Occurrence of virus-induced COPD exacerbations during four seasons.
In this study, we investigated the occurrence of viral infections in acute exacerbations of chronic obstructive pulmonary disease (COPD) during four seasons. Viral infections were detected by the use of real-time reverse transcriptase polymerase chain reaction on pharyngeal swabs. During a 12-month period pharyngeal swabs were obtained in 136 exacerbations of 63 patients. In 35 exacerbations (25.7%) a viral infection was detected. Most viral infections occurred in the winter (n = 14, 40.0%), followed by summer (n = 9, 25.7%), autumn (n = 6, 17.1%), and spring (n = 6, 17.1%). Rhinovirus was the most frequently isolated virus (n = 19, 51.4%), followed by respiratory syncytial virus (n = 6, 16.2%), human metapneumovirus (n = 5, 13.5%), influenza A (n = 4, 10.8%), parainfluenza 4 (n = 2, 5.4%), and parainfluenza 3 (n = 1, 2.7%). This study showed that virus-induced COPD exacerbations occur in all four seasons with a peak in the winter months. However, the distribution of rhinovirus infections showed a different pattern, with most infections occurring in July.


Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renal injury.
Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), are associated with inflammation. The mechanism that regulates inflammation in these renal injuries remains unclear. Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase, was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice. Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries. Furthermore, increased H3K18ac was recruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice. In vitro studies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led to downregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-κB (p50), and MCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level. Consistent with these, overexpression of PCAF enhanced the expression of inflammatory molecules. Furthermore, PCAF deficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, as well as inhibited palmitate-induced upregulation of these inflammatory molecules. In summary, the present work demonstrates that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases.


Comparison of effect between group discussion and educational booklet on Iranian nursing students' attitude and practice toward patient privacy.
This study aimed to compare the effects between group discussion and educational booklet on nursing students' attitude and practice toward patient privacy in Iran. A two-group, pre-test and post-test design study was conducted in 2015. The study was conducted on 60 nursing students in Kashan, Iran who were randomly allocated into two groups to be trained on patient privacy either through group discussion or by an educational booklet. The students' attitude and practice was assessed before and after the education using a questionnaire and a checklist. Data analysis was performed through paired t-test, Wilcoxon signed ranks test, and independent samples t-tests. Before the intervention, no significant difference was found between the group designated to group discussion and that designated to the educational booklet in the mean overall score of attitude (P=0.303) and practice (P=0.493) toward patient privacy. After the intervention, the mean attitude score significantly increased in the two groups (P=0.001). Moreover, the students' practice score increased in the discussion group while it did not significantly change in the booklet group (P=0.001). Both methods were effective on the students' attitude; however, the educational booklet did not affect their practice toward patient privacy. Group discussion can effectively improve the students' attitude and practice toward patient privacy.


Treatment of large distal extremity skin wounds with autogenous full-thickness mesh skin grafts in 5 cats.
Five cats with large, distal extremity abrasion wounds were treated with an autogenous, full-thickness, mesh skin graft. Survival of the mesh grafts in all five cats was considered between 90 and 100%. Successful grafting requires asepsis, an adequately prepared recipient bed consisting of healthy granulation tissue, proper harvesting and preparation of the graft, meticulous surgical technique and strict postoperative care. Factors that are essential for the survival of skin grafts include good contact between the graft and the recipient bed, normal tension on the sutured graft, strict immobilization after grafting and prevention of accumulation of blood or serum under the graft. Meshing the graft provides more graft flexibility over uneven surfaces and allows adequate drainage. In contrast to previous proposals, the authors recommend no bandage change before the fourth day after grafting. Full-thickness mesh skin grafting can be used to successfully treat large distal skin wounds in cats.


[Biological function of CoQ10 and its effect on the quality of spermatozoa].
Oxidative damage is one of the important factors inducing the regression of sperm quality. CoQ10 is a liposoluble antioxidant that exists in mitochondria and its levels in semen and spermatozoa have an important role in the oxidation resistance of the male genital system. Exogenous administration of CoQ10 can improve the sperm quality and reproductive ability of infertile patients as well as exert the effects of an adjunctive therapy on male infertility. This review describes the biological function of CoQ10 and its effect on the quality of spermatozoa and its effect as an adjunctive therapy on male infertility.


Distinct Roles for Intracellular and Extracellular Lipids in Hepatitis C Virus Infection.
Hepatitis C is a chronic liver disease that contributes to progressive metabolic dysfunction. Infection of hepatocytes by hepatitis C virus (HCV) results in reprogramming of hepatic and serum lipids. However, the specific contribution of these distinct pools of lipids to HCV infection remains ill defined. In this study, we investigated the role of hepatic lipogenesis in HCV infection by targeting the rate-limiting step in this pathway, which is catalyzed by the acetyl-CoA carboxylase (ACC) enzymes. Using two structurally unrelated ACC inhibitors, we determined that blockade of lipogenesis resulted in reduced viral replication, assembly, and release. Supplementing exogenous lipids to cells treated with ACC inhibitors rescued HCV assembly with no effect on viral replication and release. Intriguingly, loss of viral RNA was not recapitulated at the protein level and addition of 2-bromopalmitate, a competitive inhibitor of protein palmitoylation, mirrored the effects of ACC inhibitors on reduced viral RNA without a concurrent loss in protein expression. These correlative results suggest that newly synthesized lipids may have a role in protein palmitoylation during HCV infection.


Metrology and characterization of SU-8 microstructures using autofluorescence emission.
Sophisticated three-dimensional microstructures fabricated using the negative tone SU-8 photoresist are used in many biomedical and microfluidic applications. Scanning electron microscopy (SEM) and profilometry are commonly used metrological techniques for the dimensional characterization of fabricated SU-8 microstructures but are not viable for non-destructive measurements and characterization of subsurface features like hidden microchannels. In this study, we report a unique methodology for the non-destructive dimensional characterization of SU-8 microstructures using the emitted autofluorescence radiation from fabricated SU-8 microstructures to generate depth profiles. The relationship between autofluorescence emission intensities and the thicknesses of the microstructures measured using SEM was determined and used to characterize the dimensions of unknown SU-8 microstructures based on their autofluorescence intensities. Lateral dimensions were also measured. This relationship was used to create highly accurate depth profiles for different types of microstructures including hidden subsurface features. These results were validated by comparison with SEM. The results suggest a feasible and accurate non-destructive, low cost, metrological technique to characterize SU-8 surface and subsurface microstructures using autofluorescence emission intensities.


Reading between the menu lines: Are restaurants' descriptions of "healthy" foods unappealing?
As obesity rates continue to climb in America, much of the blame has fallen on the high-calorie meals at popular chain restaurants. Many restaurants have responded by offering "healthy" menu options. Yet menus' descriptions of healthy options may be less attractive than their descriptions of less healthy, standard options. This study examined the hypothesis that the words describing items in healthy menu sections are less appealing than the words describing items in standard menu sections. Menus from the top-selling American casual-dining chain restaurants with dedicated healthy submenus (N = 26) were examined, and the library of words from health-labeled items (N = 5,873) was compared to that from standard menu items (N = 38,343) across 22 qualitative themes (e.g., taste, texture). Log-likelihood ratios revealed that restaurants described healthy items with significantly less appealing themes and significantly more health-related themes. Specifically, healthy items were described as less exciting, fun, traditional, American regional, textured, provocative, spicy hot, artisanal, tasty, and indulgent than standard menu items, but were described with significantly more foreign, fresh, simple, macronutrient, deprivation, thinness, and nutritious words. Describing the most nutritious menu options in less appealing terms may perpetuate beliefs that healthy foods are not flavorful or indulgent, and may undermine customers' choice of healthier dining options. From a public health perspective, incorporating more appealing descriptive language to boost the appeal of nutritious foods may be one avenue to improve dietary health. (PsycINFO Database Record


The Bacteroidetes Q-Rule: Pyroglutamate in Signal Peptidase I Substrates.
Bacteroidetes feature prominently in the human microbiome, as major colonizers of the gut and clinically relevant pathogens elsewhere. Here, we reveal a new Bacteroidetes specific feature in the otherwise widely conserved Sec/SPI (Sec translocase/signal peptidase I) pathway. In Bacteroidetes, but not the entire FCB group or related phyla, signal peptide cleavage exposes N-terminal glutamine residues in most SPI substrates. Reanalysis of published mass spectrometry data for five Bacteroidetes species shows that the newly exposed glutamines are cyclized to pyroglutamate (also termed 5-oxoproline) residues. Using the dental pathogen Porphyromonas gingivalis as a model, we identify the PG2157 (also called PG_RS09565, Q7MT37) as the glutaminyl cyclase in this species, and map the catalytic activity to the periplasmic face of the inner membrane. Genetic manipulations that alter the glutamine residue immediately after the signal peptide in the pre-pro-forms of the gingipains affect the extracellular proteolytic activity of RgpA, but not RgpB and Kgp. Glutamine statistics, mass spectrometry data and the mutagenesis results show that the N-terminal glutamine residues or their pyroglutamate cyclization products do not act as generic sorting signals.


PDE5 inhibitors: considerations for preference and long-term adherence.
Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. A pubmed search was performed of all English language articles from 1996 to present reviewing PDE5i, including pharmacokinetics, efficacy profiles and comparisons, where available. Currently available PDE5i in the United States include sildenafil, vardenafil, tadalafil and avanafil, each of which has unique side effect, pharmacokinetic and outcome profiles. Sildenafil is associated with increased rate of visual changes, vardenafil with QT prolongation and tadalafil with lower back pain. Avanafil and vardenafil orodispersible tablet rapidly achieve peak plasma concentration, which results in faster onset of action, whereas tadalafil exhibits the longest half-life. First time response to PDE5i is approximately 60-70%, with no significant differences in efficacy noted among therapies. The literature does not clearly demonstrate a preference for one drug. High-treatment success rates (89%) were reported when patients were prescribed all available PDE5i. Daily dosing with tadalafil is associated with improved erectile function (EF) over time. Finally, novel modes of patient-provider interaction, including internet-based education, communication and prescribing, may also improve long-term adherence. PDE5i represent first line therapy for ED with excellent overall efficacy and satisfactory side effect profiles. Enhanced communciation, coupled with increased knowledge of drug characteristics, comparative treatment regimens and optimal prescribing patterns, offer compelling tools to improve long-term treatment success.


Morphological and Molecular Analysis Identifies the Associated Fungus ("Xianghui") of the Medicinal White Jelly Mushroom, Tremella fuciformis, as Annulohypoxylon stygium.
White jelly mushroom, Tremella fuciformis, is a popular edible mushroom with interesting medicinal properties (e.g., immunostimulating, antidiabetic). The formation of T. fuciformis basidiomes is highly dependent on the presence of a specific host fungus, both in nature and for industrial production. This host has traditionally been indicated as "Xianghui" in China, yet which or how many fungal species Xianghui comprises is unclear, with various authorities claiming different species. At present, Annulohypoxilon archeri is generally assumed to be the main Xianghui species, but this has not yet been confirmed experimentally. The implementation of older, premolecular-based research data (i.e., morphological) with present, sequence-based data to solve the identity remains confusing and studies addressing both identification methods in combination are lacking. The unclear identity of Xianghui is a major obstacle for further understanding of the important relationship between the host(s) and T. fuciformis. In this study, we collected a wild specimen of T. fuciformis together with several nearby stroma of Xianghui, cocultivated T. fuciformis with the Xianghui isolates, and observed basidiome formation. Internal transcribed spacer (ITS) sequence analysis showed that all Xianghui spore isolates belonged to the same species and both morphological analysis of sexual stages and ITS β-tubulin and actin gene sequences of the Xianghui specified it as Annulohypoxylon stygium. The ITS sequences of the newly identified Xianghui further closely matched those of the Xianghui strains used in the mushroom industry, showing that wild and culture spawn Xianghui in China consist of A. stygium. In contrast with previous conclusions, A. stygium, and not A. archeris, seems to be the preferred host of T. fuciformis.


HLX1 gene variants influence the development of childhood asthma.
Major transcription factors controlling T(H)1 and T(H)2 development, such as T-box transcription factor and GATA3, might be centrally involved in asthma and atopic diseases. Only recently, the homeobox transcription factor H.20-like homeobox 1 (HLX1), interacting closely with T-box transcription factor, has been identified as an important regulator of T(H)1 differentiation and suppressor of T(H)2 commitment. We investigated whether genetic variations in the HLX1 gene exist and whether these could affect the development of childhood asthma. The HLX1 gene was resequenced in 80 chromosomes. Associations between identified polymorphisms, asthma, and atopic diseases were investigated in German children (total n = 3099) from the cross-sectional International Study of Asthma and Allergy in Childhood phase II. Functional properties of polymorphisms were studied by using luciferase reporter gene assays and electrophoretic mobility shift assays in T cells. All statistical analyses were performed with SAS/Genetics software (SAS Institute, Inc, Cary, NC). Nineteen polymorphisms were identified in the HLX1 gene, and 2 tagging single nucleotide polymorphisms representing 7 polymorphisms were associated with childhood asthma in our study population. Two promoter polymorphisms, C-1407T and C-742G, contained in 1 tagging block were associated with asthma (odds ratio, 1.44; 95% CI, 1.11-1.86; P = .0061), significantly decrease promoter transactivation, and disrupt specificity protein-transcription factor binding in in vitro experiments. Our data suggest that polymorphisms in the HLX1 gene increase the risk for childhood asthma. On the cellular level, altered binding of specificity protein-transcription factors to the HLX1 promoter and subsequent changes in HLX1 gene expression might contribute to these effects.


Management of hemobilia with transarterial angiographic embolization: report of one case.
A nine-year-old girl who developed life threatening hemobilia after blunt abdominal trauma was successfully managed by embolization of the hepatic artery aneurysm. However, biliary fistula persisted and subcapsular liver abscess occurred after the endoscopic sphincterotomy and the placement of a nasobiliary drain for bile leakage. Debridement of the abscess and insertion of a drain tube eventually cured the event. The relevant literature is reviewed and the management of the hemobilia is discussed.


[Treatment of critically ill influenza A H1N1 patients in plateau region].
To discuss the strategy of treatment of critically ill influenza A H1N1 patients in plateau region. Four seriously ill and 4 critically ill patients suffering from influenza A H1N1 were admitted to the intensive care unit during October 10th through December 19th 2009. They were treated with antivirus drug, antibiotics, corticosteroid, measures to enhance immune function, fluid and electrolyte supplementation, symptomatic treatment, and mechanical ventilation. With their clinical data the distinguishing features in the treatment of these patients were analyzed. Oseltamivir as an antivirus drug, and moxifloxacin together with ceftriaxone or cefoperazone were given to all the patients. Fluid replacement was controlled to avoid over hydration. Corticosteroid was administered to 3 seriously ill patients and 3 critically ill patients. Methylprednisolone was given to 1 critically ill patient. gamma-globulin was given to 7 patients. Four patients underwent atraumatic mechanical ventilation with bi-level positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) with good result. Owing to deterioration in respiratory function, traumatic mechanical ventilation was instituted in a critically ill patient, primarily with synchronized intermittent mandatory ventilation (SIMV)+pressure support ventilation (PSV)+high positive end expiratory pressure (PEEP). The condition of the patient was improved, and ventilation modality was changed to spontaneous respiration+PSV+low PEEP before weaning. Finally the patient was weaned from respirator successfully. All the 8 patients survived and discharged from the hospital. Short term, full dosage of corticosteroid should be given to seriously ill and critically ill influenza A H1N1 patients according to specification, and atraumatic mechanical ventilation should be installed early in the treatment.


[Upright walking as a factor in the development of arterial hypertension in primates].
Time-course changes in the cardiovascular function of rhesus monkeys were investigated during forced orthograde statics and upright walking. Arterial pressure by Korotkoff sounds (in certain cases by a direct method in the femoral artery) and major parameters of central hemodynamics by tetrapolar thoracic rheography were measured. The monkeys developed stable arterial hypertension 3 months after the onset of the upright study. Hemodynamic parameters reflected circulation centralization, formation of the hyperkinetic type of the orthostatic reaction and development of arterial hypertension of the resistive type. It is suggested that orthostatics may contribute to the development of arterial hypertension.


Functionalization of diamond (100) by organic cycloaddition reactions of nitrenes: a theoretical prediction.
[structure: see text] We predict the viability of organic cycloadditions of nitrenes onto the diamond (100) surface. This new type of surface reaction can be employed to functionalize diamond surface at low temperature, which might introduce new functionalities to the diamond surface for novel applications in a diversity of fields.


Keratoacanthoma of the Nasal Septum Secondary to Ranibizumab Use.
Keratoacanthoma (KA) is a benign epithelial tumor that typically presents as a firm, cone-shaped, flesh-colored nodule with a central horn-filled crater. KA is considered to be a low-grade variant of squamous cell carcinoma (SCC). We report a rare case of a 72-year-old male who presented with a KA involving the nasal septum, possibly related to ranibizumab use. A flesh-colored lesion on the right anterior nasal septum lesion was visualized on examination. Histologic examination revealed a well-circumscribed, dome-shaped central crater filled with keratin, well-differentiated squamous epithelium with ground-glass cytoplasm with pushing margins, and intraepithelial microabscesses establishing the diagnosis of KA. KA of the nasal septum has only been reported once in the literature. This case is unusual because it normally presents on sun-exposed areas. Additionally, this patient was taking ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor for macular degeneration. Despite ranibizumab not being directly linked to precancerous and cancerous skin lesions, agents in this medication class have been. Although it is difficult to prove associations in this isolated case, the role of ranibizumab causing cutaneous lesions should be further investigated.


Pressure Distribution during Negative Pressure Wound Therapy of Experimental Abdominal Compartment Syndrome in a Porcine Model.
(1) Introduction: Negative pressure wound therapy (NPWT) is a frequently applied open abdomen (OA) treatment. There are only a few experimental data supporting this method and describing the optimal settings and pressure distribution in the abdominal cavity during this procedure. The aim of our study was to evaluate pressure values at different points in the abdominal cavity during NPWT in experimental abdominal compartment syndrome (ACS) animal model; (2) Methods: In this study (permission Nr. 13/2014/UDCAW), 27 Hungahib pigs (15.4-20.2 kg) were operated on. ACS was generated by implanting a plastic bag in the abdomen through mini-laparotomy and filled with 2100-3300 mL saline solution (37 °C) to an intraabdominal pressure (IAP) of 30 mmHg. After 3 h, NPWT (Vivano Med® Abdominal Kit, Paul Hartmann AG, Germany) or a Bogota bag was applied. The NPWT group was divided into -50, -100 and -150 mmHg suction groups. Pressure distribution to the abdominal cavity was monitored at 6 different points of the abdomen via a multichannel pressure monitoring system; (3) Results: The absolute pressure levels were significantly higher above than below the protective layer. The values of the pressure were similar in the midline and laterally. Amongst the bowels, the pressure values changed periodically between 0 and -12 mmHg which might be caused by peristaltic movements; (4) Conclusions: The porcine model of the present study seems to be well applicable for investigating ACS and NPWT. It was possible to provide valuable information for clinicians. The pressure was well distributed by the protective layer to the lateral parts of the abdomen and this phenomenon did not change considerably during the therapy.


Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors.
Genetic perturbations of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are widely used to dissect molecular mechanisms of sensory coding, learning, and memory. In this study, we investigated the role of Ca2+-permeable AMPARs in olfactory behavior. AMPAR modification was obtained by depletion of the GluR-B subunit or expression of unedited GluR-B(Q), both leading to increased Ca2+ permeability of AMPARs. Mice with this functional AMPAR switch, specifically in forebrain, showed enhanced olfactory discrimination and more rapid learning in a go/no-go operant conditioning task. Olfactory memory, however, was dramatically impaired. GluR-B depletion in forebrain was ectopically variable ("mosaic") among individuals and strongly correlated with decreased olfactory memory in hippocampus and cortex. Accordingly, memory was rescued by transgenic GluR-B expression restricted to piriform cortex and hippocampus, while enhanced odor discrimination was independent of both GluR-B variability and transgenic GluR-B expression. Thus, correlated differences in behavior and levels of GluR-B expression allowed a mechanistic and spatial dissection of olfactory learning, discrimination, and memory capabilities.


Status of bone health and association of socio-demographic characteristics with Bone Mineral Density in Pakistani Females.
The "silent thief" of bone osteoporosis is associated with various modifiable factors, identifying these factors is important in decreasing the prevalence of this highly prevalent disease. Therefore, this study was planned to identify these risk factors for osteoporosis in premenopausal and postmenopausal Pakistani women. A total of 1205 pre and postmenopausal females between the ages of 20 to 80 years were selected. Detailed history about the socio-demographic characteristics including age, education, profession, marital and resident status was recorded. Medical and gynecological history was also taken after informed consent Bone health of females was assessed using calcaneal ultrasound bone densitometer. SPSS 22.0 was used to analyze data. Univariate analysis showed that age (30-39 yrs, and 60-69 yrs), occupation (housewives) and education (secondary and primary education, illiterate) were significantly associated with low bone mass density (LBMD). Multivariate analysis showed that age 30-39 years (OR=0.25 95%CI 0.13 - 0.49), age 40-49 years (OR=0.30 95%CI 0.15 - 0.59), age 50-59 years (OR=0.42 95%CI 0.22 - 0.79), primary education (OR=3.83, 95%CI 2.30 - 6.38) and illiteracy (OR=3.83 95%CI 2.52 - 5.82), were significantly associated with LBMD. The prevalence of osteopenia and osteoporosis was 29.8%, 27.2%, respectively, while 43% subjects had normal BMD. It is concluded that, within Pakistani population, the prevalence of osteopenia is high even at an early age group and the odds of having LBMD are more in less educated or illiterate women.


Physical fitness and shapes of subcortical brain structures in children.
A few studies have recently reported that higher cardiorespiratory fitness is associated with higher volumes of subcortical brain structures in children. It is, however, unknown how different fitness measures relate to shapes of subcortical brain nuclei. We aimed to examine the association of the main health-related physical fitness components with shapes of subcortical brain structures in a sample of forty-four Spanish children aged 9·7 (sd 0·2) years from the NUtraceuticals for a HEALthier life project. Cardiorespiratory fitness, muscular strength and speed agility were assessed using valid and reliable tests (ALPHA-fitness test battery). Shape of the subcortical brain structures was assessed by MRI, and its relationship with fitness was examined after controlling for a set of potential confounders using a partial correlation permutation approach. Our results showed that all physical fitness components studied were significantly related to the shapes of subcortical brain nuclei. These associations were both positive and negative, indicating that a higher level of fitness in childhood is related to both expansions and contractions in certain regions of the accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. Cardiorespiratory fitness was mainly associated with expansions, whereas handgrip was mostly associated with contractions in the structures studied. Future randomised-controlled trials will confirm or contrast our findings, demonstrating whether changes in fitness modify the shapes of brain structures and the extent to which those changes influence cognitive function.


Case Report and Review of Literature: Familial Malignant Pleural Mesothelioma in a 39 Years Old Patient With an Inconclusive 18F-FDG PET/CT Result.
Malignant pleural mesothelioma (MPM) is a rare yet aggressive neoplasm that was linked only to asbestos exposure for decades, although familial clusters were diagnosed with MPM without a known history of asbestos exposure most likely due to genetic susceptibility. Here, we describe a case of familial malignant mesothelioma in a 39 years old patient with a confirmed BAP1 mutation in addition to a known family history with the same mutation. The patient presented with progressive shortness of breath and recurrent pleural effusions and diagnosis was made through biopsies taken during uniportal Video-Assisted Thoracoscopic Surgery. After the inconclusive result of 18F-FDG PET/CT scan, subxiphoid uniportal Video-Assisted Thoracoscopic Surgery left pleural and laparoscopic peritoneal biopsies were obtained for staging and evaluating contralateral lung and peritoneal cavity. Finally, two important educational values should be acquired from this case: genetic predisposition and BAP1 tumor suppressor gene mutation might affect the age of presentation and overall prognosis of the disease. Also, 18F-FDG PET/CT scan may not be the best modality for staging and confirming the diagnosis of malignant pleural mesothelioma.


A new classification of developmental language disorders (DLD).
Eighty children with DLD were examined with 18 language tests, mainly derived from a neuropsychological investigation called NEPSY (NEuroPSYchological Investigation for Children). The children were 6-0 to 7-9 years old and attended kindergarten. The test profiles of the first 40 children, Group 1, were utilized for the elaboration of a classification of DLD. The test profiles were grouped into five subgroups with the aid of a Q-type factor analysis. Then the classification was modified to suit clinical application by collapsing two pairs of subgroups. The resulting categories were called: the Global Subtype, the Specific Dyspraxia Subtype, and the Specific Comprehension Subtype. The classification was validated, first, by a follow-up study. It was predicted that spelling problems would occur in the Global and the Specific Comprehension Subtypes, but not in the Specific Dyspraxia Subtype. At follow-up, 3 years later, the hit rate was found to be 80.5%. In a second validation procedure, the classification was tried out on the 40 children examined later, Group 2. The coverage of the classification was 85%. Five outliers (12.5%) seemed to form a fourth category, called the Specific Dysnomia Subtype. An expressive subtype was not observed.


Reduced efficiency roll-off in organic light-emitting diodes by a novel short-lived organoeuropium emitter.
In this paper, we report a novel organoeuropium complex [Eu(DPDBM)(3)DPPZ] based on a triphenylamine-derived beta-diketone ligand for short-lived emitter exploration. The (5)D(0) --> (7)F(2) ( approximately 610 nm) luminescence lifetime of Eu(DPDBM)(3)DPPZ is only 30 mus, which is 1 order of magnitude shorter than that of a typical Eu(3+) complex. The electroluminescence device using Eu(DPDBM)(3)DPPZ as the emitter achieves a maximum current efficiency of 3.0 cd/A, and the efficiency roll-off is largely reduced because of the emitter's short luminescence lifetime.


Anaerobic Methane Oxidation Driven by Microbial Reduction of Natural Organic Matter in a Tropical Wetland.
Wetlands constitute the main natural source of methane on Earth due to their high content of natural organic matter (NOM), but key drivers, such as electron acceptors, supporting methanotrophic activities in these habitats are poorly understood. We performed anoxic incubations using freshly collected sediment, along with water samples harvested from a tropical wetland, amended with 13C-methane (0.67 atm) to test the capacity of its microbial community to perform anaerobic oxidation of methane (AOM) linked to the reduction of the humic fraction of its NOM. Collected evidence demonstrates that electron-accepting functional groups (e.g., quinones) present in NOM fueled AOM by serving as a terminal electron acceptor. Indeed, while sulfate reduction was the predominant process, accounting for up to 42.5% of the AOM activities, the microbial reduction of NOM concomitantly occurred. Furthermore, enrichment of wetland sediment with external NOM provided a complementary electron-accepting capacity, of which reduction accounted for ∼100 nmol 13CH4 oxidized · cm-3 · day-1 Spectroscopic evidence showed that quinone moieties were heterogeneously distributed in the wetland sediment, and their reduction occurred during the course of AOM. Moreover, an enrichment derived from wetland sediments performing AOM linked to NOM reduction stoichiometrically oxidized methane coupled to the reduction of the humic analogue anthraquinone-2,6-disulfonate. Microbial populations potentially involved in AOM coupled to microbial reduction of NOM were dominated by divergent biota from putative AOM-associated archaea. We estimate that this microbial process potentially contributes to the suppression of up to 114 teragrams (Tg) of CH4 · year-1 in coastal wetlands and more than 1,300 Tg · year-1, considering the global wetland area.IMPORTANCE The identification of key processes governing methane emissions from natural systems is of major importance considering the global warming effects triggered by this greenhouse gas. Anaerobic oxidation of methane (AOM) coupled to the microbial reduction of distinct electron acceptors plays a pivotal role in mitigating methane emissions from ecosystems. Given their high organic content, wetlands constitute the largest natural source of atmospheric methane. Nevertheless, processes controlling methane emissions in these environments are poorly understood. Here, we provide tracer analysis with 13CH4 and spectroscopic evidence revealing that AOM linked to the microbial reduction of redox functional groups in natural organic matter (NOM) prevails in a tropical wetland. We suggest that microbial reduction of NOM may largely contribute to the suppression of methane emissions from tropical wetlands. This is a novel avenue within the carbon cycle in which slowly decaying NOM (e.g., humic fraction) in organotrophic environments fuels AOM by serving as a terminal electron acceptor.


Association between statin use, atherosclerosis, and mortality in HIV-infected adults.
While HIV infection is associated with increased cardiovascular risk, benefit from statin is not well established in HIV-infected adults. We assessed whether statins are associated with a decrease in carotid artery intima-media thickness (cIMT) progression and all-cause mortality in HIV-infected adults who are at elevated ASCVD risk and recommended for statins. Carotid IMT was measured at baseline and follow-up in 127 HIV-infected adults who meet ACC/AHA criteria to be on statins. Inverse probability of treatment weighting (IPTW) was used to address selection bias. Multivariable models were used to control for baseline characteristics. 28 subjects (22%) were on statins and 99 subjects (78%) were not. Mean cIMT at baseline was 1.2 mm (SD = 0.34) in statin users and 1.1 mm (SD = 0.34) in non-users, and the multivariable adjusted difference was 0.05mm (95%CI -0.11, 0.21 p = 0.53). After 3.2 years of follow-up, average cIMT progression was similar in statin users and non-users (0.062mm/yr vs. 0.058 mm/yr) and the multivariable adjusted difference over the study period was 0.004 mm/yr (95% CI -0.018, 0.025, p = 0.74). All-cause mortality appeared higher in non-statin users compared with statin users, but the difference was not significant (adjusted HR = 0.74, 95%CI 0.17-3.29, p = 0.70). In a HIV cohort who had elevated ASCVD risk and meet ACC/AHA criteria for statins, treatment with statins was not associated with a reduction in carotid atherosclerosis progression or total mortality. Future studies are needed to further explore the impact of statins on cardiovascular risk in the HIV-infected population.


Analysis of recent literature concerning relaxation and imagery interventions for cancer pain.
A review of literature concerning relaxation and imagery interventions for cancer pain is necessary because major review articles have excluded nursing research or were written prior to the publication of controlled studies in cancer pain conducted by nurses. This review of published nursing/medical/psychological literature of adults with cancer pain conducted over the past 14 years (1982-95) revealed few controlled studies, weak theoretical frameworks, few complete descriptions of the nature of the pain problem, and lack of control over the interventions. Most had very small sizes and could not demonstrate significant effects. Additionally, the intervention methods and length of the interventions were highly variable. Despite these design shortcomings, relaxation and imagery appear to reduce the sensory experience of pain, have equivocal effects on affective measures, and appear to have no effect on functional status. Suggestions for improvement include the need for more experimental studies, more complete descriptions of pain, improved statistical reporting, controls over adequacy of and compliance to the interventions, use of single interventions, and use of more complex measures of affective outcomes. Additionally, the paper contains a discussion of the problems of measuring selected outcome variables in this type of research.


Exploring the impact of drug properties on the extent of intestinal lymphatic transport - in vitro and in vivo studies.
Intestinal lymphatic transport of specific lipophilic drugs offers therapeutic advantages and maximises oral bioavailability. The aims of this study were; to compare intestinal lymphatic transport of a range of drugs and to investigate the influence of cyclosporine A on the mechanism/extent of lymphatic transport. Caco2 cells and an anaesthetised mesenteric lymphatic cannulated rat model were used for in vitro and in vivo studies. Lymphatic transport of three lipophilic drugs was directly compared in a long chain fatty acid formulation. In addition, the impact of cyclosporine A on triglyceride turnover was evaluated in vivo and in vitro. The extent of intestinal lymphatic transport in rats was positively correlated with drug solubility in triglyceride and negatively correlated with drug aqueous solubility. Cyclosporine A displayed non-linear lymphatic transport kinetics and reduced intestinal lymph triglyceride. In vitro experiments indicated that the cellular processes affected were intracellular lipid processing and/or lipid secretion. The linear correlations obtained using a range of lipophilic drugs confirm that the simplified approach of determining aqueous or triglyceride drug solubility is useful in predicting the extent of lymphatic transport. In vitro experiments correlated with in vivo observations, demonstrating the usefulness of the Caco-2 model for mechanistic investigations.


Kinase modulation of androgen receptor signaling: implications for prostate cancer.
Androgens and androgen receptors play essential roles in the development and progression of prostate cancer, a disease that claims roughly 28,000 lives annually. In addition to androgen biding, androgen receptor activity can be regulated via several post-translational modifications such as ubiquitination, acetylation, phosphorylation, methylation & SUMO-ylation. Off these modifications, phosphorylation has been the most extensively studied. Modification by phosphorylation can alter androgen receptor localization, protein stability and transcriptional activity, ultimately leading to changes in the biology of cancer cells and cancer progression. Understanding, role of phosphorylated androgen receptor species holds the key to identifying a potential therapeutic drug target for patients with prostate cancer and castrate resistant prostate cancer. Here, we present a brief review of recently discovered protein kinases phosphorylating AR, focusing on the functional role of phosphorylated androgen receptor species in prostate cancer and castrate resistant prostate cancer.


A closer look at diagnosis in clinical dental practice: part 4. Effectiveness of nonradiographic diagnostic procedures and devices in dental practice.
This article, the fourth in a series, examines nonradiographic procedures and devices such as standard clinical and visual examination, apex locators, vitality testers and colour shade guides in light of the tools described in the first 2 articles in the series. A variety of nonradiographic indices and scales are used in detecting periodontal disease and monitoring and assessing its treatment. The reliability of these diagnostic procedures directly affects treatment success, decisions to initiate more aggressive clinical interventions, and the ability to make an informed prognosis about the course of the disease. However, in many instances, the dependability of the measurements remains to be established.


Left atrial versus bi-atrial Maze operation using intraoperatively cooled-tip radiofrequency ablation in patients undergoing open-heart surgery: safety and efficacy.
We sought to determine whether limited left atrial Maze surgery encircling each of the pulmonary veins, using cooled-tip radiofrequency (RF) ablation, is as effective as the bi-atrial approach? The original Cox/Maze operation effectively restores sinus rhythm (SR) in patients with atrial fibrillation (AF). Ablation procedures aimed at eliminating pulmonary vein foci have produced promising short-term success. This was a prospective analysis of patients with chronic AF undergoing open-heart surgery in addition to the Maze operation, using intraoperatively cooled-tip RF ablation either in the left atrium alone (group A) or in both atria (group B). Patients in group A (n = 21) and group B (n = 49) did not differ in terms of their baseline characteristics. Concomitant open-heart surgical procedures included mitral valve replacement (3 vs. 25), mitral valve plasty (0 vs. 2), mitral and aortic valve replacement (1 vs. 1), aortic valve replacement (4 vs. 6) and coronary artery bypass grafting (13 vs. 15) in groups A and B, respectively. Follow-up ranged from 1 to 50 months. The overall cumulative rates of SR were 82% in group A and 75% in group B, without a statistically significant difference (p = 0.571). Bi-atrial contraction was revealed in 92.3% of patients in SR in group A and in 79.2% in group B. The cumulative survival rates were 90.5% in group A and 77.9% in group B (p = 0.880). A left or bi-atrial Maze operation using intraoperatively cooled-tip RF ablation can safely be combined with open-heart surgery. A left atrial Maze procedure seems to be as effective as the bi-atrial procedure and restores SR in 82% of patients.


Scenedesmus obliquus Sexuality.
The flagellated cells of two mixed strains of Scenedesmus obliquus can initiate a sexual cycle when grown at 15 degrees C in a defined medium lacking a nitrogen source. Clumps of five to ten cells, paired gametes, plasmogamy, and quadriflagellated zygotes were observed.


Right ventricular myxoma - a case report.
Myxomas arising from the right ventricle are extremely rare. We presented a 71-year-old patient with worsening symptoms of the exertional dyspnea and atypical chest pains lasting 6 months. A transthoracic and transesophageal echocardiogram revealed a large, 2.6 x 2.2 cm, ovoid, well-circumscribed, echogenic mass in the right ventricle outflow tract attached by small pedicle, partly obstructing the right ventricular outflow tract and protruding through the pulmonic valve during systole. The tumor was completely removed with the stalk and 5 mm of the surrounding tissue. The histopathological findings confirmed the diagnosis of myxoma. This case illustrates the usefulness of echocardiography both in diagnosis of patients with atypical symptoms without family history and associated syndromes (like Carney's complex), and in surgical approach planning. It also stresses the importance of surgical excision of tumor as soon as possible following the diagnosis to prevent the complications such are: valvular obstruction, pulmonary embolization and syncopes.


Occupational Therapists' Implementation of Evidence-Based Practice: A Cross Sectional Survey.
Evidence-based practice (EBP) implementation has been associated with quality health care outcomes, yet only a small proportion of occupational therapists implement EBP. We conducted a cross-sectional survey measuring EBP implementation, skill and knowledge, self-reflection behavior, and practice demographics to clarify implementation of EBP and factors acting as supports. A random sample of occupational therapists practicing in the U.S. was invited to participate; 578 surveys were included in the final analysis. Participants implemented EBP less than 1 time over the previous 8 weeks; EBP use was highest in those with a doctorate (p = .002) and high self-reflection behavior (p = .001); EBP use was marginally higher in those with organizational support (p = .008; p = .009), time for EBP (p = .009), and access to full text articles (p = .006). Further investigation of how reflective practice and levels of doctoral education support EBP use are recommended.


Effect of recombinant bovine somatotropin (rbST) treatment on follicular population and development in non-lactating dairy cows.
The aim of this study was to evaluate the long-term effects of recombinant bovine somatotropin (rbST) on follicle population and ovulatory follicle development in non-lactating dairy cows. Twenty-one Jersey cows were allocated in rbST (n=11) or control (n=10) groups. On day -60, cows in rbST group received 500 mg of somatotropin (s.c. Lactotropin®, Elanco). On day 0, control and rbST cows received an intravaginal progesterone-releasing device (1.9 g, CIDR®, Zoetis) and GnRH (100 mg, IM, Factrel®, Zoetis). On day 8, cows received PGF2α (25 mg, IM, Lutalyse®, Zoetis) and the CIDR® was removed. Twelve hours after device removal (D8), serum, follicular fluid and granulosa cells samples were collected. Serum and follicular concentration of estradiol (E2) and progesterone (P4) were analyzed. Total RNA was extracted from granulosa cells to measure gene expression of LHCGR, STAR, HSD-3B1, CYP11A1, CYP19A1, CYP17A1, IGFR and PAPPA by real-time PCR. Ultrasonography was performed on days -60, -53, -46, -14, -7, 0 and 8 for antral follicle count. Results were analyzed by repeated measures ANOVA and t-test. There was no effect of rbST treatment on the number of follicles during the 60 days period, as well as no effect on serum and follicular fluid E2 and follicular fluid P4 at the moment of follicle aspiration. There was a reduction in PAPPA (P = 0.006), CYP11A1 (P = 0.04) and CYP19A1 (P = 0.002) mRNA levels in granulosa cells of the pre-ovulatory follicle of rbST treated cows. In conclusion, a single dose of rbST did not have long-term effects on antral follicle population, serum and follicular E2/P4 concentrations in non-lactating dairy cows. Despite that, rbST injection decreased granulosa cell expression of genes related to steroidogenesis in the pre-ovulatory follicle.


High pressure Raman scattering and synchrotron X-ray diffraction studies of benzyl azide.
Benzyl azide was investigated by high-pressure Raman scattering spectroscopy and X-ray diffraction technologies. A complete vibrational analysis of benzyl azide was performed by combining the experimental measurements and theoretical calculations using DFT-based scaled quantum chemical approach. The high-pressure Raman spectra and calculation results indicate that benzyl azide underwent a conformational change at 0.67 GPa accompanied by rotation of methylene group and azide group. The frequency of the CH2 bending mode decreases with increasing pressure due to the increase of the C-H···π interactions, which is similar to the role of the hydrogen bond. A liquid to solid phase transition occurred at 2.7 GPa, which was confirmed by the X-ray diffraction measurements. As the pressure reached 25.6 GPa, all the azide group vibrations vanished, indicating that the decomposition pressure of the molecular azide groups in organic azides is lower than that of the azide ions in inorganic azides.


Elucidating the signaling mechanism of an epithelial tight-junction opening induced by chitosan.
Chitosan (CS) and its derivatives have been investigated as paracellular permeation enhancers for facilitating the oral bioavailability of hydrophilic macromolecules. As is well known, CS can transiently open the tight junctions (TJs) between epithelial cells, thus enhancing the paracellular permeability. However, the signaling mechanism that is related to the effect of CS on TJs remains unclear. Therefore, this study elucidates the potential transduction cascade of TJ opening in Caco-2 cell monolayers subsequent to CS exposure. Experimental results indicate that activation of integrin receptors on cell membranes significantly contributes to CS-mediated TJ disruption, initiating the cascade of TJ opening. Additionally, treatment of Caco-2 cell monolayers with CS leads to the clustering of integrins along the cell border, phosphorylation of FAK and Src tyrosine kinases, and results in the regulation of TJ permeability via the redistribution of TJ protein CLDN4 from the cell membrane to the cytosol. Elucidating the signaling mechanism of CS-induced TJ opening in intestinal cells significantly contributes to efforts to use CS and its derivatives as paracellular permeation enhancers.


Dry powder formulation of kanamycin with enhanced aerosolization efficiency for drug-resistant tuberculosis.
Kanamycin, an injectable agent, is currently used to treat drug-resistant tuberculosis (TB). Parenteral kanamycin causes high systemic toxicity which could be avoided by direct delivery to the lungs. This study focused on producing a highly aerosolizable dry-powder of hygroscopic kanamycin by spray-drying with l-leucine. Kanamycin powders were prepared with different concentrations (0, 5, 10, 15 and 20% w/w) of l-leucine using the Buchi B-290 Mini Spray-Dryer. In vitro aerosolization efficiency, particle size, morphology, crystallinity, surface composition, drug-excipient interaction and moisture content of the powders were characterized by a Next Generation Impactor (NGI), laser diffraction, scanning electron microscopy, X-ray diffractometry, XPS, ATR-FTIR and thermogravimetric analysis. The physicochemical and aerosolization stability of the powders were investigated after one-month storage at 25±2°C/15% RH and 25±2°C/75% RH. The cytotoxicity on Calu-3 and A549 cells of the kanamycin powders was evaluated by MTT assay. The spray-dried powder particles were in the inhalable size range (<6.1μm). The powders with l-leucine were wrinkled in shape, amorphous in nature and had low moisture content (<5.0%). Kanamycin with 5% (w/w) of l-leucine showed the best aerosolization efficiency of 73.0±2.5%. The powders remained stable during storage at 25±2°C/15% RH and tolerated by respiratory cell lines. l-leucine improved the aerosolization of kanamycin by surface modification, which may be helpful for the effective treatment of drug-resistant tuberculosis.


Extrafollicular dermal melanocyte stem cells and melanoma.
Recent studies suggest that extrafollicular dermal melanocyte stem cells (MSCs) persist after birth in the superficial nerve sheath of peripheral nerves and give rise to migratory melanocyte precursors when replacements for epidermal melanocytes are needed on the basal epidermal layer of the skin. If a damaged MSC or melanocyte precursor can be shown to be the primary origin of melanoma, targeted identification and eradication of it by antibody-based therapies will be the best method to treat melanoma and a very effective way to prevent its recurrence. Transcription factors and signaling pathways involved in MSC self-renewal, expansion and differentiation are reviewed. A model is presented to show how the detrimental effects of long-term UVA/UVB radiation on DNA and repair mechanisms in MSCs convert them to melanoma stem cells. Zebrafish have many advantages for investigating the role of MSCs in the development of melanoma. The signaling pathways regulating the development of MSCs in zebrafish are very similar to those found in humans and mice. The ability to easily manipulate the MSC population makes zebrafish an excellent model for studying how damage to MSCs may lead to melanoma.


Cell and Tissue Display: An Alternative Multipurpose Tool for Microscopy.
We developed a method, termed Cell and Tissue Display (CTD), for embedding 16 or more different tissue samples in multi-compartment agarose blocks. The CTD-generated blocks allow uniform multiplexing of cell lines and small tissue fragments within a single histologic block. The distribution of individual cells within the CTD blocks is improved, likely because the individual agarose compartments are small and uniform. The composition of each CTD block can be customized based on intended use. Some potential uses of CTD histologic blocks include improved sectioning of small tissue fragments, such as needle biopsy specimens or punch biopsies; multiplexing of tissue fragments within a single block; and the generation of control slides for laboratory proficiency testing. .


[Individual differences in the marginal periodontium of crowned and non-crowned topographically identical teeth].
A comparison was made on 191 crowned teeth in 125 patients altogether with removable partial replacements after average wear of 4.8 years with the corresponding number of contralateral uncrowned teeth. It could be shown that there was no significant difference between crowned and uncrowned teeth in respect of periodontal changes (loosening and deepening of pockets of pockets, periodontal diagnosis). Findings in crowned teeth had a frequent tendency to worsen.


The p53-Mdm2 network in progenitor cell expansion during mouse postnatal development.
Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality. This phenotype was rescued by the p53(515C) allele, which encodes an apoptosis-deficient p53R172P protein. However, these mice died within 2 weeks of birth, due to a severe impairment of progenitor cell expansion during postnatal haematopoiesis and cerebellar development, leading to p53-dependent cell cycle arrest. Loss of Mdm2 led to phosphorylation of the p53R172P protein, p53R172P stability and activation of the cell cycle inhibitor p21 in proliferating cells, but not in differentiated cells, in multiple tissue compartments. Proliferating cells of epithelial origin were not affected. The haematopoietic and neural defects were alleviated in mice lacking Mdm2 and containing one p53(515C) and one p53-null allele, but spermatogenesis was arrested. These findings establish a crucial role for the p53-Mdm2 network in regulating proliferation and progenitor expansion in many cell lineages and have important implications for the use of drugs that aim to disrupt the p53-Mdm2 interaction.


Posterolateral Reconstruction of the Knee: Two-Tailed Surgical Techniques.
Reconstruction of the posterolateral corner of the knee using two-tailed techniques involved grafts originating from the femur and inserting on the proximal tibia and fibular head. This method reconstructs the fibular collateral ligament, popliteofibular ligament, and popliteus tendon using anatomically placed grafts. This article describes the history, anatomy, indications, and authors' preferred technique for a two-tailed posterolateral corner reconstruction. In addition, biomechanical and clinical outcomes of this technique will be compared.


The activity-stress paradigm: possible mechanisms and applications.
The mechanisms and applications of the activity-stress (A-S) research paradigm are examined in this article. Past research has reflected the value of this paradigm in the investigation of ulcerogenesis. Evidence is offered to support a theory explaining the excessive running observed in the A-S animals, according to which, animals commence running to increase body temperature after failing to adapt to the restricted feeding regime. Further, excessive running levels are hypothesized to be sustained by reinforcement resulting from increased mesolimbic dopaminergic activity. Finally, parallels between the behavior observed in the A-S animals and some forms of maladaptive behavior observed in humans are discussed.


Druggable molecular alterations in bile duct cancer: potential and current therapeutic applications in clinical trials.
Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.


Combined micrococcal nuclease and exonuclease III digestion reveals precise positions of the nucleosome core/linker junctions: implications for high-resolution nucleosome mapping.
Micrococcal nuclease (MNase) is extensively used in genome-wide mapping of nucleosomes but its preference for AT-rich DNA leads to errors in establishing precise positions of nucleosomes. Here, we show that the MNase digestion of nucleosomes assembled on a strong nucleosome positioning sequence, Widom's clone 601, releases nucleosome cores whose sizes are strongly affected by the linker DNA sequence. Our experiments produced nucleosomal DNA sizes varying between 147 and 155 bp, with positions of the MNase cuts reflecting positions of the A⋅T pairs rather than the nucleosome core/linker junctions determined by X-ray crystallography. Extent of chromatosomal DNA protection by linker histone H1 also depends on the linker DNA sequence. Remarkably, we found that a combined treatment with MNase and exonuclease III (exoIII) overcomes MNase sequence preference producing nucleosomal DNA trimmed symmetrically and precisely at the core/linker junctions regardless of the underlying DNA sequence. We propose that combined MNase/exoIII digestion can be applied to in situ chromatin for unbiased genome-wide mapping of nucleosome positions that is not influenced by DNA sequences at the core/linker junctions. The same approach can be also used for the precise mapping of the extent of linker DNA protection by H1 and other protein factors associated with nucleosome linkers.


Immediate single-tooth implant placement with simultaneous bone augmentation versus delayed implant placement after alveolar ridge preservation in bony defect sites in the esthetic region: A 5-year randomized controlled trial.
It is unclear if an intact buccal bony plate is a prerequisite for immediate implant placement in post-extraction sockets. The aim of this 5-year randomized controlled trial was therefore comparison of peri-implant soft and hard tissue parameters, esthetic ratings, and patient-reported satisfaction of immediate implant placement in post-extraction sockets with buccal bony defects of ≥ 5 mm in the esthetic zone, with delayed implant placement after ridge preservation. Patients presenting a failing tooth in the esthetic region and a buccal bony defect of ≥ 5 mm after extraction were randomly assigned to immediate (Immediate group, n = 20) or delayed (Delayed group, n = 20) implant placement. Second-stage surgery and placement of a provisional restoration occurred 3 months after implant placement in both groups, followed by definitive restorations 3 months thereafter. The follow-up was 5 years. Marginal bone level (primary outcome), buccal bone thickness, soft tissue parameters, esthetics, and patient-reported satisfaction were recorded. Mean marginal bone level change was -0.71 ± 0.35 mm and -0.54 ± 0.41 mm in respectively the Immediate group and the Delayed group after 5 years (P = 0.202). This difference, and in other variables, was not significant. Marginal bone level changes, buccal bone thickness, clinical outcomes, esthetics, and patients' satisfaction following immediate implant placement, in combination with bone augmentation in post-extraction sockets with buccal bony defects of ≥ 5 mm, were comparable to those following delayed implant placement after ridge preservation in the esthetic zone.


[Effect of dihydroetorphine on contraction response of guinea pig ileum, mouse, and rabbit vas deferens induced by electric field stimulation in vitro].
Dihydroetorphine (DHE) inhibited contraction response of isolated guinea pig ileum and mouse vas deferens induced by electric field stimulation with IC50 values of (4.4 +/- 4.3) x 10(-16) mol.L-1 and (1.1 +/- 1.4) x 10(-18) mol.L-1 respectively. These effects of DHE were antagonized by naloxone (Nal). On guinea pig ileum, the antagonistic effect of Nal against DHE was similar to those against morphine and etorphine. However, on mouse vas deferens, the antagonistic effect of Nal against DHE was more potent than those against morphine and etorphine. Besides, DHE showed antagonistic effect on k-receptors in isolated rabbit vas deferens.


Pollen-mediated gene flow from transgenic perennial creeping bentgrass and hybridization at the landscape level.
The planting of 162 ha of transgenic glyphosate-resistant creeping bentgrass (Agrostis stolonifera) near Madras, OR, USA, allowed a unique opportunity to study gene flow over time from a perennial outcrossing species at the landscape level. While conducting a four year in situ survey, we collected panicles and leaf tissue samples from creeping bentgrass and its sexually compatible species. Seeds from the panicles were planted, and seedlings were tested in the greenhouse for expression of the transgene. Gene flow via pollen was found in all four years, at frequencies of 0.004 to 2.805%. Chloroplast markers, in combination with internal transcribed spacer nuclear sequence analysis, were used to aid in identification of transgenic interspecific and intergeneric hybrid seedlings found during the testing and of established plants that could not be positively identified in the field. Interspecific transgenic hybrids produced on redtop (Agrostis gigantea) plants in situ were identified three of the four years and one intergeneric transgenic creeping bentgrass x rabbitfoot grass (Polypogon monspeliensis) hybrid was identified in 2005. In addition, we confirmed a non-transgenic creeping bentgrass x redtop hybrid in situ, demonstrating that interspecific hybrids have established in the environment outside production fields. Results of this study should be considered for deregulation of transgenic events, studies of population dynamics, and prediction of gene flow in the environment.


Effects of the Targeted Regulation of CCRK by miR-335-5p on the Proliferation and Tumorigenicity of Human Renal Carcinoma Cells.
Cell cycle-related kinase (CCRK) is most closely related to cyclin-dependent protein kinase, which may activate cyclin-dependent kinase 2 and is associated with the growth of human cancer cells. However, the expression and function of CCRK in the pathogenesis of clear cell renal cell cancer (ccRCC) are unclear. Herein, this research aimed to explore the potential mechanism of the targeted regulation of CCRK by miR-335-5p on the proliferation and tumorigenicity of human ccRCC cells. The results showed that CCRK was significantly overexpressed in ccRCC tissues and cells, and knockdown of the CCRK expression by shRNA inhibited cell proliferation in vitro and in vivo and enhanced cell apoptosis in vitro, which indicated that CCRK could be a potential target for antitumour drugs in the treatment of ccRCC. Moreover, miR-335-5p was found to bind directly to the 3' untranslated region of CCRK, was expressed at markedly low levels in ccRCC cells, and was closely associated with the tumour stage. The overexpression of CCRK partially reversed the inhibitory effects of miR-335-5p on the cell growth of ccRCC, which implied that miR-335-5p could serve as a promising tumour inhibitor for ccRCC. In summary, CCRK could serve as an alternative antitumour drug target, and miR-335-5p could be a promising therapeutic tumour inhibitor for ccRCC treatment.


Successful conversion surgery for stage IV gastric cancer with liver metastases after second-line chemotherapy with ramucirumab and paclitaxel: a case report.
In recent years, conversion surgery after chemotherapy has been considered a promising strategy for improving the prognosis of patients with stage IV gastric cancer. However, there are few reports on conversion gastrectomy after second-line chemotherapy. Here, we report a case of long-term survival of a patient with liver metastases from gastric cancer who underwent conversion surgery after second-line chemotherapy with ramucirumab and paclitaxel. A 77-year-old man complaining of weight loss was diagnosed with human epidermal growth factor receptor 2-positive gastric cancer with multiple liver metastases. Although the patient initially received trastuzumab-based chemotherapy, it was discontinued, because he experienced trastuzumab-induced infusion reactions. Thereafter, he was treated with six courses of S-1 plus cisplatin and six courses of ramucirumab plus paclitaxel as the first- and second-line regimens, respectively. The primary tumor and liver metastases remarkably shrank, and the reduction rate of the measurable metastatic liver lesions was 81.1%. According to the Response Evaluation Criteria in Solid Tumors, the patient responded partially. Therefore, he underwent total gastrectomy with D2 lymphadenectomy and partial hepatectomy of segments 3 and 4. Pathological examination revealed tumor invasion into the muscularis propria, a grade 1a histological response, and no lymph node metastases. No viable cancer cells were identified in the specimens resected from liver segments 3 and 4. Accordingly, the patient was pathologically diagnosed with stage IB (ypT2N0M0). Postoperatively, the patient received adjuvant chemotherapy with S-1 for 6 months, and he survived without recurrence for 42 months after conversion surgery. Conversion surgery might be clinically useful for improving survival in certain patients with gastric cancer, including those who previously received second-line chemotherapy.


Advanced Developments in Cyclic Polymers: Synthesis, Applications, and Perspectives.
Due to the topological effect, cyclic polymers demonstrate different and unique physical and biological properties in comparison with linear counterparts having the same molecular-weight range. With advanced synthetic and analytic technologies, cyclic polymers with different topologies, e.g. multicyclic polymers, have been reported and well characterized. For example, various cyclic DNA and related structures, such as cyclic duplexes, have been prepared conveniently by click chemistry. These types of DNA have increased resistance to enzymatic degradation and have high thermodynamic stability, and thus, have potential therapeutic applications. In addition, cyclic polymers have also been used to prepare organic-inorganic hybrids for applications in catalysis, e.g. catalyst supports. Due to developments in synthetic technology, highly pure cyclic polymers could now be produced in large scale. Therefore, we anticipate discovering more applications in the near future. Despite their promise, cyclic polymers are still less explored than linear polymers like polyolefins and polycarbonates, which are widely used in daily life. Some critical issues, including controlling the molecular weight and finding suitable applications, remain big challenges in the cyclic-polymer field. This review briefly summarizes the commonly used synthetic methodologies and focuses more on the attractive functional materials and their biological properties and potential applications.


The usefulness of serum amyloid A as a postoperative inflammatory marker after posterior lumbar interbody fusion.
The post-operative changes in the serum levels of CRP and serum amyloid A (SAA) were investigated prospectively in 106 patients after posterior lumbar interbody fusion. In 96 patients who did not have complications related to infection within the first year after operation, the median levels of CRP before operation and on days 3, 7 and 13 after were 0.02 (0.01 to 0.03), 9.12 (2.36 to 19.82), 1.64 (0.19 to 6.10) and 0.53 (0.05 to 2.94) mg/dl, respectively and for SAA, 2.6 (2.0 to 3.8), 1312.1 (58.0 to 3579.8), 77.3 (1.8 to 478.4), 14.1 (0.5 to 71.9) mug/ml, respectively. The levels on day 3 were the highest for both CRP and SAA and significantly decreased (p < 0.01) by day 7 and day 13. In regard to CRP, no patient had less than the reference level (0.1 mg/dl) on day 7. In only three had the level decreased to the reference level, while in 93 it was above this on day 13. However, for SAA, the levels became normal on day 7 in 10 cases and on day 13 in 34 cases. The ratios relative to the levels on day 3 were significantly lower for SAA compared with CRP on day 7 and day 13. Of the ten patients with infection in the early stages, the level of CRP decreased slightly but an increase in SAA was observed in six. We concluded that SAA is better than CRP as a post-operative inflammatory marker.


Tolerance induction by veto CTLs in the TCR transgenic 2C mouse model. I. Relative reactivity of different veto cells.
Several bone marrow cells and lymphocyte subpopulations, known as veto cells, were shown to induce transplantation tolerance across major histocompatibility Ags. Due to the low frequency of the effector T cells against which the veto cells inhibitory activity is aimed, the fate of the effector cells was traditionally followed indirectly by functional limiting dilution assays, which are cumbersome and depend on numerous parameters. In the present study the fate of the effector T cells was monitored directly by FACS, using TCR transgenic mouse CD8(+) T cells in which the transgene is directed against H-2(d) (the 2C model). This assay is validated by demonstrating the potency, selectivity, radiation sensitivity, and contact dependency of anti-third-party CTLs previously demonstrated by the limiting dilution assay. In contrast to veto CTLs, nonactivated CD8(+) T cells lack veto activity. Comparison by FACS in the 2C model revealed a hierarchy of veto cells, in the order of veto CTLs activated NK cells, activated CD4(+) T cells, and activated B cells. The latter cells as well as nonactivated CD4(+) or NK cells were shown to be completely devoid of veto activity.


SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.
Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.


Carcinoma of the cervix uteri in Ibadan: coital characteristics.
Carcinoma of the cervix uteri has been found to be the most common female malignancy in Ibadan, excluding the reticuloendothelial tumors. In a study to investigate associated etiological factors in this environment, it was demonstrated that certain coital characteristics of women with cervical cancer can be identified. These were a common denominator which could explain the frequency of the disease among some categories of patients who engage in early sexual practice, have intercourse frequently and with multiple partners, and have many pregnancies. Support was given to the view that a sexually transmitted factor might be important in the cause of carcinoma of the cervix.


Advanced MR Imaging Techniques for Differentiation of Neuropathic Arthropathy and Osteomyelitis in the Diabetic Foot.
Diagnosis and treatment of foot disease in patients with diabetes is a common clinical-radiologic challenge, particularly the differentiation of neuropathic arthropathy from osteomyelitis. Conventional clinical tests and imaging techniques have limited accuracy for evaluation of the diabetic foot. The introduction of morphologic magnetic resonance (MR) imaging in these patients has provided a qualitative leap in diagnosis. The characteristics of soft-tissue and bone marrow edema and their patterns of distribution throughout the foot allow discrimination between both entities. However, in certain scenarios, the application of MR imaging to this problem is limited because of overlapping features between the two and the coexistence of infection and neuropathic changes. Recent technical advances in MR imaging sequences have increased the capability to add functional quantitative information to structural information. Diffusion-weighted imaging is useful to determine the presence and extension of osteomyelitis. Dynamic contrast-enhanced MR imaging may help to detect differences between the vascularization patterns of neuropathic arthropathy and osteomyelitis. MR angiography (with or without contrast material) is used in clinical practice to identify candidate distal vessels for revascularization. MR neurography, and especially diffusion-tensor imaging, provides quantitative information about neural damage. These new sequences may help in assessment of the different pathophysiologic conditions that occur in the diabetic foot. The physical basis of these techniques, their limitations, and their potential applications for diabetic foot assessment are detailed in this article. The introduction of advanced MR imaging multiparametric protocols, with the aim of enhancing the overall diagnostic accuracy of MR imaging, may help in treatment decision making and lead to improved patient outcomes. © RSNA, 2017.


Decarbonylative halogenation by a vanadium complex.
Metal-catalyzed halogenation of the C-H bond and decarbonylation of aldehyde are conventionally done in nature. However, metal-mediated decarbonylative halogenation is unknown. We have developed the first metal-mediated decarbonylative halogenation reaction starting from the divanadium oxoperoxo complex K3V(5+)2(O2(2-))4(O(2-))2(μ-OH) (1). A concerted decarbonylative halogenation reaction was proposed based on experimental observations.


Anticipation by basketball defenders: an explanation based on the three-dimensional inverted pendulum model.
We previously estimated the timing when ball game defenders detect relevant information through visual input for reacting to an attacker's running direction after a cutting manoeuvre, called cue timing. The purpose of this study was to investigate what specific information is relevant for defenders, and how defenders process this information to decide on their opponents' running direction. In this study, we hypothesised that defenders extract information regarding the position and velocity of the attackers' centre of mass (CoM) and the contact foot. We used a model which simulates the future trajectory of the opponent's CoM based upon an inverted pendulum movement. The hypothesis was tested by comparing observed defender's cue timing, model-estimated cue timing using the inverted pendulum model (IPM cue timing) and cue timing using only the current CoM position (CoM cue timing). The IPM cue timing was defined as the time when the simulated pendulum falls leftward or rightward given the initial values for position and velocity of the CoM and the contact foot at the time. The model-estimated IPM cue timing and the empirically observed defender's cue timing were comparable in median value and were significantly correlated, whereas the CoM cue timing was significantly more delayed than the IPM and the defender's cue timings. Based on these results, we discuss the possibility that defenders may be able to anticipate the future direction of an attacker by forwardly simulating inverted pendulum movement.


Assessing the anthropometric status of Hawaii's preschoolers participating in feeding programs in day care centers.
A survey of low and middle income preschoolers who were exposed to similar feeding programs and physical activities showed similarity of physical growth between the two groups of children. Mean values of arm size, muscularity, triceps skinfold, and fat area were similar and signified adequate protein status and caloric reserves in both groups of children. Comparison of data from preschoolers in Oahu and on the United States mainland showed that all left arm triceps skinfold medians of preschoolers in Oahu were 1) smaller than the medians recorded for right arms in the Health and Nutrition Examination Survey and 2) greater than the values on the 50th percentile for right arms of white children of the Ten-State Nutrition Survey, which indicated that Oahu preschoolers occupied a caloric reserve intermediate between the two mainland United States populations surveyed. Medians of heights and weights were lower than the median values of the Health and Nutrition Examination Survey and were closer to the 50th percentile of while children in the Ten-State Nutrition Survey.


Hepatocyte transplantation for glycogen storage disease type Ib.
Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia, caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib, caused by a deficiency of glucose-6-phosphate transporter (G6PT). We report that a substantial improvement was achieved following several infusions of hepatocytes in a patient with GSD-Ib. Hepatocytes were isolated from the unused cadaveric whole livers of two donors. At the first transplantation, approximately 2 x 10(9) cells (2% of the estimated recipient's total hepatocytes) were infused. Seven days later 1 x 10(9) (1% of liver mass) cryopreserved hepatocytes from the same donor were infused, and an additional 3 x 10(9) (3% of liver mass) cells from the second donor were infused 1 month after the second transplantation. After the hepatocyte transplantation, the patient showed no hypoglycemic symptoms despite the discontinuation of cornstarch meals. Liver biopsies on posttransplantation days 20 and 250 showed a normal level of glucose-6-phosphatase activity in presolubilization assay that was very low before transplantation. This was the first and successful clinical hepatocyte transplantation in Korea. In this study, hepatocyte transplantation allowed a normal diet in a patient with GSD-Ib, with substantial improvement in their quality of life. Hepatocyte transplantation might be an alternative to liver transplantation and dietary therapy in GSD-Ib.


Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4.
Iroquois Homeobox 4 (IRX4) belongs to a family of homeobox TFs having roles in embryogenesis, cell specification, and organ development. Recently, large scale genome-wide association studies and epigenetic studies have highlighted the role of IRX4 and its associated variants in prostate cancer. No studies have investigated and characterized the structural aspect of the IRX4 homeodomain and its potential to bind to DNA. The current study uses sequence analysis, homology modeling, and molecular dynamics simulations to explore IRX4 homeodomain-DNA recognition mechanisms and the role of somatic mutations affecting these interactions. Using publicly available databases, gene expression of IRX4 was found in different tissues, including prostate, heart, skin, vagina, and the protein expression was found in cancer cell lines (HCT166, HEK293), B cells, ascitic fluid, and brain. Sequence conservation of the homeodomain shed light on the importance of N- and C-terminal residues involved in DNA binding. The specificity of IRX4 homodimer bound to consensus human DNA sequence was confirmed by molecular dynamics simulations, representing the role of conserved amino acids including R145, A194, N195, S190, R198, and R199 in binding to DNA. Additional N-terminal residues like T144 and G143 were also found to have specific interactions highlighting the importance of N-terminus of the homeodomain in DNA recognition. Additionally, the effects of somatic mutations, including the conserved Arginine (R145, R198, and R199) residues on DNA binding elucidated the importance of these residues in stabilizing the protein-DNA complex. Secondary structure and hydrogen bonding analysis showed the roles of specific residues (R145, T191, A194, N195, R198, and R199) in maintaining the homogeneity of the structure and its interaction with DNA. The differences in relative binding free energies of all the mutants shed light on the structural modularity of this protein and the dynamics behind protein-DNA interaction. We also have predicted that the C-terminal sequence of the IRX4 homeodomain could act as a potential cell-penetrating peptide, emphasizing the role these small peptides could play in targeting homeobox TFs.


Efficacy and fMRI-based response predictors to mindfulness-based cognitive therapy in obsessive-compulsive disorder: Study protocol for a randomised clinical trial.
Around 40-50% of patients with obsessive-compulsive disorder (OCD) suffer from obsessions and compulsions after receiving first-line treatments. Mindfulness-based cognitive therapy (MBCT) has been proposed as a reasonable augmentation strategy for OCD. MBCT trains to decentre from distressful thoughts and emotions by focusing on them voluntarily and with consciousness. This practice develops alternative ways to deal with obsessions, which could increase non-reactivity behaviours and, in turn, reduce compulsions. This study aims to investigate the efficacy of MBCT to improve OCD symptoms. Secondly, it pursues to investigate which socio-demographic, clinical, and neurobiological characteristics mediate or moderate the MBCT response; and identify potential biomarkers of positive/negative response. This study is a randomised clinical trial (RCT) of 60 OCD patients who do not respond to first-line treatments. Participants will be randomised to either an MBCT program or treatment as usual. The MBCT group will undergo 10 weekly sessions of 120min. Principal outcome: change in OCD severity symptoms using clinician and self-reported measures. Also, participants will undergo a comprehensive evaluation assessing comorbid clinical variables, neuropsychological functioning and thought content. Finally, a comprehensive neuroimaging protocol using structural and functional magnetic resonance imaging will be acquired in a 3T scanner. All data will be obtained at baseline and post-intervention. This study will assess the efficacy of mindfulness in OCD patients who do not achieve clinical recovery after usual treatment. It is the first RCT in this subject examining clinical, neuropsychological and neuroimaging variables to examine the neural patterns associated with the MBCT response. NCT03128749.


Apogossypolone induces apoptosis and autophagy in nasopharyngeal carcinoma cells in an in vitro and in vivo study.
Nasopharyngeal carcinoma (NPC) has a high incidence and mortality rate, particularly in Southern China. Apogossypolone (ApoG2) is a novel derivative of gossypol with antitumor activity and less toxicity. The human NPC CNE-2 cell line was studied in the in vitro model; whilst 4 week-old male nude mice (BALB/c-nu) were inoculated subcutaneously with CNE-2 cells, and xenograft tumors were studied in the in vivo model. Graded concentrations of ApoG2 were used in treatment studies. In ApoG2-treated and control in vitro and in vivo tumor cells, cell apoptosis, and autophagy were evaluated and quantified using fluorescent and transmission electron microscopy and flow cytometry. Hoechst-33258 fluorescence staining was used to evaluate apoptosis in treated and non-treated cell culture and xenograft NPC cells. Western blotting was performed on lysed tumor cells using primary antibodies to B-cell lymphoma-2 (Bcl-2), beclin-1, and β-actin, and flow cytometry results indicated cell apoptosis rates of 3.90±0.34 and 19.52±1.18% in the control and ApoG2-treated cells, respectively (F=485.294, P<0.001). Western blot analysis showed that ApoG2 significantly decreased expression of the Bcl-2 protein in CNE-2 cells, when compared with control cells (F=68.909, P=0.001) and flow cytometry showed cell autophagy rates of 0.92±3.10% of control cells compared with 28.24±7.35% of ApoG2-treated cells (F=31.035, P=0.003). ApoG2 treatment significantly increased beclin-1 protein expression in CNE-2 cells (F=497.906, P<0.001). ApoG2 treatment inhibited NPC xenograft tumor growth by 65.49% (P<0.05). In conclusion, these results support a role for ApoG2 in inhibiting the growth of human NPC cells by inducing apoptosis and autophagy. Future controlled clinical studies could be planned, to define safety, efficacy and dosing regimens for ApoG2 as a potential treatment for patients with NPC.


Clinical and histological evaluation in patients with mycosis fungoides treated with UVA1.
UVA1 phototherapy is a valid therapeutic alternative for skin lymphoproliferative disorders, although there are few studies concerning its role in mycosis fungoides (MF). Our aim was to evaluate and confirm the effectiveness of UVA1 phototherapy in patients in early stage MF. We enrolled 12 patients, 9 males and 3 females (mean age 54.83±9.99, range 36-74) with a histological diagnosis of mycosis fungoides at early stage. All patients were treated with UVA1 for 22 sessions with two different protocols (3 times or 5 times per week) at the dose of 45 J/cm2. A punch biopsy was performed before and after the treatment, to evaluate the variation of histological features and of the proliferation index (Ki67/MIB1). At the end of the study, we found a marked clinical improvement in all patients, associated to a statistically significant reduction of the proliferation index Ki67/MIB1. Five patients achieved a complete clinical and histological response, while six a partial one and only one a minimal response. Although in recent years the number of the therapeutic options available for all types of skin lymphoproliferative disorders, in particular mycosis fungoides, has increased considerably, there are few studies concerning UVA1 phototherapy. Our results represent a starting point for further studies, in order to investigate the role that these UV-rays can play either alone or in combination with other therapeutic regimens.


Residential proximity to agricultural fumigant use and IQ, attention and hyperactivity in 7-year old children.
Our objective was to examine the relationship between residential proximity to agricultural fumigant use and neurodevelopment in 7-year old children. Participants were living in the agricultural Salinas Valley, California and enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We administered the Wechsler Intelligence Scale for Children (4th Edition) to assess cognition and the Behavioral Assessment System for Children (2nd Edition) to assess behavior. We estimated agricultural fumigant use within 3, 5 and 8km of residences during pregnancy and from birth to age 7 using California's Pesticide Use Report data. We evaluated the association between prenatal (n = 285) and postnatal (n = 255) residential proximity to agricultural use of methyl bromide, chloropicrin, metam sodium and 1,3-dichloropropene with neurodevelopment. We observed decreases of 2.6 points (95% Confidence Interval (CI): -5.2, 0.0) and 2.4 points (95% CI: -4.7, -0.2) in Full-Scale intelligence quotient for each ten-fold increase in methyl bromide and chloropicrin use within 8km of the child's residences from birth to 7-years of age, respectively. There were no associations between residential proximity to use of other fumigants and cognition or proximity to use of any fumigant and hyperactivity or attention problems. These findings should be explored in larger studies.


The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV.
Cytosolic carbonic anhydrase II (CAII) and the cytoplasmic C-terminal tails of chloride/bicarbonate anion exchange (AE) proteins associate to form a bicarbonate transport metabolon, which maximizes the bicarbonate transport rate. To determine whether cell surface-anchored carbonic anhydrase IV (CAIV) interacts with AE proteins to accelerate the bicarbonate transport rate, AE1-mediated bicarbonate transport was monitored in transfected HEK293 cells. Expression of the inactive CAII V143Y mutant blocked the interaction between endogenous cytosolic CAII and AE1, AE2, and AE3 and inhibited their transport activity (53 +/- 3, 49 +/- 10, and 35 +/- 1% inhibition, respectively). However, in the presence of V143Y CAII, expression of CAIV restored full functional activity to AE1, AE2, and AE3 (AE1, 101 +/- 3; AE2, 85 +/- 5; AE3, 108 +/- 1%). In Triton X-100 extracts of transfected HEK293 cells, resolved by sucrose gradient ultracentrifugation, CAIV recruitment to the position of AE1 suggested a physical interaction between CAIV and AE1. Gel overlay assays showed a specific interaction between CAIV and AE1, AE2, and AE3. Glutathione S-transferase pull-down assays revealed that the interaction between CAIV and AE1 occurs on the large fourth extracellular loop of AE1. We conclude that AE1 and CAIV interact on extracellular loop 4 of AE1, forming the extracellular component of a bicarbonate transport metabolon, which accelerates the rate of AE-mediated bicarbonate transport.


Electronic structure of the peroxy intermediate and its correlation to the native intermediate in the multicopper oxidases: insights into the reductive cleavage of the o-o bond.
The multicopper oxidases (MCOs) utilize a blue type 1 (T1) copper site and a trinuclear Cu cluster composed of a type 2 (T2) and a binuclear type 3 (T3) site that together catalyze the four-electron reduction of O2 to H2O. Reaction of the fully reduced enzyme with O2 proceeds via two sequential two-electron steps generating the peroxy intermediate (PI) and the native intermediate (NI). While a detailed description of the geometric and electronic structure of NI has been developed, this has been more elusive for PI largely due to the diamagnetic nature of its ground state. Density functional theory (DFT) calculations have been used to correlate to spectroscopic data to generate a description of the geometric and electronic structure of PI. A highly conserved carboxylate residue near the T2 site is found to play a critical role in stabilizing the PI structure, which induces oxidation of the T2 and one T3 Cu center and strong superexchange stabilization via the peroxide bridge, allowing irreversible binding of O2 at the trinuclear Cu site. Correlation of PI to NI is achieved using a two-dimensional potential energy surface generated to describe the catalytic two-electron reduction of the peroxide O-O bond by the MCOs. It is found that the reaction is thermodynamically driven by the relative stability of NI and the involvement of the simultaneous two-electron-transfer process. A low activation barrier (calculated approximately 5-6 kcal/mol and experimental approximately 3-5 kcal/mol) is produced by the triangular topology of the trinuclear Cu cluster site, as this symmetry provides good donor-acceptor frontier molecular orbital (FMO) overlap. Finally, the O-O bond cleavage in the trinuclear Cu cluster can be achieved via either a proton-assisted or a proton-unassisted process, allowing the MCOs to function over a wide range of pH. It is found that while the proton helps to stabilize the acceptor O22- sigma* orbital in the proton-assisted process for better donor-acceptor FMO overlap, the third oxidized Cu center in the trinuclear site assumes the role as a Lewis acid in the proton-unassisted process for similarly efficient O-O bond cleavage.


Randomized double-blind study of nabumetone and piroxicam in the treatment of osteoarthritis in Dutch general practice: efficacy and tolerability.
To study nabumetone (1,000 mg once daily) by comparison with piroxicam (20 mg once daily) in patients with osteoarthritis, a randomized, double-blind trial was set up in 40 general practices. Evaluation was based on clinical outcome in 198 patients. There was some evidence that nabumetone is associated with a lower and less severe occurrence of gastric pain, and with more withdrawals due to lack of efficacy. Although the differences between nabumetone and piroxicam were small in this study, these were clinically relevant. The general practitioner should balance the respective benefits of greater safety and tolerance against greater efficacy in meeting the requirements of an individual patient with osteoarthritis.


Geometric and electronic properties of endohedral Si @ C74.
The generalized gradient approximation based on density functional theory is used to analyze the geometric and electronic properties of Si @ C(74). It is found that among the five possible optimized geometries of Si @ C(74), the most favorable endohedral site of Si atom is under the center of a pentagon ring on the sigma(h) plane, i.e., Si @ C(74)-5, which is different from the center stable site for Si in C(74) calculated by the semiempirical molecular orbital calculations and molecular mechanics calculations, and it is also different from the stable site, i.e., under a [6, 6] bond along the C(2) axis on the sigma(h) plane in C(74) for metal atoms Ba, Ca, and Eu. The deformation charge density on the sigma(h) plane reveals that the Si-C bonds in Si @ C(74)-5 have covalent character, while the Mulliken charge analysis together with a longer Si-C bond length reveals that the Si-C bonds in Si @ C(74)-5 have ionic character. Therefore, we infer that Si-C bonds in Si @ C(74)-5 contain both covalent and ionic characters.


Heterogeneous impact of body mass index on in-hospital mortality in acute heart failure syndromes: An analysis from the ATTEND Registry.
Although the obesity paradox may vary depending upon clinical background factors such as age, gender, aetiology of heart failure and comorbidities, the reasons underlying the heterogeneous impact of body mass index (BMI) on in-hospital cardiac mortality under various conditions in patients with acute heart failure syndromes (AHFSs) remain unclear. Among 4617 hospitalised patients with AHFSs enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, the patient characteristics and in-hospital cardiac mortality rates in those with low BMI (BMI <25 kg/m2, n = 3263) were compared to those with high BMI (BMI ⩾25 kg/m2, n = 1354). Compared to the high-BMI group, the low-BMI group was significantly older, less likely to be male and to have hypertensive or idiopathic dilated aetiologies and more likely to have valvular aetiologies and a history of prior hospitalisation for AHFS. The low-BMI group also had lower prevalence rates of diabetes, dyslipidaemia, hypertension and atrial fibrillation and higher prevalence rates of anaemia and chronic obstructive pulmonary disease. In addition, cardiac mortality was significantly higher in the low-BMI group than in the high-BMI group (5.5 vs. 1.5%, p < 0.001). Logistic regression analysis demonstrated that low BMI was a predictor of cardiac mortality (odds ratio: 3.89, 95% confidence interval: 2.44-6.21). In subgroup analyses, the impact of BMI on cardiac mortality differed depending on the presence of hypertensive aetiology, hypertension, chronic obstructive pulmonary disease and hyponatremia (all p < 0.05), although there were no interactions between the impacts of BMI and age, gender, other aetiologies, prior hospitalisation, diabetes, anaemia, cardio-renal function and in-hospital management. It is necessary to appreciate the obesity paradox in AHFS patients, and a patient's heterogeneous background should also be considered.