Periodontal healing and bone regeneration in response to azithromycin.
Azithromycin, first synthesized in 1980, is a macrolide antibiotic related to erythromycin. It is widely used by the medical profession as a broad-spectrum antibiotic in the treatment of pneumonia, urinary tract infections and tonsillitis. In addition to its antibiotic properties, azithromycin has immune-modulating effects and is used for this reason in the management of cystic fibrosis and chronic obstructive pulmonary diseases. The drug is taken up by neutrophils, macrophages and fibroblasts, and is slowly released by these cells. Three diverse case reports are presented in which a single course of azithromycin (consisting of one 500 mg tablet being taken a day for three days) was prescribed before any periodontal intervention occurred. Azithromycin was the principal mode of treatment of severe chronic and aggressive periodontitis in Cases 1 and 2. Azithromycin, together with monthly subgingival debridement, was the treatment in Case 3 (severe chronic periodontitis in a poorly controlled diabetic complicated by gingival overgrowth related to medication with a calcium channel blocker). Favourable resolution of inflammation, reduction in pocket depths and evidence of bone regeneration were evident, even when no periodontal treatment had occurred. In Case 3, resolution of gingival overgrowth occurred over eight months. The potential implications for periodontal management, understanding of the pathogenesis of periodontal diseases and periodontal research are briefly discussed.


Comparative randomised trial of online cognitive-behavioural therapy and an information website for depression: 12-month outcomes.
An earlier paper reported positive outcomes immediately following access to a cognitive-behavioural therapy (CBT) internet intervention and a depression information website. To determine 6-month and 12-month outcomes of the interventions relative to a placebo control condition. Participants allocated to the depression information website condition, the CBT internet intervention and the placebo control condition were followed up at 6 and 12 months by survey. The primary outcome measure was the Center for Epidemiologic Studies-Depression (CES-D) scale. Of 525 participants recruited, 79% completed their assigned intervention and 60% were retained at 12-month follow-up. Attrition was handled using mixed-model repeated-measures ANOVA. Both the CBT site and depression information sites were associated with statistically significant benefits in CES-D score reduction compared with controls at post-test. At 6-months follow-up, the reduction seen for the people allocated to the CBT arm remained significant, whereas that for the depression information website arm was not. At 12 months, both active interventions were statistically significantly superior to the control condition. There is some evidence that benefits of these brief internet interventions are retained beyond their endpoint. The impact of human support provided by interviewers in the trial must be considered when comparing these outcomes to routine use of both internet interventions.


The future of urology in Europe: an overview from the European association of urology.
In order to be able to influence and monitor future developments for urologists, strategies should be promoted in advance to guarantee the future of the speciality and to accommodate the inevitable changes. Faced with this challenge, the EAU, through its Strategy Planning Office (SPO), has prepared a document which is offered, here, in abbreviated form, to the European and international urological communities for general consideration. A group of subjects, related to the domains and internal consistency of urology as a speciality, were selected and discussed among the members of the SPO and later submitted to open consultation among distinguished members of the urological community. The topics selected for discussion included: what is urology; urology in the university; sub-specialization in urology; training in urology; does kidney transplantation belong to urology, and others. It is shown that urology is going through an exciting and hazardous transition period. Urology has conflicting problems in its traditional domains due to changes in health care policy, and internal identification problems due to its permanent expansion and sub-specialization options. Weaker points are its relation with primary care medicine (shared care options), the presence and role of urology in institutions such as the university, department of surgery, children's hospitals, administration, etc.; the desegregating effect of the sub-specialities; the increasing encroachment of other specialities, and the increasing outpatient effect of technological progress. An action plan is proposed to confront these changes without loosing manpower, internal consistency or social image and improving patient care quality, excellence of training and scientific progress.


Deranged jaw-neck motor control in whiplash-associated disorders.
Recent findings of simultaneous and well coordinated head-neck movements during single as well as rhythmic jaw opening-closing tasks has led to the conclusion that 'functional jaw movements' are the result of activation of jaw as well as neck muscles, leading to simultaneous movements in the temporomandibular, atlanto-occipital and cervical spine joints. It can therefore be assumed that disease or injury to any of these joint systems would disturb natural jaw function. To test this hypothesis, amplitudes, temporal coordination, and spatiotemporal consistency of concomitant mandibular and head-neck movements during single maximal jaw opening-closing tasks were analysed in 25 individuals suffering from whiplash-associated disorders (WAD) using optoelectronic movement recording technique. In addition, the relative durations for which the head position was equal to, leading ahead of, or lagging behind the mandibular position during the entire jaw opening-closing cycle were determined. Compared with healthy individuals, the WAD group showed smaller amplitudes, and changed temporal coordination between mandibular and head-neck movements. No divergence from healthy individuals was found for the spatiotemporal consistency or for the analysis during the entire jaw opening-closing cycle. These findings in the WAD group of a 'faulty', but yet consistent, jaw-neck behavior may reflect a basic importance of linked control of the jaw and neck sensory-motor systems. In conclusion, the present results suggest that neck injury is associated with deranged control of mandibular and head-neck movements during jaw opening-closing tasks, and therefore might compromise natural jaw function.


Ag44(SeR)30: A Hollow Cage Silver Cluster with Selenolate Protection.
Selenolate protected, stable and atomically precise, hollow silver cluster was synthesized using solid state as well as solution state routes. The optical absorption spectrum shows multiple and sharp features similar to the thiolated Ag44 cluster, Ag44(SR)30 whose experimental structure was reported recently. High-resolution electrospray ionization mass spectrometry (HRESI MS) shows well-defined molecular ion features with two, three, and four ions with isotopic resolution, due to Ag44(SePh)30. Additional characterization with diverse tools confirmed the composition. The closed-shell 18 electron superatom electronic structure, analogous to Ag44(SR)30 stabilizes the dodecahedral cage with a large HOMO-LUMO gap of 0.71 eV. The time-dependent density functional theory (TDDFT) prediction of the optical absorption spectrum, assuming the Ag44(SR)30 structure, matches the experimental data, confirming the structure.


Novel steroidogenic factor-1 homolog (ff1d) is coexpressed with anti-Mullerian hormone (AMH) in zebrafish.
ff1d is a novel zebrafish FTZ-F1 gene with sequence characteristics indicating similar basic regulatory mechanisms as the previously characterized ff1 based on the presence of an FTZ-F1 box in the DNA binding domain and an interactive domain (I-Box) and an AF-2 in the ligand binding domain. The highest sequence similarity was found between ff1d and ff1b (NR5A4), a gene previously shown to be a functional homolog to the steroidogenic factor 1 (SF-1). The expression pattern of ff1d was comparable to ff1b both in brain and gonads in adults and in the pituitary and interrenal cells in embryos. SF-1 is crucial in mammalian steroidogenesis and in sex determination by regulating the anti-Mullerian hormone (AMH). In fish, AMH has not been described previously. In this study, we cloned a partial zebrafish AMH. AMH was detected in growing oocytes, the ovarian follicular layer and testicular Sertoli cells, similar to the mammalian pattern, suggesting a conserved role between zebrafish and mammalian AMH. Teleosts lack a gene homolog to SRY, which constitute the universal testis-determining factor in mammalian sex determination. Comparison of sequences and expression patterns indicate that ff1d is a new candidate for sex determination and differentiation in a way similar to SF-1, possibly involving AMH.


[P,P-Di-tert-butyl-N-trimethylsilyl-P-(trimethylsilylamino)phosphine imidato-kappa2N,N']bis(pyridine-kappaN)lithium(I).
In the title compound, [Li(C(14)H(36)N(2)PSi(2))(C(5)H(5)N)(2)], the bulky chelating monoanionic P,P-di-tert-butyl-N-trimethylsilyl-P-(trimethylsilylamino)phosphine imidate ligand and two pyridine ligands bind to Li in a pseudo-tetrahedral arrangement with twofold symmetry. The Li-N(phosphine) distance is 2.048 (5) A, while the Li.P distance is 2.520 (6) A.


Complexation of Arsenite, Arsenate, and Monothioarsenate with Oxygen-Containing Functional Groups of Natural Organic Matter: An XAS Study.
Arsenic (As) is reported to be effectively sorbed onto natural organic matter (NOM) via thiol coordination and polyvalent metal cation-bridged ternary complexation. However, the extent of sorption via complexation with oxygen-containing functional groups of NOM is poorly understood. By equilibrating arsenite, arsenate, and monothioarsenate with purified model-peat, followed by As K-edge X-ray absorption spectroscopic analysis, this study shows that complexation with oxygen-containing functional groups can be an additional or alternative mode of As sorption to NOM. The extent of complexation was highest for arsenite, followed by monothioarsenate and arsenate. Complexation was higher at pH 7.0 compared to 4.5 for arsenite and arsenate and vice versa for monothioarsenate because of partial transformation to arsenite at pH 4.5. Modeling of the As K-edge extended X-ray absorption fine structure data revealed that As···C interatomic distances were relatively longer in arsenate- (2.83 ± 0.01 Å) and monothioarsenate-treated peat (2.80 ± 0.02 Å) compared to arsenite treatments (2.73 ± 0.01 Å). This study suggests that arsenite was predominantly complexed with carboxylic groups, whereas arsenate and monothioarsenate were complexed with alcoholic groups of the peat. This study further implies that in systems, where NOM is the major sorbent, arsenate and monothioarsenate can have higher mobility than arsenite.


Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.
To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups. The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.


Knockdown of ADAMDEC1 ameliorates ox-LDL-induced endothelial cell injury and atherosclerosis progression.
This study was designed to investigate the role of a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC-1) in atherosclerosis (AS). The Gene Expression Omnibus (GEO) database was utilized to identify differentially expressed genes (DEGs) between carotid atheroma plaque and carotid tissue adjacent atheroma plaque obtained from AS patients. Gene functional enrichment analysis was conducted on DEGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). QRT-PCR was employed to quantify mRNAs expression. AS animal model was established using ApoE-/- mice; serum triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were detected. Aortic sinus atherosclerotic lesions were observed using H&E staining and Oil Red O staining. ADAMDEC-1 was silenced using small interfering RNAs (siRNAs) in human vascular smooth muscle cells (HVSMCs). Cell proliferation, migration, and cell cycle progression were detected by cell count kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EDU), wound scratch healing assay, transwell assay, and flow cytometry, respectively. Western blot was used to evaluate various protein expression levels. Our results showed that ADAMDEC-1 was highly expressed in the serum of AS patients, consistent with the in silico results. The elevated TG, LDL-C, and HDL-C levels along with H&E and Oil Red O staining confirmed the successful establishment of the AS mouse model. ADAMDEC-1 expression was also elevated in AS mice. ADAMDEC-1 knockdown in HVSMCs suppressed cell proliferation, inhibited the expression of proliferating cell nuclear antigen (PCNA), and reduced the levels of matrix metalloproteinases (MMP2 and MMP9) proteins. Protein-protein interaction (PPI) analysis indicated that ADAMDEC-1 was associated with CXCL9, CCR5, TNF-α, TNFR1, and NF-κB-p50. The expression levels of CXCL9, CCR5, TNF-α, TNFR1, and NF-κB-p50 increased, while ADAMDEC-1 knockdown attenuated the expression of these proteins. Our study findings substantiate that ADAMDEC-1 may represent a novel target for AS.


[Do tissue marker clips after sonographically or stereotactically guided breast biopsy improve follow-up of small breast lesions and localisation of breast cancer after chemotherapy?].
We wanted to determine if tissue marker clips after sonographically or stereotactically guided breast biopsy improve the follow-up of small breast lesions classified BI-RADS 4/5 and the localisation of breast cancer (TNM stage 2 or 3) after neoadjuvant chemotherapy. Prospective analysis was performed of 108 breast lesions 1 cm or smaller mammographically classified as BI-RADS 4/5 and 14 breast lesions larger than 2 cm mammographically classified as BI-RADS 5. 33 of the 108 breast lesions 1 cm or smaller underwent sonographic core cut breast biopsy (group 1) and 75 stereotactic vacuum-assisted breast biopsy (group 2). All 14 lesions greater than 2 cm were stereotactically vacuum-assisted breast biopsied (group 3). The centre of the lesion was marked by a clip after the biopsy. Mammographies were performed in all patients of group 1 and 2 with a histologically benign finding (n = 31, n = 69, respectively) and in all patients of group 3 directly after clip placement and after 6 and 12 months. Clip localisation and possible divergence from the original position were verified by a grid. Two patients of group 1 and 6 patients of group 2 had breast conservative surgery (BET) because of the histological diagnosis of a ductal carcinoma in situ or invasive breast cancer. The tissue marker clips of the remaining 31 patients of group 1 and 69 patients of group 2 diverged with a mean value of 0.4 cm (standard deviation +/- 0.23 cm; range 0.1 cm to 0.9 cm) from their placement position after 6 months. After 12 months the marker clips deviated with a mean value of 0.4 cm (standard deviation +/- 0.21 cm; range 0.1 cm to 0.9 cm) in 94 patients and 0.8 cm (standard deviation +/- 0.25 cm; range 0.1 cm to 0.9 cm) in 6 patients from their original location. No tumour progression of the benign lesions in group 1 and 2 was diagnosed in follow-up mammograms. In all patients of group 3 the tissue marker clips were the only possibility to localize the tumour after neoadjuvant chemotherapy as all other diagnostic methods showed inconsistent results. Positioning a tissue marker clip in the tumour centre seems to be reasonable after interventional biopsy of breast lesions of 1.0 cm or smaller and before neoadjuvant chemotherapy.


Rational design of monocrystalline (InP)(y)Ge(5-2y)/Ge/Si(100) semiconductors: synthesis and optical properties.
In this work, we extend our strategy previously developed to synthesize functional, crystalline Si(5-2y)(AlX)y {X = N,P,As} semiconductors to a new class of Ge-III-V hybrid compounds, leading to the creation of (InP)(y)Ge(5-2y) analogues. The compounds are grown directly on Ge-buffered Si(100) substrates using gas source MBE by tuning the interaction between Ge-based P(GeH3)3 precursors and In atoms to yield nanoscale "In-P-Ge3" building blocks, which then confer their molecular structure and composition to form the target solids via complete elimination of H2. The collateral production of reactive germylene (GeH2), via partial decomposition of P(GeH3)3, is achieved by simple adjustment of the deposition conditions, leading to controlled Ge enrichment of the solid product relative to the stoichiometric InPGe3 composition. High resolution XRD, XTEM, EDX, and RBS indicate that the resultant monocrystalline (InP)(y)Ge(5-2y) alloys with y = 0.3-0.7 are tetragonally strained and fully coherent with the substrate and possess a cubic diamond-like structure. Molecular and solid-state ab initio density functional theory (DFT) simulations support the viability of "In-P-Ge3" building-block assembly of the proposed crystal structures, which consist of a Ge parent crystal in which the P atoms form a third-nearest-neighbor sublattice and "In-P" dimers are oriented to exclude energetically unfavorable In-In bonding. The observed InP concentration dependence of the lattice constant is closely reproduced by DFT simulation of these model structures. Raman spectroscopy and ellipsometry are also consistent with the "In-P-Ge3" building-block interpretation of the crystal structure, while the observation of photoluminescence suggests that (InP)(y)Ge(5-2y) may have important optoelectronic applications.


Comparative Genomics of Pathogenic and Nonpathogenic Strains of Xanthomonas arboricola Unveil Molecular and Evolutionary Events Linked to Pathoadaptation.
The bacterial species Xanthomonas arboricola contains plant pathogenic and nonpathogenic strains. It includes the pathogen X. arboricola pv. juglandis, causing the bacterial blight of Juglans regia. The emergence of a new bacterial disease of J. regia in France called vertical oozing canker (VOC) was previously described and the causal agent was identified as a distinct genetic lineage within the pathovar juglandis. Symptoms on walnut leaves and fruits are similar to those of a bacterial blight but VOC includes also cankers on trunk and branches. In this work, we used comparative genomics and physiological tests to detect differences between four X. arboricola strains isolated from walnut tree: strain CFBP 2528 causing walnut blight (WB), strain CFBP 7179 causing VOC and two nonpathogenic strains, CFBP 7634 and CFBP 7651, isolated from healthy walnut buds. Whole genome sequence comparisons revealed that pathogenic strains possess a larger and wider range of mobile genetic elements than nonpathogenic strains. One pathogenic strain, CFBP 7179, possessed a specific integrative and conjugative element (ICE) of 95 kb encoding genes involved in copper resistance, transport and regulation. The type three effector repertoire was larger in pathogenic strains than in nonpathogenic strains. Moreover, CFBP 7634 strain lacked the type three secretion system encoding genes. The flagellar system appeared incomplete and nonfunctional in the pathogenic strain CFBP 2528. Differential sets of chemoreceptor and different repertoires of genes coding adhesins were identified between pathogenic and nonpathogenic strains. Besides these differences, some strain-specific differences were also observed. Altogether, this study provides valuable insights to highlight the mechanisms involved in ecology, environment perception, plant adhesion and interaction, leading to the emergence of new strains in a dynamic environment.


Extrasynaptic Communication.
Streams of action potentials or long depolarizations evoke a massive exocytosis of transmitters and peptides from the surface of dendrites, axons and cell bodies of different neuron types. Such mode of exocytosis is known as extrasynaptic for occurring without utilization of synaptic structures. Most transmitters and all peptides can be released extrasynaptically. Neurons may discharge their contents with relative independence from the axon, soma and dendrites. Extrasynaptic exocytosis takes fractions of a second in varicosities or minutes in the soma or dendrites, but its effects last from seconds to hours. Unlike synaptic exocytosis, which is well localized, extrasynaptic exocytosis is diffuse and affects neuronal circuits, glia and blood vessels. Molecules that are liberated may reach extrasynaptic receptors microns away. The coupling between excitation and exocytosis follows a multistep mechanism, different from that at synapses, but similar to that for the release of hormones. The steps from excitation to exocytosis have been studied step by step for the vital transmitter serotonin in leech Retzius neurons. The events leading to serotonin exocytosis occur similarly for the release of other transmitters and peptides in central and peripheral neurons. Extrasynaptic exocytosis occurs commonly onto glial cells, which react by releasing the same or other transmitters. In the last section, we discuss how illumination of the retina evokes extrasynaptic release of dopamine and ATP. Dopamine contributes to light-adaptation; ATP activates glia, which mediates an increase in blood flow and oxygenation. A proper understanding of the workings of the nervous system requires the understanding of extrasynaptic communication.


[Antioxidant agents in neuroprotection treatment of glaucoma].
Purpose was to study efficiency and safety of mexidol in combined therapy in patients with primary open-angle glaucoma (POAG). 94 patients (185 eyes) at the age of 18-75 years old with POAG I-III stages were divided into 3 groups: 50 patients received combined therapy of mexidol 100 mg and picamilon 150 mg, 22 patients received combined therapy of mexidol 300 mg and picamilon 150 mg, 22 patients received only picamilon 150 mg. All medicine was administered qd during 14 or 21 days. Examination included standard ophthalmologic methods, perimetry, electroretinography, retinal and optic nerve heard arterial blood flow. Improvement of visual acuity, perimetric, electrofisiological indicies and increased blood flow velocity of central retinal artery were registrated. Combined mexidol therapy allows improving results in treatment of patients with POAG.


Reproduction of the male eastern pipistrelle, Pipistrellus subflavus, in the north-eastern United States.
The major reproductive events in the male eastern pipistrelle, are similar to those of other hibernating vespertilionids. The eastern pipistrelle stores epididymal spermatozoa throughout hibernation, a time when the testes are involuted but accessory gland activity is maintained. However, this species differs from others in that epididymal and testicular spermatozoa persist longer and the weights of the accessory glands are not strongly differentiated between winter and spring/summer. It is suggested that the reproductive period is extended in this species as a function of a more prolonged period of hibernation, resulting in only a brief period of sexual quiescence in mid-summer. The eastern pipistrelle (Pipistrellus subflavus) resembles the canyon bat (P. hesperus) in that some testicular spermatozoa persist during winter. Many aspects of the reproductive anatomy and chronology of these two species are similar; however, eastern pipistrelles apparently lack a seminal vesicle and possess a distinctly different baculum.


Ethanol alters the osteogenic differentiation of amniotic fluid-derived stem cells.
Fetal alcohol spectrum disorder (FASD) is a set of developmental defects caused by prenatal alcohol exposure. Clinical manifestations of FASD are highly variable and include mental retardation and developmental defects of the heart, kidney, muscle, skeleton, and craniofacial structures. Specific effects of ethanol on fetal cells include induction of apoptosis as well as inhibition of proliferation, differentiation, and migration. This complex set of responses suggests that a bioinformatics approach could clarify some of the pathways involved in these responses. In this study, the responses of fetal stem cells derived from the amniotic fluid (AFSCs) to treatment with ethanol have been examined. Large-scale transcriptome analysis of ethanol-treated AFSCs indicates that genes involved in skeletal development and ossification are up-regulated in these cells. Therefore, the effect of ethanol on osteogenic differentiation of AFSCs was studied. Exposure to ethanol during the first 48 hours of an osteogenic differentiation protocol increased in vitro calcium deposition by AFSCs and increased alkaline phosphatase activity. In contrast, ethanol treatment later in the differentiation protocol (day 8) had no significant effect on the activity of alkaline phosphatase. These results suggest that transient exposure of AFSCs to ethanol during early differentiation enhances osteogenic differentiation of the cells.


Effects of the integration of sunn hemp and soil solarization on plant-parasitic and free-living nematodes.
Sunn hemp (SH), Crotolaria juncea, is known to suppress Rotylenchulus reniformis and weeds while enhancing free-living nematodes involved in nutrient cycling. Field trials were conducted in 2009 (Trial I) and 2010 (Trial II) to examine if SH cover cropping could suppress R. reniformis and weeds while enhancing free-living nematodes if integrated with soil solarization (SOL). Cover cropping of SH, soil solarization, and SH followed by SOL (SHSOL) were compared to weedy fallow control (C). Rotylenchulus reniformis population was suppressed by SHSOL at the end of cover cropping or solarization period (Pi) in Trial I, but not in Trial II. However, SOL and SHSOL did not suppress R. reniformis compared to SH in either trial. SH enhanced abundance of bacterivores and suppressed the % herbivores only at Pi in Trial II. At termination of the experiment, SH resulted in a higher enrichment index indicating greater soil nutrient availability, and a higher structure index indicating a less disturbed nematode community compared to C. SOL suppressed bacterivores and fungivores only in Trial II but not in Trial I. On the other hand, SHSOL enhanced bacterivores and fungivores only at Pi in Trial I. Weeds were suppressed by SH, SOL and SHSOL throughout the experiment. SHSOL suppressed R. reniformis and enhanced free-living nematodes better than SOL, and suppressed weeds better than SH.


Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators.
Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.


Cardiovascular effect of low-dose epinephrine infusions in relation to the extent of preoperative beta-adrenoceptor blockade.
The relationship between the extent of preoperative beta-adrenoceptor blockade and the hemodynamic properties of epinephrine was investigated in patients scheduled for elective myocardial revascularization during the immediate preoperative period under steady-state hemodynamic and anesthetic conditions. Twenty patients had been treated with beta-adrenoceptor blocking drugs for at least 3 weeks before the study; 11 unblocked patients served as control group. The extent of clinical beta-adrenoceptor blockade was quantified using the isoproterenol sensitivity test. The dose of isoproterenol required to increase heart rate by 25 beats per min was defined as the chronotropic dose 25 (CD25), representing the degree of beta-adrenoceptor blockade. Geometric mean CD25 per 70 kg was 3.0 micrograms in the control group and 21.8 micrograms in the patients receiving beta-adrenoceptor blocking drugs. The authors found a significant inverse relationship between CD25 values and changes in cardiac index in response to three epinephrine infusion rates (0.01, 0.02, and 0.04 micrograms.kg-1.min-1), the correlation coefficients being -0.71, -0.81, and -0.86, respectively. Compared to unblocked patients, almost no change, or even a decrease, of the cardiac index was observed at greater degrees of clinical beta-adrenoceptor blockade, particularly in patients receiving nonselective blockers. Moreover, there was a significant linear correlation (r = 0.76-0.86) between CD25 values and the effects of epinephrine on systemic vascular resistance index (SVRI); i.e., SVRI significantly decreased in control patients but markedly increased in patients with high degrees of preoperative beta-adrenoceptor blockade. This unmasked vasoconstrictive response to low doses of epinephrine was observed despite the fact that the majority of our patients had received cardioselective adrenergic blocking drugs.(ABSTRACT TRUNCATED AT 250 WORDS)


Interaction of a high affinity anti-estrogen (alpha-[4-pyrrolidinoethoxy]phenyl-4-hydroxy-alpha'-nitrostilbene, CI628M) with uterine estrogen receptors.
The polar metabolite of the anti-estrogen alpha-[4-pyrrolidinoethoxy]phenyl-4-methoxy-alpha'-nitrostilbene (CI628), that is selectively accumulated by the nuclear estrogen receptor in vivo, is identified as the corresponding free phenol (alpha-[4-pyrrolidinoethoxyl]phenyl-4-hydroxy-alpha'-nitrostilbene (CI628M) and has been prepared in high specific activity tritium-labeled form to study its interaction with the rat uterine estrogen receptor. CI628M has an affinity for the cytosol receptor that is comparable to that of estradiol (Kd (CI628M) = 0.16 nM; Kd (estradiol) = 0.28 nM), and the binding of these two compounds is mutually competitive. Dissociation of the CI628M complex with the estrogen receptor is somewhat slower than that of the estradiol complex, and prewarming the complexes at 28 degrees C causes a characteristic decrease in the rate of dissociation. On low salt sucrose gradients, the CI628M and estradiol cytoplasmic receptor complexes both sediment as 8S species; their sedimentation profiles on high salt gradients are somewhat different, however. While the estradiol receptor complex shows mainly a 4.6S species that shifts to a 5.8S species upon warming, the unwarmed CI628M complex is predominantly 5.8S and becomes somewhat more disperse upon warming. Under high salt conditions, there is a progressive shift of the 4.6S to the 5.8S species as cytosol concentration increases; the CI628M complex shows a greater tendency to form the more rapidly sedimenting form at all cytosol concentrations. After in vivo injection of [3H]CI628M, the uterine nuclear receptor sediments as a characteristic 5S species. Cytosol receptor complexes with estradiol and CI628M, maintained at 0 degrees C, show very little binding to ATP-Sepharose, while after warming, 50-60% of both complexes are bound by the resin. Both complexes also show similar elution profiles from DNA-cellulose columns; however, the extent of binding of the [3H]CI628M receptor complex to the column is consistently only 40-50% that of the estradiol receptor complex. These results indicate that the properties of the uterine estrogen receptor complexed with estradiol and with the high affinity anti-estrogen CI628M are very similar. The differences observed in the behavior of the CI628M cytosol receptor complex on high salt sucrose gradients and on DNA-cellulose columns, though quantitative rather than qualitative, may be indicative of differences in receptor properties that are important to the antagonist activity of this compound.


High expression of VAT1 is a prognostic biomarker and predicts malignancy in glioblastoma.
Vesicle amine transport protein 1 (VAT1) has been reported as a pathogenic factor in a variety of tumors. VAT1 has been revealed to be upregulated in glioblastoma (GBM) and promotes cell migration. However, the possible mechanism of VAT1 in promoting malignant development in GBM is unclear. The present study applied transcriptome data and functional experiments to explore the exact role of VAT1. Kaplan‑Meier survival analysis, univariate and multivariate Cox analyses were used to perform survival analysis. Furthermore, Gene Ontology analysis was used to analyze the biological implication of VAT1 expression. The in vitro experiment was performed to verify the hypothesis. The expression of VAT1 was detected in gliomas and control tissues. A functional experiment was performed and the sensitivity to TMZ was assessed after knocking down the expression of VAT1. In total, 120 patients with GBM were enrolled in the present study. The results of multivariate analysis revealed that VAT1 was an independent prognostic factor for survival. Patients with high VAT1 expression levels had shorter overall survival (P=0.009) and progression‑free survival (P=0.055) than those with low expression levels. Gene Ontology analysis revealed that the genes which were positively associated with VAT1 were functionally involved in proteolysis, oxidation‑reduction processes and immune response. The results of functional experiments demonstrated that VAT1 exhibited high expression levels in GBM, which could be inhibited by microRNA‑218. Upon VAT1 knockdown, cell proliferation and migration were markedly suppressed, while the sensitivity toward temozolomide chemotherapy was enhanced. Thus, VAT1 expression was revealed to be a prognostic factor for GBM. High expression of VAT1 may promote cell proliferation, migration and temozolomide chemotherapy‑resistance, which may be a potential therapeutic target for GBM.


An (In)Significant Ventricular Septal Defect and/or Double-Chambered Right Ventricle: Are There Any Differences in Diagnosis and Prognosis in Adult Patients.
A double-chambered right ventricle (DCRV) is an uncommon congenital anomaly: the right ventricle (RV) is divided into two chambers due to the presence of an abnormally located muscular band or anomalous muscle hypertrophy in the subinfundibular part of RV outflow tract, with a variable degree of obstruction. Generally, DCRV is well recognized in childhood and misdiagnosed in adult patients. Transthoracic and/or transesophageal echocardiography are the mx0435;thods of choice for the diagnosis of DCRV. Due to limitations of echocardiography in adult patients, this entity may be missed, particularly if it presents concomitant with other congenital defects, and therefore additional imaging methods such as MRI or cardiac catheterization are required for a definitive diagnosis.


3D printing technology to control BMP-2 and VEGF delivery spatially and temporally to promote large-volume bone regeneration.
When large engineered tissue structures are used to achieve tissue regeneration, formation of vasculature is an essential process. We report a technique that combines 3D printing with spatial and temporal control of dual growth factors to prevascularize bone tissue. Human dental pulp stem cells (DPSCs) that have both osteogenic and vasculogenic potential were printed with bone morphogenetic protein-2 (BMP-2) in the peripheral zone of the 3D printed construct, and with the vascular endothelial growth factor (VEGF) in the central zone, in which a hypoxic area forms. The structure was implanted in the back of a mouse and tissue regeneration was assessed after 28 d. Microvessels were newly formed in the hypoxic area of the printed large volume structure, and angiogenesis from the host tissue was also observed. Bone regeneration was faster in prevascularized structures than in nonvascularized structures. The 3D-printed prevascularized structure could be a promising approach to overcome the size limitation of tissue implants and to enhance bone regeneration.


Effect of centrally administered oxytocin on the association between cortical electroencephalogram and milk ejection in the rat.
Abstract The milk-ejection reflex of the rat is closely associated with synchronized activity of the cortical electroencephalogram (EEG), and the frequency of milk ejections has been shown to be greatly facilitated by central oxytocin. The following experiments were undertaken to examine the changes in the EEG during facilitation of the reflex by central oxytocin. Intracerebroventricular injection of 1 mU (2.2 ng) oxytocin during suckling caused a rapid increase in the frequency of milk ejections but no change in the predominantly synchronized pattern of the EEG. However, after a delay (11.3 +/- 0.8 min, mean +/- SE) there appeared to be an increasing proportion of desynchronization, which correlated with cessation of the facilitated milk-ejection responses. Hence, the observed EEG desynchronization may signal activation of mechanisms inhibitory to the milk-ejection reflex. In the absence of the suckling stimulus oxytocin also caused a change to desynchronization. However, this effect was more pronounced and commenced after a much shorter latency (1.7 +/- 0.4 min, mean +/- SE; P < 1.001), suggesting that the desynchronizing effect of oxytocin on the EEG can be attenuated by the suckling stimulus. These results demonstrate two phases in the action of central oxytocin in the suckled rat. During the initial phase, the milk-ejection reflex is facilitated and although there may be a concomitant desynchronizing influence on the EEG this is prevented by the influence of the suckling stimulus. In the later phase, this desynchronizing influence predominates and is accompanied by cessation of milk-ejection responses. Although milk ejections were generally restricted to periods of a synchronized EEG as previously reported, during the oxytocin-induced change to desynchronization a number of milk ejections were observed to occur in the absence of a synchronized EEG. These results provide further evidence that the association between milk ejection and the EEG state is not an absolute causal relationship.


Effective bioremediation strategy for rapid in situ cleanup of anoxic marine sediments in mesocosm oil spill simulation.
The purpose of present study was the simulation of an oil spill accompanied by burial of significant amount of petroleum hydrocarbons (PHs) in coastal sediments. Approximately 1000 kg of sediments collected in Messina harbor were spiked with Bunker C furnace fuel oil (6500 ppm). The rapid consumption of oxygen by aerobic heterotrophs created highly reduced conditions in the sediments with subsequent recession of biodegradation rates. As follows, after 3 months of ageing, the anaerobic sediments did not exhibit any significant levels of biodegradation and more than 80% of added Bunker C fuel oil remained buried. Anaerobic microbial community exhibited a strong enrichment in sulfate-reducing PHs-degrading and PHs-associated Deltaproteobacteria. As an effective bioremediation strategy to clean up these contaminated sediments, we applied a Modular Slurry System (MSS) allowing the containment of sediments and their physical-chemical treatment, e.g., aeration. Aeration for 3 months has increased the removal of main PHs contaminants up to 98%. As revealed by CARD-FISH, qPCR, and 16S rRNA gene clone library analyses, addition of Bunker C fuel oil initially affected the activity of autochthonous aerobic obligate marine hydrocarbonoclastic bacteria (OMHCB), and after 1 month more than the third of microbial population was represented by Alcanivorax-, Cycloclasticus-, and Marinobacter-related organisms. In the end of the experiment, the microbial community composition has returned to a status typically observed in pristine marine ecosystems with no detectable OMHCB present. Eco-toxicological bioassay revealed that the toxicity of sediments after treatment was substantially decreased. Thus, our studies demonstrated that petroleum-contaminated anaerobic marine sediments could efficiently be cleaned through an in situ oxygenation which stimulates their self-cleaning potential due to reawakening of allochtonous aerobic OMHCB.


TGF-{beta}2 induces senescence-associated changes in human trabecular meshwork cells.
Recent studies have revealed an accumulation of senescent cells in the outflow pathways in primary open-angle glaucoma (POAG). Transforming growth factor (TGF)-β2 is thought to be involved in the pathologic changes of the trabecular meshwork (TM) of POAG eyes. The goal of this study was to determine whether TGF-β2 triggers senescence-associated changes in human TM cells in vitro. Cultured human TM cells were exposed to 1.0 ng/mL TGF-β2 for 12, 24, and 48 hours. Senescence-associated β-galactosidase (SA-β-Gal) activity was investigated by histochemical staining. Lipid peroxidation was assessed after TGF-β2 treatment. Levels of apolipoprotein J (Apo J), SM22, and osteonectin (SPARC) mRNA were determined by real-time PCR analysis. Furthermore, the effects of antioxidants on these TGF-β2-mediated changes were tested. Induction of senescence-related signal transduction proteins (p16, p21, and pRb) was examined by real-time PCR and Western blot analysis. TGF-β2 increased SA-β-Gal activity, lipid peroxidation, and the mRNA expressions of Apo J, SM22, and SPARC. These TGF-β2-induced changes were attenuated by antioxidants. TGF-β2 increased p16 mRNA and protein expression, which was paralleled by a downregulation of pRb protein. There was no effect on p21 mRNA and protein expression after exposure to TGF-β2. TGF-β2 induces senescence-associated TM changes and activates the senescence-related p16-pRb signal transduction pathway in vitro. Thus, minimizing TGF-β2 levels may help to prevent the ageing process in the TM as seen in POAG.


Doppler assessment of the interventricular pressure drop in patients with ventricular septal defects.
Doppler ultrasound was used to assess the pressure drop between the ventricles in 109 infants and children (61 less than two years old) with a ventricular septal defect who underwent cardiac catheterisation. The pressure in both ventricles was measured at catheterisation in 103 patients either simultaneously through two catheters (41) or with a single catheter withdrawn across the septum or removed from one ventricle to the other (62). When pressure was measured simultaneously with two catheters (41 patients) the peak to peak and instantaneous gradients showed a maximum difference of 20 mm Hg with levels within 10 mm Hg of each other in 36. Comparison of the difference in the gradients with the average of the measurements demonstrated a tendency for Doppler to underestimate the difference when it was high (greater than 50 mm Hg) and overestimate it when it was low. A Doppler estimate of a low pressure difference between the ventricles indicates pulmonary arterial hypertension and a high one low pulmonary artery pressure, but in the intermediate group Doppler is as yet not sufficiently sensitive to allow selection of those patients who require further investigation and possible operation. Doppler ultrasound was found to be a sensitive method of detecting a very small ventricular septal defect. Thus although Doppler is a very useful means of assessing and following patients with a ventricular septal defect, further studies are required to determine its exact place in clinical practice.


[Dynamic spatial organization of enzymes in the cell and the regulation of metabolism].
The proteins in membranes and cytosol are often distributed unevenly in space and form the dynamic aggregates and functional assemblies. This property is important for functioning of multienzyme systems. The experimental results indicate the existence of a special type of regulation and integration of cellular metabolism based on the change of mutual rearrangement of enzymes in the cell and formation of transient protein assemblies.


A simulation platform to examine heterogeneity influence on treatment.
Although a protocol aims to guide treatment management and optimize overall outcomes, the benefits and harms for each individual vary due to heterogeneity. Some protocols integrate clinical and genetic variation to provide treatment recommendation; it is not clear whether such integration is sufficient. If not, treatment outcomes may be sub-optimal for certain patient sub-populations. Unfortunately, running a clinical trial to examine such outcome responses is cost prohibitive and requires a significant amount of time to conduct the study. We propose a simulation approach to discover this knowledge from electronic medical records; a rapid method to reach this goal. We use the well-known drug warfarin as an example to examine whether patient characteristics, including race and the genes CYP2C9 and VKORC1, have been fully integrated into dosing protocols. The two genes mentioned above have been shown to be important in patient response to warfarin.


Metastasis from a primary hepatic angiosarcoma to the colon: A case report and literature review.
Primary hepatic angiosarcoma is a rare type of tumor with a poor prognosis. To the best of our knowledge, curative surgery of a metastatic gastrointestinal angiosarcoma from a hepatic angiosarcoma has not been reported previously. In the present report, a case of colonic metastasis from a primary hepatic angiosarcoma is discussed. A rapidly growing mass was identified in the liver of an 84-year-old Japanese male who underwent a subsegmentectomy of the liver. Microscopic examination determined that the mass was an angiosarcoma composed of sheets of spindle cells. Immunohistochemical studies confirmed the diagnosis with positive CD31 staining, which indicated the endothelial nature of the malignancy. A total of 14 months following surgery, the patient did not exhibit any symptoms; however, follow-up positron emission tomography and computed tomography images revealed a mass in the cecum. The patient underwent an ileocolectomy, and the microscopic and immunohistochemical findings indicated that the mass was a metastasized colorectal angiosarcoma. At a 4-year post-surgery follow-up appointment the patient was alive with no evidence of recurrence or metastasis.


Beneficial effects of biota, a traditional Chinese herbal medicine on learning impairment induced by basal forebrain-lesion in mice.
The effects of biota (Biota orientalis ENDL.) on learning impairment produced by bilateral lesion of basal forebrain in mice were studied using step-through and step-down type passive avoidance tasks. Basal forebrain-lesion was generated by applying radiofrequency current. Behavioral experiment, started 15d after the survey, revealed prominent delay in the memory acquisition process in the lesioned mice. The operation also induced memory retention deficit in both learning tests. Chronic oral administration of ethanol extract of biota seeds at doses of 250 and 500 mg/kg/d, from the day of surgery until the end of the behavioral test, dose-dependently improved memory acquisition impairment in the step-down test and memory retention disturbance in both behavioral tasks. The preparation also had a tendency to alleviate memory acquisition impairment in the step-through test. Although precise action mechanisms of biota extract remains speculative, such as what component works on which target, the present results clearly suggest that the preparation affects the learning and memory processes in the central nervous system and improves the impairment of memory acquisition and retention disturbances produced by basal forebrain-lesion.


Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine.
In the present study we investigated a possible involvement of the intestinal sodium-dependent glucose transporter (SGLT)1 in the absorption of quercetin-3-glucoside (Q3G). Pieces of rat jejunum or proximal colon were mounted in Ussing-type chambers and incubated under short-circuited conditions. Test flavonols were added to the mucosal or serosal bathing solution (initial concentration, 100 micromol/L) and disappearance from the donor compartment was monitored for 2 h. With jejunal tissue, only 13.6 +/- 3.5% of the initial dose of Q3G was found in the mucosal compartment 2 h after mucosal addition. Simultaneous addition of D-glucose (10 mmol/L) significantly reduced the disappearance of Q3G (remaining concentration, 33.4 +/- 6.9%) as did a Na(+)-free buffer solution containing phloridzin (final mucosal concentration of Q3G, 54.2 +/- 7.7%). In these experiments, disappearance of Q3G was paralleled by the appearance of quercetin in the mucosal solutions. In contrast, D-fructose (10 mmol/L) did not influence the disappearance of Q3G (Na(+)-free conditions). With proximal colon, 78.2 +/- 11.5% of the initial concentration of Q3G was still present in the mucosal solution after 2 h. When added to the serosal side, the concentration of Q3G decreased only slightly (jejunum, 96.1 +/- 2.1%; proximal colon, 90.7 +/- 1.2%). The concentration of rutin did not change after mucosal or serosal addition. Neither transport of intact glycosides nor of free quercetin from the donor into the acceptor compartment was observed under our experimental conditions. Taken together, the results clearly indicate a role of SGLT1 in mucosal uptake of the Q3G.


Dataset for the reporting of carcinoma of the esophagus in resection specimens: recommendations from the International Collaboration on Cancer Reporting.
A standardized data set for esophageal carcinoma pathology reporting was developed based on the approach of the International Collaboration on Cancer Reporting (ICCR) for the purpose of improving cancer patient outcomes and international benchmarking in cancer management. The ICCR convened a multidisciplinary international expert panel to identify the best evidence-based clinical and pathological parameters for inclusion in the data set for esophageal carcinoma. The data set incorporated the current edition of the World Health Organization Classification of Tumours of the Digestive System, and Tumour-Node-Metastasis staging systems. The scope of the data set encompassed resection specimens of the esophagus and esophagogastric junction with tumor epicenter ≤20 mm into the proximal stomach. Core reporting elements included information on neoadjuvant therapy, operative procedure used, tumor focality, tumor site, tumor dimensions, distance of tumor to resection margins, histological tumor type, presence and type of dysplasia, tumor grade, extent of invasion in the esophagus, lymphovascular invasion, response to neoadjuvant therapy, status of resection margin, ancillary studies, lymph node status, distant metastases, and pathological staging. Additional non-core elements considered useful to report included clinical information, specimen dimensions, macroscopic appearance of tumor, and coexistent pathology. This is the first international peer-reviewed structured reporting data set for surgically resected specimens of the esophagus. The ICCR carcinoma of the esophagus data set is recommended for routine use globally and is a valuable tool to support standardized reporting, to benefit patient care by providing diagnostic and prognostic best-practice parameters.


Systematic review and a meta-analysis of hospital and surgeon volume/outcome relationships in colorectal cancer surgery.
Numerous hospitals worldwide are considering setting minimum volume standards for colorectal surgery. This study aims to examine the association between hospital and surgeon volume on outcomes for colorectal surgery. Two investigators independently reviewed six databases from inception to May 2016 for articles that reported outcomes according to hospital and/or surgeon volume. Eligible studies included those in which assessed the association hospital or surgeon volume with outcomes for the surgical treatment of colon and/or rectal cancer. Random effects models were used to pool the hazard ratios (HRs) for the association between hospital/surgeon volume with outcomes. There were 47 articles pooled (1,122,303 patients, 9,877 hospitals and 9,649 surgeons). The meta-analysis demonstrated that there is a volume-outcome relationship that favours high volume facilities and high volume surgeons. Higher hospital and surgeon volume resulted in reduced 30-day mortality (HR: 0.83; 95% CI: 0.78-0.87, P<0.001 & HR: 0.84; 95% CI: 0.80-0.89, P<0.001 respectively) and intra-operative mortality (HR: 0.82; 95% CI: 0.76-0.86, P<0.001 & HR: 0.50; 95% CI: 0.40-0.62, P<0.001 respectively). Post-operative complication rates depended on hospital volume (HR: 0.89; 95% CI: 0.81-0.98, P<0.05), but not surgeon volume except with respect to anastomotic leak (HR: 0.59; 95% CI: 0.37-0.94, P<0.01). High volume surgeons are associated with greater 5-year survival and greater lymph node retrieval, whilst reducing recurrence rates, operative time, length of stay and cost. The best outcomes occur in high volume hospitals with high volume surgeons, followed by low volume hospitals with high volume surgeons. High volume by surgeon and high volume by hospital are associated with better outcomes for colorectal cancer surgery. However, this relationship is non-linear with no clear threshold of effect being identified and an apparent ceiling of effect.


[Urethral and scrotal pain syndromes].
Painful diseases of the pelvis are not rare. Urethral and scrotal pains are part of the chronic pelvic pain syndromes along with chronic prostatitis and painful bladder syndrome/interstitial cystitis. The objective of this review is to update the current knowledge about epidimiology, etiology, diagnosis and best treatment for patients with urethral and scrotal pain syndromes. Epidemiological data for both syndromes are scant. We lack of uniform definition or readily available diagnostic marker and aetiology remains unclear. The pain could be a neuropathic without a specific stimulus or disproportionate to the stimulus intensity. Regarding diagnosis, there is no evidence to qualify or quantify the symptoms to include or exclude patients. Nevertheless, it is very important to know functional neuroanatomy in the evaluation of these patients. Treatment always should be primary conservatively. Surgery should be avoided if possible. As no specific treatment is available, decrease the pain is the main objective, therefore urologist should know how to manage analgesics, antidepressant and anticonvulsants.


Reduced respiratory responses to carbon dioxide after propranolol: a central action.
In a double-blind study in six subjects propranolol significantly reduced the respiratory sensitivity to carbon dioxide rebreathing. This effect seems to have been due to beta-adrenergic blockade, since it was not seen with D-propranolol. In two subjects increasing doses of propranolol caused progressive reductions in respiratory sensitivity to values below normal and similar to those of patients with ventilatory failure. These changes are probably due to a central action of propranolol.


Features of the Vision of Elderly Pedestrians when Crossing a Road.
The present study clarifies the mechanism by which an accident occurs when an elderly pedestrian crosses a road in front of a car, focusing on features of the central and peripheral vision of elderly pedestrians who are judging when it is safe to cross the road. For the pedestrian's central visual field, we investigated the effect of age on the timing judgment using an actual car. The results for daytime conditions indicate that the elderly pedestrians tended to make later judgments of when they crossed the road from the right side of the driver's view at high car velocities. At night, for a car with its headlights on high beam, the average car-pedestrian distances of elderly pedestrians on the left side of the driver's view were significantly longer than those of young pedestrians at velocities of 20 and 40 km/h. The eyesight of the elderly pedestrians during the day did not affect the timing judgment of crossing a road. At night, for a car with its headlights on either high or low beam, the average car-pedestrian distances of elderly pedestrians having good eyesight were longer than those of elderly pedestrians having poor eyesight, for all car velocities. The color of the car body in the central visual field did not affect the timing judgment of elderly pedestrians crossing the road. Meanwhile, the car-body color in the elderly pedestrian's peripheral vision strongly affected the pedestrian's awareness of the car.


Human APOER2 Isoforms Have Differential Cleavage Events and Synaptic Properties.
Human apolipoprotein E receptor 2 (APOER2) is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail. APOER2-ECD contains several ligand-binding domains (LBDs) that are organized into exons with aligning phase junctions, which allows for in-frame exon cassette splicing events. We have identified 25 human APOER2 isoforms from cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events within the N-terminal LBD regions compared with six identified in the heart. APOER2 undergoes proteolytic cleavage in response to ligand binding that releases a C-terminal fragment (CTF) and transcriptionally active intracellular domain (ICD). We tested whether the diversity of human brain-specific APOER2 variants affects APOER2 cleavage. We found isoforms with differing numbers of ligand-binding repeats generated different amounts of CTFs compared with full-length APOER2 (APOER2-FL). Specifically, APOER2 isoforms lacking exons 5-8 (Δex5-8) and lacking exons 4-6 (Δex4-6) generated the highest and lowest amounts of CTF generation, respectively, in response to APOE peptide compared with APOER2-FL. The differential CTF generation of Δex5-8 and Δex4-6 coincides with the proteolytic release of the ICD, which mediates transcriptional activation facilitated by the Mint1 adaptor protein. Functionally, we demonstrated loss of mouse Apoer2 decreased miniature event frequency in excitatory synapses, which may be because of a decrease in the total number of synapses and/or VAMP2 positive neurons. Lentiviral infection with human APOER2-FL or Δex4-6 isoform in Apoer2 knockout neurons restored the miniature event frequency but not Δex5-8 isoform. These results suggest that human APOER2 isoforms have differential cleavage events and synaptic properties.SIGNIFICANCE STATEMENT Humans and mice share virtually the same number of protein-coding genes. However, humans have greater complexity of any higher eukaryotic organisms by encoding multiple protein forms through alternative splicing modifications. Alternative splicing allows pre-mRNAs transcribed from genes to be spliced in different arrangements, producing structurally and functionally distinct protein variants that increase proteomic diversity and are particularly prevalent in the human brain. Here, we identified 25 distinct human APOER2 splice variants from the cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events that exclude N-terminal ligand-binding regions of APOER2. We show that some of the APOER2 variants have differential proteolytic properties in response to APOE ligand and exhibit distinct synaptic properties.


Predictors of eating attitudes and behaviors among gay Hispanic men.
Gay men are a vulnerable population at risk for a number of health disparities, but little is known about eating disorders among gay Hispanic men. The purpose of this study was to examine the relationship of eating attitudes and behaviors with alcohol abuse, body image, depression, self-esteem, and sexual behaviors to determine predictors of eating attitudes and behaviors in a community sample of gay Hispanic men. Significant numbers of the participants were at risk for eating disorders (13%), alcohol abuse (18%), body image disturbance (29%), depression (25%), low self-esteem (12%), and high-risk sexual behaviors (34%). Alcohol abuse, body image, depression, self-esteem, and sexual behaviors were significant predictors of eating attitudes and behaviors and accounted for 38% of the variance in eating attitudes and behaviors. Nurses providing care to this population of gay men must be aware of this cluster of related mental health conditions that are experienced by these men. Addressing and treating these health conditions as a group of related mental health conditions are necessary. More research is needed to further explore this cluster of health issues among gay Hispanic men.


Effect of bare and coated nanoscale zerovalent iron on tceA and vcrA gene expression in Dehalococcoides spp.
Nanoscale zerovalent iron (NZVI) can be used to dechlorinate trichloroethylene (TCE) in contaminated aquifers. Dehalococcoides spp. is the only microbial genus known to dechlorinate TCE to ethene as a respiratory process. However, little is known about how NZVI affects the expression of genes coding for reductive dechlorination. We examined a high-rate TCE-dechlorinating mixed culture which contains organisms similar to known Dehalococcoides to study the effects of NZVI on the expression of two model genes coding for reductive dehalogenases (tceA and vcrA). A novel pretreatment approach, relying on magnetic separation of NZVI prior to reverse transcription qPCR (to avoid RNA adsorption by NZVI), was developed and used with relative quantification (relative to 16S rRNA as endogenous housekeeping gene) to quantify reductive dehalogenase gene expression. Both tceA and vcrA were significantly down-regulated (97- and 137-fold, respectively) relative to baseline (time 0) conditions after 72-h exposure to chlorinated ethenes (0.12 ± 0.03 mg/L cis-DCE, 0.69 ± 0.11 mg/L t-DCE, and 0.54 ± 0.16 mg/L VC) and bare-NZVI (1 g-NZVI/L). However, coating NZVI with an olefin maleic acid copolymer (a common approach to enhance its mobility in aquifers) overcame this significant inhibitory effect, and both tceA and vcrA were up-regulated (3.0- and 3.5-fold, respectively) after 48-h exposure. Thus, NZVI coating might enhance the expression of dechlorinating genes and the concurrent or sequential participation of Dehalococcoides spp. in the remediation process.


[Regulation of growth and lysine-synthesizing activity of the lysine producer, Brevibacterium SP 22 L., by the intensity of stirring of the medium].
The intensity of medium stirring at a constant pO2 influenced the specific rate of Brevibacterium sp. 22 L growth and lysine synthesis. During periodic cultivation the maximum specific rate of the culture growth can be achieved with a more intensive stirring than the maximum lysine synthesizing activity. At different intensities of medium stirring the lysins synthesizing activity was directly related to the activity of tricarboxylic acid cycle dehydrogenases. It is suggested that a decrease in the lysine synthesizing activity of the bacterial culture at a high intensity of medium stirring is connected with an inhibition or repression of tricarboxylic acid cycle enzymes.


[Medical emergencies in oncology: from case reports to recommendations].
The knowledge of most oncologic emergencies is crucial in daily practice. Treatment options for the superior vena cava syndrome include chemotherapy, radiation, and intravenous stenting. Hypercalcemia due to malignancy is treated with aggressive rehydration and intravenous bisphosphonates. Febrile neutropenia is a hematologic emergency that usually requires inpatient therapy with broad-spectrum antibiotics. Epidural spinal cord compression must be recognized early and can be treated with dexamethason, radiation, or surgery.


Evaluation of limited and unlimited food intake during withdrawal in triazolam-dependent baboons.
Chronic administration of benzodiazepine (BZ) agonists in baboons typically increases food intake, in a dose-dependent manner, during drug administration and suppresses food intake after termination of drug dosing. To determine if suppressed food intake after termination of chronic BZ administration (i.e. withdrawal) was related to increased food consumption during drug administration, the effects of chronic triazolam (1.0 mg/kg/day, intragastrically, for 30-34 days) and subsequent triazolam withdrawal on food intake was studied under two conditions in each of four baboons: (1) when the number of pellets was unlimited; and (2) when the number of pellets was limited so that pellet intake could not increase above the mean number of pellets per day obtained during a preceding vehicle condition. Pellets were available during daily 20-h sessions under a fixed-ratio 10 schedule of reinforcement. All baboons completed both pellet conditions, and the order of exposure was counterbalanced across subjects. During the unlimited pellet condition, pellets per day were increased during triazolam administration and then were suppressed in a time-limited manner when triazolam was discontinued in all four baboons. When pellet intake was limited during triazolam administration, pellet intake after triazolam discontinuation was suppressed in three of four baboons, and the magnitude and duration of suppression was generally less than during the unlimited pellet condition. Other behavioral signs of withdrawal (e.g., tremor/jerk, vomit/retch) were observed in all four baboons under both pellet conditions. These data suggest that the hyperphagic effects of triazolam appear to contribute to the subsequent suppression of food intake during triazolam withdrawal. However, these hyperphagic effects do not account for the entire phenomenon of suppressed food intake during BZ withdrawal.


Functional decline during the COVID-19 pandemic among U.S. military veterans: Results from the National Health and Resilience in Veterans Study.
The coronavirus disease-2019 pandemic has contributed to widespread social and economic stressors, along with substantial health problems, including loss of life. To date, however, relatively few studies have examined the prevalence and correlates of declines in mental and physical functioning in U.S. military veterans, an older and potentially vulnerable segment of the U.S. adult population. Data were analyzed from the 2019-2020 National Health and Resilience in Veterans Study, a nationally representative, longitudinal study of 3078 veterans. Veterans were surveyed prior to the pandemic (pre-pandemic) and 1 year later during the height of the pandemic (peri-pandemic). Multivariable analyses were conducted to identify risk and protective variables associated with pre-to-peri pandemic declines in self-reported physical and mental functioning. The prevalence of veterans who experienced functional decline (≥0.5 standard deviation reductions) pre-to-peri-pandemic was 18.1% (N = 541) for physical functioning and 18.3% (N = 547) for mental functioning. Older age, greater adverse childhood experiences (ACEs), and pandemic-related posttraumatic stress symptoms were the strongest correlates of physical functional decline, while greater ACEs, loneliness, pandemic-related posttraumatic and social restriction stress symptoms, and lower protective psychosocial characteristics were the strongest correlates of mental functional decline. Although the majority of U.S. Veterans showed functional maintenance or improvement 1 year into the pandemic, nearly one-in-five experienced a decline in physical or mental functioning. Results could help inform identification of veterans who may be at risk for functional decline during large-magnitude stressors, such as national or global pandemics.


Ultrafast shifted-core coaxial nano-emitter.
We present an ultrafast nanoscale light source utilizing a shifted-core coaxial nano-cavity, with a footprint of merely one-third of its emission wavelength in all three dimensions at telecommunication wavelengths. We show that, by shifting the metallic core off center of the coaxial structure, the effective mode volume of the cavity can be as small as 0.0078 × (λ0/na)3, resulting in a Purcell factor over 390 and a modulation bandwidth exceeding 60GHz. We further show that the evolution trend of the cavity Q factor as a function of core-shifting distance can be engineered by choosing proper substrate material. Compared to its symmetric counterpart, this shifted-core coaxial nano-cavity features not only higher Q factor, Purcell factor, and modulation bandwidth but also an improved emission directivity that is essential in its coupling with other on-chip components. The proposed nano-emitter also features robust single mode operation over the entire core-shifting range, resulting in a near-unity spontaneous emission factor. Therefore, this device can be a good candidate for low power optical interconnect applications.


Good long-term outcome of the untreated contralateral hip in unilateral slipped capital femoral epiphysis : Forty hips with a mean follow-up of 41 years.
There is no consensus regarding prophylactic fixation of the contralateral hip in slipped capital femoral epiphysis (SCFE). In order to further study this question, we evaluated the long-term natural history of untreated contralateral hips. Forty patients treated for unilateral SCFE without evidence of subsequent contralateral slip during adolescence were reviewed with a mean follow-up of 36 years (range 21-50 years). The deformity after SCFE may demonstrate radiographic signs of cam-type femoroacetabular impingement. We, therefore, measured α-angles in the contralateral hips on anteroposterior (AP) and frog-leg lateral radiographs. The angles were compared with those of a control group of adults without SCFE. Five years after the radiographic examination, with a mean follow-up of 41 years, all patients were evaluated by telephone interview. As range of motion and deformity could not be examined, a modified Harris hip score (HHS) (maximum score of 91 points) was used. A modified HHS <76 points and/or radiographic osteoarthritis (OA) was classified as a poor long-term outcome. The mean value of the AP α-angle was significantly higher in the contralateral hips in SCFE patients than in the control group (55° vs. 46°), while the mean value of the lateral α-angle was not. Abnormally high values for one or both α-angles were found in 16 contralateral hips (40 %), of which five patients had abnormal values for both α-angles and were considered to have had an asymptomatic contralateral slip. Five patients (13 %) had a poor outcome in the contralateral hip, of which three patients (8 %) had OA. There was a significant association between hips with both α-angles that were abnormal and poor outcome. Since the natural history showed good long-term radiographic and clinical outcome in 35 of 40 patients and only three had OA, we conclude that routine prophylactic fixation of the contralateral hip is not indicated.


Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.


[Effects of surgical intervention and intravascular irradiation of blood with helium-neon laser on the state humoral autoimmunity in oncological patients].
Humoral autoimmunity of patients with malignant gastrointestinal tumors was studied by different variants of enzyme immunoassay. In the preoperative period the frequency of detecting autoantibodies binding to DNA and components of external and internal membranes of cells of different tissues was not higher in patients (n-55) than in donors (n-45). Beginning from the 7th postoperative day all patients were found to have a significantly increased level of autoantibodies to DNA (p less than 0.01), fibroblasts (p less than 0.01), hepatocytes (p less than 0.01), islet cells (p less than 0.01), hepatic or pancreatic microsomes (p less than 0.05). There was a tendency towards normalization of these level by the 21st day in all cases. In patients (n-10) treated by blood intravascular laser irradiation after the operation the level of IgG (but not IgM) autoantibodies to DNA by the 14th postoperative day was significantly (p less than 0.01) higher than that in patients whose blood was not exposed to radiation. It is suggested that the discovered humoral immune reaction is a necessary component of wound immunity and develops in response to hetero-organic autoantigens which are unmasked in injury of the tissues during the operation. Laser therapy ensures a more intensive development of this reaction without altering its direction.


Use of Ultraviolet Photodissociation Coupled with Ion Mobility Mass Spectrometry To Determine Structure and Sequence from Drift Time Selected Peptides and Proteins.
We demonstrate the capabilities of a laser-coupled ion mobility mass spectrometer for analysis of peptide sequence and structure showing ultraviolet photodissociation (UVPD) spectra of mass and mobility selected ions. A Synapt G2-S mass spectrometer has been modified to allow photointeraction of ions post the mobility cell. For this work, we have employed a single wavelength laser, which irradiates at 266 nm. We present the unique capabilities of this instrument and demonstrate several key features. Irradiation of luteinizing hormone releasing hormone (LHRH), growth hormone releasing hexapeptide (GHRP-6), and TrpCage (sequence NLYIQWLKDGGPSSGRPPPS) yields extensive b- and y-type fragmentation as well as a- and c-type ions. In addition, we observe side chain losses, including the indole group from tryptophan, and immonium ions. For negatively charged ions, we show the advantage of using collision-induced dissociation (CID) post-UVPD: radical ions are produced following irradiation, and these fragment with higher efficiency. Further, we have incorporated ion mobility and subsequent drift time gating into the UVPD method allowing the separate analysis of m/z-coincident species, both conformers and multimers. To demonstrate, we selectively dissociate the singly charged dimer or doubly charged monomer of the peptide gramicidin A and conformers of the [M + 5H]5+ form of the peptide melittin. Each mobility selected form has a different "fingerprint" dissociation spectrum, both predominantly containing b and y fragments. Differences in the intensities of various loss channels between the two species were revealed. The smaller conformer of melittin has fewer cleavage sites along the peptide backbone than the larger conformer suggesting considerable structural differences. For gramicidin, a single laser shot UVPD discriminates between primary photodissociation and subsequent fragmentation of fragments. We also show how this modified instrument facilitates activated electron photodissociation. UVPD-IM-MS analysis serves both as a method for peptide sequencing for peptides of similar (or identical) m/z and a method for optical analysis of mobility separated species.


Automatic segmentation of cartilage in high-field magnetic resonance images of the knee joint with an improved voxel-classification-driven region-growing algorithm using vicinity-correlated subsampling.
Anatomical structures that can deteriorate over time, such as cartilage, can be successfully delineated with voxel-classification approaches in magnetic resonance (MR) images. However, segmentation via voxel-classification is a computationally demanding process for high-field MR images with high spatial resolutions. In this study, the whole femoral, tibial, and patellar cartilage compartments in the knee joint were automatically segmented in high-field MR images obtained from Osteoarthritis Initiative using a voxel-classification-driven region-growing algorithm with sample-expand method. Computational complexity of the classification was alleviated via subsampling of the background voxels in the training MR images and selecting a small subset of significant features by taking into consideration systems with limited memory and processing power. Although subsampling of the voxels may lead to a loss of generality of the training models and a decrease in segmentation accuracies, effective subsampling strategies can overcome these problems. Therefore, different subsampling techniques, which involve uniform, Gaussian, vicinity-correlated (VC) sparse, and VC dense subsampling, were used to generate four training models. The segmentation system was experimented using 10 training and 23 testing MR images, and the effects of different training models on segmentation accuracies were investigated. Experimental results showed that the highest mean Dice similarity coefficient (DSC) values for all compartments were obtained when the training models of VC sparse subsampling technique were used. Mean DSC values optimized with this technique were 82.6%, 83.1%, and 72.6% for femoral, tibial, and patellar cartilage compartments, respectively, when mean sensitivities were 79.9%, 84.0%, and 71.5%, and mean specificities were 99.8%, 99.9%, and 99.9%.


Development and validation of a disease-targeted quality of life instrument for chronic diverticular disease: the DV-QOL.
Colonic diverticular disease is typically conceived as acute diverticulitis attacks surrounded by periods of clinical silence. However, evolving data indicate that many patients have persistent symptoms and diminished health-related quality of life (HRQOL) long after acute attacks. We developed a disease-targeted HRQOL measure for symptomatic uncomplicated diverticular disease (SUDD)-the diverticulitis quality of life (DV-QOL) instrument. We conducted a systematic literature review to craft a conceptual model of SUDD HRQOL. This was complemented by three focus groups including 45 SUDD patients. We developed items based on our literature search, focus groups, and cognitive debriefings. We administered the items to SUDD patients with persistent symptoms following a confirmed diverticulitis event. We created scales based on factor analysis and evaluated the scales for reliability and validity. Concept elicitation revealed a range of illness experiences attributed to SUDD. Coding of 20,490 transcribed words yielded a 52-code network with four primary, condition-related concepts: (1) physical symptoms (e.g., bloating); (2) behaviors (e.g., restrictions); (3) cognitions and concerns (e.g., fear); and (4) impact and consequences (e.g., absenteeism, anxiety). Based on patient language, we developed the 17-item DV-QOL instrument. In a cross-sectional validation sample of 197 patients, DV-QOL discriminated between patients with recent versus distant diverticulitis events and correlated highly with Short Form 36 and hospital anxiety and depression scores. Patients with SUDD attribute a wide range of negative psychological, social, and physical symptoms to their condition, both during and after acute attacks; DV-QOL captures these symptoms in a valid, reliable manner.


Induced ankylosis of a primary molar for skeletal anchorage in the mandible as alternative to mini-implants.
Mesial protraction of mandibular posterior teeth requires increased anchorage to avoid undesired tooth movements. Orthodontic mini-implants have become a popular and successful way to increase skeletal anchorage in such cases. However, mini-implants may cause injury to adjacent teeth or anatomical structures and may lead to tissue inflammation. Induced ankylosed primary teeth have been used in the past as abutments for the protraction of the maxilla in cases of maxillary retrognathism. However, this technique has not been described in the literature for the protraction of mandibular molars. The aim of this paper is to present, through a case report, an alternative to mini-implant devices to maximize anchorage in the mandible by inducing ankylosis on a primary molar. A 13-year-old female with class II right malocclusion, deep bite, and congenitally missing right second premolars was referred for orthodontic treatment. Treatment plan involved removal of the primary teeth and mesial protraction of the posterior. In the mandible, ankylosis was induced on the retained primary second molar by extraction, bisection, replantation of the mesial part after endodontic treatment, and bonding of a rigid splint. Ankylosis was diagnosed after 10 weeks and a closing T-loop sectional wire was inserted to move the permanent first molar mesially. At 6 months, the remaining space was closed using elastic chain on a rectangular stainless steel wire with tip-back bends, supported by class II elastics. Induced ankylosis of primary teeth can be an alternative to orthodontic mini-implants in selected cases, with minimal risks and maximum biocompatibility.


Measurement-Induced Strong Kerr Nonlinearity for Weak Quantum States of Light.
Strong nonlinearity at the single photon level represents a crucial enabling tool for optical quantum technologies. Here we report on experimental implementation of a strong Kerr nonlinearity by measurement-induced quantum operations on weak quantum states of light. Our scheme coherently combines two sequences of single photon addition and subtraction to induce a nonlinear phase shift at the single photon level. We probe the induced nonlinearity with weak coherent states and characterize the output non-Gaussian states with quantum state tomography. The strong nonlinearity is clearly witnessed as a change of sign of specific off-diagonal density matrix elements in the Fock basis.


Whole family-based physical activity promotion intervention: the Families Reporting Every Step to Health pilot randomised controlled trial protocol.
Family-based physical activity (PA) interventions present a promising avenue to promote children's activity; however, high-quality experimental research is lacking. This paper describes the protocol for the FRESH (Families Reporting Every Step to Health) pilot trial, a child-led family-based PA intervention delivered online. FRESH is a three-armed, parallel-group, randomised controlled pilot trial using a 1:1:1 allocation ratio with follow-up assessments at 8 and 52 weeks postbaseline. Families will be eligible if a minimum of one child in school Years 3-6 (aged 7-11 years) and at least one adult responsible for that child are willing to participate. Family members can take part in the intervention irrespective of their participation in the accompanying evaluation and vice versa.Following baseline assessment, families will be randomly allocated to one of three arms: (1) FRESH; (2) pedometer-only or (3) no-intervention control. All family members in the pedometer-only and FRESH arms receive pedometers and generic PA promotion information. FRESH families additionally receive access to the intervention website; allowing participants to select step challenges to 'travel' to target cities around the world, log steps and track progress as they virtually globetrot. Control families will receive no treatment. All family members will be eligible to participate in the evaluation with two follow-ups (8 and 52 weeks). Physical (eg, fitness and blood pressure), psychosocial (eg, social support) and behavioural (eg, objectively measured family PA) measures will be collected at each time point. At 8-week follow-up, a mixed methods process evaluation will be conducted (questionnaires and family focus groups) assessing acceptability of the intervention and evaluation. FRESH families' website engagement will also be explored. This study received ethical approval from the Ethics Committee for the School of the Humanities and Social Sciences at the University of Cambridge. Findings will be disseminated via peer-reviewed publications, conferences and to participating families. ISRCTN12789422.


Isolated naso-ocular cleft: a one-stage repair.
The naso-ocular cleft is a rare defect; however, isolated alar clefts with or without additional hamartomatous local tissue are an even rarer problem. The authors describe six unilateral and one bilateral cleft patients who were all initially repaired using the same operative procedure. The concept of this procedure is based on the principle that there is basically no soft-tissue deficiency but rather a malpositioning of the parts. The leading edge of the ala is re-created by a rotation advancement of both the medial and the lateral segments adjacent to the cleft. The created secondary defect is filled with a paranasal transposition flap. Three of our patients had hamartomatous excesses and were the most difficult to balance, and at the same time, two of these patients required subsequent bridging or augmentation using a free conchal cartilage graft. Examples of the operative procedures are outlined both schematically and clinically.


Mutual exclusivity of hyaluronan and hyaluronidase in invasive group A Streptococcus.
A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen.


Trait-based cue Utilization and initial skill acquisition: implications for models of the progression to expertise.
The primary aim of this study was to examine the role of cue utilization in the initial acquisition of psycho-motor skills. Two experiments were undertaken, the first of which examined the relationship between cue utilization typologies and levels of accuracy following four simulated, power-off landing trials in a light aircraft simulator. The results indicated that higher levels of cue utilization were associated with a greater level of landing accuracy following training exposure. In the second study, participants' levels of cue utilization were assessed prior to two 15 min periods during which they practiced take-offs and landings using a simulated unmanned aerial vehicle (UAV). Consistent with Study 1, the outcomes of Study 2 revealed a statistically significant relationship among levels of cue utilization and the number of trials to criterion on the take-off task, and the proportion of successful trials during both take-off and landing. In combination, the results suggest that the capacity for the acquisition and the subsequent utilization of cues is an important predictor of skill acquisition, particularly during the initial stages of the process. The implications for theory and applied practice are discussed.


A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.
Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.


beta-Bungarotoxin antagonizes the effect of alpha-latrotoxin from black widow spider venom on the neuromuscular junction.
Sustained contraction of the chick biventer cervicis nerve-muscle preparations evoked by alpha-latrotoxin was antagonized quickly by beta-bungarotoxin. This effect of beta-bungarotoxin was dependent on its phospholipase A2 activity. In contrast, pancreatic phospholipase A2 was ineffective even at a much higher dose. It is concluded that alpha-latrotoxin needs intact presynaptic membrane to exert its effect.


Health counseling in adolescent preventive visits: effectiveness, current practices, and quality measurement.
Most morbidity and mortality among adolescents results from their participation in health-compromising behaviors. Recent guidelines for clinical adolescent preventive services recommend that primary care clinicians routinely screen for and counsel adolescents about these behaviors, identify and address related social, psychological, and biologic factors. Office-based counseling can influence adult health behaviors, but little is known about the effectiveness of office-based counseling for adolescents. In this review we: (a) evaluate available information about the effectiveness of office-based health counseling to improve outcomes; (b) report what is known about the health counseling adolescents receive from primary care clinicians; and (c) critically review different approaches that have been, or might be, used to measure the content and quality of health counseling provided during adolescent medical visits. With the emphasis on accountability in the current health care environment, evidence supporting the effectiveness of counseling is needed to justify investment in this aspect of clinical adolescent preventive services. Challenges to studying the effectiveness of health counseling include the lack of well-defined theory-based models for adolescent office-based counseling, the complexity of measuring counseling quality, and the many factors that influence adolescent outcomes. Reliable and valid measures of counseling quality are needed both to study and to ensure the quality of counseling received by adolescents. No single measure can be expected to fully capture counseling quality, although patient self-report deserves further development.


Maternal melatonin or agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light.
Hypertension can originate from early-life insults, whereas maternal melatonin therapy can be protective in a variety of models of programmed hypertension. We hypothesize that melatonin or melatonin receptor agonist agomelatine can prevent programmed hypertension in adult offspring induced by maternal exposure to continuous light. Female Sprague-Dawley pregnant rats randomly divided into four groups: controls, rats exposed to continuous light, exposed to continuous light plus treated with agomelatine (50 mg/day i.p.), and exposed to continuous light plus treated with 0.01% melatonin in drinking water throughout pregnancy and lactation period. Male offspring (n = 10/group) from three litters were examined at 12 weeks of age. Maternal continuous light exposure-induced hypertension in male offspring, which was prevented by melatonin or agomelatine therapy. Continuous light exposure did not affect melatonin pathway in adult offspring kidney. Genes that belong to the renin-angiotensin system (RAS), sodium transporters, AMP-activated protein kinase pathway, and circadian rhythm were potentially involved in the maternal exposure to continuous light-induced programmed hypertension. Maternal agomelatine therapy decreased Ace expression but increased Agtr2 and Mas1. Maternal melatonin therapy prevented the increases of Slc9a3, Slc12a3, and Atp1a1 expression induced by maternal continuous light exposure. In conclusion, maternal melatonin or agomelatine therapy prevents programmed hypertension induced by maternal exposure to continuous light. Agomelatine and melatonin reprogram the RAS and sodium transporters differentially, to prevent negative programming of continuous light. Our data highlight candidate genes and pathways in renal programming as targets for therapeutic approaches to prevent programmed hypertension caused by early-life disturbance of the circadian rhythm.