Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome.
Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca(2+)-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly(204)Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals. In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca(2+) binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca(2+) during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder. We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca(2+) binding during biosynthesis.


Sonic hedgehog signaling in Basal cell nevus syndrome.
The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein-coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012.


Stress related changes during TeamGym competition.
The aim of the present study was to investigate the stress--related changes of a TeamGym competition considering both physiological [i.e. salivary cortisol (sC) and alpha--amylase (sAA)] and psychological (i.e. state anxiety) responses in relation to exercise intensity and competition outcomes. Eleven (5 males and 6 females) elite TeamGym athletes (age: 21--28 yrs) were administered the State--Trait Anxiety Inventory before an official international TeamGym competition. sAA and sC samples were collected 15 minutes prior to competition, after each apparatus, 10--min and 30--min after competition. Exercise intensity was estimated by heart rate (HR) recording and performance was evaluated by three international judges. All these parameters were correlated with competition outcomes. TeamGym competition posed a low exercise load (most of exercise was performed below 85% of the individual HR max ). Significant increases (P<0.004) in sAA (3.53 fold induction) and state anxiety (P=0.045) were observed, with respect to baseline values. Conversely, sC remained stable throughout the competition. Significant (P=0.029) correlation between sAA, state anxiety and competition outcomes emerged. Present findings provide the first evidence that the psycho--physiological stress response prior to and during competition can affect performance outcome, especially in a technical sport such as TeamGym.


Manipulation of phasic arousal by auditory cues is associated with subsequent changes in visual orienting to faces in infancy.
This eye-tracking study investigated the effect of sound-induced arousal on social orienting under different auditory cue conditions in 5-month-old (n = 25; n = 13 males) and 10-month-old infants (n = 21; n = 14 males) participating in a spontaneous visual search task. Results showed: (1) larger pupil dilation discriminating between high and low volume (b = 0.02, p = 0.007), but not between social and non-social sounds (b = 0.004, p = 0.64); (2) faster visual orienting (b = - 0.09, p < 0.001) and better social orienting at older age (b = 0.94, p < 0.001); (3) a fast habituation effect on social orienting after high-volume sounds (χ2(2) = 7.39, p = 0.025); (4) a quadratic association between baseline pupil size and target selection (b = - 1.0, SE = 0.5, χ2(1) = 4.04, p = 0.045); (5) a positive linear association between pupil dilation and social orienting (b = 0.09, p = 0.039). Findings support adaptive gain theories of arousal, extending the link between phasic pupil dilation and task performance to spontaneous social orienting in infancy.


Anti-Proliferative Effects of Compound A and Its Effect in Combination with Cisplatin in Cholangiocarcinoma Cells.
Cholangiocarcinoma (CCA) is a fatal cancer with high resistance to anticancer drugs. The development of new drugs or compounds to be used alone or in combination with currently available chemotherapeutic agents to improve the treatment of CCA is needed. Compound A (CpdA), which is a small plant-derived glucocorticoid receptor modulator, strongly inhibited the growth and survival of several cancers. However, the effect of CpdA on cholangiocarcinoma has not been elucidated. The aim of this study was to investigate the effect of CpdA on CCA. Cytotoxicity of CpdA was tested in primary cells including peripheral blood mononuclear cells (PBMCs), fibroblasts, and human umbilical vein endothelial cells (HUVECs), as well as on CCA cell lines (KKU-100, KKU-055, and KKU-213) was examined. Cell cycle distribution and IL-6 expression was assessed by flow cytometry and real-time polymerase chain reaction, respectively. The effect of combination CpdA and cisplatin was evaluated by cell viability assay. CpdA significantly inhibited cell cycle at G1 phase in CCA cell lines, and reduced IL-6 mRNA expression. However, combination CpdA and cisplatin did not enhance the inhibitory effect. TGFβR-II expression was increased in CCA cells after the combination treatment. These results indicate the potential of CpdA for CCA treatment. However, combination treatment with CpdA and cisplatin increased CCA cell survival. The molecular mechanism is likely attributable to promotes cell survival via the TGFβR-II signaling pathway. The combination of CpdA with other anticancer drugs for CCA treatment should be further examined.


Sapling growth rates reveal conspecific negative density dependence in a temperate forest.
Local tree species diversity is maintained in part by conspecific negative density dependence (CNDD). This pervasive mechanism occurs in a variety of forms and ecosystems, but research to date has been heavily skewed toward tree seedling survival in tropical forests. To evaluate CNDD more broadly, we investigated how sapling growth rates were affected by conspecific adult neighbors in a fully mapped 25.6 ha temperate deciduous forest. We examined growth rates as a function of the local adult tree neighborhood (via spatial autoregressive modeling) and compared the spatial positioning of faster-growing and slower-growing saplings with respect to adult conspecific and heterospecific trees (via bivariate point pattern analysis). In addition, to determine whether CNDD-driven variation in growth rates leaves a corresponding spatial signal, we extended our point pattern analysis to a static, growth-independent comparison of saplings and the next larger size class. We found that negative conspecific effects on sapling growth were most prevalent. Five of the nine species that were sufficiently abundant for analysis exhibited CNDD, while only one species showed evidence of a positive conspecific effect, and one or two species, depending on the analysis, displayed heterospecific effects. There was general agreement between the autoregressive models and the point pattern analyses based on sapling growth rates, but point pattern analyses based on single-point-in-time size classes yielded results that differed markedly from the other two approaches. Our work adds to the growing body of evidence that CNDD is an important force in temperate forests, and demonstrates that this process extends to sapling growth rates. Further, our findings indicate that point pattern analyses based solely on size classes may fail to detect the process of interest (e.g., neighborhood-driven variation in growth rates), in part due to the confounding of tree size and age.


Production history matching to determine reservoir properties of important coal groups in the Upper Pottsville formation, Brookwood and Oak Grove fields, Black Warrior Basin, Alabama.
The Black Warrior Basin of Alabama is one of the most important coal mining and coalbed methane production areas in the United States. Methane control efforts through degasification that started almost 25 years ago for the sole purpose of ensuring mining safety resulted in more than 5000 coalbed methane wells distributed within various fields throughout the basin. The wells are completed mostly in the Pratt, Mary Lee, and Black Creek coal groups of the Upper Pottsville formation and present a unique opportunity to understand methane reservoir properties of these coals and to improve their degasification performances. The Brookwood and Oak Grove fields in the Black Warrior Basin are probably two of the most important fields in the basin due to current longwall coal mining activities. In this work, methane and water productions of 92 vertical wellbores drilled, some completed 20 years ago, over a current large coal mine district located in these two fields, were analyzed by history matching techniques. The boreholes were completed at the Mary Lee coal group, or at combinations of the Pratt, Mary Lee, and Black Creek groups. History matching models were prepared and performed according to properties of each coal group. Decline curve analyses showed that effective exponential decline rates of the wells were between 2% and 25% per year. Results of production history matching showed, although they varied by coal group, that pressure decreased as much as 80% to nearly 25 psi in some areas and resulted in corresponding decreases in methane content. Water saturation in coals decreased from 100% to between 20 and 80%, improving gas relative permeabilities to as much as 0.8. As a result of primary depletion, permeability of coal seams increased between 10 and 40% compared to their original permeability, which varied between 1 and 10 md depending on depth and coal seam. These results not only can be used for diagnostic and interpretation purposes, but can be used as parameter distributions in probabilistic simulations, as illustrated in the last section of this paper. They can also be used in conjunction with spatial modeling and geological considerations to calculate potential methane emissions in operating mines.


Re-assessment of phenotypic identifications of Bacteroides putredinis to Alistipes species using molecular methods.
Alistipes (previously Bacteroides) are strictly anaerobic gram-negative rods that resemble the Bacteroides fragilis group in that most species are bile-resistant and indole-positive; however, they are only weakly saccharolytic and most species produce light brown pigment only on laked rabbit blood agar. In this retrospective study, we re-identified 18 organisms previously identified phenotypically as "Bacteroides putredinis-like", but that did not produce pigment on routine media. The strains were identified with 16S rDNA sequencing and pigment production was evaluated on several different culture media. Only 12/18 strains had molecular identifications of Alistipes species, while the remaining strains phylogenetically resembled Butyricimonas and Odoribacter spp. Pigment production was not a reliable test for those Alistipes strains that are described as pigment producers.


Evaluation of breast cancer awareness in female patients diagnosed with schizophrenia.
In this study, it was aimed to investigate the awareness of female patients diagnosed with schizophrenia about breast cancer and to evaluate whether there was a difference in this awareness between the control group and individuals diagnosed with schizophrenia. Secondly, the frequency of breast cancer screenings of patients diagnosed with schizophrenia and the control group was compared. Individuals between 18 and 65 years of age who were literate and voluntarily gave informed consent to participate after being informed about the study were included. The research study group comprised of 82 individuals, 35 patients with schizophrenia and 47 healthy individuals. Patients with schizophrenia were required to have no clinically severe disease picture (CGI-S score of 3 or below). Individuals were given the Breast Cancer Awareness Scale (B-CAS) to fill in. The patient group had less awareness of breast cancer than the control group; conversely, they faced more barriers in breast cancer screening. The number of those who stated that they did not know about breast cancer early diagnosis methods was higher in the patient group than in the control group. In the evaluation of health attitudes toward breast cancer, it was found that the healthy control group was better than the patient group in performing regular breast self-exam. Educating individuals with schizophrenia about the signs and symptoms of cancer and adapting healthcare systems to facilitate rapid and early cancer diagnosis may result in cost-effective and applicable cancer control strategies for curable cancers.


Adenosine depresses a Ca(2+)-independent step in transmitter exocytosis at frog motor nerve terminals.
The depressant action of adenosine on acetylcholine release at frog motor nerve terminals was studied by intracellular recording and Ca(2+)-imaging techniques. Adenosine (200 microm) quickly and reversibly decreased the amplitude and quantal content of end-plate potentials (EPPs) with no change in quantal size in a low-Ca(2+), high-Mg(2+) solution, and EPP amplitude in normal Ringer containing d-tubocurarine. Likewise, adenosine (200 microm) reduced miniature EPP (MEPP) frequency, but not amplitude, in a high-K(+) (6 mm) solution. Adenosine (40-200 microm), however, did not affect single or repetitive impulse(s)-induced rises in Ca(2+) in the nerve terminals or its basal level. Adenosine (100-200 microm) reduced the Ca(2+)-independent enhancement of MEPP frequency caused by hypertonicity. EPPs induced by tetanic stimulation (33 Hz) in Ringer with d-tubocurarine initially increased in amplitude within 10 stimuli and then declined to the minimum. Adenosine (200 microm) decreased EPP amplitude in the initial phase of the tetanus, but enhanced it in the middle phase, thus prolonging the decay of EPP amplitude. The total sum of these EPPs, reflecting the readily releasable pool of vesicles and its refilling, however, was not changed. The results suggest that adenosine inhibits a Ca(2+)-independent step of transmitter exocytosis at frog motor nerve terminals.


Treatment-related death from chemotherapy and thoracic radiotherapy for advanced cancer.
Pneumonia and sepsis during neutropenia are common complications from chemotherapy and they are sometimes lethal. Radiation pneumonitis is also a common toxicity after thoracic radiotherapy, and severe pneumonitis causes hypoxia and death. However, the incidence and risk factors of treatment-related death from the treatment of advanced cancer using chemotherapy and/or thoracic radiotherapy are not well understood. Between July 1992 and December 1997, 1799 patients were diagnosed as having lung cancer and 784 of 1799 patients received chemotherapy in the National Cancer Center Hospital East. Of 784 patients, 18 (2.3%) died from toxicity of the initial chemotherapy. In the Japan Clinical Oncology Group (JCOG) trials for lung cancer, 29 of 1176 patients (2.5%) were reported to have died from toxicity of the treatments. Several papers have reported the risk factors of early death after chemotherapy or treatment-related death caused by chemotherapy in patients with cancer. Only poor performance status was a vigorous risk factor. Reported mortality rates of radiation pneumonitis range from 0 to 9.9% from 7 reports and 29 of 1244 patients (2.3%) died of pneumonitis after thoracic radiotherapy or chemoradiotherapy. Our previous report suggested that pulmonary fibrosis identified on plain chest X-ray film is a very strong risk factor of treatment-related death from radiation pneumonitis. At least 1-2% mortality should be expected for chemotherapy and thoracic radiotherapy. And in patients with poor PS, the expected mortality rate from chemotherapy is increased.


Parainfluenza Virus 5 Expressing Wild-Type or Prefusion Respiratory Syncytial Virus (RSV) Fusion Protein Protects Mice and Cotton Rats from RSV Challenge.
Human respiratory syncytial virus (RSV) is the leading cause of pediatric bronchiolitis and hospitalizations. RSV can also cause severe complications in elderly and immunocompromised individuals. There is no licensed vaccine. We previously generated a parainfluenza virus 5 (PIV5)-vectored vaccine candidate expressing the RSV fusion protein (F) that was immunogenic and protective in mice. In this work, our goal was to improve the original vaccine candidate by modifying the PIV5 vector or by modifying the RSV F antigen. We previously demonstrated that insertion of a foreign gene at the PIV5 small hydrophobic (SH)-hemagglutinin-neuraminidase (HN) junction or deletion of PIV5 SH increased vaccine efficacy. Additionally, other groups have demonstrated that antibodies against the prefusion conformation of RSV F have more potent neutralizing activity than antibodies against the postfusion conformation. Therefore, to improve on our previously developed vaccine candidate, we inserted RSV F at the PIV5 SH-HN gene junction or used RSV F to replace PIV5 SH. We also engineered PIV5 to express a prefusion-stabilized F mutant. The candidates were tested in BALB/c mice via the intranasal route and induced both humoral and cell-mediated immunity. They also protected against RSV infection in the mouse lung. When they were administered intranasally or subcutaneously in cotton rats, the candidates were highly immunogenic and reduced RSV loads in both the upper and lower respiratory tracts. PIV5-RSV F was equally protective when administered intranasally or subcutaneously. In all cases, the prefusion F mutant did not induce higher neutralizing antibody titers than wild-type F. These results show that antibodies against both pre- and postfusion F are important for neutralizing RSV and should be considered when designing a vectored RSV vaccine. The findings also that indicate PIV5-RSV F may be administered subcutaneously, which is the preferred route for vaccinating infants, who may develop nasal congestion as a result of intranasal vaccination.IMPORTANCE Despite decades of research, human respiratory syncytial virus (RSV) is still a major health concern for which there is no vaccine. A parainfluenza virus 5-vectored vaccine expressing the native RSV fusion protein (F) has previously been shown to confer robust immunity against RSV infection in mice, cotton rats, and nonhuman primates. To improve our previous vaccine candidate, we developed four new candidates that incorporate modifications to the PIV5 backbone, replace native RSV F with a prefusion-stabilized RSV F mutant, or combine both RSV F and PIV5 backbone modifications. In this work, we characterized the new vaccine candidates and tested their efficacies in both murine and cotton rat models of RSV infection. Most importantly, we found that PIV5-based RSV vaccine candidates were efficacious in preventing lower respiratory tract infection as well as in reducing the nasal viral load when administered via the subcutaneous route.


Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice.
Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown. APOE (apolipoprotein E) or low-density lipoprotein receptor null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2MKO:ApoE-/- or Shp2MKO:Ldlr-/- mice and exo-AAV8-SHP2E76K/ApoE-/- mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice. Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and low-density lipoprotein receptor null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and low-density lipoprotein receptor null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels. Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/low-density lipoprotein receptor null mice.


Effects of lovastatin on cognitive function and psychological well-being.
Animal research and cross-sectional studies suggest that serum lipid concentrations may influence cognitive function, mood, and behavior, but few clinical trials have studied these effects. In this double-blind investigation, 209 generally healthy adults with a serum low-density-lipoprotein (LDL) cholesterol level of 160 mg/dL or higher were randomly assigned to 6-month treatment with lovastatin (20 mg) or placebo. Assessments of neuropsychological performance, depression, hostility, and quality of life were conducted at baseline and at the end of the treatment period. Summary effect sizes were estimated as z scores on a standard deviation (SD) scale. Placebo-treated subjects improved between baseline and posttreatment periods on neuropsychological tests in all five performance domains, consistent with the effects of practice on test performance (all P <0.04), whereas those treated with lovastatin improved only on tests of memory recall (P = 0.03). Comparisons of the changes in performance between placebo- and lovastatin-treated subjects revealed small, but statistically significant, differences for tests of attention (z score = 0.18; 95% confidence interval (CI), 0.06 to 0.31; P = 0.005) and psychomotor speed (z score = 0.17; 95% CI, 0.05 to 0.28; P = 0. 004) that were consistent with greater improvement in the placebo group. Psychological well-being, as measured several ways, was not affected by lovastatin. Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function. Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed, the clinical importance of which is uncertain.


Effects of endurance exercise on mitochondrial function in mice.
[Purpose] The purpose of this study was to investigate the effects of 8 weeks of endurance exercise on the cardiac mitochondrial function of mice. [Subjects] Ten 129 SvJ/C57BL6 Male mice were used. The mice were randomly divided into an exercise group (n=5; mean ± SD weight, 27.4 ± 1.6 g) and a control (n=5; mean ± SD weight, 28.2 ± 1.1 g). The exercise mice ran on a motor driven treadmill 5 days per week for 30 minutes at a speed of 24 m/min for 8 weeks. Mitochondrial function as measured RCI was compared between the exercise and control group mice using an independent t test. [Results] The exercise mice had a significantly greater state 4 respiration than to the sedentary control mice. There was also a significant difference in RCI between exercise and sedentary control mice. [Conclusion] Endurance exercise decreased RCI, indicating an uncoupling of respiration and oxidative phosphorylation.


Associations between self-reported sleep characteristics and incident mild cognitive impairment: The Heinz Nixdorf Recall Cohort Study.
Associations of sleep characteristics with mild cognitive impairment (MCI) have been examined in cross-sectional, but rarely in longitudinal studies. Incident MCI and sleep characteristics were assessed in 1,890 participants of the first and second follow-up of the Heinz Nixdorf Recall study, a population-based cohort study in Germany (age at first follow-up 50-80 years, mean follow-up 5.2 years). MCI was assessed with extensive cognitive tests. Sleep questionnaires including PSQI (Pittsburgh Sleep Quality Index) were used to assess sleep quality, sleep disturbances, time asleep, and time in bed. Relative risks (RR) of developing MCI when exposed to sleep characteristics were assessed in regression models adjusted for sociodemographic and cardiovascular risk factors. Poor sleep quality (PSQI > 5) (RR = 1.43, 95% CI: 1.12-1.82, fully adjusted, reference: PSQI ≤ 5) and difficulties initiating sleep (almost nightly versus never) (RR = 1.40, 0.94-2.08) were associated with incident MCI. For time in bed, the risk of MCI was increased for ≤ 5 hours (RR = 2.86, 1.24─6.60, reference:7 to <8 hours). In this longitudinal study with older participants, MCI risk was increased in persons with poor sleep quality, difficulties initiating sleep, and short time in bed.


Acoustic changes in voice after surgery for snoring: preliminary results.
All surgical procedures for treatment of snoring and obstructive sleep apnoea modify the anatomical structure of the upper airways and the resonance characteristics of the vocal tract; this can lead to a modification in voice quality. Purpose of this study was to evaluate the possible modifications of the fundamental frequency (F0) and of the frequency and amplitude of the first (F1) and second (F2) formants of the 5 Italian vowels after different surgical procedures for snoring, to verify if and how these operations can influence voice quality. A total of 40 snoring or obstructive sleep apnoea syndrome patients, not affected by laryngeal, pulmonary or neurologic disorders likely to alter voice production, were selected for the study. All were submitted to acoustic voice analysis prior to surgery and again 1 month after discharge. F0 was unchanged. The frequency of F1 of the vowel /a/ audio of F2 of the vowel /e/ were significantly higher, while F1 of /i/ and F2 of /o/ and /u/ were significantly lower compared to pre-operative values. The modifications in the anatomical structure and volume of the vocal tract, induced by the surgical procedures used for the treatment of snoring, can modify the values of the formants and, as a consequence, quality of the voice. This change can be detected not only by means of the acoustic analysis but also by the patient itself. For this reason, singers and all professional voice users about to undergo surgical treatment for snoring should be informed of this potential modification of the voice not only for clinical reasons but also for legal purposes.


Is it safe for pregnant health-care professionals to handle cytotoxic drugs? A review of the literature and recommendations.
The information related to health risks to foetuses due to the handling of chemotherapeutic agents by nurses during pregnancy is limited. The risks involved can be reduced significantly if nurses adhere to standard safety precautions while handling cytotoxic drugs. Nurses in patient areas where chemotherapy is administered are at constant low-level risk of exposure. The authors tried to gather evidence in this article from the recent literature to help to formalise policies for pregnant mothers working in these settings.


Understanding the Behavior of the Above-Room-Temperature Molecular Ferroelectric 5,6-Dichloro-2-methylbenzimidazole Using Symmetry Adapted Distortion Mode Analysis.
The exploitable properties of many functional materials are intimately linked with symmetry-changing phase transitions. These include properties such as ferroelectricity, second harmonic generation, conductivity, magnetism and many others. We describe a new symmetry-inspired method for systematic and exhaustive evaluation of the symmetry changes possible in molecular systems using molecular distortion modes, and how different models can be automatically tested against diffraction data. The method produces a quantitative structural landscape from which the most appropriate structural description of a child phase can be chosen. It can be applied to any molecular or molecular-fragment containing material where a (semi) rigid molecule description is appropriate. We exemplify the method on 5,6-dichloro-2-methylbenzimidazole (DC-MBI), an important molecular ferroelectric. We show that DC-MBI undergoes an unusual symmetry-lowering transition on warming from orthorhombic Pca21 ( T ≲ 400 K) to monoclinic Pc. Contrary to expectations, the high temperature phase of DC-MBI remains polar.


Dose levels outside radiotherapy beams.
The specification of a radiotherapy generator calls for the leakage radiation through the housing of the source to be 0.1% (the ICRP has recently (1982) changed this figure to 0.2% of the dose rate inside the useful beam). When a patient is irradiated, the dose level outside the useful beam is not only determined by this leakage radiation, but also by scattered radiation from the beam-defining system and from the treatment volume of the patient. Measurements have been made on a 300 kV X-ray unit, and on two different 4 MV and one 8 MV linear accelerators to determine the levels of leakage radiation and scattered radiation in air, and in a phantom comparable in size to the trunk of the patient. Similar measurements have also been made for a 15 MeV neutron generator. It is shown that for all these generators the dose delivered outside the radiation beam is determined mainly by the two scattering processes mentioned, and it is argued that for linear accelerators it would be feasible to increase the permitted level of leakage radiation by a factor of 2 or 3 without a significant increase in the stray radiation delivered to the patient.


Stroke.
Stroke is the second most common cause of death and major cause of disability worldwide. Because of the ageing population, the burden will increase greatly during the next 20 years, especially in developing countries. Advances have occurred in the prevention and treatment of stroke during the past decade. For patients with acute stroke, management in a stroke care unit, intravenous tissue plasminogen activator within 3 h or aspirin within 48 h of stroke onset, and decompressive surgery for supratentorial malignant hemispheric cerebral infarction are interventions of proven benefit; several other interventions are being assessed. Proven secondary prevention strategies are warfarin for patients with atrial fibrillation, endarterectomy for symptomatic carotid stenosis, antiplatelet agents, and cholesterol reduction. The most important intervention is the management of patients in stroke care units because these provide a framework within which further study might be undertaken. These advances have exposed a worldwide shortage of stroke health-care workers, especially in developing countries.


Spiers Memorial Lecture: Nanoalloys of multiple components; the road to advance the field and experimental and theoretical challenges.
The field of nanoalloys has been advancing at a rapid pace in the last two decades. Many new characterization methods and theoretical advances have produced a substantial knowledge of the nanoalloys' properties and structure. Most of the work has been limited to binary alloys. A path forward for the field will be the study of nanoalloys with three or more metals. Adding new components will produce new properties and possibly more fabrication controls. In this paper, we will discuss the challenges that will arise in multi-metallic nanoalloys. We will show that entropy and twin boundaries play a dominant role in multi-metallic alloys.


[Clinical and epidemiological study of boutonneuse fever in Andalusia: apropos of 36 cases].
Boutonneuse fever is a rare disease, it accounts for 0.091% of all the patients who consult the Department of Medical-Surgical Dermatology in the Faculty of Medicine of Seville. It is clearly a disease of seasonal incidence, appearing most frequently during the summer, which affects both sexes equally at middle age, and is most frequent in rural areas, although it is increasing in urban districts. The term "Mediterranean fever" is correct, understanding that it is a disease afflicting Mediterranean countries, but has nothing to do with proximity to the sea.


Reversible, light-screening pigment of elasmobranch eyes: chemical identity with melanin.
There lies directly beneath the tapetum lucidum, in the eyes of many elasmobranch fishes, a layer of darkly pigmented choroid cells which, in bright light, extend individual strands that aggregate to form a dark, compound curtain which shields the reflecting tapetal cells. This process is reversed in dim light or in darkness; the tapetum is exposed and visual sensitivity presumably Increased. The black choroid pigment has been isolated, analyzed, and shown to possess the properties of melanin.


miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.
MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.


Role of PET/CT in ovarian cancer.
The purpose of this article is to review the role of FDG PET/CT in ovarian cancer, which is the leading cause of death among gynecologic cancers. FDG PET/CT can significantly modify the assessment of the extent of primary and recurrent ovarian cancer and, hence, often alters patient management substantially. FDG PET/CT has thus become a critical tool for the preoperative evaluation of women with primary ovarian cancer and for postoperative follow-up assessment for evidence of recurrence in these patients.


Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice.
Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH oxidase 4 (NOX4) mRNA expression and reactive oxygen species (ROS) production. In addition, the increased production of ROS in HSCs was associated with a significant reduction in HSC quiescence and an increase in DNA damage. These findings indicate that exposure to proton radiation can lead to long-term HSC injury, probably in part by radiation-induced oxidative stress.


Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001-2006).
Owing to the paucity of evidence available on the risks and benefits of drug use in pregnancy, the use of prescription medicines is a concern for both pregnant women and their health care providers. The aim of this study was to measure the frequency, timing, and type of medicines used before, during, and after pregnancy in a Canadian population. This retrospective cohort analysis used population-based health care data from all pregnancies ending in live births in hospitals in British Columbia from April 2001 to June 2006 (n = 163,082). Data from hospital records were linked to those in outpatient prescription-drug claims. Data from prescriptions filled from 6 months before pregnancy to 6 months postpartum were analyzed. Drugs were classified by therapeutic category and US Food and Drug Administration (FDA) pregnancy risk categories. Prescriptions were filled in 63.5% of pregnancies. Evidence on safety is limited for many of the medicines most frequently filled in pregnancy, including codeine, salbutamol, and betamethasone. At least 1 prescription for a category D or X medicine was filled in 7.8% of pregnancies (5.5% category D; 2.5% category X). The most frequently filled prescriptions for category D drugs were benzodiazepines and antidepressants. The most frequently filled prescriptions for category X drugs were oral contraceptives and ovulation stimulants filled in the first trimester. The majority of pregnant women in British Columbia filled at least 1 prescription, and ~1 in 13 filled a prescription for a drug categorized as D or X by the FDA. The prevalence of maternal prescription drug use emphasizes the need for postmarketing evaluation of the risk-benefit profiles of pharmaceuticals in pregnancy. Future research on prenatal drug use based on administrative databases should examine maternal treatment adherence and the determinants of maternal drug use, considering maternal health status, sociodemographics, and the characteristics and providers of prenatal care.


Thoracoscopic repair of esophageal atresia and tracheoesophageal fistula: a multi-institutional analysis.
For the past 60 years, successful repair of esophageal atresia (EA) and distal tracheoesophageal fistula (TEF) has been performed via a thoracotomy. However, a number of reports have described adverse musculoskeletal sequelae following thoracotomy in infants and young children. Until now, only a few scattered case reports have detailed an individual surgeon's success with thoracoscopic repair of EA/TEF. This multi-institutional review represents the largest experience describing the results with this approach. A cohort of international pediatric surgeons from centers that perform advanced laparoscopic and thoracoscopic operations in infants and children retrospectively reviewed their data on primary thoracoscopic repair in 104 newborns with EA/TEF. Newborns with EA without a distal TEF or those with an isolated TEF without EA were excluded. In these 104 patients, the mean age at operation was 1.2 days (+/-1.1), the mean weight was 2.6 kg (+/-0.5), the mean operative time was 129.9 minutes (+/-55.5), the mean days of mechanical ventilation were 3.6 (+/-5.8), and the mean days of total hospitalization were 18.1 (+/-18.6). Twelve (11.5%) infants developed an early leak or stricture at the anastomosis and 33 (31.7%) required esophageal dilatation at least once. Five operations (4.8%) were converted to an open thoracotomy and one was staged due to a long gap between the 2 esophageal segments. Twenty-five newborns (24.0%) later required a laparoscopic fundoplication. A recurrent fistula between the esophagus and trachea developed in 2 infants (1.9%). A number of other operations were required in these patients, including imperforate anus repair in 10 patients (7 high, 3 low), aortopexy (7), laparoscopic duodenal atresia repair (4), and various major cardiac operations (5). Three patients died, one related to the EA/TEF on the 20th postoperative day. The thoracoscopic repair of EA/TEF represents a natural evolution in the operative correction of this complicated congenital anomaly and can be safely performed by experienced endoscopic surgeons. The results presented are comparable to previous reports of babies undergoing repair through a thoracotomy. Based on the associated musculoskeletal problems following thoracotomy, there will likely be long-term benefits for babies with this anomaly undergoing the thoracoscopic repair.


Personalized Peptide Arrays for Detection of HLA Alloantibodies in Organ Transplantation.
In organ transplantation, the function and longevity of the graft critically rely on the success of controlling immunological rejection reactivity against human leukocyte antigens (HLA). Histocompatibility guidelines are based on laboratory tests of anti-HLA immunity, which presents either as pre-existing or de novo generated HLA antibodies that constitute a major transplantation barrier. Current tests are built on a single-antigen beads (SAB) platform using a fixed set of ~100 preselected recombinant HLA antigens to probe transplant sera. However, in humans there exist a far greater variety of HLA types, with no two individuals other than identical twins who can share the same combination of HLA sequences. While advanced technologies for HLA typing and direct sequencing can precisely capture any mismatches in DNA sequence between a donor's and recipient's HLA, the SAB assay, due to its limited variety in sequence representation, is unable to precisely detect alloantibodies specifically against the donor HLA mismatches. We sought to develop a complementary method using a different technology to detect and characterize anti-donor HLA antibodies on a personalized basis. The screening tool is a custom peptide array of donor HLA-derived sequences for probing post-transplant sera of the organ recipient to assess the risk for antibody-mediated rejection. On a single array for one donor-recipient pair, up to 600 unique peptides are made based on the donor's HLA protein sequences, each peptide carrying at least one mismatched residue in a 15-amino acid sequence. In our pilot experiments to compare antigen patterns for pre- and post-transplant sera on these arrays, we were able to detect anti-HLA signals with the resolution that also allowed us to pinpoint the immune epitopes involved. These personalized antigen arrays allow high-resolution detection of donor-specific HLA epitopes in organ transplantation.


A window of opportunity to control the bacterial pathogen Pseudomonas aeruginosa combining antibiotics and phages.
The evolution of antibiotic resistance in bacteria is a global concern and the use of bacteriophages alone or in combined therapies is attracting increasing attention as an alternative. Evolutionary theory predicts that the probability of bacterial resistance to both phages and antibiotics will be lower than to either separately, due for example to fitness costs or to trade-offs between phage resistance mechanisms and bacterial growth. In this study, we assess the population impacts of either individual or combined treatments of a bacteriophage and streptomycin on the nosocomial pathogen Pseudomonas aeruginosa. We show that combining phage and antibiotics substantially increases bacterial control compared to either separately, and that there is a specific time delay in antibiotic introduction independent of antibiotic dose, that minimizes both bacterial density and resistance to either antibiotics or phage. These results have implications for optimal combined therapeutic approaches.


Making Green Revolutions: Kansas Farms, Recovery, and the New Agriculture, 1918-1981.
The literature on the Dust Bowl conveys the impression of widespread exodus from the Great Plains. But farm populations were often more resilient than the iconic photographs of the era suggest. While recent studies highlight that tenacity, less is known about the process of recovery and postwar growth. This paper offers a window on both. The evidence discussed here survives as a legacy of a long-lived, state-run agricultural statistics program in Kansas. The State Board of Agriculture conducted annual household surveys of farms between 1873 and 1981. Linked together over time, these farm-level surveys offer a detailed record of the residential and land-use histories of three communities, and they begin to illustrate how farm households met the challenges of the drought years and adjusted to the new agriculture in the post-World War II era.


5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells.
Despite high cure rates, about 20% of patients with advanced germ cell tumors (GCTs) fail cisplatin-based chemotherapy. High levels of DNA methylation have been identified in GCTs and linked to cisplatin resistance. Here, we examined the effects of DNA hypomethylating 5-azacitidine (5-aza) on two embryonal carcinoma cell lines (NCCIT, 2102Ep) and their cisplatin-resistant isogenic derivatives. Effects on cell viability and cisplatin sensitivity were assessed by the trypan blue exclusion method. Western blotting was used to examine induction of apoptosis 5-aza and results were validated by flow cytometry. Single agent treatment with 5-aza strongly impacted viability and induced apoptosis at low nanomolar concentrations, both in cisplatin-sensitive and -resistant cell lines. 5-aza exerted an immediate apoptotic response, followed by a prolonged inhibitory effect on cell viability and cell-cycle progression. Sequential treatment with 5-aza and cisplatin reduced cellular survival of the cisplatin-resistant sublines already at nanomolar concentrations, suggesting a partial restoration of cisplatin sensitivity by the compound. 5-aza demonstrated anti-tumor activity as a single agent at low nanomolar concentrations in GCT cells, irrespective of cisplatin-sensitivity. 5-aza may also have the potential at least to partially restore cisplatin-sensitivity in non-seminoma cells, supporting the hypothesis that combining DNA demethylating agents with cisplatin-based chemotherapy may be a valid therapeutic approach in patients with refractory GCTs.


(S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid, a potent and selective agonist at the GluR5 subtype of ionotropic glutamate receptors. Synthesis, modeling, and molecular pharmacology.
We have previously described (RS)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (4-AHCP) as a highly effective agonist at non-N-methyl-d-aspartate (non-NMDA) glutamate (Glu) receptors in vivo, which is more potent than (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) but inactive at NMDA receptors. However, 4-AHCP was found to be much weaker than AMPA as an inhibitor of [(3)H]AMPA binding and to have limited effect in a [(3)H]kainic acid binding assay using rat cortical membranes. To shed light on the mechanism(s) underlying this quite enigmatic pharmacological profile of 4-AHCP, we have now developed a synthesis of (S)-4-AHCP (6) and (R)-4-AHCP (7). At cloned metabotropic Glu receptors mGluR1alpha (group I), mGluR2 (group II), and mGluR4a (group III), neither 6 nor 7 showed significant agonist or antagonist effects. The stereoisomer 6, but not 7, activated cloned AMPA receptor subunits GluR1o, GluR3o, and GluR4o with EC(50) values in the range 4.5-15 microM and the coexpressed kainate-preferring subunits GluR6 + KA2 (EC(50) = 6.4 microM). Compound 6, but not 7, proved to be a very potent agonist (EC(50) = 0.13 microM) at the kainate-preferring GluR5 subunit, equipotent with (S)-2-amino-3-(5-tert-butyl-3-hydroxyisothiazol-4-yl)propionic acid [(S)-Thio-ATPA, 4] and almost 4 times more potent than (S)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazol-4-yl)propionic acid [(S)-ATPA, 3]. Compound 6 thus represents a new structural class of GluR5 agonists. Molecular modeling and docking to a crystal structure of the extracellular binding domain of the AMPA subunit GluR2 has enabled identification of the probable active conformation and binding mode of 6. We are able to rationalize the observed selectivities by comparing the docking of 4 and 6 to subtype constructs, i.e., a crystal structure of the extracellular binding domain of GluR2 and a homology model of GluR5.


[Passive and active elements of the potassium secretion system in the skin of frogs].
A method has been evolved for studying the potassium and sodium transport without labelled ions in the frog skin. The potassium secretion sharply increased after the nystatinum had been added to the solution near the skin surface. Suppression of the apical membrane sodium permeability with amiloride or triamteren did not alter the potassium secretion velocity. The nystatinum increased both the potassium and sodium permeability. The blocking agents for sodium channels became ineffective in the presence of nystatinum. During the nystatinum action on the apical membrane the work of Na/K pump does not change in the basal plasmatic membrane, while suppression of the pump with strophantinum abolishes the potassium secretion across the apical membrane. Vasopressin and aldosterone increase the potassium secretion. Therefore, the potassium secretion level depends on the apical membrane potassium permeability and is independent of the sodium transport across this membrane, it is due to potassium inflow into the cell with the aid of Na/K pump of the basal plasmatic membrane.


Sedentary Behavior and Incident Dementia Among Older Adults.
Sedentary behavior is associated with cardiometabolic disease and mortality, but its association with dementia is unclear. To investigate whether accelerometer-assessed sedentary behavior is associated with incident dementia. A retrospective study of prospectively collected data from the UK Biobank including 49 841 adults aged 60 years or older without a diagnosis of dementia at the time of wearing the wrist accelerometer and living in England, Scotland, or Wales. Follow-up began at the time of wearing the accelerometer (February 2013 to December 2015) and continued until September 2021 in England, July 2021 in Scotland, and February 2018 in Wales. Mean daily sedentary behavior time (included in the primary analysis) and mean daily sedentary bout length, maximum daily sedentary bout length, and mean number of daily sedentary bouts (included in the secondary analyses) were derived from a machine learning-based analysis of 1 week of wrist-worn accelerometer data. Incident all-cause dementia diagnosis from inpatient hospital records and death registry data. Cox proportional hazard models with linear and cubic spline terms were used to assess associations. A total of 49 841 older adults (mean age, 67.19 [SD, 4.29] years; 54.7% were female) were followed up for a mean of 6.72 years (SD, 0.95 years). During this time, 414 individuals were diagnosed with incident all-cause dementia. In the fully adjusted models, there was a significant nonlinear association between time spent in sedentary behavior and incident dementia. Relative to a median of 9.27 hours/d for sedentary behavior, the hazard ratios (HRs) for dementia were 1.08 (95% CI, 1.04-1.12, P < .001) for 10 hours/d, 1.63 (95% CI, 1.35-1.97, P < .001) for 12 hours/d, and 3.21 (95% CI, 2.05-5.04, P < .001) for 15 hours/d. The adjusted incidence rate of dementia per 1000 person-years was 7.49 (95% CI, 7.48-7.49) for 9.27 hours/d of sedentary behavior, 8.06 (95% CI, 7.76-8.36) for 10 hours/d, 12.00 (95% CI, 10.00-14.36) for 12 hours/d, and 22.74 (95% CI, 14.92-34.11) for 15 hours/d. Mean daily sedentary bout length (HR, 1.53 [95% CI, 1.03-2.27], P = .04 and 0.65 [95% CI, 0.04-1.57] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 0.48 hours) and maximum daily sedentary bout length (HR, 1.15 [95% CI, 1.02-1.31], P = .02 and 0.19 [95% CI, 0.02-0.38] more dementia cases per 1000 person-years for a 1-hour increase from the mean of 1.95 hours) were significantly associated with higher risk of incident dementia. The number of sedentary bouts per day was not associated with higher risk of incident dementia (HR, 1.00 [95% CI, 0.99-1.01], P = .89). In the sensitivity analyses, after adjustment for time spent in sedentary behavior, the mean daily sedentary bout length and the maximum daily sedentary bout length were no longer significantly associated with incident dementia. Among older adults, more time spent in sedentary behaviors was significantly associated with higher incidence of all-cause dementia. Future research is needed to determine whether the association between sedentary behavior and risk of dementia is causal.


The control of testicular androgen production in the goldfish: effects of activators of different intracellular signalling pathways.
The putative roles of different signal transduction pathways in the regulation of testicular androgen production in goldfish were investigated. In addition to the role of the gonadotropin-adenylate cyclase pathway, which was studied using human chorionic gonadotropin and forskolin, we determined the effects of changes in intracellular calcium content and protein kinase C activation on androgen production using calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA), respectively. Testis fragments incubated in vitro respond to hCG in a time- and dose-dependent manner with a resultant increase in the secretion of testosterone (T) and 11-ketotestosterone (11-KT). Although ineffective alone, PMA (400 nM) and A23187 (4000 nM) stimulate a small but significant increase (3-fold above basal) in T production. This response is minor compared to the up to 200-fold increase in T secretion observed in response to either hCG or forskolin. PMA (25-400 nM) alone and A23187 (250-4000 nM) alone inhibit the stimulatory actions of hCG on T production. Unlike PMA, the inactive phorbol 4 alpha-phorbol didecanoate, which does not activate PKC, had no effect on hCG-stimulated T production. PMA and A23187 did not influence the effects of forskolin on T production, suggesting that the compounds exert their effects prior to adenylate cyclase activation. In summary, the present studies suggest that in addition to the stimulatory actions of the adenylate cyclase second messenger system, changes in intracellular calcium content and protein kinase C activation may modulate testicular androgen production in the goldfish.


Vacuum-assisted venous drainage in extrathoracic cardiopulmonary bypass management during minimally invasive cardiac surgery.
The diffusion of minimally invasive cardiac surgery (MICS) during open-heart surgery has increased the use of assisted venous drainage support for cardiopulmonary bypass (CPB). Peripheral cannulation with small cannulae and vacuum-assisted venous drainage (VAVD) during MICS has been adopted in our institution since 1998. After the Heartport technique (HP) experience, the trans-thoracic clamp technique is now currently used. The aim of this study is to report our experience with extrathoracic CPB with VAVD application (on CPB) during open-heart MICS. From October 1999 to June 2006, 193 patients underwent MICS. Thirty-seven (19.2%) patients were treated with the HP--13 (35%) with robotic technology and 156 (80.8%) with trans-thoracic aortic clamping (TTAC). Mean age was 39 years (range: 12-77), and 114 patients (59.1%) were female. A total of 128 patients (66.3%) underwent mitral valve surgery, 57 (29.6%) atrial septal defect closure, five (2.6%) cardiac mass removal, and three (1.5%) tricuspid valve repair. Four patients (2.0%) had a previous cardiac procedure. Peripheral CPB was established with a standard coated circuit. A 14 Fr arterial cannula was inserted into the right jugular vein and positioned at the atrial/superior vena cava junction. A 21 or 28 percutaneous femoral cannula, depending on body surface area, was inserted in the femoral vein and an arterial cannula in the right femoral artery. Gravitational drainage was combined with VAVD. To improve the safety and effectiveness of this technique, we monitored the pressure on each venous cannula and in the reservoir. The mean CPB time was 74.8 +/- 30 min (TTAC) and 119 +/- 48 min (HP); mean aortic clamping time was 51 +/- 19 min (TTAC) and 73 +/- 29 min (HP). We did not record any neurological complication. Two patients (1.0%), one from each group, were converted to sternotomy. Three patients (1.5%) underwent re-exploration for bleeding. In-hospital mortality was 0.5% (N = 1) (HP). Mechanical ventilation time and intensive care unit stay were comparable to those recorded with conventional sternotomy. In conclusion, we found that extrathoracic CPB and VAVD during trans-thoracic clamping is a safe, simple, and effective technique for MICS. However, there is a potential risk of haemolysis and air embolism, which can be prevented with vacuum monitoring, and with the addition of gravitational drainage to reduce vacuum pressure.


The early impact of the Covid-19 pandemic on the global and Turkish economy
Individuals infected by the Covid-19 potentially are at risk of health and economic well-being. Today, the Covid-19 is a global issue, and the world economy can be interpreted as almost at the standstill. In this context, this study aims to discuss the potential first reactions of short and long term global economic impacts of the pandemic through sectors by assessing its costs according to the data announced for both the world and Turkey. In addition, this study tries to put forth possible economic and political scenarios for the post-pandemic world. This is a review article that summarizes the current reports and discussions about the economic consequences of this historical event, and tries to make some inferences considering them. This pandemic has severe adverse effects on the employees, customers, supply chains and financial markets, in brief, most probably it will cause a global economic recession. Nevertheless, due to the uncertainty of the end of this pandemic, both the length and scale of this contraction are not predictable. It takes a while for the world economy to recover from the contraction. It seems that this pandemic will lead to a permanent shift in the world and its politics, especially in health, security, trade, employment, agriculture, manufacturing goods production and science policies. Since this new world might provide great opportunities for some countries that did not dominate world production before, governments should develop new strategies to adjust the new world order without much delay.


Heart retransplantation.
Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.


Acute HIV Diagnosis After Initiation of Pre-exposure Prophylaxis in a Young Adult Patient: A Case Report.
Oral pre-exposure prophylaxis (PrEP) in the prevention of human immunodeficiency virus (HIV) infection is highly effective, yet the majority of sexually active adolescents and young adults (AYAs) at highest risk for HIV infection, particularly AYA males who have sex with males, have not been prescribed this medication. Provider hesitancy in prescribing PrEP to at-risk AYA patients is often associated with concerns about patient nonadherence and its effect on inducing HIV medication resistance. This case report has two aims. First, to outline the clinical course for an AYA patient prescribed PrEP for 3 months and then found to have HIV with an M184V resistance mutation and subsequently started on HIV treatment. And second, to illustrate how the benefits of PrEP initiation outweigh its risks by presenting clinical data on resistance patterns to PrEP medications. The patient eventually achieved viral suppression within 5 months of starting HIV treatment which has been sustained up to 2 years. This case illustrates that M184V resistance mutations, although rarely associated with PrEP, are unlikely to impact options for HIV treatment. Providers should recommend and prescribe oral PrEP to AYA patients at risk for HIV infection without concern for nonadherence leading to HIV medication resistance.


[Treatment of liver metastasis of endocrine tumors of the pancreas].
The aim of this review article is to analyze the diagnostic approach, presentation and therapeutic modalities in patients with liver metastasis from endocrine tumors. The paper shows the "state of the art" of therapeutic approaches with emphasis on the roll of different surgery, radio and chemotherapy, arterial embolization and other palliative procedures. The overall results of each of this modalities are also shown.


A scoping review of the application of motor learning principles to optimize myoelectric prosthetic hand control.
Although prosthetic hand rejection rates remain high, evidence suggests that effective training plays a major role in device acceptance. Receiving training early in the rehabilitation process also enhances functional prosthetic use, decreases the likelihood of developing an overreliance on the intact limb, and reduces amputation-related pain. Despite these obvious benefits, there is a current lack of evidence regarding the most effective training techniques to facilitate myoelectric prosthetic hand control, and it remains unknown whether training is effective in facilitating the acquisition and transfer of prosthetic skill. In this scoping review, we introduced and summarized key motor learning principles related to attentional focus, implicit motor learning, training eye-hand coordination, practice variability, motor imagery, and action observation, and virtual training and biofeedback. We then reviewed the existing literature that has applied these principles for training prosthetic hand control before outlining future avenues for further research. The importance of optimizing early and appropriate training cannot be overlooked. While the intuition and experience of clinicians holds enormous value, evidence-based guidelines based on well-established motor learning principles will also be crucial for training effective prosthetic hand control. While it is clear that more research is needed to form the basis of such guidelines, it is hoped that this review highlights the potential avenues for this work.


Chicory, a typical vegetable in Mediterranean diet, exerts a therapeutic role in established atherosclerosis in apolipoprotein E-deficient mice.
Since protocatechuic acid exerts an atheroprotective role, we investigated how chicory (Cichorium intybus L. var. foliosum, Belgian endive) rich in protocatechuic acid, a typical vegetable in Mediterranean diet, affects preestablished atherosclerosis progression. Apolipoprotein E-deficient mice fed AIN diets containing 0.5% freeze-dried chicory for 10 weeks displayed a reduction in lesion size with a concomitant improvement in lesion stability indicated by fewer macrophages and more collagen content. Chicory consumption suppressed aortic cholesterol accumulation and intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 expression, whereas it increased aortic ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression. Furthermore, chicory consumption improved peritoneal macrophage phenotype with less cellular cholesterol associated with an enhancement of cholesterol efflux capacity through upregulation of ABCA1 and ABCG1, less cellular oxidative stress associated with an inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity, and weaker inflammatory responses associated with an inhibition of nuclear factor-κB activation. Interestingly, ABCA1 and ABCG1 silencing tended to completely block beneficial effects of chicory in peritoneal macrophages. Chicory exerts an atheroprotective role in mice possibly by regulating lesional macrophage content and phenotype, suggesting that chicory is one underrated contributor to Mediterranean Diet-induced atheroprotection.


PKA and AMPK Signaling Pathways Differentially Regulate Luteal Steroidogenesis.
Luteinizing hormone (LH) via protein kinase A (PKA) triggers ovulation and formation of the corpus luteum, which arises from the differentiation of follicular granulosa and theca cells into large and small luteal cells, respectively. The small and large luteal cells produce progesterone, a steroid hormone required for establishment and maintenance of pregnancy. We recently reported on the importance of hormone-sensitive lipase (HSL, also known as LIPE) and lipid droplets for appropriate secretory function of the corpus luteum. These lipid-rich intracellular organelles store cholesteryl esters, which can be hydrolyzed by HSL to provide cholesterol, the main substrate necessary for progesterone synthesis. In the present study, we analyzed dynamic posttranslational modifications of HSL mediated by PKA and AMP-activated protein kinase (AMPK) as well as their effects on steroidogenesis in luteal cells. Our results revealed that AMPK acutely inhibits the stimulatory effects of LH/PKA on progesterone production without reducing levels of STAR, CYP11A1, and HSD3B proteins. Exogenous cholesterol reversed the negative effects of AMPK on LH-stimulated steroidogenesis, suggesting that AMPK regulates cholesterol availability in luteal cells. AMPK evoked inhibitory phosphorylation of HSL (Ser565). In contrast, LH/PKA decreased phosphorylation of AMPK at Thr172, a residue required for its activation. Additionally, LH/PKA increased phosphorylation of HSL at Ser563, which is crucial for enzyme activation, and decreased inhibitory phosphorylation of HSL at Ser565. The findings indicate that LH and AMPK exert opposite posttranslational modifications of HSL, presumptively regulating cholesterol availability for steroidogenesis.


Enzymes in organic media. Forms, functions and applications.
Enzyme catalysis in low water containing organic solvents is finding an increasing number of applications in diverse areas. This review focuses on some aspects which have not been reviewed elsewhere. Different strategies for obtaining higher activity and stability in such media are described. In this context, the damaging role of lyophilization and the means of overcoming such effects are discussed. Ultrasonication and microwave assistance are two emerging approaches for enhancing reaction rates in low water media. Control of water activity and medium engineering are two crucial approaches in optimization of catalytic behaviour in nonaqueous enzymology. Organometallics and synthesis/modification of polymers are two areas where nonaqueous enzymology can play a greater role in the coming years. The greater understanding of enzyme behaviour in nonaqueous media is expected to lead to larger and even more diverse kinds of applications.


Clear cell hidradenoma: an unusual vulvar tumor.
Clear cell hidradenoma (CCH) is a benign skin appendageal tumor. Most cases occur in the skin of the head and face. The tumor usually presents as a solitary firm dermal nodule. Histologically, it is a well-circumscribed, nonencapsulated tumor formed of 2 cell types, one with clear cytoplasm and the other with dark eosinophilic cytoplasm. Although most cases are benign, occasional cases with malignant transformation have been reported. We report a case of CCH in a very unusual location. To the best of our knowledge, CCH has not been previously described in this site, in the English literature. Although rare, inclusion of CCH should be included in the differential diagnosis of benign solid and clear cell tumors of the vulvar skin.


Transport of estradiol-17β-glucuronide, estrone-3-sulfate and taurocholate across the endoplasmic reticulum membrane: evidence for different transport systems.
Important reactions of drug metabolism, including UGT mediated glucuronidation and steroidsulfatase mediated hydrolysis of sulfates, take place in the endoplasmic reticulum (ER) of hepatocytes. Consequently, UGT generated glucuronides, like estradiol-17β-glucuronide, have to be translocated back into the cytoplasm to reach their site of excretion. Also steroidsulfatase substrates, including estrone-3-sulfate, have to cross the ER membrane to reach their site of hydrolysis. Based on their physicochemical properties such compounds are not favored for passive diffusion and therefore likely necessitate transport system(s) to cross the ER membrane in either direction. The current study aims to investigate the transport of taurocholate, estradiol-17β-glucuronide, and estrone-3-sulfate in smooth (SER) and rough (RER) endoplasmic reticulum membrane vesicles isolated from Wistar and TR(-) rat liver. Time-dependent and bidirectional transport was demonstrated for taurocholate, showing higher uptake rates in SER than RER vesicles. For estradiol-17β-glucuronide a fast time-dependent efflux with similar efficiencies from SER and RER but no clear protein-mediated uptake was shown, indicating an asymmetric transport system for this substrate. Estrone-3-sulfate uptake was time-dependent and higher in SER than in RER vesicles. Inhibition of steroidsulfatase mediated estrone-3-sulfate hydrolysis decreased estrone-3-sulfate uptake but had no effect on taurocholate or estradiol-17β-glucuronide transport. Based on inhibition studies and transport characteristics, three different transport mechanisms are suggested to be involved in the transport of taurocholate, estrone-3-sulfate and estradiol-17β-glucuronide across the ER membrane.


Neuropsychological rehabilitation for multiple sclerosis.
Cognitive deficits are a common manifestation in multiple sclerosis (MS) and have a wide effect on the patient's quality of life. Alleviation of the harmful effects caused by these deficits should be a major goal of MS research and practice. The aim of this review was to evaluate the effects of neuropsychological/cognitive rehabilitation in MS by conducting a systematic review. A systematic literature search was carried out on reports drawn from Cochrane MS Group Specialised Register (To October 2010), Evidence-based medicine (EBM) reviews (To September 2010), MEDLINE (January 1950 to September 2010), EMBASE (1974 to September 2010), PsycINFO (January 1806 to September 2010), WEB OF SCIENCE (WOS) (January 1986 to September 2010), CINAHL (1982 to September 2010), and identified from the references in these reports. Randomised Controlled Trials (RCTs) and quasi-randomised trials evaluating the effects of neuropsychological rehabilitation in MS compared to other interventions or no intervention at all and employing neuropsychological rehabilitation methods and outcome measures were included. Two review authors individually judged the relevance, risk of bias, and content of the included studies. Results were combined quantitatively with meta-analyses according to the intervention type: 1) Cognitive training and 2) Cognitive training combined with other neuropsychological rehabilitation methods. In addition, narrative presentation was used in reporting the results of those studies which were inappropriate to be included in the meta-analysis. Fourteen studies (770 MS patients) fulfilled the inclusion criteria. On the basis of these studies, low level evidence was found that neuropsychological rehabilitation reduces cognitive symptoms in MS. Cognitive training was found to improve memory span (standardised mean difference 0.54 (95% confidence interval 0.2 to 0.88, P = 0.002)), working memory (standardised mean difference 0.33 (95% confidence interval 0.09 to 0.57, P = 0.006)), and immediate visual memory (standardised mean difference 0.32 (95% confidence interval 0.04 to 0.6, P = 0.02)). There was no evidence of an effect of cognitive training combined with other neuropsychological rehabilitation methods on cognitive or emotional functions. The overall quality as well as the comparability of the included studies were relatively low due to methodological limitations and heterogeneity of outcome measures. Although most of the pooled results in the meta-analyses yielded no significant findings, twelve of the fourteen studies showed some evidence of positive effects when the studies were individually analysed. The review indicates low level evidence for the positive effects of neuropsychological rehabilitation in MS. Interventions included in the review were heterogeneous. Consequently, clinical inferences can basically be drawn from single studies. Therefore, new trials may change the strength and direction of the evidence. To further strengthen the evidence, well-designed high quality studies are needed. In this systematic review, recommendations are given for improving the quality of future studies on the effects of neuropsychological rehabilitation in MS.


Characterization of the maize Mutator transposable element MURA transposase as a DNA-binding protein.
The autonomous MuDR element of the Mutator (Mu) transposable element family of maize encodes at least two proteins, MURA and MURB. Based on amino acid sequence similarity, previous studies have reported that MURA is likely to be a transposase. The functional characterization of MURA has been hindered by the instability of its cDNA, mudrA, in Escherichia coli. In this study, we report the first successful stabilization and expression of MURA in Saccharomyces cerevisiae. Gel mobility shift assays demonstrate that MURA is a DNA-binding protein that specifically binds to sequences within the highly conserved Mu element terminal inverted repeats (TIRs). DNase I and 1,10-phenanthroline-copper footprinting of MURA-Mu1 TIR complexes indicate that MURA binds to a conserved approximately 32-bp region in the TIR of Mu1. In addition, MURA can bind to the same region in the TIRs of all tested actively transposing Mu elements but binds poorly to the diverged Mu TIRs of inactive elements. Previous studies have reported a correlation between Mu transposon inactivation and methylation of the Mu element TIRs. Gel mobility shift assays demonstrate that MURA can interact differentially with unmethylated, hemimethylated, and homomethylated TIR substrates. The significance of MURA's interaction with the TIRs of Mu elements is discussed in the context of what is known about the regulation and mechanisms of Mutator activities in maize.


[A new universal program of postgraduate physician instruction in dermatology and venereology].
The Chair for Dermatology and Venereology at the Central Institute for Advanced Medical Training has developed a new universal programme for advanced training of physicians in this field; this programme is the sole document regulating continuous education of dermatologists and venereologists. It was approved by the Head Administration of Educating Institutions of the USSR Ministry of Health. The programme structure is based on a block system. Of the 8 blocks (courses) one deals with organizational aspects of dermatological and venereological care, five with dermatology, one with syphilis, one with gonorrhea and nongonorrheal diseases. The Programme includes curricula for two cycles of general and eight cycles of topical continuous education, defines the purposes of these cycles, and specifies who should be admitted for these cycles. The Universal Programme may be used parallel with other forms of continuous education (workshops, ten-day courses, etc.) and for individual education.


Alternative Geometries for 3D Bioprinting of Calcium Phosphate Cement as Bone Substitute.
In the literature, many studies have described the 3D printing of ceramic-based scaffolds (e.g., printing with calcium phosphate cement) in the form of linear structures with layer rotations of 90°, although no right angles can be found in the human body. Therefore, this work focuses on the adaptation of biological shapes, including a layer rotation of only 1°. Sample shapes were printed with calcium phosphate cement using a 3D Bioplotter from EnvisionTec. Both straight and wavy spokes were printed in a round structure with 12 layers. Depending on the strand diameter (200 and 250 µm needle inner diameter) and strand arrangement, maximum failure loads of 444.86 ± 169.39 N for samples without subsequent setting in PBS up to 1280.88 ± 538.66 N after setting in PBS could be achieved.


[Factors predicting blood pressure normalization in hypertensive patients treated with a fixed-dose combination of bisoprolol 2.5 mg/hydrochlorothiazide/6.25 mg].
It is not clear which duration of treatment is needed to achieve complete efficacy with fixed low dose antihypertensive therapy. The aim of this study was to compare blood pressure control rate in patients treated with bisoprolol 2.5 mg/HCTZ 6.25 mg, not controlled after 4 weeks, but treated at the same dosage for one more month to patients not controlled after 4 weeks, and uptitrated to bisoprolol 5 mg/HCTZ 6.25 mg for one month. The 641 patients who entered the study had a mean age of 58 +/- 12 with SBP/DBP at baseline of 165 +/- 12/96 +/- 7 mmHg. After 4 weeks, 252 (39%) where normalized (< 140/90) with SBP/DBP reductions of -27/-15 mmHg. In uncontrolled patients, 19% of those randomized to B 2.5 mg/H 6.25 mg and 33% of those treated with B 5 mg/H 6.25 mg where normalized at the end of the study (p < 0.001). Multivariate analysis indicates determinants of blood pressure normalisation after 4 weeks with B2.5 mg/HCTZ 6.25 mg as female gender, initial BP < 175/105 mmHg, previously untreated hypertension, age < 50 years. In conclusion, when the initial therapy with bisoprolol 2.5 mg/HCTZ 6.25 mg is not sufficient to control blood pressure, continuation with the same dosage 4 weeks longer increases the rate of blood pressure control. However, up-titration to bisoprolol 5 mg/6.25 mg is more efficacious to increase the number of patients with a final blood pressure < 140/90 mmHg.


Functionalization of carbon nanotubes: manufacturing techniques and properties of customized nanocomponents for molecular-level technology.
Carbon nanotubes (CNTs) since their discovery have been the focus of research on account of exceptional chemical, mechanical and electrical properties. However, manipulation and processing of CNTs have been limited by their compatibility with other materials. Considerable efforts have therefore been devoted to the surface modification of CNTs to pave the way to many useful applications and to realize the potential applications in successful products, especially composite manufacturing. The chemical modification, dispersion and solubilization of CNTs represent an emerging area in the research on nanotubes-based materials. Several research groups have reported successful and doable functionalization techniques for single-walled (SWCNT) and multi-wall (MWCNT) carbon nanotubes. This paper presents an overview of the functionalization of the carbon nanotubes covering both covalent and non-covalent techniques at tips and walls of SWCNTs and MWCNTs, and summarizes recent patents possessing significant commercial value and large-scale practicality. The principal aim is to review main approaches to chemical functionalization of CNTs and to account for the advances that have been made so far.


Biphasic regulation of the gonadotropin-releasing hormone receptor by receptor microaggregation and intracellular Ca2+ levels.
In the present work we show that Ca2+ is both necessary and sufficient to evoke homologous up-regulation of the gonadotropin-releasing hormone (GnRH) receptor. Extracellular Ca2+ as well as RNA and protein synthesis were required for this event, and it was blocked by Ca2+ ion channel blockers. Drugs which stimulated increased intracellular Ca2+ levels also stimulated receptor up-regulation and enhanced responsiveness even in the absence of added GnRH. Such drugs were effective below the concentrations needed to evoke luteinizing hormone (LH) release, suggesting that enhanced levels of Ca2+ ion, rather than LH depletion, is the responsible agent. A GnRH antagonist did not evoke up- or down-regulation; however, a conjugate of this antagonist, which stimulated microaggregation of the GnRH receptor, also stimulated these biphasic actions. In contrast to up-regulation, down-regulation of the GnRH receptor appears to be Ca2+-independent and does not require RNA or protein synthesis. These data are consistent with a model in which microaggregation of the GnRH receptor is the final step in common to a branched pathway consisting of Ca2+-dependent (LH release, enhanced sensitivity, up-regulation) and Ca2+-independent (desensitization, down-regulation) events.


Screw loosening in the Dynesys stabilization system: radiographic evidence and effect on outcomes.
Dynamic stabilization systems are used to stabilize degenerative lumbar spondylosis. Loosening of the pedicle screws in such nonfusion implants is predictable. This retrospective study evaluated the incidence of screw loosening and its effect on clinical outcomes. Charts, radiographic films, and medical records of 71 consecutive patients who underwent decompression using Dynesys dynamic stabilization for 1- or 2-level lumbar spondylosis were reviewed. Radiographic films were evaluated and compared to detect screw loosening. A visual analog scale (VAS) for back pain and the Oswestry Disability Index (ODI) were used for measuring clinical outcome. Statistical analysis was conducted using the chi-square test and Student t-test. The 71 patients in the study sample had a mean age of 59.2 +/- 11.65 years (range 23-80 years), with slight female predominance (39 women, 32 men). The mean follow-up duration was 16.6 months (range 8-29 months). There were loose screws in 14 of 71 patients (19.7%), for a rate of 4.6% per screw (17 of 368 screws). Most screw loosening occurred in patients >/= 55 years old (13 of 14 patients) although age and sex had no effect on screw loosening (p = 0.233 and 0.109, respectively). Both the loose screw and solid screw groups experienced significant improvement after the surgery in VAS and ODI scores. On the VAS, scores improved from 5.9 +/- 2.99 to 2.1 +/- 2.14 in the loose screw group (p = 0.003), and from 5.7 +/- 3.45 to 2.9 +/- 2.68 in the solid screw group (p < 0.001). For the ODI scale, scores improved from 43.5 +/- 16.78% to 28.0 +/- 18.18% (p = 0.006) in the loose screw group, and from 52.1 +/- 20.92% to 24.6 +/- 19.78% (p < 0.001) in the solid screw group. There were no significant differences between the 2 groups (p = 0.334 for VAS, p = 0.567 for ODI). The preliminary study of this pedicle-based dynamic stabilization device for 1- and 2-level lumbar spondylosis shows radiographic evidence of screw loosening in 19.7% of patients and 4.6% of screws. Nonetheless, the loosening of screws has no adverse effect on clinical improvement.


A comparison of assertive community treatment fidelity measures and patient-centered medical home standards.
OBJECTIVE This study compared program measures of assertive community treatment (ACT) with standards of accreditation for the patient-centered medical home (PCMH) to determine whether there were similarities in the infrastructure of the two methods of service delivery and whether high-fidelity ACT teams would qualify for medical home accreditation. METHODS The authors compared National Committee for Quality Assurance PCMH standards with two ACT fidelity measures (the Dartmouth Assertive Community Treatment Scale and the Tool for Measurement of Assertive Community Treatment [TMACT]) and with national ACT program standards. RESULTS PCMH standards pertaining to enhanced access and continuity, management of care, and self-care support demonstrated strong overlap across ACT measures. Standards for identification and management of populations, care coordination and follow-up, and quality improvement demonstrated less overlap. The TMACT and the program standards had sufficient overlap to score in the range of a level 1 PCMH, but no ACT measure sufficiently detailed methods of population-based screening and tracking of referrals to satisfy "must-pass" elements of the standards. CONCLUSIONS ACT measures and medical home standards had significant overlap in innate infrastructure. ACT teams following the program standards or undergoing TMACT fidelity review could have the necessary infrastructure to serve as medical homes if they were properly equipped to supervise general medical care and administer activities to improve management of chronic diseases.


Cloning of ligand targets: systematic isolation of SH3 domain-containing proteins.
Based on the prevalence of modular protein domains, such as Src homology domain 3 and 2 (SH3 and SH2), among important signaling molecules, we have sought to identify new SH3 domain-containing proteins. However, modest sequence similarity among these domains restricts the use of DNA-based methods for this purpose. To circumvent this limitation, we have developed a functional screen that permits the rapid cloning of modular domains based on their ligand-binding activity. Using operationally defined SH3 ligands from combinatorial peptide libraries, we screened a series of mouse and human cDNA expression libraries. We found that 69 of the 74 clones isolated encode at least one SH3 domain. These clones encode 18 different SH3-containing proteins, 10 of which have not been described previously. The isolation of entire repertoires of modular domain-containing proteins will prove invaluable in genome analysis and in bringing new targets into drug discovery programs.


[Conceptions of normality and mental health among prisoners in a correctional institution in the city of Salvador].
Although in Brazil some recent studies analyzed the concepts of normality and mental health, there are still no investigations dealing with this question among prisoners. Thus, this work aims specifically at investigating this subject in this segment of the population. The methodology used in this study was collection of data and practical analysis according to the theory of systems of signs, meanings and practices. We verified that the interviewees associated normality and mental health with the behaviors considered normal and sane in the scientific literature. The inverse occurred in relation to the concepts of abnormality and insanity. A relevant aspect of this study was the prisoner's approach to criminal violence. At the same time they considered such type of violence as characteristic of an abnormality or illness, they did not consider themselves abnormal or violent for having committed a crime. This aspect seems to point to the existence of two different perspectives: one considering criminal violence as abnormal or insane and another that admits the coexistence of a moment of criminal violence with normality and mental health.


Synthesis and coordination compounds of a bis(imino)acenaphthene (BIAN)-supported N-heterocyclic carbene.
The bis(imino)acenaphthene-supported N-heterocyclic carbene IPr(BIAN) has been prepared by deprotonation of the precursor imidazolium chloride. Treatment of IPr(BIAN) imidazolium chloride with Ag(2)O afforded the silver complex [IPr(BIAN)]AgCl which can be converted into the corresponding gold complex [IPr(BIAN)]AuCl by reaction with (tht)AuCl (tht = tetrahydrothiophene). The iridium complex [IPr(BIAN)]Ir(COD)Cl was prepared by reaction of the imidazolium chloride with KO(t)Bu and [Ir(COD)Cl](2) and subsequently converted to the carbonyl complex [IPr(BIAN)]Ir(CO)(2)Cl by exposure to an atmosphere of CO. All new compounds were characterized by single-crystal X-ray diffraction, multinuclear NMR, MS and HRMS data.


Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine.
In experimental visceral leishmaniasis, euthymic but not athymic (nude) BALB/c mice respond to conventional treatment with pentavalent antimony, indicating that the in vivo efficacy of antimony is T cell dependent. This finding correlates with frequent antimony treatment failures for T-cell-deficient patients with visceral leishmaniasis. To determine whether the in vivo efficacies of alternative antileishmanial agents also require T cells, Leishmania donovani-infected euthymic and nude BALB/c mice were treated with pentamidine or amphotericin B. Pentamidine induced leishmanistatic activity in euthymic mice but had little effect in nude mice. In contrast, amphotericin B exerted potent leishmanicidal activities in both euthymic and nude animals. These results suggest that amphotericin B may be of particular use for T-cell-deficient patients with visceral leishmaniasis.


Futile cycling increases sensitivity toward oxidative stress in Escherichia coli.
Reactive oxygen species (ROS) are toxic molecules utilized by the immune system to combat invading pathogens. Recent evidence suggests that inefficiencies in ATP production or usage can lead to increased endogenous ROS production and sensitivity to oxidative stress in bacteria. With this as inspiration, and knowledge that ATP is required for a number of DNA repair mechanisms, we hypothesized that futile cycling would be an effective way to increase sensitivity to oxidative stress. We developed a mixed integer linear optimization framework to identify experimentally-tractable futile cycles, and confirmed metabolic modeling predictions that futile cycling depresses growth rate, and increases both O2 consumption and ROS production per biomass generated. Further, intracellular ATP was decreased and sensitivity to oxidative stress increased in all actively cycling strains compared to their catalytically inactive controls. This research establishes a fundamental connection between ATP metabolism, endogenous ROS production, and tolerance toward oxidative stress in bacteria.


New Directions in Cancer Control and Population Sciences.
Cancer control science has been evolving since it first became a focus for cancer research and program activities a century ago. The evolution of the field has responded to historical megatrends along the way that keep it relevant to the cancer-related needs of society. This commentary describes some of the key trends and developments now influencing cancer control and population sciences that reflect societal change and new tools and concepts in modern biomedical science. New directions include the impact of climate change, health care delivery research, the growth of population health science, data science, precision medicine, data sharing, implementation science, and new technologies, including social media and new geospatial methodologies. Cancer Epidemiol Biomarkers Prev; 26(8); 1165-9. ©2017 AACR.


Insight into the Development of Dissolution Media for BCS Class II Drugs: A Review from Quality Control and Prediction of In Vivo Performance Perspectives.
To assess in vivo behavior through in vitro method, the dissolution test is mostly used, both for quality control (QC) and for development purpose. In view of the fact that a dissolution test can hardly achieve two goals at the same time, the design of dissolution testing generally varies along with the development stage of drug products and therefore the selection of dissolution media may change with the goals of the dissolution test. To serve the QC purpose, a dissolution medium is designed to provide a sink condition; for development purpose, the dissolution medium is required to simulate the physiological conditions in the gastrointestinal tract as far as possible. In this review, we intended to provide an initial introduction to the various dissolution media applied for QC and formulation development purposes for poorly water soluble drugs. We focused on these methods like addition of cosolvents, surfactants and utilization of biphasic media, applied to provide sink conditions which are difficult to be achieved by simple aqueous buffers for lipophilic drugs, and introduced the development of physiologically relevant media for human and animals like dog and rat with respect to the choice of buffers, bile salts, lipids and so on. In addition, we further discussed the influence of biorelevant dissolution media on the modification of drug Biopharmaceutical Classification System (BCS) classification, especially for BCS class II drugs with low solubility and high permeability, the solubility of which is relatively sensitive to the presence of bile salts and lipids.


The development of cannabinoid antagonists.
The discovery of two distinct cannabinoid receptors (CB1 and CB2) in the early 1990's has revived the research on cannabinoid antagonists. While the search for antagonists based on the structure of agonists (classical cannabinoids or aminoalkylindoles) appeared rather disappointing, the first potent cannabinoid antagonists were developed in a new chemical series: the diarylpyrazoles. Since its discovery in 1994, the selective CB1 antagonist SR 141716 has became a major pharmacological tool to elucidate the physiological role of the CB1 cannabinoid receptor and its endogenous ligand. The selective CB2 antagonist SR 144528 is expected to play the same role for the CB2 receptors, while the recent development of cannabinoid antagonists belonging to other chemical series illustrates the interest of these compounds which are now considered as interesting therapeutic targets by many pharmaceutical companies.


[Assessment of the association of morbidity due to parasitic diseases with the inoculation of the environment with their pathogens].
The paper gives a conceptual design of field parasitological studies of the association of the inoculation of the environment with the pathogens of parasitic diseases with their spread among humans. The design includes 6 stages that reflect their object, the problems to be solved, guidelines, and expected results. It is of great importance in defining a factorial (environmental) risk for infection with the causative agents of parasitoses and in substantiating and implementing measures to protect the environment from pollution and to prevent parasitic diseases in man and animals.