproductive Concerns after Cancer Scale (RCACS), the Fear of Progression Questionnaire-Short Form (FOP-Q-SF), and the Medical Coping Modes Questionnaire (MCMQ). Structural equation models were utilized to evaluate the multiple effects of coping styles on FOP and reproductive concerns. Reproductive concerns in breast cancer patients had a mean score of 53.02 (SD, 10.69), out of a total score of 90, and coping styles for cancer (confrontation, avoidance) were closely associated with FOP and reproductive concerns. FOP showed a significant positive correlation with reproductive concerns (r=.52, p<.01). At the same time, confrontation was significantly negatively correlated with both FOP (r=-.28, p<.01) and reproductive concerns (r=-.39, p<.01). Avoidance was positively correlated to both FOP (r=.25, p<.01) and reproductive concerns (r=.34, p<.01). The impact of fear of progression on reproductive concerns is partially mediated by confrontation and avoidance, with effect sizes of .07 and .04, respectively. These mediating factors account for 22.0% of the total effect. The FOP directly impacted reproductive concerns, while coping styles could partially mediate the association between FOP and reproductive concerns. This study illustrates the role of confrontation and avoidance in alleviating reproductive concerns, suggesting that it is necessary to focus on the changes in reproductive concerns among reproductive-age breast cancer patients. Healthcare professionals can improve disease awareness and reduce patients' fear of progression, thereby promoting positive psychological and coping behaviors and ultimately alleviating reproductive concerns.


Anomalous elasticity and plastic screening in amorphous solids.
Amorphous solids appear to react elastically to small external strains, but in contrast to ideal elastic media, plastic responses abound immediately at any value of the strain. Such plastic responses are quasilocalized in nature, with the "cheapest" one being a quadrupolar source. The existence of such plastic responses results in screened elasticity in which strains and stresses can either quantitatively or qualitatively differ from the unscreened theory, depending on the specific screening mechanism. Here we offer a theory of such screening effects by plastic quadrupoles, dipoles, and monopoles, explain their natural appearance, and point out the analogy to electrostatic screening by electric charges and dipoles. For low density of quadrupoles the effect is to normalize the elastic moduli without a qualitative change compared to pure elasticity theory; for higher density of quadrupoles the screening effects result in qualitative changes. Predictions for the spatial dependence of displacement fields caused by local sources of strains are provided and compared to numerical simulations. We find that anomalous elasticity is richer than electrostatics in having a screening mode that does not appear in the electrostatic analog.


Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis.
Aortic valve sclerosis (AVSc) is a hallmark of several cardiovascular conditions ranging from chronic heart failure and myocardial infarction to calcific aortic valve stenosis (AVS). AVSc, present in 25-30% of patients over 65 years of age, is characterized by thickening of the leaflets with marginal effects on the mechanical proprieties of the valve making its presentation asymptomatic. Despite its clinical prevalence, few studies have investigated the pathogenesis of this disease using human AVSc specimens. Here, we investigate in vitro and ex vivo BMP4-mediated transdifferentiation of human valve interstitial cells (VICs) towards an osteogenic-like phenotype in AVSc. Human specimens from 60 patients were collected at the time of aortic valve replacement (AVS) or through the heart transplant programme (Controls and AVSc). We show that non-calcified leaflets from AVSc patients can be induced to express markers of osteogenic transdifferentiation and biomineralization through the combinatory effect of BMP4 and mechanical stimulation. We show that BMP4 antagonist Noggin attenuates VIC activation and biomineralization. Additionally, patient-derived VICs were induced to transdifferentiate using either cell culture or a Tissue Engineering (TE) Aortic Valve model. We determine that while BMP4 alone is not sufficient to induce osteogenic transdifferentiation of AVSc-derived cells, the combinatory effect of BMP4 and mechanical stretch induces VIC activation towards a phenotype typical of late calcified stage of the disease. This work demonstrates, for the first time using AVSc specimens, that human sclerotic aortic valves can be induced to express marker of osteogenic-like phenotype typical of advanced severe aortic stenosis.


Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis.
MbtA catalyzes the first committed step of mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) and is responsible for the incorporation of salicylic acid into the mycobactin siderophores. 5'-O-[N-(Salicyl)sulfamoyl]adenosine (Sal-AMS) is an extremely potent nucleoside inhibitor of MbtA that possesses excellent activity against whole-cell Mtb but suffers from poor bioavailability. In an effort to improve the bioavailability, we have designed four conformationally constrained analogues of Sal-AMS that remove two rotatable bonds and the ionized sulfamate group on the basis of computational and structural studies. Herein we describe the synthesis, biochemical, and microbiological evaluation of chromone-, quinolone-, and benzoxazinone-3-sulfonamide derivatives of Sal-AMS. We developed new chemistry to assemble these three heterocycles from common β-ketosulfonamide intermediates. The synthesis of the chromone- and quinolone-3-sulfonamide intermediates features formylation of a β-ketosulfonamide employing dimethylformamide dimethyl acetal to afford an enaminone that can react intramolecularly with a phenol or intermolecularly with a primary amine via addition-elimination reaction(s). The benzoxazinone-3-sulfonamide was prepared by nitrosation of a β-ketosulfonamide followed by intramolecular nucleophilic aromatic substitution. Mitsunobu coupling of these bicyclic sulfonamides with a protected adenosine derivative followed by global deprotection provides a concise synthesis of the respective inhibitors.


[Effects of selenium supplement on acute lower respiratory tract infection caused by respiratory syncytial virus].
An intervention study was conducted in 75 young children under one year hospitalized with pneumonia or bronchiolitis caused by respiratory syncytial virus (RSV) to evaluate therapeutic effectiveness of selenium (Se) supplement on acute respiratory lower tract infection caused by RSV with randomly controlled and double-masked method. Trial subjects were divided into two groups, one with 37 children in routine treatment and the other with 38 children in routine treatment plus Se supplement. The control group derived from 35 normal children during their physical check-up in the out-patient department. Sodium selenite was supplemented orally with 1 mg on the second day of hospitalization. Results showed that days needed for their relief of symptoms and signs were fewer in Se supplement group than that in controls and recovery in indicators of cell immune was better in the former than that in the latter. Levels of Se and glutathione peroxidase in plasma and white cells could be increased by Se supplement. It suggests that Se supplement can promote recovery from RSV infection.


Nasal allergies in the Middle Eastern population: results from the "Allergies in Middle East Survey".
Chronic respiratory diseases such as asthma and allergic rhinitis (AR) are a major public health problem in developing countries including those in the Middle East. However, to date, there is a paucity of information related to physician-diagnosed AR in this region. The Allergies in Middle East Survey was undertaken to help clarify and broaden the understanding of physician-diagnosed AR across Egypt, Iran, Lebanon, Saudi Arabia, and the United Arab Emirates. The survey explores the frequency of physician-diagnosed AR, prevalence and types of associated symptoms, the impact on quality of life (QOL), current treatment practices, and therapy expectations. In total, 7411 households in five countries (Egypt, Lebanon, Saudi Arabia, Iran and the United Arab Emirates) were screened to identify individuals that were ≥4 years old with a physician diagnosis of AR and either symptoms and/or treatment in the past 12 months. A total of 501 respondents from the five countries completed the survey. Standardized questionnaires were used to make comparisons across the regions; however, the data collection procedures were tailored for each country. The sample was probability based to ensure valid statistical inference to the population. Ten percent of the Middle East population surveyed had a physician diagnosis of AR, with 65% of respondents stating that their allergies were intermittent in nature. An otolaryngologist or allergist diagnosed the majority of the individuals surveyed. Runny nose, nasal and throat itching, postnasal drip, and nasal congestion or stuffed up nose were the most common and bothersome symptoms of AR. The majority of survey participants (58% of the overall survey population) with AR reported that the condition had an impact on their daily private and professional life. Seventy-two percent of adults reported that their AR symptoms limited their work/school activities and 35% reported that their AR interfered with and caused them to miss work or school within the past 12 months. One factor, in addition to the outward AR symptoms, that could have contributed to these function impairments may have been sleep disturbances. Although a secondary symptom to AR, sleep disturbances (difficulty getting to sleep, waking up during the night or lack of a good night's sleep) were shown in this survey to be extremely troubling in ∼15% of AR sufferers. In the past year >90% of patients reported taking a medication of any type for their AR, with nearly a 4:1 ratio of patients taking a prescription medication versus an over-the-counter (OTC) medication in the past 4 weeks. Over 75% of survey respondents reported taking an intranasal corticosteroid (INCS) in the last 4 weeks and the satisfaction rate of INCS medications was similar to that reported for OTC medications. The most common reasons cited for dissatisfaction with INCS medications were inadequate effectiveness, bothersome side effects (e.g., unpleasant taste and retrograde drainage into the pharynx), decreased effectiveness with chronic use, and failure to provide 24-hour relief. These data show that AR is common in the Middle East region as elsewhere in the world. Many patients with AR in Middle East region suffer from their symptoms (e.g., runny nose, nasal itching, nasal congestion, postnasal drip, and other symptoms) on all or most days during the times of the year that their allergies are worst. These symptoms have been shown to reduce QOL and performance at work/school to a significant degree. Additionally, the survey data underscore a considerable treatment gap with current therapies for AR and that many AR patients still have not found adequate effectiveness with currently available medications. Thus, through identification of disease impact on the Middle East population and highlighting treatment gaps, clinicians in the Middle East may better understand and treat AR, leading to improvements in overall patient satisfaction and QOL.