Neuromotor ability in 5- to 7-year-old children with very low or extremely low birthweight.
This study was intended to determine the effects of extremely low birthweight (ELBW, 500 to 999 g) and very low birthweight (VLBW, 1000 to 1499 g) on neuromotor ability in 5- to 7-year-old children. Fourteen ELBW and 20 VLBW children were compared with 24 term control children of normal birthweight (NBW, >2500 g). Using quantitative assessment instruments, the following data were collected: maximal cycling speed during 30 seconds of cycling at 'zero' resistance, simple reaction time of the legs, and performance on components of a whole-body coordination test. The main findings were a slower reaction time, lower maximal cycling speed, and lower coordination scores in the ELBW group compared with the NBW group and, for some variables, with the VLBW group. The reduced motor performance in these children appears for the most part to be a reflection of impaired neuromotor control and motor development, rather than merely a smaller body or muscle size.


Nasal interferon responses in leukaemia.
Nasal concentrations of leucocyte interferon measured immunoradiometrically were appreciably higher in children infected with influenza viruses than those infected with paramyxoviruses. Regardless of the infecting virus, leukaemic children produced normal amounts of interferon, but this appeared to have little effect on the duration of excretion of virus.


UV resonance raman spectra of ligand binding intermediates of sol-gel encapsulated hemoglobin.
We report for the first time specific conformational changes for a homogeneous population of ligand-bound adult deoxy human hemoglobin A (HbA) generated by introducing CO into a sample of deoxy-HbA with the effector, inositol hexaphosphate, encapsulated in a porous sol-gel. The preparation of ligand-bound deoxy-HbA results from the speed of ligand diffusion relative to globin conformational dynamics within the sol-gel (1). The ultraviolet resonance Raman (UVRR) difference spectra obtained reveal that E helix motion is initiated upon ligand binding, as signaled by the appearance of an alpha14beta15 Trp W3 band difference at 1559 cm(-1). The subsequent appearance of Tyr (Y8a and Y9a) and W3 (1549 cm(-1)) UVRR difference bands suggest conformational shifts for the penultimate Tyralpha140 on the F helix, the "switch" region Tyralpha42, and the "hinge" region Trpbeta37. The UVRR results expose a sequence of conformational steps leading up to the ligation-induced T to R quaternary structure transition as opposed to a single, concerted switch. More generally, this report demonstrates that sol-gel encapsulation of proteins can be used to study a sequence of specific conformational events triggered by substrate binding because the traditional limitation of substrate diffusion times is overcome.


Laparoscopy for Benign Diseases of the Colon.
Laparoscopic surgery has revolutionized the delivery of care to the surgical patient undergoing colorectal resection. Since the first laparoscopic-assisted colectomy in 1991, significant advances have been made in minimally invasive colorectal surgery. For many benign conditions, laparoscopic colectomy has been proven to be safe and effective, and in some instances superior when compared with open surgery. Complex laparoscopic resections such as those for diverticulitis and inflammatory bowel disease have also been shown to have equivalent outcomes when compared with open surgery. Short-term benefits of a minimally invasive approach include less pain, decreased rates of wound infection and postoperative morbidity, faster return of bowel function, and shorter length of stay. Improvements in long-term complications have also been noted with lower incidence of incisional hernias and small bowel obstructions secondary to adhesions. As surgeons become more facile with laparoscopic resection, more complex cases such as those for complicated diverticulitis and reoperative surgery for inflammatory bowel disease can be completed with shorter operative times and decreased cost.


Size-Dependent Local Ordering in Melanin Aggregates and Its Implication on Optical Properties.
We present atomic scale models of differently sized eumelanin nanoaggregates from molecular dynamics simulations combined with a simulated annealing procedure. The analysis reveals the formation of secondary structures due to π-stacking on one hand, but on the other hand a broad distribution of stack geometries in terms of stack size, horizontal displacement angles, and relative torsion angles. The displacement angle distribution, which is a measure of the occurrence of zigzag and linear stacking motives, respectively, strongly depends on the aggregate size-and is hence controlled by the interplay of surface and bulk energy terms. Semiempirical spectra calculations of small stacks (up to five protomolecules) reveal a strong dependence on the precise stack structure and allow for a direct structure-property correlation. The observed spectral shifts result in an overall spectral broadening and, hence, further support the geometric disorder model, which complements the chemical disorder model in the interpretation of eumelanin's monotonically increasing broad-band absorption.


PTEN inhibits AMPK to control collective migration.
Pten is one of the most frequently mutated tumour suppressor gene in cancer. PTEN is generally altered in invasive cancers such as glioblastomas, but its function in collective cell migration and invasion is not fully characterised. Herein, we report that the loss of PTEN increases cell speed during collective migration of non-tumourous cells both in vitro and in vivo. We further show that loss of PTEN promotes LKB1-dependent phosphorylation and activation of the major metabolic regulator AMPK. In turn AMPK increases VASP phosphorylation, reduces VASP localisation at cell-cell junctions and decreases the interjunctional transverse actin arcs at the leading front, provoking a weakening of cell-cell contacts and increasing migration speed. Targeting AMPK activity not only slows down PTEN-depleted cells, it also limits PTEN-null glioblastoma cell invasion, opening new opportunities to treat glioblastoma lethal invasiveness.


The MAP kinase signal transduction network in Candida albicans.
MAP (mitogen-activated protein) kinase-mediated pathways are key elements in sensing and transmitting the response of cells to environmental conditions by the sequential action of phosphorylation events. In the fungal pathogen Candida albicans, different routes have been identified by genetic analysis, and especially by the phenotypic characterization of mutants altered in the Mkc1, Cek1/2 and Hog1 MAP kinases. The cell integrity (or MKC1-mediated) pathway is primarily involved in the biogenesis of the cell wall. The HOG pathway participates in the response to osmotic stress while the Cek1 pathway mediates mating and filamentation. Their actual functions are, however, much broader and Mkc1 senses several types of stress, while Hog1 is also responsive to other stress conditions and participates in two morphogenetic programmes: filamentation and chlamydospore formation. Furthermore, it has been recently shown that Cek1 participates in a putative pathway involved in the construction of the cell wall and which seems to be operative under basal conditions. As these stimuli are frequently encountered in the human host, they provide a reasonable explanation for the significant reduction in pathogenicity that several signal transduction mutants show in certain animal models of virulence. MAPK pathways therefore represent an attractive multienzymic system for which novel antifungal therapy could be designed.


Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis.
DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G>A and c.2846A>T) or 50% (DPYD*2A and c.1679T>G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G>A, 25 DPYD*2A, 13 c.2846A>T, and-when pooled-93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P = .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P = .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P = .007) was found in c.1236G>A variant carriers, whereas no differences were found for DPYD*2A and c.2846A>T carriers. In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose.


Normal aging and forgetting rates on the Wechsler Memory Scale-Revised.
The deleterious effects of aging on various cognitive abilities are widely recognized, yet little is known regarding what constitutes "normal" memory test performance in individuals over the age of 74. In this study, forgetting rates for verbal and nonverbal material from the Wechsler Memory Scale-Revised (WMS-R) were examined in groups of older healthy individuals, age 50-70 and 75-95. Despite equivalent scores on measures of global cognitive status and attention/ concentration, the older group demonstrated significantly more rapid forgetting rates on the Visual Reproduction, Verbal Paired Associates, and Visual Paired Associates subtests of the WMS-R. Although patients with Alzheimer's disease also evidence very rapid forgetting on some subtests, the severity and pattern of losses appears useful in differentiating "abnormal" forgetting from that exhibited by normal elderly subjects. Preliminary normative data for normal elderly subjects on the WMS-R are presented, and the need for appropriate norms for elderly individuals is discussed.


Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy. AIEOP/FONOP-TMO Group. Italian Association of Paediatric Haemato-Oncology.
From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3-21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in >2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1-42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in >2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P < 0.0001) and TBI containing regimen (TBI vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in >2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P < 0.0001). In conclusion, ABMT is an effective treatment after one early IE relapse. Few patients can be rescued after BM relapse.


Factors associated with health-related quality of life among pulmonary tuberculosis patients in Manila, the Philippines.
Health-related quality of life (HRQOL) among pulmonary tuberculosis (PTB) patients has not been investigated in the Philippines. This study aimed to describe HRQOL among PTB patients and to determine factors that are associated with HRQOL. A cross-sectional survey was conducted at 10 public health centers and 2 non-government organization clinics in District I, Tondo, Manila. Face-to-face interviews using a structured questionnaire including Short Form-8, Duke-UNC Functional Social Support Questionnaire, and Medical Research Council (MRC) dyspnea scale were performed with 561 PTB patients from September to November 2012. HRQOL among PTB patients was generally impaired. Factors associated with lower physical component summary were exposure to secondhand smoke (SHS) (P = 0.038), positive sputum smear result (P = 0.027), not working (P = 0.038), lower education level (P < 0.01), number of symptoms (P < 0.01), number of adverse drug reactions (ADRs) (P < 0.01), higher score on the MRC dyspnea scale (P < 0.01), and low perceived social support (P = 0.027). Lower body mass index (P = 0.016), non-SHS exposure (P = 0.033), number of symptoms (P < 0.01), number of ADRs (P < 0.01), low perceived social support (P < 0.01), and negative perception for waiting time in the clinic (P = 0.026) were identified to be factors significantly associated with lower mental component summary. Socioeconomic status including SHS exposure and low perceived social support, in addition to clinical factors, may be associated with poor HRQOL. Further study would be needed to assess our findings.


Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors.
The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order k(th) (W(k)). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the W(k)(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated W(k)(i) values were used as inputs for different ANNs in order to discriminate correct node connectivity patterns from incorrect random patterns. The MIANN models obtained present good values of Sensitivity/Specificity (%): MRNs (78/78), IWDBNs (90/88), and SFLN (86/84). These preliminary results are very promising from the point of view of a first exploratory study and suggest that the use of these models could be extended to the high-throughput re-evaluation of connectivity in known complex networks (collation).


Lactosyl ceramidosis: normal activity for two lactosyl ceramide beta-galactosidases.
Lactosyl ceramide beta-galactosidase activities in the fibroblasts from the previously described patient with so-called "lactosyl ceramidosis" were reexamined with the two recently developed assay methods which appear to measure two genetically distinct enzymes that can degrade this substrate. No deficiency of either of the lactosyl ceramide-cleaving enzymes was observed. In addition, sphingomyelinase activity was only one-sixth of normal, while all other enzymes examined were within the normal ranges.


HEPATOMAS IN MICE: INCIDENCE INCREASED AFTER GAMMA IRRADIATION AT LOW DOSE RATES.
Irradiation of LAf(1) mice with gamma-rays (total doses of 618 to 1335 rad) at a rate of 1.45 rad per hour markedly increased the incidence of hepatomas and ovarian adenomas, compared with incidence of these tumors in mice irradiated with x-rays at 30 rad per minute. This was somewhat unexpected, since chromosome aberrations in the liver cells were less frequent after irradiation at the low dose rate. Other types of tumors were not increased by irradiation with gamma-rays at the low dose rate. It is suggested that indirect hormonal mechanisms may contribute to the production of the hepatomas as well as of the ovarian adenomas.


Traumatic osteoarthrosis of the ankle joint secondary to ankle fractures.
Arthritis, in one form or another, is one of the most common disorders that affect man. Whether the etiology is systemic, neurologic, or traumatic, the one common finding is the destruction of joint cartilage. Although there have been massive amounts of literature concerning osteoarthritis, little has been written about arthritis of the ankle joint. Current concepts in the pathology, terminology, symptomatology, and treatment of the arthritic ankle are discussed.


The diagnostic significance of the correlation between the effectiveness of subendocardial perfusion and the energy output compatible with the coronary reserve.
The effectivity of subendocardial perfusion was investigated in 266 probands aged 40-68 years (112 patients with ischaemic heart disease, 116 patients with essential hypertension, and 38 practically healthy persons) by a noninvasive technique - the myocardial vitality index (MVI) or the quotient of the diastolic and systolic tension-time indexes (DTTI/STTI). The close and statistically significant correlation was found between the MVI, findings of selective coronarography, and total physical performance (exercise tolerance threshold) in per cent of the maximal oxygen consumption (MOC) adequate to the given subject's age, sex, and body mass. Attention is drawn to the diagnostic potential of the novel mode of a rapid assessment of the expected exercise tolerance threshold in per cent of the admissible MOC, determined by the magnitude of the coronary reserved of energy output (in kcal/min or kJ/min), and to the possibilities of predicting the maximal admissible heart rate during exercise on the basis of the myocardial oxygen supply/consumption quotient during a state of relative muscular rest, reflecting the MVI.


DNA Binding and Molecular Dynamic Studies of Polycyclic Tetramate Macrolactams (PTM) with Potential Anticancer Activity Isolated from a Sponge-Associated Streptomyces zhaozhouensis subsp. mycale subsp. nov.
A sponge-associated actinomycete (strain MCCB267) was isolated from a marine sponge Mycale sp. collected in the Indian Ocean off the Southeast coast of India. Phylogenetic studies of this strain using 16S rRNA gene sequencing showed high sequence similarity to Streptomyces zhaozhouensis. However, strain MCCB267 showed distinct physiological and biochemical characteristic features and was thus designated as S. zhaozhouensis subsp. mycale. subsp. nov. A cytotoxicity-guided fractionation of the crude ethyl acetate extract of strain MCCB267 culture medium yielded four pure compounds belonging to the polycyclic tetramate macrolactam (PTM) family of natural products: ikarugamycin (IK) (1), clifednamide A (CF) (2), 30-oxo-28-N-methylikarugamycin (OI) (3), and 28-N-methylikarugamycin (MI) (4). The four compounds exhibited promising cytotoxic activity against NCI-H460 lung carcinoma cells in vitro, by inducing cell death via apoptosis. Flow cytometric analysis revealed that 1, 3, and 4 induced cell cycle arrest during G1 phase in the NCI-H460 cell line, whereas 2 induced cell arrest in the S phase. A concentration-dependent accumulation of cells in the sub-G1 phase was also detected upon treatment of the cancer cell line with compounds 1-4. The in vitro cytotoxicity studies were supported by molecular docking and molecular dynamic simulation analyses. An in silico study revealed that the PTMs can bind to the minor groove of DNA and subsequently induce the apoptotic stimuli leading to cell death. The characterization of the isolated actinomycete, the study of the mode of action of the four PTMs, 1-4, and the molecular docking and molecular dynamic simulations analyses are herein described.


The dose-response relationship between cigarette consumption, biochemical markers and risk of lung cancer.
The relationship between the number of cigarettes smoked per day and the incidence of lung cancer is linear but, from the multistage model of carcinogenesis, it should be quadratic (upwards curving). We investigated this anomaly in a study of 11,403 male never smokers and current smokers in whom carboxyhaemoglobin (COHb) was measured in all and serum cotinine in 1175. The relationship between the biochemical markers and the reported number of cigarettes per day was approximately linear up to 20 cigarettes per day as expected. But above 20 cigarettes per day the marker levels increased less steeply and were 35% lower than expected in men who smoked more than 40 cigarettes per day. Less smoke is inhaled from each cigarette by men with high daily cigarette consumption than by men with lower consumption. Allowance for this transforms the observed linear dose-response relationship into one consistent with the expected quadratic relationship. The anomaly is explained by the observation that heavier smokers inhale less smoke from each cigarette.


Re-assessing the effectiveness of wire-marking to mitigate bird collisions with power lines: A meta-analysis and guidelines for field studies.
The expansion of overhead power lines worldwide challenges companies of energy transmission and distribution, regulators and environmental consultants, among other stakeholders, to effectively mitigate their negative impacts on wildlife. Wire-marking is currently the most widespread and recommended measure to reduce bird collisions with these infrastructures. Nevertheless, and despite its importance for a bird-friendly development of energy projects, there is still much uncertainty about what explains wire-marking effectiveness. We performed an extensive literature review and meta-analysis to evaluate the overall effectiveness of wire-marking in reducing bird collisions with power lines, including the possible influencing factors of power line voltage, habitat and type of device. We gathered data from 35 field studies across the world (which included 66 trials) assessing the effectiveness of wire-marking based on regular carcass searches beneath power lines. Overall, wire-marking reduced bird collisions with power lines by half (50.4%; 95% Confidence Interval Estimate: 40.4-58.8%), although this estimate of effectiveness is lower than the one reported in a meta-analysis performed in 2011. Despite the effort to include both peer-reviewed and grey literature studies in the present meta-analysis, the risk of publication bias could not be entirely excluded and may be still overestimating the true overall effect of wire-marking. High heterogeneity among the study outcomes hindered the power to detect clear moderating effects, with none of explanatory variables being statistically significant. Large between-study heterogeneity is (to some extent) explained by the variety of anti-collision devices available, wire-marking intensities used and ecological circumstances in which the experiments were carried out. Nonetheless, it may be also related to within-study methodological biases and reporting gaps in the existing field studies. Robust experimental designs (ideally using Before-After-Control-Impact approaches), comprehensive reporting of results and broad dissemination of study findings are needed to increase the statistical power of future meta-analyses. Ways to achieve these improvements in field studies are presented in detail. Their inclusion in future meta-analyses will increase the knowledge on the drivers of wire-marking effectiveness, which is critical to better inform decision-making processes and environmental management plans.


Intravascular ultrasound for the evaluation of therapies targeting coronary atherosclerosis.
Many cardiovascular events are clinical manifestations of underlying atherosclerotic disease. The progression of atherosclerosis, traditionally measured by angiography, is predictive of future clinical events and is a valid surrogate marker of cardiovascular (CV) disease. There is growing interest in using novel surrogate end points in clinical trials to expedite the development of new CV therapies. Innovative imaging technologies, such as intravascular ultrasound (IVUS), may carry advantages for the evaluation of coronary atherosclerotic burden and disease progression. Unlike angiography, which displays only the opacified luminal "silhouette," IVUS provides transmural imaging of the entire arterial wall and permits both detection of early-stage atherosclerosis and accurate cross-sectional and even 3-dimensional quantification of plaques. Intravascular ultrasound is now used to guide therapeutic interventions and for diagnostic purposes, primarily for the evaluation of ambiguous lesions and left main coronary artery disease. In addition, clinical studies are using IVUS serially to measure plaque progression, which appears to be related to future CV events. Although the probative force of clinical end point studies still is stronger, IVUS is catching up. Currently, several trials of CV therapies use IVUS-determined plaque progression as the end point. The rationale for using IVUS-based surrogate end points in clinical trials is discussed in the present review. Key advantages of using IVUS-based surrogate end points versus clinical outcome include smaller patient numbers and substantially shorter trial durations; this reduces costs and may expedite the development and testing of new drugs. We expect in the near future a further increase of the use of IVUS-based surrogate end points in trials that evaluate novel CV therapies targeting on coronary atherosclerosis.


Enteritis and Severe Abdominal Pain as the First Presentation of Covid-19.
Presentation A male patient with no significant past medical history presented to emergency department with progressive in severity abdominal pain, associated with mild nausea and diarrhea. No other significant symptoms were reported. Diagnosis On investigation with CT, duodenojejunitis was diagnosed as the cause of abdominal pain. Lung basal changes were also visualized and subsequently proven to be secondary to Covid-19 infection. Treatment After few days of hospitalization and supportive treatment, the patient improved clinically and was discharged. Conclusion Covid-19 infection typically presents with respiratory symptoms associated with fever and myalgia. Anorexia, diarrhea and nausea have been reported. Severe abdominal pain is rare, particularly as the initial presenting compliant. It is important to be aware of the varied clinical presentations that may occur in Covid-19, including isolated gastrointestinal symptoms. This will allow to increase the timely detectability of infected patients and more effective contact control measures.


Test non-inferiority (and equivalence) based on the odds ratio under a simple crossover trial.
For testing the non-inferiority (or equivalence) of a generic drug to a standard drug, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of a random effects logistic regression model, we develop asymptotic test procedures for testing non-inferiority and equivalence with respect to the OR of patient response rates under a simple crossover design. We further derive exact test procedures, which are especially useful for the situations in which the number of patients in a crossover trial is small. We address sample size calculation for testing non-inferiority and equivalence based on the asymptotic test procedures proposed here. We also discuss estimation of the OR of patient response rates for both the treatment and period effects. Finally, we include two examples, one comparing two solution aerosols in treating asthma, and the other one studying two inhalation devices for asthmatics, to illustrate the use of the proposed test procedures and estimators.


Disruption of CLOCK-BMAL1 transcriptional activity is responsible for aryl hydrocarbon receptor-mediated regulation of Period1 gene.
The aryl hydrocarbon receptor (AhR) is a period-aryl hydrocarbon receptor nuclear transporter-simple minded domain transcription factor that shares structural similarity with circadian clock genes and readily interacts with components of the molecular clock. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters behavioral circadian rhythms and represses the Period1 (Per1) gene in murine hematopoietic stem and progenitor cells. Per1 expression is driven by circadian locomotor activity cycles kaput-brain muscle ARNT-like (CLOCK-BMAL1)-dependent activation of Eboxes in the Per1 promoter. We hypothesized that the effects of AhR activation on the circadian clock are mediated by disruption of CLOCK-BMAL1 function and subsequent Per1 gene suppression. Effects of AhR activation on rhythmic Per1 transcripts were examined in livers of mice after treatment with the AhR agonist, TCDD; the molecular mechanisms of Per1 repression by AhR were determined in hepatoma cells using TCDD and beta-napthoflavone as AhR activators. This study reports, for the first time, that AhR activation by TCDD alters the Per1 rhythm in the mouse liver and that Per1 gene suppression depends upon the presence of AhR. Furthermore, AhR interaction with BMAL1 attenuates CLOCK-BMAL1 activity and decreases CLOCK binding at Ebox1 and Ebox3 in the Per1 promoter. Taken together, these data suggest that AhR activation represses Per1 through disrupting CLOCK-BMAL1 activity, producing dysregulation of rhythmic Per1 gene expression. These data define alteration of the Per1 rhythm as novel signaling events downstream of AhR activation. Downregulation of Per1 could contribute to metabolic disease, cancer, and other detrimental effects resulting from exposure to certain environmental pollutants.


Evaluation of hepatic-metastasis risk of colorectal cancer upon the protein signature of PI3K/AKT pathway.
Liver is the most common organ of colorectal cancer (CRC) metastasis, and hepatic metastasis (HM) is regulated by complex protein network. Hence, we initiated a proteomic survey to seek interrelated multiplex markers related with HM. A total of 34 unique differential proteins were identified in the primary tumor tissues from 14 CRC patients with/without HM. A differential protein cluster, consisting of 17 proteins throughout PI3K/AKT pathway, was deduced and validated by Western blot. A three-protein signature elicited from the protein cluster, phosphorylated IkappaBalpha, TNFalpha and MFAP3L, was detected by immunohistochemistry on 105 pairs of CRC and normal samples. The positive protein signature was specifically correlated with HM (P < 0.001), and classified the HM risk of CRC patients with high sensitivity (92.85 +/- 4.87%) and specificity (94.94 +/- 2.5%). The high-risk group had significantly decreased overall survival (P < 0.001). Furthermore, RKO and HT29, two colon cancer cells with different expression status of the protein signature, were used to construct the nude mouse model of HM. And the HM occurrence of RKO cell (4/5) was dramatically higher than that of HT29 cell (1/5). Therefore, the protein signature derived from PI3K/AKT pathway is likely a promising multiplex biomarker for HM of CRC.


A one-dimensional zigzag coordination polymer: catena-poly[[diaquapyridinenickel(II)]-mu-pyridine-2,3-dicarboxylato-kappa3N,O2:O3].
The asymmetric unit of the title one-dimensional coordination polymer, [Ni(C(7)H(3)NO(4))(C(5)H(5)N)(H(2)O)(2)](n), contains a quinolinate dianion, a nickel(II) ion, two water molecules and a pyridine molecule. The pyridine-2,3-dicarboxylate (quinolinate) ligands connect the nickel(II) ions in a head-to-tail fashion, resulting in the formation of a one-dimensional zigzag chain. Adjacent chains form pairs via an extensive network of hydrogen-bonding interactions. A weak C--H...O intermolecular hydrogen bond links neighboring pairs of chains, thus generating two-dimensional double-sheet layers that are stabilized via pi-pi-stacking interactions between adjacent quinolinate pyridyl rings.


Properties of the ubiquitin-pex5p thiol ester conjugate.
Pex5p, the peroxisomal protein cycling receptor, binds newly synthesized peroxisomal matrix proteins in the cytosol and promotes their translocation across the organelle membrane. During its transient passage through the membrane, Pex5p is monoubiquitinated at a conserved cysteine residue, a requisite for its subsequent ATP-dependent export back into the cytosol. Here we describe the properties of the soluble and membrane-bound monoubiquitinated Pex5p species (Ub-Pex5p). Our data suggest that 1) Ub-Pex5p is deubiquitinated by a combination of context-dependent enzymatic and nonenzymatic mechanisms; 2) soluble Ub-Pex5p retains the capacity to interact with the peroxisomal import machinery in a cargo-dependent manner; and 3) substitution of the conserved cysteine residue of Pex5p by a lysine results in a quite functional protein both in vitro and in vivo. Additionally, we show that MG132, a proteasome inhibitor, blocks the import of a peroxisomal reporter protein in vivo.


A multiplex serological assay for the characterization of IgG immune response to SARS-CoV-2.
In the fight against SARS-COV-2, the development of serological assays based on different antigenic domains represent a versatile tool to get a comprehensive picture of the immune response or differentiate infection from vaccination beyond simple diagnosis. Here we use a combination of the Nucleoprotein (NP), the Spike 1 (S1) and Spike 2 (S2) subunits, and the receptor binding domain (RBD) and N-terminal domain (NTD) of the Spike antigens from the CoViDiag® multiplex IgG assay, to follow the immune response to SARS-CoV-2 infection over a long time period and depending on disease severity. Using a panel of 209 sera collected from 61 patients up to eight months after infection, we observed that most patients develop an immune response against multiple viral epitope, but anti-S2 antibodies seemed to last longer. For all the tested IgGs, we have found higher responses for hospitalized patients than for non-hospitalized ones. Moreover the combination of the five different IgG responses increased the correlation to the neutralizing antibody titers than if considered individually. Multiplex immunoassays have the potential to improve diagnostic performances, especially for ancient infection or mild form of the disease presenting weaker antibody responses. Also the combined detection of anti-NP and anti-Spike-derived domains can be useful to differentiate vaccination from viral infection and accurately assess the antibody potential to neutralize the virus.


Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation.
Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy. To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone. Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019. Participants received either OAC plus AP or OAC alone. Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications. A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months). This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.


Fabrication of Thin Films from Powdered Cesium Lead Bromide (CsPbBr3) Perovskite Quantum Dots for Coherent Green Light Emission.
High-quality thin films were obtained directly by spin-coating glass substrates with suspensions of powdered cesium lead bromide (CsPbBr3) perovskite quantum dots (PQDs). The structural properties of the films were characterized via transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD) analysis, and atomic force microscopy (AFM). The crystal structure of the CsPbBr3 PQDs was unique. The optical behavior of the CsPbBr3 PQDs, including absorption and emission, was then investigated to determine the absorption coefficient and band gap of the material. The CsPbBr3 PQDs were evaluated as active lasing media and irradiated with a pulsed laser under ambient conditions. The PQDs were laser-active when subjected to optical pumping for pulse durations of 70-80 ps at 15 Hz. Amplified spontaneous emission (ASE) by the CsPbBr3 PQD thin films was observed, and a narrow ASE band (∼5 nm) was generated at a low threshold energy of 22.25 μJ cm-2. The estimated ASE threshold carrier density (n th) was ∼7.06 × 1018 cm-3. Band-gap renormalization (BGR) was indicated by an ASE red shift and a BGR constant of ∼27.10 × 10-8 eV. A large optical absorption coefficient, photoluminescence (PL), and a substantial optical gain indicated that the CsPbBr3 PQD thin films could be embedded in a wide variety of cavity resonators to fabricate unique on-chip coherent light sources.


Subclavian vascular injuries.
This study comprises 228 patients with penetrating injuries of the subclavian vessels. The vein alone was involved in 44 per cent, the artery alone in 39 per cent, and both vessels in 17 per cent. The majority of the victims (61 per cent) did not reach the hospital alive, and in those who were operated on the mortality was 15.5 per cent (overall mortality 66 per cent). The overall mortality of venous injuries was significantly higher than the arterial ones (P less than 0.01), probably because of the dangerous complication of air embolism. Physical examination is reliable in the diagnosis of these injuries and there is no need for an emergency angiogram. The clavicular incision was the preferred approach. Repair was performed in 94 per cent of those with arterial injury. Vein injuries were treated by suture in 60 per cent and ligation in 40 per cent. A selective conservative approach is advised.


[Functional differentiation of the theta-rhythm of the hippocampus in the cat].
On the model of discriminating alimentary conditioned reflex with spatial separation of the sources of conditioned (CR, light flashes) and unconditioned (feeding trough) stimuli the theta-rhythm of the dorsal hippocampus was evaluated in cats. Two types of the theta-rhythm were observed in the spectrum of the hippocampal electrical activity: low-amplitude, consisting of a slow growing theta-waves (type I) and high-amplitude consisting of rapidly increasing theta-waves (type II). The type I theta-rhythm is sensitive to noradrenaline and correlates with behavioural forms directed immediately to the realization of alimentary motivation, while the type II is sensitive to serotonin and correlates with behavioural forms directed to the source of the conditioned stimulus. Enhancement of the type II theta-rhythm takes place during a delay of the expected conditioned stimulus. It is suggested that type I theta-rhythm reflects a level of activity of the brain structures connected with unconditioned mechanisms, with realization of biological motivations, while type II theta-rhythm is connected with conditioned reinforcing stimuli; it correlates with various forms of conditioned orienting reflexes and reflects the work of the "nervous model of reinforcing stimulus".


Two-dimensional Guinier analysis: application to single aerosol particles in-flight.
This work presents an apparatus that measures near-forward two-dimensional elastic scattering patterns of single aerosol particles and proposes a two-angle extension of the Guinier law to analyze these patterns. The particles, which approximately range from 2 to 8 micrometers in size, flow through the apparatus in an aerosol stream. A spatial filtering technique separates the near-forward portion of the patterns from the illumination light. Contours intended to represent the geometrical profile of the particles are generated from the patterns using the extension of the Guinier law. The analysis is applied to spherical and nonspherical particles, and the resulting contours are found to be consistent with particle shape only for spherical particles.


Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors.
Molecular interactions between RGD peptides and integrins are known to mediate many biological and pathological processes. This has led to an increased interest in the development of RGD compounds with high affinity and improved selectivity for integrin receptors. In this study, we synthesized and evaluated a series of multimeric RGD compounds constructed on a dicarboxylic acid-containing near-infrared (NIR) fluorescent dye (cypate) for tumor targeting. An array of NIR fluorescent RGD compounds was prepared efficiently, including one RGD monomer (cypate-(RGD)(2)-NH(2)), two RGD dimers (cypate-(RGD)(2)-NH(2) and cypate-(RGD-NH(2))(2)), one trimer (cypate-(RGD)(3)-NH(2)), two tetramers (cypate-(RGD)(4)-NH(2) and cypate-[(RGD)(2)-NH(2)](2)), one hexamer (cypate-[(RGD)(3)-NH(2)](2)), and one octamer (cypate-[(RGD)(4)-NH(2)](2)). The binding affinity of the multimeric RGD compounds for alpha(v)beta(3) integrin receptor (ABIR) showed a remarkable increase relative to the monomer cypate-RGD-NH(2). Generally, the divalent linear arrays of the multimeric RGD units bound the ABIR with slightly higher affinity than their monovalent analogues. These results suggest that the receptor binding affinity was not only dependent on the number of RGD moieties but also on the spatial alignments of the pendant peptides. Internalization of the compounds by ABIR-positive tumor cells (A549) was monitored by NIR fluorescence microscopy. The data showed that endocytosis of the octameric RGD derivative was significantly higher by comparison to other compounds in this study. In vivo noninvasive optical imaging and biodistribution data showed that the compounds were retained in A549 tumor tissue. These results clearly demonstrated that an array of simple RGD tripeptides on a NIR fluorescent dye core can be recognized by ABIR. Optimization of the spatial alignment of the RGD moieties through careful molecular design and library construction could induce multivalent ligand-receptor interactions useful for in vivo tumor imaging and tumor-targeted therapy.


Growth factor receptor signalling in human lens cells: role of the calcium store.
In the human lens, stimulation of tyrosine-kinase coupled growth factor receptors such as epidermal growth factor receptor (EGFR) can induce calcium release from endoplasmic reticulum (ER) stores. The present study investigated the impact of calcium store inactivation on EGFR signalling, cell growth and death in a well-characterised human lens cell line (FHL124). FHL124 cells were routinely cultured in Eagle's minimum essential medium (EMEM) supplemented with 10% foetal calf serum (FCS) and seeded on 24-well plates (DNA and protein synthesis), tissue culture dishes (growth assay, western immunoblot), and glass coverslips (immunocytochemistry). DNA and protein synthesis rates were quantified by measuring the incorporation of (3)H-thymidine and (35)S-methionine into FHL124 cells in serum-free EMEM or EMEM supplemented with thapsigargin (Tg) (100 nM and 1 microM). Longer-term growth was assessed by quantifying the increase in area over time of a circular patch of seeded cells. EGFR was identified using anti-EGFR mouse monoclonal antibody and visualised by fluorescence microscopy with ALEXA 488 conjugated secondary antibody. Programmed cell death was determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay method. Activation of the mitogen-activated protein kinase (MAPK) signalling protein extracellular signal-regulated kinase (ERK) and the cell cycle proteins CDK2 and P27(kip1) were detected by western immunoblot techniques. Inactivation by > or =100 nM Tg inhibited both protein and DNA synthesis although the effect on the latter was greatest. The cell cycle activator CDK2 was reduced by Tg, while the inhibitor P27(kip1) was increased along with the percentage of apoptotic cells. A single, maximal epidermal growth factor (EGF) (10 ng ml(-1)) exposure induced receptor internalization and increased ERK phosphorylation. Both internalisation and ERK activation were unaffected by the presence of Tg. However, reduced internalisation and ERK activation followed repeated EGF applications in the presence of Tg. Additionally, ERK activation by submaximal EGF concentrations was reduced by store depletion. An intact endoplasmic reticulum calcium store therefore plays a significant role in human lens cell survival and growth.


Core Network Contributions to Remembering the Past, Imagining the Future, and Thinking Creatively.
The core network refers to a set of neural regions that have been consistently associated with episodic memory retrieval and episodic future simulation. This network is thought to support the constructive thought processes that allow the retrieval and flexible combination of stored information to reconstruct past and construct novel future experiences. Recent behavioral research points to an overlap between these constructive processes and those also engaged during divergent thinking-the ability to think creatively and generate novel ideas-but the extent to which they involve common neural correlates remains unclear. Using fMRI, we sought to address this question by assessing brain activity as participants recalled past experiences, simulated future experiences, or engaged in divergent thinking. Consistent with past work, we found that episodic retrieval and future simulation activated the core network compared with a semantic control condition. Critically, a triple conjunction of episodic retrieval, future simulation, and divergent thinking revealed common engagement of core network regions, including the bilateral hippocampus and parahippocampal gyrus, as well as other regions involved in memory retrieval (inferior frontal gyrus) and mental imagery (middle occipital gyrus). The results provide further insight into the roles of the hippocampus and the core network in episodic memory retrieval, future simulation, and divergent thinking and extend recent work highlighting the involvement of constructive episodic processes in creative cognition.


Use of an online portal to facilitate clinical trial recruitment: a preliminary analysis of Fox Trial Finder.
As in other therapeutic areas, clinical studies in Parkinson's disease (PD) face significant recruitment challenges. However, qualitative surveys suggest that individuals with PD are willing to participate in clinical research. The Michael J. Fox Foundation therefore established Fox Trial Finder in 2011 to facilitate connection between PD research teams and volunteers. Characterize the research volunteers (with and without PD) registered on Fox Trial Finder as of June 2014, and the published, recruiting studies to identify trends and highlight gaps between research requirements and available volunteers. Profiles of volunteers with and without PD were analyzed to explore trends in geography, demographics, family history and, for those volunteers with PD, disease progression and treatment history. Clinical study profiles were analyzed to determine study type, phase, sponsor, focus, location and eligibility criteria. The analysis focused on volunteers and studies based in the United States. The database contained 26,261 US-based volunteers, including 19,243 volunteers (73%) with PD and 7,018 (27%) controls without PD. The average time since diagnosis for PD volunteers was 5.7 years and the average age at diagnosis was 58 years. Control volunteers were more likely than volunteers with PD to be female (67% vs. 35%) and to have a family history of PD (49% vs. 12%). Fox Trial Finder's registration history to date demonstrates the high level of willingness among individuals affected by PD to participate in clinical research and provide a significant amount of personal health information to facilitate that participation.


A follow-up study of physical activity and incidence of colorectal polyps in African-American women.
Physical activity is associated with a reduced risk of colon cancer, but the effect of activity on colorectal adenomas, which are precursors to colon cancer, is uncertain. The influence of physical activity on colorectal adenomas among African-American women is of particular interest because African-American women have an increased risk of colon cancer relative to other U.S. women. We prospectively assessed the relation of physical activity to the incidence of colorectal polyps among African-American women. We followed 45,400 women in the Black Women's Health Study from 1997 to 2003. Data were obtained by biennial mailed questionnaires. During 287,029 person-years of follow-up, 1,390 women reported having been diagnosed with colorectal polyps. A review of medical records of 58 women who reported colorectal polyps indicated that 59% had adenomas and 41% had hyperplastic polyps. We converted hours per week of vigorous exercise and hours per week of walking to metabolic equivalent (MET)-hours. We estimated incidence rate ratios with Cox proportional hazard models, controlling for age, body mass index, smoking, family history of colorectal cancer, and education. For total MET-hours/wk spent in walking and vigorous exercise, the incidence rate ratio decreased from 0.94 for <5 MET-hours/wk to 0.72 for >or=40 MET-hours/wk (P(trend) = 0.01). The inverse association was apparent among most subgroups examined, including women who may be at higher risk of colorectal adenomas because of being obese. Increased physical activity is associated with a reduced incidence of colorectal polyps among African-American women.


Multifunctional gold nanorods for selective plasmonic photothermal therapy in pancreatic cancer cells using ultra-short pulse near-infrared laser irradiation.
Gold nanorods (AuNRs) have attracted considerable attention in plasmonic photothermal therapy for cancer treatment by exploiting their selective and localized heating effect due to their unique photophysical properties. Here we describe a strategy to design a novel multifunctional platform based on AuNRs to: (i) specifically target the adenocarcinoma MUC-1 marker through the use of the EPPT-1 peptide, (ii) enhance cellular uptake through a myristoylated polyarginine peptide (MPAP) and (iii) selectively induce cell death by ultra-short near infrared laser pulses. We used a biotin-avidin based approach to conjugate EPPT-1 and MPAP to AuNRs. Dual-peptide (EPPT-1+MPAP) labelled AuNRs showed a significantly higher uptake by pancreatic ductal adenocarcinoma cells when compared to their single peptide or avidin conjugated counterparts. In addition, we selectively induced cell death by ultra-short near infrared laser pulses in small target volumes (∼1 μm3), through the creation of plasmonic nanobubbles that lead to the destruction of a local cell environment. Our approach opens new avenues for conjugation of multiple ligands on AuNRs targeting cancer cells and tumors and it is relevant for plasmonic photothermal therapy.


Composition of bacterial and archaeal communities in freshwater sediments with different contamination levels (Lake Geneva, Switzerland).
The aim of this study was to compare the composition of bacterial and archaeal communities in contaminated sediments (Vidy Bay) with uncontaminated sediments (Ouchy area) of Lake Geneva using 16S rRNA clone libraries. Sediments of both sites were analysed for physicochemical characteristics including porewater composition, organic carbon, and heavy metals. Results show high concentrations of contaminants in sediments from Vidy. Particularly, high contents of fresh organic matter and nutrients led to intense mineralisation, which was dominated by sulphate-reduction and methanogenesis. The bacterial diversity in Vidy sediments was significantly different from the communities in the uncontaminated sediments. Phylogenetic analysis revealed a large proportion of Betaproteobacteria clones in Vidy sediments related to Dechloromonas sp., a group of dechlorinating and contaminant degrading bacteria. Deltaproteobacteria, including clones related to sulphate-reducing bacteria and Fe(III)-reducing bacteria (Geobacter sp.) were also more abundant in the contaminated sediments. The archaeal communities consisted essentially of methanogenic Euryarchaeota, mainly found in the contaminated sediments rich in organic matter. Multiple factor analysis revealed that the microbial community composition and the environmental variables were correlated at the two sites, which suggests that in addition to environmental parameters, pollution may be one of the factors affecting microbial community structure.


DNA analysis of ancient skeletal remains.
Non-Governmental Organization Archaia (http://www.archaia.cz) carried out the rescue archaeological research at Knezeves near Prague in 1998. Most of dating objects in Knezeves come from the period of Late and Final Bronze Age. The approximately 3,000 years old set, which included 11 human remains from three settlement features, was collected for the study. First, gender was determined according to anthropological characteristics. Ancient DNA from bones was extracted by the phenol-chloroform procedure and N-phenacetylthiazolum bromide reagent. Polymerase chain reaction amplification of AMEL XY, part of amelogenin gene, with subsequent polyacrylamide gel electrophoresis and Short Tandem Repeats analysis followed. DNA profiles of skeletal remains were obtained by the fragmentation analysis of autosomal short tandem repeat markers. Genetic profiles showed us whether individuals from Knezeves were in mutual relationship (parent - descendant). The congruence of results in sex determination supported reliability of genetic methods, which are suitable for sex determination of fragmental and subadult skeletal remains.


SATB2-associated syndrome (SAS) and associated dental findings.
Identify, diagnose, and document oral clinical and radiographic evidence associated with the genetic condition known as special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome. Through identifying and publishing these common dental and behavioral findings, we hope to educate oral and medical healthcare providers to identify this condition in an attempt to develop meaningful comprehensive care to this patient population. A total of 37 patients (19 female), ranging from ages 2 to 20 were evaluated at Arkansas Children's Hospital in Little Rock, Arkansas. Patient geographic distribution included: the United States, Canada, Portugal, Spain, and the Netherlands. Patients were clinically and radiographically examined for oral findings. Panoramic radiographs were obtained when patient's behavior allowed. Patient's parents or guardians were also interviewed concerning dental, medical, and behavioral histories. Clinical findings included delayed tooth eruption, bruxism, sialorrhea, larger than normal teeth with an increased propensity for maxillary anterior tooth trauma due to unsteady ambulation. Radiographic findings included delayed permanent root formation, significantly delayed or missing second bicuspids, malformed teeth, and taurodontism. Medical and behavioral issues included: insomnia, hyperphagia, cognitive delays, and an extremely high pain threshold. Patients with SATB2-associated syndrome have shown to have a consistent and unique set of dental findings both clinically and radiographically. A thorough health and dental history along with the aforementioned results of the study may facilitate a diagnosis of this syndrome. Due to the complexity of the patient's dental needs and behavior, a health practitioner with special needs care experience on a comprehensive craniofacial team would be optimal.


A ring shear device to simulate cryosphere processes.
We have developed a new cryogenic ring shear device at the University of Wisconsin-Madison to simulate cryosphere processes, with an emphasis on the physics of glacier slip. The device spins a ring of ice (inner diameter of 20 cm, outer diameter of 60 cm, height of ∼20-30 cm) at the pressure melting point over a rotationally fixed bed. The ice ring is spun at a prescribed velocity (range of ∼0.01-1000 m a-1) while the resistance to slip is measured. A ram at the base of the device applies a vertical load to the sample chamber to simulate the overburden pressure (range ∼5-915 kPa) felt at a glacier's base. The sample chamber is constructed with transparent acrylic walls, allowing subglacial processes to be observed directly by a series of cameras. The entire device is housed in a large walk-in freezer. In the freezer, the sample chamber is submerged in a tub of temperature-controlled fluid that precisely regulates heat flux into the sample chamber, replicating in situ conditions and allowing for prolonged experiments that last weeks to months. This device can be used to study several of the most unconstrained physical processes that regulate glacier movement and, in doing so, greatly improve predictions of glacier contributions to sea-level rise.


Current Epidemiology and Co-Infections of Avian Immunosuppressive and Neoplastic Diseases in Chicken Flocks in Central China.
The avian immunosuppressive and neoplastic diseases caused by Marek's disease virus (MDV), avian leucosis virus (ALV), and reticuloendotheliosis virus (REV) are seriously harmful to the global poultry industry. In recent years, particularly in 2020-2022, outbreaks of such diseases in chicken flocks frequently occurred in China. Herein, we collected live diseased birds from 30 poultry farms, out of 42 farms with tumour-bearing chicken flocks distributed in central China, to investigate the current epidemiology and co-infections of these viruses. The results showed that in individual diseased birds, the positive infection rates of MDV, ALV, and REV were 69.5% (203/292), 14.4% (42/292), and 4.7% (13/277), respectively, while for the flocks, the positive infection rates were 96.7% (29/30), 36.7% (11/30), and 20% (6/30), respectively. For chicken flocks, monoinfection of MDV, ALV, or REV was 53.3% (16/30), 3.3% (1/30), and 0% (0/30), respectively, but a total of 43.3% (13/30) co-infections was observed, which includes 23.3% (7/30) of MDV+ALV, 10.0% (3/30) of MDV+REV, and 10.0% (3/30) of MDV+ALV+REV co-infections. Interestingly, no ALV+REV co-infection or REV monoinfection was observed in the selected poultry farms. Our data indicate that the prevalence of virulent MDV strains, partially accompanied with ALV and/or REV co-infections, is the main reason for current outbreaks of avian neoplastic diseases in central China, providing an important reference for the future control of disease.


Controlled cooling during semen cryopreservation does not induce capacitation of spermatozoa from two portions of the boar ejaculate.
Cryopreservation imposes dramatic changes in boar sperm survivability but it is as yet unclear which part of the process affects the spermatozoa the most. The present study monitored, along the entire process of cryopreservation, the stability (PMS) of the architecture of the lipid plasma membrane and its integrity (PMI), as well as the kinetics of the processed spermatozoa using two portions from the boar ejaculate (P1 = the first 10 mL of the sperm-rich fraction, SRF; P2 = the rest of the ejaculate), frozen in a recently developed package, the MiniFlatPack (MFPs, 0.5 x 10(9) sperm/dose). Evaluation was made at four specific stages, viz. S1 = after collection (suspended in Beltsville thawing solution, BTS); S2 = at 15 degrees C (suspended in lactose-egg yolk, LEY); S3 = at 5 degrees C (suspended in LEY plus glycerol); and S4 = post-thaw. Both sperm kinetics (using computer-assisted sperm analysis, CASA) and PMS [i.e. the degree of lipid disorder and of the exteriorization of phosphatidylserine (PS) in the plasma membrane, measured by flow cytometry using Merocyanine-540 (M-540), and Annexin-V (AV) respectively], as well as plasma membrane integrity [PMI, i.e. the degree of membrane damage, measured using Yo-Pro-1 or propidium iodide (PI)] were assessed after incubation in BTS at 38 degrees C. Moreover, spermatozoa were challenged by incubation in modified Brackett-Oliphant medium (mBO+) with 37 mm of bicarbonate at 38 degrees C for 30 min, and their PMS and PMI further explored. Total sperm motility was significantly higher in P1 than in P2 along the entire process (S1-S4; p < 0.01), decreasing significantly at S4 for both fractions (p < 0.0001). The proportion of spermatozoa showing linear motility (LinM) was similar between ejaculate portions (P1 and P2), with a significant increase post-thaw (S4; p < 0.0001). During cooling (S1-S3) but not post-thaw (S4), lateral head displacement (LHD) differed between portions and changed along the stages (p < 0.01). Sperm velocity differed between portions in S1 (p < 0.01), but remained similar, independently of the portion, thereafter (S2-S4). Both PMS and the total number of live spermatozoa remained similar between S1 and S3 while incubated in BTS for both ejaculate portions. Sperm mortality increased post-thaw (S4) in both portions but the degree of lipid disorder remained low in the live cells (1.28% for P1; 1.55% for P2). Exposure to mBO+, on the other hand, significantly increased membrane lipid disorder along cooling (S1-S3; p < 0.0001), increasing the percentages of dead spermatozoa, especially post-thaw (around 70%, both portions). PS-exteriorization (AV) was not evident along the cryopreservation process in control (BTS) samples and exposure to mBO+ only induced minor variations. The data showed that kinetics, PMS and PMI of boar spermatozoa suspended in BTS (S1), LEY (S2) or LEY plus glycerol (S3) were maintained during controlled cooling but were altered by thawing, showing more characteristics of cell injury than of sperm capacitation. The spermatozoa were able to capacitate but the bicarbonate challenge destabilized the plasma membrane during initial cooling and accelerated membrane changes post-thaw. We conclude that capacitation of boar spermatozoa does not occur during controlled cooling.


Recurrent duplication mutation in HRAS causing mild Costello syndrome in a Chinese patient.
Costello syndrome (CS; OMIM 218040) is caused by heterozygous germline mutations of HRAS (OMIM 190020).We report on a patient with sporadic CS presenting with characteristic craniofacial dysmorphism, congenital cardiopulmonary disorders, intellectual impairment, and skin abnormalities manifesting as loose redundant skin of the hands and feet, acanthosis nigricans, multiple naevi and hypotrichosis. Using Sanger sequencing for the case-parents trio, we detected a de novo insertion mutation (c.187_207dup) in HRAS, which was predicted to result in duplication of amino acids 63-69 (p.E63_D69dup). This mutation was recently described in a mild case of CS, with hyperactivation of HRAS and disrupted capacity to respond to incoming signals. Our study delineates the detailed clinical features associated with this noncanonical HRAS mutation and further expands the phenotypic spectrum of CS.


Solvent drag measurement of transcellular and basolateral membrane NaCl reflection coefficient in kidney proximal tubule.
The NaCl reflection coefficient in proximal tubule has important implications for the mechanisms of near isosmotic volume reabsorption. A new fluorescence method was developed and applied to measure the transepithelial (sigma NaClTE) and basolateral membrane (sigma NaClcl) NaCl reflection coefficients in the isolated proximal straight tubule from rabbit kidney. For sigma NaClTE measurement, tubules were perfused with buffers containing 0 Cl, the Cl-sensitive fluorescent indicator 6-methoxy-N-[3-sulfopropyl] quinolinium and a Cl-insensitive indicator fluorescein sulfonate, and bathed in buffers of differing cryoscopic osmolalities containing NaCl. The transepithelial Cl gradient along the length of the tubule was measured in the steady state by a quantitative ratio imaging technique. A mathematical model based on the Kedem-Katchalsky equations was developed to calculate the axial profile of [Cl] from tubule geometry, lumen flow, water (Pf) and NaCl (PNaCl) permeabilities, and sigma NaClTE. A fit of experimental results to the model gave PNaCl = (2.25 +/- 0.2) x 10(-5) cm/s and sigma NaClTE = 0.98 +/- 0.03 at 23 degrees C. For measurement of sigma NaClbl, tubule cells were loaded with SPQ in the absence of Cl. NaCl solvent drag was measured from the time course of NaCl influx in response to rapid (less than 1 s) Cl addition to the bath solution. With bath-to-cell cryoscopic osmotic gradients of 0, -60, and +30 mosmol, initial Cl influx was 1.23, 1.10, and 1.25 mM/s; a fit to a mathematical model gave sigma NaClbl = 0.97 +/- 0.04. These results indicate absence of NaCl solvent drag in rabbit proximal tubule. The implications of these findings for water and NaCl movement in proximal tubule are evaluated.


Pathogenesis of fever: effects of various endogenous pyrogens upon the level of circulating granulocytes in normal rabbits.
The endogenous pyrogen in the serum or plasma of rabbits 2 hours after the intravenous injection of typhoid vaccine had a marked effect on the circulating leucocytes of normal rabbits. Immediately following intravenous injection there was a brief, but marked, granulocytopenia which was quickly followed by a granulocytosis. Under the same circumstances pooled heterologous serum or plasma from normal rabbits produced no fever or significant change in the level of circulating leucocytes. The cell-free fluid of sterile peritoneal exudates produced a marked leucocytosis without a preceding leucopenia when injected intravenously into normal rabbits. When comparably pyrogenic doses of typhoid vaccine were injected in the same manner no significant change in the level of circulating leucocytes occurred. The relevance of these findings to the pathogenesis of fever is discussed.


Possibilities of monitoring intraocular pressure in children using EASYTON transpalpebral tonometer.
To compare the effectiveness of transpalpebral scleral tonometry (TPST) and corneal pneumotonometry in children, and assess the discomfort level when measuring intraocular pressure (IOP) by these methods. TPST using EASYTON tonometer (Russia) and pneumotonometry using Reichert 7 Non-contact AutoTonometer (USA) have been sequentially performed on 84 eyes (42 children aged 5-14, ave. 9.3 ± 2.7), including 64 myopic eyes (-0.5 to 6.75D), 18 hyperopic eyes (+ 0.75 to + 3.75D), and 2 emmetropic eyes. We assessed tolerance to the procedure on a five-point scale using a questionnaire which listed several criteria: discomfort, presence of pain, fear or anxiety during the procedure, the child's resistance to measurement. EASYTON tonometry demonstrated repeatability of IOP indicators when measuring the same eye three times sequentially and almost the same IOP level in paired eyes of isometropic children. Pneumotonometry reveals a greater individual data variability and a more pronounced asymmetry of the paired eyes' indicators. IOP measured using the TPST was 18.3 ± 2.3 mmHg across the whole group, 18.2 ± 2.3 mmHg in myopic, and 18.5 ± 2.3 mmHg in hyperopic children. With pneumotonometry, the corresponding indicators were 17.1 ± 3.9 mmHg, 16.9 ± 3.8 mmHg, and 18.2 ± 4.0 mmHg. The average score for the TPST (4.64 ± 0.60 points) was significantly higher than that for pneumotonometry (3.85 ± 0.90 points) (p < 0.05). TPST provides broader possibilities for IOP control in pediatric practice, yielding more reliable and accurate results than pneumotonometry, eliminating the influence of corneal thickness and irregularity on the measurement result, and ensuring a calmer behavior and more comfort of children during the procedure.


Women, Culture and Africa's Land Reform Agenda.
Pre-colonial Africa prides itself on adherence to diverse cultural affinity and traditional belief systems, which defines the place of women in respect to land access, use and ownership. Land resources continue to play important roles in both agrarian and industrial societies; thus the absence of effective land management and gender construction in land allocations has deepened gender inequality, restricted women's capacity building and agricultural development in Africa. This article explores the impact of traditional African practices and cultural beliefs on women's land ownership and use, and also reconciles women's land rights (access and control) with the realities of land reform in post-colonial Africa. It explores how gender inequalities, in terms of land ownership and rights, have jeopardized attempts at agricultural productivity and sustainable development in Africa. However, it is tasking to 'universalize' African culture and locate it in a center, due to the diverse cultural values found in Africa. However, there are certain belief systems that run through most African communities, such as the denial of women's land rights and the patriarchal nature of societies. Thus, the article found that, despite the development of legal frameworks that expand women's property rights, cases of cultural impediments to the exercise of land rights abound in Africa.


Moving toward standardization: physician reporting of sleep studies.
Detailed primary data collected from sleep studies should lead to specific and clear reports with evidence-based clinical recommendations that, when introduced by sleep medicine specialists, create a window of opportunity to support our non-sleep medicine referring teams and to engage patients and caregivers in their care as recipients of the reports. This is how sleep study reporting differs from other test reports; currently, there is wide variation in how the data collected are presented and summarized. The goal of this document is to offer recommendations for structured reporting of sleep studies. We offer a practical, complete, and relevant document and a structure that can be implemented across sleep centers nationwide and does not burden the interpreter. We anticipate some readers will opine that some of the content is beyond the scope of what the interpreter physician needs to include, while others will propose missing data that they feel should have been included. We feel that the flexibility of the proposal accommodates for this and allows for a "first step" toward standardization of physician reporting of sleep studies. High-quality structured reporting of sleep studies is becoming ever more important for patient care, benefiting patients, caregivers, clinicians, durable medical equipment companies, and payers. Lastra AC, Ingram D, Park J, et al. Moving toward standardization: physician reporting of sleep studies. J Clin Sleep Med. 2023;19(3):595-603.


Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3.
We assessed the magnitude of the genetic component in the variation of circulating levels of insulin-like growth factors I and II (IGF-I and IGF-II), and their binding proteins IGFBP-1 and IGFBP-3 by measuring their serum concentrations in 32 monozygotic and 47 dizygotic adult twin pairs of the same sex. The intrapair correlation for the IGF-I levels was r = 0.41 (P < 0.009) for monozygotic twins and r = 0.12 (P < 0.22) for dizygotic twins. For the IGF-II concentration the intrapair correlations were r = 0.66 (P < 0.0001) for the monozygotic and r = 0.34 (P < 0.01) for the dizygotic twins. No significant intrapair correlation was found for IGFBP-1 levels in either group. The correlations for IGFBP-3 concentration were r = 0.65 (P < 0.0001) and r = 0.23 (P < 0.06) for monozygotic and dizygotic twins, respectively. Women had higher IGF-II levels than men (635+/-175 vs. 522+/-144 microg/liter; P < 0.0001) and IGFBP-3 levels were also higher in women compared with men (5441+/-1018 vs. 4496+/-1084 microg/liter; P < 0.001). The proportion of variance attributable to genetic effects was 38% for the IGF-I concentration, 66% for the IGF-II concentration, and 60% for the IGFBP-3 concentration. No significant heritability was found for the IGFBP-1 concentrations. Our results show that, in adults, there is a substantial genetic contribution responsible for interindividual variation of the circulating levels of IGF-I, IGF-II, and IGFBP-3, but not for the IGFBP-1 levels.


Cytotoxicity of Different Nano Composite Resins on Human Gingival and Periodontal Ligament Fibroblast Cell Lines: An In Vitro Study.
The aim of this study is to determine the cytotoxicity of three different nano composite resins (CRs) on human gingival fibroblast (hGF) and periodontal ligament fibroblast (hPDLF) cell lines. These CRs selected were nanohybrid organic monomer-based Admira Fusion (AF), nanohybrid Bis-(acryloyloxymethyl) tricyclo 18.104.22.168.sup.2,6 decane-based Charisma Topaz (CT), and supra nano filled resin-based Estelite Quick Sigma (EQS). MTT assay was performed to assess the cytotoxicity of CRs at 24 h and one week. AF and EQS applied on hGF cells at 24 h and one week demonstrated similar cytotoxic outcomes. Cytotoxicity of CT on hGF cells at one week was higher than 24 h (p = 0.04). Cytotoxicity of CT on hGF cells was higher at 24 h (p = 0.002) and one week (p = 0.009) compared to control. All composites showed higher cytotoxicity on hPDLF cells at one week than the 24 h (AF; p = 0.02, CT; p = 0.02, EQS; p = 0.04). AF and EQS demonstrated lower cytotoxicity on hPDLF cells than the control group at 24 h (AF; p = 0.01, EQS; p = 0.001). CT was found more cytotoxic on hPDLF cells than the control (p = 0.01) and EQS group (p = 0.008) at one week. The cytotoxicity of CRs on hGF and hPDLF cells vary, according to the type of composites, cell types, and exposure time.


Demographic response to perturbations: the role of compensatory density dependence in a North American duck under variable harvest regulations and changing habitat.
1. Most wild animal populations are subjected to many perturbations, including environmental forcing and anthropogenic mortality. How population size varies in response to these perturbations largely depends on life-history strategy and density regulation. 2. Using the mid-continent population of redhead Aythya americana (a North American diving duck), we investigated the population response to two major perturbations, changes in breeding habitat availability (number of ponds in the study landscape) and changes in harvest regulations directed at managing mortality patterns (bag limit). We used three types of data collected at the continental scale (capture-recovery, population surveys and age- and sex ratios in the harvest) and combined them into integrated population models to assess the interaction between density dependence and the effect of perturbations. 3. We observed a two-way interaction between the effects on fecundity of pond number and population density. Hatch-year female survival was also density dependent. Matrix modelling showed that population booms could occur after especially wet years. However, the effect of moderate variation in pond number was generally offset by density dependence the following year. 4. Mortality patterns were insensitive to changes in harvest regulations and, in males at least, insensitive to density dependence as well. We discuss potential mechanisms for compensation of hunting mortality as well as possible confounding factors. 5. Our results illustrate the interplay of density dependence and environmental variation both shaping population dynamics in a harvested species, which could be generalized to help guide the dual management of habitat and harvest regulations.


[Biogenic amines in duodenal contents in various forms of biliary tract dyskinesia].
The concentration and secretion of adrenaline and noradrenaline with different portions of the bile seem to significantly reflect the function of the vegetative innervation apparatus of the biliary tract. A correlation was established between the pattern of motor and tonic disorders and the pattern of catecholamine secretion during multi-stage duodenal exploration. The data obtained make it possible to outline approaches to adequate therapy.


Short-Term Reproducibility of MUC5AC Measurement in Human Tear Fluid.
The assessment of tear fluid components is a common and valuable approach to understanding ocular surface disease and testing the efficacy of novel therapeutic strategies. However, the interpretation and utility of the findings can be limited by changes in the composition of the tear film, particularly in studies requiring repetitive patient sampling. Here, tear samples were collected twice within a one-hour interval to evaluate the short-term reproducibility of an immunoassay aimed to measure the amount of MUC5AC mucin. We found no statistical difference in total protein or MUC5AC content between the two consecutive collections of tear fluid, although the inter-individual variability in each group was high, with coefficients of variation exceeding 30% and 50%, respectively. Scatterplots showed a significant correlation in both protein and MUC5AC following collection within a one-hour interval. These data indicate that, regardless of the high inter-individual variability, repeated collection of tear fluid within an hour interval produces reproducible intra-individual data in terms of MUC5AC mucin content, and suggest that the normal mucin composition of the tear fluid can be re-established within an hour of the initial collection.


[Carbon source apportionment of PM2.5 in Chongqing based on local carbon profiles].
PM2.5 was sampled from commercial, industrial and residential areas in Chongqing urban city from 2nd May to 10th May 2012 in order to find out characteristics and sources of carbon in PM2.5. Eight kinds of carbons were analyzed by the TOR method. Characteristics of carbon pollution in PM2.5 from three kinds of functional areas and six kinds of sources, including coal-combustion, exhausts (vehicle, boat and construction machine), biomass burning, cooking smoke, were analyzed. Based on carbon source profiles, local indicating components of carbon sources in PM2.5 were obtained used the chemical mass balance (CMB) model. Contribution rate of different sources to PM2.5 carbon were parsed out by factor analysis. The results showed the OC/EC of coal-combustion, vehicle exhausts, boat exhausts, construction machine exhausts, biomass burning and cooking smoke were 6.3, 3.0, 1.9, 1.4, 12.7 and 31.3, respectively. High loads of EC2 and EC3 indicated diesel vehicle exhaust emissions, high loads of OC2, OC3, OC4 and OPC indicated coal-combustion emissions, OC1, OC2, OC3, OC4 and EC1 indicated gasoline vehicle exhaust emissions, OC3 indicated cooking emissions, and OPC indicated biomass burning emissions. OC/PM2.5, EC/PM2.5, secondary organic carbon (SOC)/OC in the commercial area were 17.4%, 6.9% and 40.0%, respectively. OC/PM2.5, EC/PM2.5 and SOC/OC in the industrial area were 15.5%, 6.6% and 37.4%, respectively. OC/PM2.5, EC/PM2.5 and SOC/OC in the residential area were 14.6% 5.6% and 42.8%, respectively. In the industrial area, the main sources of carbon in PM2.5 were coal combustion, gasoline vehicle exhausts and diesel exhaust. In the commercial area, the main sources of carbon were gasoline vehicle exhausts, diesel exhausts and cooking. In the residential area, the main sources of carbon were gasoline vehicle exhausts, cooking smoke and diesel exhausts.


Inherited thrombophilia with recurrent pregnancy loss in Turkish women--a real phenomenon?
To determine the prevalence and the role of hereditary thrombophilia caused by Factor V Leiden (G1691A), prothrombin G20210A or methylenetetrahydrofolate reductase (MTHFR) C677T gene mutations in recurrent pregnancy loss. One hundred and nine patients, who were admitted to the 3rd Obstetrics and Gynecology Outpatient Clinic in Goztepe Training and Research Hospital between 2006 and 2008, were included into the study The study group consisted of fifty-seven patients with a history of 3 miscarriages before 20 weeks of gestation and the control group consisted of forty-seven patients with at least one live birth without any history of miscarriage or pregnancy complications. The maternal blood was evaluated for Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations. No statistically significant difference was found between the study and the control groups in terms of the prevalence of Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations (p=0.534/ p=0.452/p=0.656, respectively and p<0.05). Furthermore, the prevalence of multiple gene mutations was not statistically different between the groups (p=0.375 and p<0.05) either. Routine screening for Factor V Leiden (G1691A), prothrombin G20210A and MTHFR C677T gene mutations in patients with a history of recurrent pregnancy loss is not recommended in Turkish women.


Mapping alterations in the local synchrony of the cerebral cortex in schizophrenia.
Observations from different fields of research coincide in indicating that a defective gamma-aminobutyric acid (GABA) interneuron system may be among the primary factors accounting for the varied clinical expression of schizophrenia. GABA interneuron deficiency is locally expressed in the form of neural activity desynchronization. We mapped the functional anatomy of local synchrony in the cerebral cortex in schizophrenia using functional connectivity MRI. Data from 86 patients with schizophrenia and 137 control subjects were obtained from publicly available repositories. Resting-state functional connectivity maps based on Iso-Distant Average Correlation measures across three distances were estimated detailing the local functional structure of the cerebral cortex. Patients with schizophrenia showed weaker local functional connectivity (i.e., lower MRI signal synchrony) in (i) prefrontal lobe areas, (ii) somatosensory, auditory, visual, and motor cortices, (iii) paralimbic system at the anterior insula and anterior cingulate cortex, and (iv) hippocampus. The distribution of the defect in cortical area synchrony largely coincided with the synchronization effect of the GABA agonist alprazolam previously observed using identical functional connectivity measures. There was also a notable resemblance between the anatomy of our findings and cortical areas showing higher density of parvalbumin (prefrontal lobe and sensory cortices) and somatostatin (anterior insula and anterior cingulate cortex) GABA interneurons in humans. Our results thus provide detail of the functional anatomy of synchrony changes in the cerebral cortex in schizophrenia and suggest which elements of the interneuron system are affected. Such information could ultimately be relevant in the search for specific treatments.


Miniaturized two-photon microscope based on a flexible coherent fiber bundle and a gradient-index lens objective.
We present a miniature, flexible two-photon microscope consisting of a fused coherent optical fiber bundle with 30,000 cores and a gradient-index lens objective. The laser focus of a standard two-photon laser-scanning microscope was scanned over the entrance surface of the fiber bundle, resulting in sequential coupling into individual cores. Fluorescent light was detected through the fiber bundle. Micrometer-sized fluorescent beads and pollen grains were readily resolved. In addition, fluorescently labeled blood vessels were imaged through the fiber bundle in rat brain in vivo.


Human health and climate change: leverage points for adaptation in urban environments.
The design of adaptation strategies that promote urban health and well-being in the face of climate change requires an understanding of the feedback interactions that take place between the dynamical state of a city, the health of its people, and the state of the planet. Complexity, contingency and uncertainty combine to impede the growth of such systemic understandings. In this paper we suggest that the collaborative development of conceptual models can help a group to identify potential leverage points for effective adaptation. We describe a three-step procedure that leads from the development of a high-level system template, through the selection of a problem space that contains one or more of the group's adaptive challenges, to a specific conceptual model of a sub-system of importance to the group. This procedure is illustrated by a case study of urban dwellers' maladaptive dependence on private motor vehicles. We conclude that a system dynamics approach, revolving around the collaborative construction of a set of conceptual models, can help communities to improve their adaptive capacity, and so better meet the challenge of maintaining, and even improving, urban health in the face of climate change.


Move the Neighbourhood: Study design of a community-based participatory public open space intervention in a Danish deprived neighbourhood to promote active living.
A limited amount of research has examined the effect of changing public open spaces on active living. This paper will present the study protocol of a community-based intervention study co-designed in an interdisciplinary collaboration with community members to develop urban installations highly tailored to promote active living among children (10-13-years-old) and seniors (>60-years-old) in a deprived neighbourhood in Copenhagen. The study builds on a quasi-experimental study design with two sub-studies: 1) a children study and 2) a senior study. The interventions will be developed, designed and implemented in collaboration with local children and seniors, respectively, using different co-design tools and methods. We will evaluate the effect of the interventions on children's and senior's use of the new-built urban installations using accelerometers in combination with GPS as well as systematic observation using the System for Observing Play and Recreation in Communities (SOPARC). A process evaluation with focus groups consisting of the various stakeholders in the two sub-studies will be used to gain knowledge of the intervention processes. The paper presents new approaches in the field of public open space interventions through interdisciplinary collaboration, participatory co-design approach and combination of measurements. Using both effect and process evaluations the study will provide unique insights in the role and importance of the interdisciplinary collaboration, participatory processes, and tailoring changes in public open space to local needs and wishes. These results can be used to guide urban renewal projects in deprived neighbourhoods in the future. Retrospectively registered with study ID ISRCTN50036837 . Date of registration: 16 December 2016.


Y Haplogroup Diversity of the Dominican Republic: Reconstructing the Effect of the European Colonization and the Trans-Atlantic Slave Trades.
The Dominican Republic is one of the two countries on the Hispaniola island, which is part of the Antilles. Hispaniola was affected by the European colonization and massive deportation of African slaves since the XVI century and these events heavily shaped the genetic composition of the present-day population. To shed light about the effect of the European rules, we analyzed 92 single nucleotide polymorphisms on the Y chromosome in 182 Dominican individuals from three different locations. The Dominican Y haplogroup composition was characterized by an excess of northern African/European lineages (59%), followed by the African clades (38%), whereas the Native-American lineages were rare (3%). The comparison with the mitochondrial DNA variability, dominated by African clades, revealed a sex-biased admixture pattern, in line with the colonial society dominated by European men. When other Caribbean and non-Caribbean former colonies were also considered, we noted a difference between territories under a Spanish rule (like the Dominican Republic) and British/French rule, with the former characterized by an excess of European Y lineages reflecting the more permissive Iberian legislation about mixed people and slavery. Finally, we analyzed the distribution in Africa of the Dominican lineages with a putative African origin, mainly focusing on central and western Africa, which were the main sources of African slaves. We found that most (83%) of the African lineages observed in Santo Domingo have a central African ancestry, suggesting that most of the slaves were deported from regions.


Association between liver stiffness measurement by transient elastography and chronic kidney disease.
Transient elastography or elastometry (TE) is widely used for clinically cirrhosis and liver steatosis examination. Liver fibrosis and fatty liver had been known to share some co-morbidities that may result in chronic impairment in renal function. We conducted a study to analyze the association between scores of 2 TE parameters, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), with chronic kidney disease among health checkup population.This was a retrospective, cross-sectional study. Our study explored the data of the health checkup population between January 2009 and the end of June 2018 in a regional hospital. All patients were aged more than 18 year-old. Data from a total of 1940 persons were examined in the present study. The estimated glomerular filtration rate (eGFR) was calculated by the modification of diet in renal disease (MDRD-simplify-GFR) equation. Chronic kidney disease (CKD) was defined as eGFR < 60 mL/min/1.73 m2.The median of CAP and LSM score was 242, 265.5, and 4.3, 4.95 in non-CKD (eGFR > 60) and CKD (eGFR < 60) group, respectively. In stepwise regression model, we adjust for LSM, CAP, inflammatory markers, serum biochemistry markers of liver function, and metabolic risks factors. The P value of LSM score, ALT, AST, respectively is .005, <.001, and <.001 in this model.The LSM score is an independent factor that could be used to predict renal function impairment according to its correlation with eGFR. This result can further infer that hepatic fibrosis may be a risk factor for CKD.


Comparative Study of Ocular Pharmacokinetics of Gatifloxacin Between Continuous Lavage and Hourly Topical Instillation in Rabbits.
To investigate the ocular pharmacokinetics and distribution of gatifloxacin between continuous lavage through the Morgan lens and repeated topical drop instillation in rabbits. Thirty-six healthy rabbits were randomly divided into 2 groups, and 0.3% gatifloxacin ophthalmic solution was instilled by continuous lavage using the Morgan lens onto the left eyes at 15 mL/h (or 50 μL of the same solution repeatedly administered topically every hour). The animals were killed at 2, 4, 8, and 12 hours in the Morgan lens group or at 12 and 24 hours in the topical instillation group. Aqueous humor specimens were collected from the anterior chamber first, and other ocular tissues and plasma were collected subsequently. Pharmacokinetic and pharmacodynamic indices, other than the minimum inhibitory concentration (MIC), were used as therapeutic parameters in ocular tissues. The highest concentration was found in the corneas in both groups. With continuous lavage, gatifloxacin reached an efficacious high concentration in 4 hours in the cornea, which is equivalent to about 23 times the concentration reached in the same tissue by hourly topical instillation for 12 to 24 hours. Using historic data as references, C/MIC90 was 105 (>10) and AUC0-t/MIC90 was 194 h (>125) in the cornea in the continuous lavage group at 4 hours, whereas these values were 5 and 73 hours for the topical hourly instillation group. Compared with hourly topical instillation, continuous lavage through the Morgan lens could achieve significantly higher concentrations in ocular tissues within a short period, especially in the cornea. Continuous lavage may be a much more efficient way to treat recalcitrant corneal infections.


Association of endothelial nitric oxide synthase Glu298Asp polymorphism with end-stage renal disease.
Impairment of nitric oxide generation caused by gene polymorphism is considered as a major factor in the deterioration of progressive renal disease, including diabetic nephropathy and hypertension. The aim of the present study was to examine the Glu298Asp polymorphism of endothelial nitric oxide synthase (eNOS) in patients with end-stage renal disease (ESRD). The Glu298Asp polymorphism in exon 7 was determined in 100 ESRD patients who were maintained on hemodialysis at Dr. Soetomo Hospital, Surabaya, Indonesia, and in a control group of 100 unrelated healthy individuals. In the patient group, 39 patients had Type 2 diabetes mellitus (DM), 44 hypertension (HT) and 17 miscellaneous conditions. The mean length of time from onset of ESRD to the start of this study was 24.37 +/- 32.37 months (Mean +/- SD). The positivity of Glu298Asp in the ESRD group was significantly higher than that in the control group (p < 0.0001). The odds ratio for this group was 4.57 (95% confidence interval 2.52 - 8.31). The positivity of 298Asp in Type 2 DM ESRD with subgroup was significantly higher than that in healthy controls (p < 0.0001). The positivity of 298Asp in the subgroup of patients with HT-derived ESRD was also significantly higher (males p < 0.036, females p < 0.005) than that in healthy control group. Homozygotes with glutamate to aspartate substitution at nucleotide position 7702 showed a single band at 457 bp. It appears that Glu298Asp may be a predisposing factor in DM-derived and HT-derived ESRD.


Treating Addictions: Harm Reduction in Clinical Care and Prevention.
This paper examines the role of clinical practitioners and clinical researchers internationally in establishing the utility of harm-reduction approaches to substance use. It thus illustrates the potential for clinicians to play a pivotal role in health promoting structural interventions based on harm-reduction goals and public health models. Popular media images of drug use as uniformly damaging, and abstinence as the only acceptable goal of treatment, threaten to distort clinical care away from a basis in evidence, which shows that some ways of using drugs are far more harmful than others and that punitive approaches and insistence on total abstinence as the only goal of treatment often increases the harms of drug use rather than reducing drug use. Therefore the leadership and scientific authority of clinicians who understand the health impact of harm-reduction strategies is needed. Through a review of harm-reduction interventions in Canada, the United Kingdom, the United States, Australia, Switzerland, and the Netherlands, we identify three ways that clinicians have helped to achieve a paradigm shift from punitive approaches to harm-reduction principles in clinical care and in drug policy: (1) through clinical research to provide data establishing the effectiveness and feasibility of harm-reduction approaches, (2) by developing innovative clinical programmes that employ harm reduction, and thereby (3) changing the standard of care to include routine use of these evidence-based (but often misunderstood) approaches in their practices. We argue that through promotion of harm-reduction goals and methods, clinicians have unique opportunities to improve the health outcomes of vulnerable populations.