Proteome patterns in uremic plasma.
In patients with chronic kidney disease (CKD), peptides and proteins circulate at altered concentrations versus in healthy individuals. We have characterized proteome samples from 7 pooled CKD stage 5 patients not yet on dialysis and with no known co-morbidities. We also analyzed pooled plasma samples from 7 healthy age- and sex-matched controls. After immunodepletion of the 6 most abundant plasma proteins, HPLC and SDS-PAGE patterns differed between the healthy and disease groups. The differing proteins were identified by peptide mass fingerprinting using MALDI mass spectrometry and verified with electrospray tandem mass spectrometry sequence analysis. Multiple differences in at least 19 HPLC fractions were observed, from which we identified 29 proteins, 25 in greater yield and 4 in lower yield than in the healthy controls, adding at least 6 protein components to those that were previously known to be altered in CKD.


Adenomatous polyp at the ureterocaecal anastomosis.
A case of adenomatous polyp occurring at a ureterocaecal anastomosis, 25 years after urinary diversion following a total cystectomy for carcinoma of the bladder, is reported. Bilateral nephrectomy for chronic pyelonephritis was carried out 25 years after the initial surgery and, following this, a sinus formed at the incision at the right loin. A sinogram showed contrast filling the right ureter and caecum, and outlined a lobulated filling defect at the ureterocaecal anastomosis. Subsequent histology revealed a dysplastic tubulovillous adenoma. The clinical presentation and management of tumours at the ureterointestinal junction are discussed.


Short-term bioassays of fractionated emission samples from wood combustion.
Extracts of an emission sample from wood burning, consisting of particles and volatiles, have been fractionated on an HPLC silica gel column into five fractions of increasing polarity. Nonfractionated samples and the individual fractions have been tested in three different short-term bioassays: the Ames Salmonella assay, the sister chromatid exchange (SCE) induction-test in Chinese hamster ovary cells (CHO), and the cell transformation test on Syrian hamster embryo (SHE) cells. Most of the total activity was found in the volatile part of the sample with all three bioassays, whereas the particle extract had the highest activity per unit mass extracted. The second most polar fraction contained most of the mass and was also highly active in all assays. The most polar fraction was very potent in the Salmonella assay, but showed only a weak response in the eukaryotic bioassays. Storage of the samples for several months at 0 degrees C revealed that the bacterial mutagens present in the most polar fraction were labile; the mutagenicity was almost totally lost after 1 year's storage.


DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature.
A decline in the function of the macro- and micro-vasculature occurs with ageing. DNA damage also accumulates with ageing, and thus DNA damage and repair have important roles in physiological ageing. Considerable evidence also supports a crucial role for DNA damage in the development and progression of macrovascular disease such as atherosclerosis. These findings support the concept that prolonged exposure to risk factors is a major stimulus for DNA damage within the vasculature, in part via the generation of reactive oxygen species. Genomic instability can directly affect vascular cellular function, leading to cell cycle arrest, apoptosis and premature vascular cell senescence. In contrast, the study of age-related impaired function and DNA damage mechanisms in the microvasculature is limited, although ageing is associated with microvessel endothelial dysfunction. This review examines current knowledge on the role of DNA damage and DNA repair systems in macrovascular disease such as atherosclerosis and microvascular disease. We also discuss the cellular responses to DNA damage to identify possible strategies for prevention and treatment.


Clopidogrel generic formulations in the era of new antiplatelets: a systematic review.
Clopidogrel is a thienopyridine that selectively and irreversibly inhibits the ADP purinergic receptor P2Y12 and the subsequent ADP-mediated platelet activation. Clopidogrel has been approved for clinical use as clopidogrel hydrogen sulfate (bisulfate) salt. The clinical usefulness of clopidogrel bisulfate salt has been proved in a wide variety of large scale clinical trials, thus clopidogrel bisulfate has been extensively used in a large spectrum of patients been under thrombotic risk. Recently, several generic clopidogrel formulations have been approved for clinical use. Consequently, clopidogrel is currently a cost-effective antiplatelet agent. Only small studies have compared the pharmacokinetic and pharmacodynamic properties of various clopidogrel generic salt formulations with the innovator bisulfate salt. In addition few data are available concerning the clinical efficacy and safety of these generic clopidogrel formulations in order to guide clinicians in deciding when generic substitution is appropriate. The aim of this review is to summarize the physicochemical properties as well as the pharmacokinetic and pharmacodynamic characteristics of the generic clopidogrel salts. We also critically present existing data on the clinical efficacy and safety of the generic clopidogrel formulations compared with the innovator clopidogrel bisulfate salt in patients with cardiovascular disease.


The effect of hydrogen bonding on allylic alkylation and isomerization reactions in ionic liquids.
Neutral allylic alkylation reactions, in which a base is generated in situ and which hence require no external bases, can significantly be retarded when carried out in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]). Evidence suggests that the base or base precursor enters into hydrogen bonding with the imidazolium cation and is thus made less readily available for deprotonation of pre-nucleophiles. However, the reaction proceeds well in the presence of stronger bases that are capable of deprotonation. Whilst the phenomenon of hydrogen bonding in ionic liquids can be detrimental to reactions such as allylic alkylation, it can be exploited to suppress unwanted allylic isomerization.


Impact of a computerized placement service on practice location of recent graduates.
In 1972, the University of Minnesota, the Minnesota Dental Association, and the State Board of Dentistry implemented a program known as the Dental Information Service Center. An important component of this effort was a set of computerized programs aimed at facilitating placement of recent graduates of the University's dental school. Although use of the computerized program has grown substantially during the four-year study period, personal contacts remain the source of information most frequently responsible for initial placements; they accounted for 60% of such placements. The computerized referral program accounted for 27% of first placements for the class of 1976. The program has been influential in increasing student awareness of underserved areas. Overall career satisfaction was high among recent graduates, and their subjective evaluation of the program was generally positive.


Elastic, dielectric, and piezoelectric losses in piezoceramics: how it works all together.
The quality factor along with electromechanical coupling coefficient (CEMC) is commonly used as a measure of the energy efficiency of a piezoelectric transducer (PT) working as an energy converter. Losses in piezoceramics are phenomenologically considered to have three coupled mechanisms: dielectric, elastic, and piezoelectric. Their cumulative performance first of all determines the PT quality factor characterizing the efficiency of vibrational energy accumulation, and related to it dissipative effects. The extended definition of the PT electromechanical quality factor (EMQ) with permanent energy exchange between electrical source of excitation and PT was proposed. The EMQ analysis has been conducted on the basis of complex material constants for both stiffened and unstiffened canonical vibrational modes. The efficiency of mechanically free and electrically excited piezoceramic transducers in a wide frequency range of PT harmonics, especially between the fundamental resonance and antiresonance frequencies, was investigated, and the effect of piezoelectric loss anomaly with extremely low total losses was predicted. Particularly, optimization of PT excitation with connected reactive (capacitive) element was conducted to provide higher PT mechanical vibrational characteristics with less total losses. The requirements to the piezoceramic material parameters, types of transducer vibrations, and especially to the piezoelectric loss factor in the range of physically valid values were established to provide maximal EMQ.


There is good agreement between MR enterography and bowel ultrasound with regards to disease location and activity in paediatric inflammatory bowel disease.
To investigate concordance of bowel ultrasound and magnetic resonance enterography (MRE) in identifying active disease in children with inflammatory bowel disease. The imaging of children with inflammatory bowel disease who had undergone bowel ultrasound and MRE within 30 days were retrospectively reviewed, from January 2009 to November 2015. Ultrasound was without oral contrast medium; MRI was conducted with patients unsedated with oral contrast medium and gadolinium. Imaging data included bowel thickness, markers of activity, and complications. Endoscopy and biopsy reports were also reviewed. Forty-nine patients (median age 14 years, 33 male) met the inclusion criteria, and 31 children also had endoscopy within 30 days. Active inflammation was seen in 17.6% of bowel segments at ultrasound and 17.3% at MRE. There was good agreement between ultrasound and MRE on the location and activity of disease (Cohen's kappa 0.75, 95% confidence interval [CI]: 0.66-0.83). One patient had an inflammatory phlegmon detected at MRE only; there was no other significant discrepancy in identifying complications. In patients with histopathology, MRE, and ultrasound demonstrated high specificity 85.1% (77.9-90.6) and 86.6% (79.6-91.8) at the bowel segment level. Technical difficulties, including poor tolerance of oral contrast medium and movement, were more common in MRE. There was good concordance between MRE and ultrasound for disease location and activity, and fewer technical difficulties with ultrasound. Bowel ultrasound is useful in children, and its use is advocated.


Synaptic mechanism for functional synergism between delta- and mu-opioid receptors.
By sustained activation of mu-opioid receptors (MORs), chronic opioids cause analgesic tolerance, physical dependence, and opioid addiction, common clinical problems for which an effective treatment is still lacking. Chronic opioids recruit delta-opioid receptors (DORs) to plasma membrane through exocytotic trafficking, but the role of this new DOR and its interaction with existing MOR in brain functions and in these clinical problems remain largely unknown. In this study, we investigated the mechanisms underlying synaptic and behavioral actions of chronic morphine-induced DORs and their interaction with MORs in nucleus raphe magnus (NRM) neurons important for opioid analgesia. We found that the emerged DOR inhibited GABAergic IPSCs through both the phospholipase A(2) (PLA(2)) and cAMP/protein kinase A (PKA) signaling pathways. MOR inhibition of IPSCs, normally mediated predominantly by the PLA(2) pathway, was additionally mediated by the cAMP/PKA pathway, with MOR potency significantly increased after chronic morphine treatment. Isobologram analysis revealed a synergistic DOR-MOR interaction in their IPSC inhibition, which was dependent on upregulated activities of both the PLA(2) and cAMP/PKA pathways. Furthermore, DOR and MOR agonists microinjected into the NRM in vivo also produced a PLA(2)-dependent synergism in their antinociceptive effects. These findings suggest that the cAMP/PKA pathway, upregulated by chronic opioids, becomes more important in the mechanisms of both MOR and DOR inhibition of GABA synaptic transmission after chronic opioid exposure, and DORs and MORs are synergic both synaptically and behaviorally in producing analgesic effects in a PLA(2)-dependent fashion, supporting the potential therapeutic use of DOR agonists in pain management under chronic opioid conditions.


Intravenous injection of indocyanine green to enhance laser-assisted coagulation of blood vessels in skin - an animal study.
Laser therapy of vascular lesions, such as port wine stains (PWS) or leg veins are still imperfect due to different diameters and depth of vessels in tissue. We propose to improve blood vessel coagulation by intravenous introduction of an exogenous chromophore (indocyanine green, ICG) that effectively converts near-infrared (NIR) laser light into heat. The purpose of this study was to determine the plasma clearance rate, systemic toxicity and histological effects of ICG-assisted laser therapy in an animal model. Piglets received intravenous injection of ICG. Blood samples were collected at different times. Systemic toxicity was assessed by measuring liver enzyme levels and other indicators of liver function. The plasma clearance rate of ICG was determined by light absorption measurement in blood samples. The skin was irradiated with a diode laser (810 nm) using radiant exposures from 31 to 80 J/cm². Skin reaction at the treatment site was graded, and punch biopsies were taken for histological examination at 24 and 72 h after treatment. No hepatic toxicity was observed. The clinical examination revealed no adverse skin reactions at 24 or 72 h after laser irradiation. This was confirmed by histological evaluation that showed efficient vessel coagulation without damage of the epidermis or dermis. In light of these in vivo results, we suggest that ICG-assisted laser therapy could substantially improve clinical outcomes of PWS or leg veins treatment with minimal risk of adverse reactions.


Rate of Torque Development and Torque Steadiness of the Lower Limb and Future Falls Among Community-Dwelling Older Adults Without Previous Falls: A Longitudinal 1-Year Study.
The objective was to investigate the association between rate of torque development (RTD) and torque steadiness (TS) of the lower limb and the occurrence of prospective falls in community-dwelling older adults without falls in the previous year. One hundred older adults performed the tests to obtain the RTD and TS of the hip, knee, and ankle. New episodes of falls were monitored through telephone contact for a prospective period of 12 months. The association of RTD and TS with the occurrence of prospective falls was verified by multiple logistic regression adjusted for confounding variables. There was no association between RTD of hip, knee, and ankle and prospective falls. Only the TS at 50% of the peak torque of the hip flexors was associated with the occurrence of future falls (p = .023). Identifying modifiable risk factors for the first fall in older adults is essential for the development of adequate prevention programs.


Fibronectin Splicing Variants Containing Extra Domain A Promote Atherosclerosis in Mice Through Toll-Like Receptor 4.
Cellular fibronectin containing extra domain A (EDA(+)-FN) is abundant in the arteries of patients with atherosclerosis. Several in vitro studies suggest that EDA(+)-FN interacts with Toll-like receptor 4 (TLR4). We tested the hypothesis that EDA(+)-FN exacerbates atherosclerosis through TLR4 in a clinically relevant model of atherosclerosis, the apolipoprotein E-deficient (Apoe(-/-)) mouse. The extent of atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female EDA(-/-)Apoe(-/-) mice (which lack EDA(+)-FN), EDA(fl/fl)Apoe(-/-) mice (which constitutively express EDA(+)-FN), and control Apoe(-/-) mice fed a high-fat Western diet for 14 weeks. Irrespective of sex, EDA(fl/fl)Apoe(-/-) mice exhibited a 2-fold increase in atherosclerotic lesions (aorta and aortic sinus) and macrophage content within plaques, whereas EDA(-/-)Apoe(-/-) mice exhibited reduced atherosclerotic lesions (P<0.05 versus Apoe(-/-), n=10-12 mice/group), although cholesterol and triglyceride levels and circulating leukocytes were similar. Genetic ablation of TLR4 partially reversed atherosclerosis exacerbation in EDA(fl/fl)Apoe(-/-) mice (P<0.05) but had no effect on atherosclerotic lesions in EDA(-/-)Apoe(-/-) mice. Purified cellular FN, which contains EDA, potentiated dose-dependent NFκB-mediated inflammation (increased phospho-NFκB p65/NFκB p65, tumor necrosis factor-α, and interleukin-1β) in bone marrow-derived macrophages from EDA(-/-)Apoe(-/-) mice but not from EDA(-/-)TLR4(-/-)Apoe(-/-) mice. Finally, using immunohistochemistry, we provide evidence for the first time that EDA(+)-FN colocalizes with macrophage TLR4 in murine aortic lesions and human coronary artery atherosclerotic plaques. Our findings reveal that TLR4 signaling contributes to EDA(+)-FN-mediated exacerbation of atherosclerosis. We suggest that EDA(+)-FN could be a therapeutic target in atherosclerosis.


Atropine treatment of reflex anoxic seizures.
In 7 children with unusually severe or frequent reflex anoxic seizures atropine treatment, which was well tolerated, reduced seizure frequency by a mean value of 98%. Treatment withdrawal (five patients) was followed by an increase in seizure frequency and reintroduction (three patients) by restoration of control.


Serum levels of adrenomedullin and inflammatory cytokines in women with term idiopathic intrauterine growth restriction.
This study aimed to determine the concentrations of adrenomedullin (AM), tumour necrosis factor (TNF)-α and interleukin (IL)-6 in maternal circulation of full-term idiopathic intrauterine growth restriction (IUGR) in relation to appropriate-for-gestational-age (AGA) and the possible correlation of AM to these cytokines. A case-control study included 50 idiopathic IUGR mothers and 25 AGA, who were evaluated regarding their serum levels of AM, TNF-α and IL-6. We found that women with idiopathic IUGR have significantly higher serum levels of AM, TNF-α and IL-6 (p = 0.008; 0.016; 0.029, respectively) and the level of AM was significantly correlated to serum level of TNF-α (r = 0.417, p = 0.003) but not significantly correlated to IL-6 compared with the AGA group. In conclusion, the significant increase of AM, TNF-α and IL-6 in the idiopathic IUGR group might contribute to the uteroplacental haemodynamic alterations and can serve as a useful biochemical marker. Significant correlation between AM and TNF-α could hypothesise the existence of a complex interaction between AM and this inflammatory cytokine.


Clinical experiences in hyoid arch transposition.
Autogenous hyoid bone grafts for the repair of subglottic stenosis have been used successfully in canine experiments. This technique was subsequently modified for human use, and the experience in six patients over the past year at Washington University is reported. In five of the six patients, satisfactory results were obtained. Several case reports are included, and the surgical procedure is described in detail.


Investigating the immunomodulatory activities of omadacycline.
Apart from their antimicrobial activities, some antibiotics have immunomodulatory effects on host cells, particularly monocytes. Because hyperactivation of the pro-inflammatory cytokine response contributes to acute lung injury in patients with bacterial pneumonia and other lung diseases, antimicrobial agents with immunomodulatory activity can reduce cytokine-mediated tissue injury and improve outcomes. Omadacycline has been recently FDA-approved for community-acquired bacterial pneumonia and acute bacterial skin and skin-structure infections. The present study investigated omadacycline's ability to modulate LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-1β), acute-phase reactants (IL-6) and anti-inflammatory cytokines (IL-4, IL-10) by human monocytes in vitro. Isolated human monocytes from healthy consenting adults were cultured in RPMI with 1% pooled human serum. Cells were pre-exposed to omadacycline (0.5-64 μg/mL), minocycline (25, 50 or 25 μg/mL) or azithromycin (20, 40 or 80 μg/mL) for 2 h, followed by stimulation with Escherichia coli LPS for 24 h. Cytokines elaborated in the culture supernatant were quantitated by multiplex immunoassay. Omadacycline dose-dependently suppressed LPS-induced production of all cytokines tested. Only high-dose minocycline (100 μg/mL) modestly suppressed TNF-α whereas minocycline significantly increased LPS-induced IL-1β production. Lower concentrations of minocycline were also stimulatory for IFN-γ, IL-6 and IL-4. Except for suppression of IL-6, azithromycin was largely without effect. Omadacycline has unique and broad immunomodulatory properties. Such activity supports its use in settings where hyperactivation of the immune response contributes to tissue injury and poor outcomes, especially at sites where pro-inflammatory M-type 1 macrophages dominate the cellular immune response.


Occupational injuries and sick leaves in household moving works.
This study is concerned with household moving works and the characteristics of occupational injuries and sick leaves in each step of the moving process. Accident data for 392 occupational accidents were categorized by the moving processes in which the accidents occurred, and possible incidents and sick leaves were assessed for each moving process and hazard factor. Accidents occurring during specific moving processes showed different characteristics depending on the type of accident and agency of accidents. The most critical form in the level of risk management was falls from a height in the 'lifting by ladder truck' process. Incidents ranked as a 'High' level of risk management were in the forms of slips, being struck by objects and musculoskeletal disorders in the 'manual materials handling' process. Also, falls in 'loading/unloading', being struck by objects during 'lifting by ladder truck' and driving accidents in the process of 'transport' were ranked 'High'. The findings of this study can be used to develop more effective accident prevention policy reflecting different circumstances and conditions to reduce occupational accidents in household moving works.


Gadolinium-based MR cisternography with prepontine cisternal routine for evaluating distribution pattern of intrathecal targeted drug delivery in pain management.
Gadolinium-based MR cisternography has been mainly applied in clinical evaluation of cerebrospinal fluid leaking, that is conducted by intrathecal administration of contrast media. Recently, we have reported one novel technique of intrathecal targeted drug delivery with prepontine cisternal routine to treat orofacial cancer pain. The aim of this study was to examine the distribution pattern of this intrathecal drug delivery strategy. Here, we introduce one case who suffered severe orofacial pain caused by sublingual gland tumor, and successfully attenuated by prepontine cisternal administration of analgesic agents. To assess the distribution of intrathecal drugs, postoperative MR images of brain, cervical, thoracic, and lumbar segments in axial, coronal, and sagittal planes were obtained after application of gadolinium. The perfusion rate of contrast medium was set at 0.01 mmol per hour for 24 hours prior to MR scanning. In the T1-weighted images, we can identify contrast spread not only locating around the site of the intrathecal catheter tip, but also concentrated to the lateral sides. None obvious side effect was found after intrathecal injection of contrast media. Thus, our finding demonstrated the local distribution phenomenon of intrathecal drugs through prepontine cisternal access, and the bilateral perfusion pattern may provide insights underlying the analgesic mechanism of trigeminal pain provided by this novel intrathecal therapy. Gadolinium-based MR cisternography may serve as a potential tool to confirm the therapeutic effect of intrathecal targeted drug delivery via prepontine cisternal routine in orofacial pain management.


Familial agenesis of the corpus callosum with hypothermia and apneic spells.
Two siblings, a boy and a girl, with agenesis of the corpus callosum, apneic spells, attacks of apnea, cyanosis and spontaneous hypothermia, are reported about. Both children died after a few months of life. Postmortem examination revealed a severe spongiosis of the white matter in addition to the agenesis of the corpus callosum and septum pellucidum, in both cases.


A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer.
Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC. To review the data supporting perioperative chemotherapy and emerging regimens for MIBC. Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included. The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed. Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.


Modulation of the peri-infarct neurogliovascular function by delayed COX-1 inhibition.
Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia. FR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry. Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). Treated animals exhibited sustained perilesional hyperperfusion (180 ± 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P = 0.002 at 7 vs. P = 0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 ± 1% vs. 14.9 ± 0.8%, P = 0.02) and decreased microglia/macrophage recruitment (17 ± 1% vs. 20 ± 1%, P = 0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope = 0.14 ± 0.05; R2 = 0.7, P = 0.03). These findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit. 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517.


Digital PCR Technology for Detection of Palm-Infecting Phytoplasmas Belonging to Group 16SrIV that Occur in Florida.
Phytoplasmas are an economically important group of plant pathogens that negatively impact a wide variety of plants in agricultural and natural ecosystems. In Florida, palm trees are essential elements in the nursery and landscaping industries that suffer from diseases caused by phytoplasmas that are related to each other but are classified in two different subgroups, 16SrIV-A and 16SrIV-D. In this study, a TaqMan assay was developed for digital polymerase chain reaction (dPCR) to detect both palm-infecting phytoplasmas found in Florida. When compared with real-time PCR assays and nested PCR assays, dPCR was capable of detecting the phytoplasmas at much lower concentrations than was possible by using real-time PCR and nested PCR. Additionally, the assay was capable of detecting 16SrIV-B phytoplasma as well as isolates representing the 16SrI and 16SrIII phytoplasma groups. Due to sequence identity of primer annealing regions across diverse phytoplasmas, the assay is likely to be successful for detection of a wide variety of phytoplasmas. The increased sensitivity of this dPCR assay over real-time PCR will allow for earlier detection of phytoplasma infection in palm trees, as well as for screening of salivary glands of candidate insect vector species. These advantages should aid timely management decisions to reduce disease spread and rapid determination of phytoplasma transmission by vectors.


Purification and characterization of GTP cyclohydrolase I from Drosophila melanogaster.
The enzyme GTP cyclohydrolase I, which catalyzes the first step in the pteridine biosynthetic pathway, has been purified by at least 4400-fold from Drosophila melanogaster. The active complex has an apparent molecular mass of 575,000 daltons, as estimated from gel filtration. This high molecular mass complex appears to be composed of a number of 39,000-dalton subunits. A polyspecific antiserum generated against the active complex has been used to identify this polypeptide as being severely affected by mutations in Punch, the structural gene for GTP cyclohydrolase. Enzyme activity is inhibited by divalent cations and high ionic strength buffers. No cofactors have been demonstrated to be required for enzyme activity. The enzyme displays positive cooperativity in phosphate buffer, a Hill number of 2.1, but only slight cooperativity in Tris buffer, a Hill number of 1.2.


Ag85b/ESAT6-CFP10 adjuvanted with aluminum/poly-IC effectively protects guinea pigs from latent mycobacterium tuberculosis infection.
The high global burden of tuberculosis (TB) underscores the urgent need for an effective TB vaccine since the only licensed Bacillus Calmette-Guérin (BCG) vaccine is ineffective in preventing adult pulmonary TB and affords no protection against latent TB infection (LTBI). Herein we investigated the potential of Mycobacterium tuberculosis (Mtb) antigen proteins AEC comprised of Ag85b and ESAT6-CFP10 proteins in conjunction with aluminum (Al) and polyriboinosinic-polyribocytidylic acid (poly-IC) as a novel subunit vaccine against TB. The immunogenicity and protection induced by the adjuvanted vaccine were evaluated in two animal models. Mice vaccinated with AEC/Al/poly-IC exhibited significant antigen-specific humoral immune responses and cell-mediated immunity as determined by immunoassay and multicolor flow cytometric assay, and the protective effect of the vaccine was demonstrated in a guinea pig model of latent Mtb infection. Compared to the control group, the mean pathological scores and bacterial loads in lungs and spleens of AEC/Al/poly-IC-immunized guinea pigs were significantly reduced. These data indicate that the AEC/Al/poly-IC is highly immunogenic in mice and can effectively protect guinea pigs against latent Mtb infection; it may represent a promising candidate vaccine for the control of latent TB.


X-ray Absorption Spectroscopy as a Process Analytical Technology: Reaction Studies for the Manufacture of Sulfonate-Stabilized Calcium Carbonate Particles.
Process analytical technologies are widely used to inform process control by identifying relationships between reagents and products. Here, we present a novel process analytical technology system for operando XAS on multiphase multicomponent synthesis processes based on the combination of a conventional lab-scale agitated reactor with a liquid-jet cell. The preparation of sulfonate-stabilized CaCO3 particles from polyphasic Ca(OH)2 dispersions was monitored in real time by Ca K-edge XAS to identify changes in Ca speciation in the bulk solution/dispersion as a function of time and process conditions. Linear combination fitting of the spectra quantitatively resolved composition changes from the initial conversion of Ca(OH)2 to the Ca(R-SO3)2 surfactant to the ultimate formation of nCaCO3·mCa(R- SO3)2 particles. The system provides a novel tool with strong chemical specificity for probing multiphase synthesis processes at a molecular level, providing an avenue to establishing the relationships between critical quality attributes of a process and the quality and performance of the product.


Continuous improvement learning for residents.
Physicians must be ready to assume an active role in the design, implementation, and improvement of emerging models of health care delivery. Knowledge and skill in continuous improvement prepare them to engage seriously in the processes of change, on the basis of the same scientific principles they always have relied on in the use of evidence to improve outcomes. This includes include the ability to 1) identify the health needs of the individuals and communities for which they provide health services; 2) assess the impact of current practice with appropriate outcome measures; 3) discover what in the process of health care may be contributing to less than desired outcomes; 4) design and test interventions to change the process of care to improve outcomes; 5) act as an effective member of the interdisciplinary team required to complete these tasks; and 6) consider ethical principles and professional values when making decisions about change in health services delivery. Graduate medical education presents special opportunities and challenges for learning about continuous improvement. Early experiences at Rainbow Babies and Children's Hospital in Cleveland and Children's Hospital in Boston suggest how we might prepare pediatricians and other physicians to create positive change and continually improve health care.


Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor.
The nature of the vasodilator endothelium-derived hyperpolarizing factor (EDHF) is controversial, putatively involving diffusible factors and/or electrotonic spread of hyperpolarization generated in the endothelium via myoendothelial gap junctions (MEGJs). In this study, we investigated the relationship between the existence of MEGJs, endothelial cell (EC) hyperpolarization, and EDHF-attributed smooth muscle cell (SMC) hyperpolarization in two different arteries: the rat mesenteric artery, where EDHF-mediated vasodilation is prominent, and the femoral artery, where there is no EDHF-dependent relaxation. In the rat mesenteric artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization of both ECs and SMCs, and characteristic pentalaminar MEGJs were found connecting the two cell layers. In contrast, in the femoral artery, ACh evoked hyperpolarization in only ECs but not in SMCs, and no MEGJs were present. Selective hyperpolarization of ECs or SMCs evoked hyperpolarization in the other cell type in the mesenteric artery but not in the femoral artery. Disruption of gap junctional coupling using the peptide Gap 27 markedly reduced the ACh-induced hyperpolarization in SMCs, but not in ECs, of the mesenteric artery. These results show that transfer of EC hyperpolarization or of a small molecule to SMCs through MEGJs is essential and sufficient to explain EDHF.


[Meiosis in the Siberian fir during microsporogenesis in conditions of arboretum].
Meiosis was studied in the Siberian fir (Abies sibirica Ledeb.) at the arboretum of the Sukachev Institute of Forest. Specific features of meiosis in planted trees have been described. Both general and specific types of irregularities have been identified. The range of irregularities under the arboretum conditions was much wider than in natural ecosystems.


Origins of life and biochemistry under high-pressure conditions.
Life on Earth can be traced back to as far as 3.8 billion years (Ga) ago. The catastrophic meteoritic bombardment ended between 4.2 and 3.9 Ga ago. Therefore, if life emerged, and we know it did, it must have emerged from nothingness in less than 400 million years. The most recent scenarios of Earth accretion predict some very unstable physico-chemical conditions at the surface of Earth, which, in such a short time period, would impede the emergence of life from a proto-biotic soup. A possible alternative would be that life originated in the depth of the proto-ocean of the Hadean Earth, under high hydrostatic pressure. The large body of water would filter harmful radiation and buffer physico-chemical variations, and therefore would provide a more stable radiation-free environment for pre-biotic chemistry. After a short introduction to Earth history, the current tutorial review presents biological and physico-chemical arguments in support of high-pressure origin for life on Earth.


The urine albumin-to-creatinine ratio is a reliable indicator for evaluating complications of chronic kidney disease and progression in IgA nephropathy in China.
This study investigated the correlation between the albumin-to-creatinine ratio in the urine and 24-hour urine proteinuria and whether the ratio can predict chronic kidney disease progression even more reliably than 24-hour proteinuria can, particularly in primary IgA nephropathy. A total of 182 patients with primary IgA nephropathy were evaluated. Their mean urine albumin-to-creatinine ratio and 24-hour proteinuria were determined during hospitalization. Blood samples were also analyzed. Follow-up data were recorded for 44 patients. A cross-sectional study was then conducted to test the correlation between these parameters and their associations with chronic kidney disease complications. Subsequently, a canonical correlation analysis was employed to assess the correlation between baseline proteinuria and parameters of the Oxford classification. Finally, a prospective observational study was performed to evaluate the association between proteinuria and clinical outcomes. Our study is registered in the Chinese Clinical Trial Registry, and the registration number is ChiCTR-OCH-14005137. A strong correlation (r=0.81, p<0.001) was found between the ratio and 24-hour proteinuria except in chronic kidney disease stage 5. First-morning urine albumin-to-creatinine ratios of ≥125.15, 154.44 and 760.31 mg/g reliably predicted equivalent 24-hour proteinuria 'thresholds' of ≥0.15, 0.3 and 1.0 g/24 h, respectively. In continuous analyses, the albumin-to-creatinine ratio was significantly associated with anemia, acidosis, hypoalbuminemia, hyperphosphatemia, hyperkalemia, hypercholesterolemia and higher serum cystatin C. However, higher 24-hour proteinuria was only associated with hypoalbuminemia and hypercholesterolemia. Higher tubular atrophy and interstitial fibrosis scores were also associated with a greater albumin-to-creatinine ratio, as observed in the canonical correlation analysis. Finally, the albumin-to-creatinine ratio and 24-hour proteinuria were associated with renal outcomes in univariate analyses. This study supports the recommendation of using the albumin-to-creatinine ratio, rather than 24-hour proteinuria, to monitor proteinuria and prognosis in primary IgA nephropathy.


Egg consumption and heart health: A review.
Cardiovascular disease is the leading cause of death in the United States. Until recently, reducing dietary cholesterol has been a part of the American Heart Association (AHA) and American College of Cardiology (ACC) guidelines on lifestyle management, despite inconclusive evidence to support the recommendation. Considering eggs are a rich source of dietary cholesterol (typically containing 141-234 mg per egg), individuals with increased risk for CVD are advised not to consume eggs. Furthermore, based on the 2012 AHA/ACC guidelines, individuals with lower risk for CVD have previously been advised to avoid consuming eggs due to the high content of dietary cholesterol. Rather than strictly limiting cholesterol intake, the AHA and ACC guidelines now recommend dietary patterns that emphasize fruits, vegetables, whole grains, low-fat dairy products, poultry, fish, and nuts as an approach to favorably alter blood lipid levels. Of note, the 2015-2020 Dietary Guidelines for Americans have removed the recommendation of limiting cholesterol intake to no more than 300 mg per day; however, the guidelines advise that individuals should eat as little dietary cholesterol as possible while consuming a healthy eating pattern. The purpose of this review is to summarize the documented health risks of egg consumption in individuals with low and high risk for CVD and determine whether current recommendations are warranted based on the available literature. We also aim to provide guidance for future studies that will help further elucidate the health modulating effect of eggs.


Site-specific regulation of histone H1 phosphorylation in pluripotent cell differentiation.
Structural variation among histone H1 variants confers distinct modes of chromatin binding that are important for differential regulation of chromatin condensation, gene expression and other processes. Changes in the expression and genomic distributions of H1 variants during cell differentiation appear to contribute to phenotypic differences between cell types, but few details are known about the roles of individual H1 variants and the significance of their disparate capacities for phosphorylation. In this study, we investigated the dynamics of interphase phosphorylation at specific sites in individual H1 variants during the differentiation of pluripotent NT2 and mouse embryonic stem cells and characterized the kinases involved in regulating specific H1 variant phosphorylations in NT2 and HeLa cells. Here, we show that the global levels of phosphorylation at H1.5-Ser18 (pS18-H1.5), H1.2/H1.5-Ser173 (pS173-H1.2/5) and H1.4-Ser187 (pS187-H1.4) are regulated differentially during pluripotent cell differentiation. Enrichment of pS187-H1.4 near the transcription start site of pluripotency factor genes in pluripotent cells is markedly reduced upon differentiation, whereas pS187-H1.4 levels at housekeeping genes are largely unaltered. Selective inhibition of CDK7 or CDK9 rapidly diminishes pS187-H1.4 levels globally and its enrichment at housekeeping genes, and similar responses were observed following depletion of CDK9. These data suggest that H1.4-S187 is a bona fide substrate for CDK9, a notion that is further supported by the significant colocalization of CDK9 and pS187-H1.4 to gene promoters in reciprocal re-ChIP analyses. Moreover, treating cells with actinomycin D to inhibit transcription and trigger the release of active CDK9/P-TEFb from 7SK snRNA complexes induces the accumulation of pS187-H1.4 at promoters and gene bodies. Notably, the levels of pS187-H1.4 enrichment after actinomycin D treatment or cell differentiation reflect the extent of CDK9 recruitment at the same loci. Remarkably, the global levels of H1.5-S18 and H1.2/H1.5-S173 phosphorylation are not affected by these transcription inhibitor treatments, and selective inhibition of CDK2 does not affect the global levels of phosphorylation at H1.4-S187 or H1.5-S18. Our data provide strong evidence that H1 variant interphase phosphorylation is dynamically regulated in a site-specific and gene-specific fashion during pluripotent cell differentiation, and that enrichment of pS187-H1.4 at genes is positively related to their transcription. H1.4-S187 is likely to be a direct target of CDK9 during interphase, suggesting the possibility that this particular phosphorylation may contribute to the release of paused RNA pol II. In contrast, the other H1 variant phosphorylations we investigated appear to be mediated by distinct kinases and further analyses are needed to determine their functional significance.


Efficacy and Side Effect Profile of Clobazam in Children with Different Etiologies of Epilepsy from a Single Center.
Clobazam is a long-acting antiepileptic drug that belongs to benzodiazepines used in the polytherapy of childhood epilepsy. In this study, our aim is to retrospectively evaluate the effectiveness and side effect profile of clobazam in children with different etiologies of epilepsy, mostly drug resistant. Forty patients aged 0-18 years that were admitted to Okmeydanı Training and Research Hospital pediatric neurology outpatient clinic between January 2017-January 2019 and prescribed clobazam were included in this study. The data of the patients who gave informed consent were extracted retrospectively from the outpatient clinic files. The patients with no seizures over 50% reduction in seizures were classified as clobazam-responsive, whereas the patients with less than 50% reductions in seizures, patients who had no response, and who manifested side effects and stopped using the drug were classified as clobazam-unresponsive. Twenty-three of the patients (57.5%) were male, 17 were (42.5%) were female. The average onset age of epilepsy was 31.8±37.2 months, while the average age for the prescription of clobazam was 70.6±48.9 months. The types of seizures were focal in 23 patients (57.5%) and generalized in 17 (42.5%) patients. Thirty-three (82.5%) patients had been using double or triple combinations of eight different antiepileptic drugs when clobazam was added to their treatment and accepted as drug-resistant epilepsy. The etiology of twenty one patients (52.5%) was unknown. In the remaining 19 patients (47.5%), the most common cause was structural and others were genetic, infectious and metabolic. Thirty one of the patients (77.5%) were responsive to clobazam. Of them, fifteen (37.5%) had no seizures, and 16 had a reduction in seizures (>50%). Nine (22.5%) patients were accepted as unresponsive to clobazam. The mean dose per kg was 0.7±0.3 mg/kg/day with a median of 0.63 mg/kg/day. Side effects of clobazam were encountered in 18 patients (45%); these resulted in the cessation of administration in only six (15%) patients. The side effects that cause the cessation of clobazam were sedation, refusal to take the drug due to the taste, irritability, hypersalivation, and malaise. Four patients (10%) had their doses reduced, seven patients (17.5%) responsive to clobazam although with side effects continued taking the drug as prescribed. The most common side effects of all were hyperactivity and sedation consecutively. Clobazam is an effective treatment for ensuring seizure freedom in pediatric epilepsy, mostly drug-resistant. The side effects are at tolerable levels in patients who are responsive to the drug.


[Utility of MALT (Münchner Alkoholismus Test) questionnaire for detection of alcoholism in women].
Patients identified as risk drinkers usually fill a questionnaire in order to assess their alcohol dependence. In our setting, the Münchner Alkoholismus Test (MALT) has been recommended, but there are not enough data about its validity and accuracy, particularly in women. The aim of this study was to assess the psychometric properties of this test in a female population. 414 woman were recruited in a Health Center and a Specialized Center for addiction treatment. MALT test and the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) semistructured interview (gold standard; DSM-IV and CIE-10 criteria) were performed to all patients. Internal consistence, criteria validity and the most diagnostic efficacy cut-off point (ROC curves) were assessed. The MALT average (standard deviation) score of the whole sample was 3.98 (9.48) points (95% confidence interval [CI], 3.07-4.90). Cronbach alpha was 0.939 (95% CI, 0.931-0.947). With a score of 4 or more points, the test had 100% (95% CI, 98.9-100) sensitivity and 95.4% (95% CI, 95.2-95.5) specificity. The MALT test has an excellent internal reliability and extremely good diagnostic accuracy. It is very useful to detect alcohol dependence in women. A cut-off of 4 or more points is proposed.


Leg blood flow and skeletal muscle microvascular perfusion responses to submaximal exercise in peripheral arterial disease.
Peripheral arterial disease (PAD) is characterized by stenosis and occlusion of the lower limb arteries. Although leg blood flow is limited in PAD, it remains unclear whether skeletal muscle microvascular perfusion is affected. We compared whole leg blood flow and calf muscle microvascular perfusion after cuff occlusion and submaximal leg exercise between patients with PAD ( n = 12, 69 ± 9 yr) and healthy age-matched control participants ( n = 12, 68 ± 7 yr). Microvascular blood flow (microvascular volume × flow velocity) of the medial gastrocnemius muscle was measured before and immediately after the following: 1) 5 min of thigh-cuff occlusion, and 2) a 5-min bout of intermittent isometric plantar-flexion exercise (400 N) using real-time contrast-enhanced ultrasound. Whole leg blood flow was measured after thigh-cuff occlusion and during submaximal plantar-flexion exercise using strain-gauge plethysmography. Postocclusion whole leg blood flow and calf muscle microvascular perfusion were lower in patients with PAD than control participants, and these parameters were strongly correlated ( r = 0.84, P < 0.01). During submaximal exercise, total whole leg blood flow and vascular conductance were not different between groups. There were also no group differences in postexercise calf muscle microvascular perfusion, although microvascular blood volume was higher in patients with PAD than control participants (12.41 ± 6.98 vs. 6.34 ± 4.98 arbitrary units, P = 0.03). This study demonstrates that the impaired muscle perfusion of patients with PAD during postocclusion hyperemia is strongly correlated with disease severity and is likely mainly determined by the limited conduit artery flow. In response to submaximal leg exercise, microvascular flow volume was elevated in patients with PAD, which may reflect a compensatory mechanism to maintain muscle perfusion and oxygen delivery during recovery from exercise. NEW & NOTEWORTHY This study suggests that peripheral arterial disease (PAD) has different effects on the microvascular perfusion responses to cuff occlusion and submaximal leg exercise. Patients with PAD have impaired microvascular perfusion after cuff occlusion, similar to that previously reported after maximal exercise. In response to submaximal exercise, however, the microvascular flow volume response was elevated in patients with PAD compared with control. This finding may reflect a compensatory mechanism to maintain perfusion and oxygen delivery during recovery from exercise.


Detection of low molecular weight GTP-binding proteins associated with rat atrial secretory granules.
Recent studies suggest that low molecular weight (LMW) GTP-binding proteins are involved in the vesicular transport of proteins along the secretory pathway. In order to determine whether LMW GTP-binding proteins are potentially involved in the regulated secretion of atrial natriuretic factor (ANF) from the atrial myocyte, rat atrial secretory granules were purified and the LMW GTP-binding proteins associated with these granules were detected in [alpha-32P]GTP-blotting experiments. Three LMW GTP-binding proteins, displaying molecular weights of 23,000, 25,000 and 29,000, were usually observed in atrial secretory granule preparations. The 29 kDa GTP-binding protein (G29), however, was typically the predominantly labelled band. The binding of [alpha-32P]GTP to G29 was guanine nucleotide specific and magnesium-dependent. Trypsin treatment of intact secretory granules markedly reduced the binding of [alpha-32P]GTP to G29. G29 is tightly associated with the granule membrane, as evidenced by its resistance to solubilization by high ionic strength buffers but its sensitivity to solubilization with sodium cholate. When secretory granule preparations of rat anterior pituitary glands were examined for the presence of LMW GTP-binding proteins, a different pattern of LMW GTP-binding proteins was observed which did not include a predominantly labelled 29 kDa protein. The results of this study indicate that: (1) LMW GTP-binding proteins are present on atrial secretory granules and may therefore be involved in the regulated secretion of ANF and (2) tissue-specific differences exist between the LMW GTP-binding proteins associated with secretory granules.


Anatomical applications of a new direct Ceromer.
Composite resin materials have become the basic restorative materials of the modern aesthetics-oriented practice. However, the application of composite resin in posterior teeth remains a challenge as a result of its handling characteristics and chairside stratification. New ceramic optimized polymers (ceromers), such as Tetric Ceram (Ivoclar Vivadent, Amherst, NY), now offer versatility and improved handling properties in response to increasing clinical demand for producing high-quality natural restorations. With a well-designed instrumentation, the work of the clinician may be greatly facilitated. This article evaluates the selection and utilization of a direct ceromer material for posterior restorations and presents a predictable method to achieve aesthetic restorations.


Four cases of keratoconus and posterior polymorphous corneal dystrophy.
We examined four young men with keratoconus and posterior polymorphous corneal dystrophy. All four patients showed central corneal steepening and irregularity, and large areas of irregular polymorphous opacification at the level of Descemet's membrane (in at least one cornea of each patient), which are consistent with posterior polymorphous dystrophy.


Signaling and transcriptional networks in heart development and regeneration.
The mammalian heart is the first functional organ, the first indicator of life. Its normal formation and function are essential for fetal life. Defects in heart formation lead to congenital heart defects, underscoring the finesse with which the heart is assembled. Understanding the regulatory networks controlling heart development have led to significant insights into its lineage origins and morphogenesis and illuminated important aspects of mammalian embryology, while providing insights into human congenital heart disease. The mammalian heart has very little regenerative potential, and thus, any damage to the heart is life threatening and permanent. Knowledge of the developing heart is important for effective strategies of cardiac regeneration, providing new hope for future treatments for heart disease. Although we still have an incomplete picture of the mechanisms controlling development of the mammalian heart, our current knowledge has important implications for embryology and better understanding of human heart disease.


Oxathiaborolium-Catalyzed Enantioselective [4 + 2] Cycloaddition and Its Application in Lewis Acid Coordinated and Chiral Lewis Acid Catalyzed [4 + 2] Cycloaddition.
The nascency of second-generation sulfur-stabilized borenium cations by halophilic Lewis acid SnCl4 leads to highly active chiral Lewis acids that are very effective catalysts for [4 + 2] cycloaddition. Oxathiaborolium pentachlorostannate (5-10 mol %) successfully catalyzed cycloaddition of various dienes and dienophiles to afford cycloadducts with excellent enantioselectivity (20 examples, up to 99% ee). This super Lewis acid also exhibited good enantioselectivity for the first Lewis acid coordinated and chiral Lewis acid catalyzed [4 + 2] cycloaddition to α,β-unsaturated mixed ester amide.


Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle.
Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration-dependent manner (10(-6) to 10(-4) M). The order of the potency was as follows: MCI-154 greater than pimobendan greater than adibendan greater than sulmazole. MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration-dependently (10(-7) to 10(-4) M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154 greater than adibendan greater than pimobendan greater than sulmazole. These results demonstrated that the Ca2+-sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.


Maternal stimulation in infancy predicts hypothalamic-pituitary-adrenal axis reactivity in young men.
Evidence from animal research has demonstrated the effect of early maternal care on the offspring's endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic-pituitary-adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring's hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.


Integration of the transcriptome and glycome for identification of glycan cell signatures.
Abnormalities in glycan biosynthesis have been conclusively linked to many diseases but the complexity of glycosylation has hindered the analysis of glycan data in order to identify glycoforms contributing to disease. To overcome this limitation, we developed a quantitative N-glycosylation model that interprets and integrates mass spectral and transcriptomic data by incorporating key glycosylation enzyme activities. Using the cancer progression model of androgen-dependent to androgen-independent Lymph Node Carcinoma of the Prostate (LNCaP) cells, the N-glycosylation model identified and quantified glycan structural details not typically derived from single-stage mass spectral or gene expression data. Differences between the cell types uncovered include increases in H(II) and Le(y) epitopes, corresponding to greater activity of α2-Fuc-transferase (FUT1) in the androgen-independent cells. The model further elucidated limitations in the two analytical platforms including a defect in the microarray for detecting the GnTV (MGAT5) enzyme. Our results demonstrate the potential of systems glycobiology tools for elucidating key glycan biomarkers and potential therapeutic targets. The integration of multiple data sets represents an important application of systems biology for understanding complex cellular processes.


Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents.
Tumors frequently contain mutations in the ras genes, resulting in the constitutive activation of the Ras-activated signaling pathway. The activation of Ras is involved not only in tumor progression but also in the development of resistance of the tumor cells to platinum-based chemotherapeutic agents. To investigate the potential mechanisms underlying this resistance, we analyzed the effect of activated H-Ras on the expression of the nucleotide excision repair genes. Here we identified ERCC1, which is one of the key enzymes involved in nucleotide excision repair, as being markedly up-regulated by the activated H-Ras. From promoter analysis of ERCC1, an increase in the Ap1 transcriptional activity as a result of the expression of the oncogenic H-Ras was found to be crucial for this induction. In addition, ERCC1 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DNA repair activity as well as to suppress the oncogenic H-Ras-mediated resistance of the cells to platinum-containing chemotherapeutic agents. These results suggest that the oncogenic H-Ras-induced ERCC1, which activates the DNA repair capacity, may be involved in the protection of the cells against platinum-based anticancer agents.


Omission of dexamethasone from antiemetic treatment for highly emetogenic chemotherapy in breast cancer patients with hepatitis B infection or diabetes mellitus.
Chemotherapy with anthracycline- and cyclophosphamide-containing regimens are classified as highly emetogenic. Combinatory treatments of aprepitant (Apr), palonosetron (Pal), or granisetron (Gra) with dexamethasone are recommended as antiemetic treatments for such emetogenic chemotherapy. We retrospectively examined whether omission of dexamethasone is tolerable for patients with hepatitis B virus (HBV) and diabetes mellitus (DM), for whom it is recommended not receive dexamethasone. During August 2009 and September 2007, we reviewed the medical records of patients with breast cancer who were HBV carriers or had been diagnosed with DM. 97 patients were treated with anthracycline- and cyclophosphamide- containing regimens with omission of dexamethasone in antiemetic treatment because of their HBV or DM status. Results The number of patients treated with Gra only, Apr and Gra, Apr and Pal, were 29, 29, and 39, respectively. Complete response (CR) in the acute phase (0-<24 hours after chemotherapy) or delayed phase (24-120 hours after chemotherapy) for Gra only, Apr-Gra, and Apr-Pal was 44.8% and 44.8%, 72.4% and 72.4%, and 76.9% and 74.4%, respectively. Complete control (CC) in the acute or delayed phase in each regimen for Gra only, Apr-Gra, and Apr-Pal was 31.0% and 27.6%, 48.2% and 51.7%, and 46.2% and 46.2%, respectively. Apr-Gra or Apr-Pal tended to be superior to Gra only in CR and CC in both the acute and delayed phases. HBV reactivation or aggravation of DM control was not observed in any of the 3 therapy options. CR and CC were about 20% higher for the dexamethasone-containing regimen than for the non-dexamethasone regimen in both the acute and delayed phases. Omission of dexamethasone in antiemetic treatment is tolerable when anthracycline- and cyclophosphamide-containing chemotherapy is administered to patients with breast cancer who have comorbidities of being HBV carriers or of DM.


Advise or consent? Issues in genetic testing of adolescents.
Medical genetics is a rapidly advancing field, and genetic testing is becoming readily accessible as well as more sophisticated. Genetic testing has the potential to be both harmful and beneficial in terms of physical, psychosocial, and reproductive health. Ethical and legal implications of genetic testing are profound and particularly confounding in children and adolescents. This chapter discusses points to consider in evaluating the potential benefit and harm of the decision to undergo testing in adolescence.


Coordinations of locomotor and respiratory rhythms in vitro are critically dependent on hindlimb sensory inputs.
A 1:1 coordination between locomotor and respiratory movements has been described in various mammalian species during fast locomotion, and several mechanisms underlying such interactions have been proposed. Here we use an isolated brainstem-spinal cord preparation of the neonatal rat to determine the origin of this coupling, which could derive either from a direct interaction between the central locomotor- and respiratory-generating networks themselves or from an indirect influence via a peripheral mechanism. We demonstrate that during fictive locomotion induced by pharmacological activation of the lumbar locomotor generators, a concomitant increase in spontaneous respiratory rate occurs without any evident form of phase coupling. In contrast, respiratory motor activity can be fully entrained (1:1 coupling) over a range of periodic electrical stimulation applied to low-threshold sensory pathways originating from hindlimb muscles. Our results provide strong support for the existence of pathways between lumbar proprioceptive afferents, medullary respiratory networks, and phrenic motoneurons that could provide the basis of the locomotor-respiratory coupling in many animals. Thus a peripheral sensory system involved in a well defined rhythmic motor function can be responsible for the tight functional interaction between two otherwise independent motor behaviors.


Anterior Vertebral Body Growth-Modulation Tethering in Idiopathic Scoliosis: Surgical Technique.
The management of idiopathic scoliosis in the skeletally immature patient can be challenging. Posterior spinal fusion and instrumentation is indicated for severe scoliosis deformities. However, the skeletally immature patient undergoing posterior fusion and instrumentation is at risk for developing crankshaft deformities. Moreover, bracing treatment remains an option for patients who are skeletally immature, and although it was found to be effective, it does not completely preclude deformity progression. Recently, fusionless treatment options, such as anterior vertebral body growth modulation, have been developed to treat these patients while avoiding the complications of posterior rigid fusion. Good results have been shown in recent literature with proper indications and planning in the skeletally immature patient.


Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway.
There is a continuous search for new therapeutic targets for treatment of multiple myeloma (MM). Here we investigated the mechanisms involved in cAMP-induced apoptosis of human MM cells. cAMP-increasing agents rapidly inhibited activation of JAK1 and its substrate STAT3. In line with STAT3 being a regulator of Mcl-1 transcription, the expression of this pro-survival factor was rapidly and selectively reduced. Notably, exogenous interleukin-6 neither prevented the inhibition of JAK1/STAT3 nor the death of MM cells induced by cAMP. Our results suggest that cAMP-mediated killing of MM cells involves inhibition of the JAK/STAT pathway, making the cAMP-pathway a promising target for treatment of MM.


Expanded Kekulenes.
The synthesis of kekulene and its higher homologues is a challenging task in organic chemistry. The first successful synthesis and characterization of the parent kekulene were reported by Diederich and Staab in 1978. Herein, we report the facile preparation of a series of edge-extended kekulenes by bismuth(III) triflate-catalyzed cyclization of vinyl ethers from the properly designed macrocyclic precursors. Their molecular structures were confirmed by X-ray crystallographic analysis and NMR spectroscopy. Their size- and symmetry-dependent electronic structures (frontier molecular orbitals, aromaticity) and physical properties (optical and electrochemical) were investigated by various spectroscopic measurements, assisted by theoretical calculations. Particularly, the acene-like units along each zigzag edge demonstrate a dominant local aromatic character. Our studies provide an easy synthetic strategy toward various fully fused carbon nanostructures and give some insights into the electronic properties of cycloarenes.


Cookbooks in U.S. history: How do they reflect food safety from 1896 to 2014?
Historical cookbooks as a source of recipes and food preparation information would be expected to document advancements in food safety related to kitchen equipment, cleaning, foodborne illness knowledge, and consumer education materials. In turn, this food safety information might be expected to contribute to consumers' food safety behaviors. Using both quantitative and qualitative research methodology, this study assessed how food safety information in cookbooks changed and how quickly advancements were incorporated. Faster assimilation into cookbooks was associated with kitchen equipment, educational resources (hotlines and websites), and foodborne illness outbreaks. The rate of incorporation of education materials was moderate. Cleaning advances were the slowest to be incorporated. Modern cookbooks published after the 1980's rapidly evolved with advances in food safety knowledge.


Synthesis of Cyclic α-Diazo-β-keto Sulfoxides in Batch and Continuous Flow.
Diazo transfer to β-keto sulfoxides to form stable isolable α-diazo-β-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived β-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile, and potential to scale up.


Single-fraction high-dose-rate brachytherapy using real-time transrectal ultrasound based planning in combination with external beam radiotherapy for prostate cancer: dosimetrics and early clinical results.
To validate the feasibility of a single-fraction high-dose-rate brachytherapy (HDRBT) boost for prostate cancer using real-time transrectal ultrasound (TRUS) based planning. From August 2012 to September 2015, 126 patients underwent a single-fraction HDRBT boost of 15 Gy using real-time TRUS based planning. External beam radiation therapy (EBRT) (37.5 Gy/15 fractions, 44 Gy/22 fractions, or 45 Gy/25 fractions) was performed before (31%) or after (69%) HDRBT boost. Genito-urinary (GU) and gastro-intestinal (GI) toxicity were assessed 4 and 12 months after the end of combined treatment using the international prostate symptom score scale (IPSS) and the common terminology criteria for adverse events (CTCAE) v3.0. All dose-planning objectives were achieved in 90% of patients. Prostate D90 ≥ 105% and ≤ 115% was achieved in 99% of patients, prostate V150 ≤ 40% in 99%, prostate V200 < 11% in 96%, urethra D10 < 120% for 99%, urethra V125 = 0% in 100%, and rectal V75 < 1 cc in 93% of patients. Median IPSS score was 4 at baseline and did not change at 4 and 12 months after combined treatment. No patients developed ≥ grade 2 GI toxicity. With a median follow-up of 10 months, only two patients experienced biochemical failure. Among patients who didn't receive ADT, cumulative percentage of patients with PSA ≤ 1 ng/ml at 4 and 18 months was respectively 23% and 66%. Single-fraction HDRBT boost of 15 Gy using real-time TRUS based planning achieves consistently high dosimetry quality. In combination with EBRT, toxicity outcomes appear promising. A longer follow-up is needed to assess long-term outcome and toxicities.


Meta-analysis of associations between childhood adversity and hippocampus and amygdala volume in non-clinical and general population samples.
Studies of psychiatric populations have reported associations between childhood adversity and volumes of stress-related brain structures. This meta-analysis investigated these associations in non-clinical samples and therefore independent of the effects of severe mental health difficulties and their treatment. The MEDLINE database was searched for magnetic resonance imaging studies measuring brain structure in adults with and without childhood adversity. Fifteen eligible papers (1781 participants) reporting hippocampal volumes and/or amygdala volumes were pooled using a random effects meta-analysis. Those with childhood adversity had lower hippocampus volumes (hedges g = - 0.15, p = 0.010). Controlling for gender, this difference became less evident (hedges g = - 0.12, p = 0.124). This association differed depending on whether studies included participants with some psychopathology, though this may be due to differences in the type of adversity these studies examined. There was no strong evidence of any differences in amygdala volume. Childhood adversity may have only a modest impact on stress-related brain structures in those without significant mental health difficulties.


Predictive Factors of Complications and Visual Outcomes after Pediatric Cataract Surgery: A Single Referral Center Study from Türkiye.
To evaluate the predictive factors of complications and visual acuity outcomes in pediatric cataract patients. This retrospective, observational clinical study included 80 eyes of 50 patients treated for pediatric cataracts between 2010 and 2020. The eyes were divided into Group I (congenital cataracts, n=38) and Group II (developmental cataracts, n=42). Group II was also divided into Group IIA (aphakic, n=21) and Group IIB (pseudophakic, n=21). The effects of the age, laterality, cataract morphology, intraocular lens implantation, preoperative nystagmus/strabismus, and intraoperative anterior hyaloid rupture on complications and final best-corrected visual acuity (BCVA; logMAR) were evaluated. The median (interquartile range) age and follow-up time were 28 (5-79) months and 60 (29-84) months, respectively. There was a significant difference in mean final BCVA between Group I (0.79±0.46) and Group II (0.57±0.51) (p=0.047); however, no difference was observed between Group IIA and Group IIB (p=0.541). Having congenital cataract (p=0.045), preoperative nystagmus/strabismus (p=0.042), total/mature cataract (p<0.001), and postoperative complications (p=0.07) were significantly associated with final BCVA. However, in multivariate analysis, only total/mature cataract (β: 0.52, p<0.001) and having any complication (β: 0.24, p=0.018) were associated with final BCVA. Congenital cataract and intraoperative anterior hyaloid rupture were the only significant risk factors of postoperative complications on univariate (p=0.027 and p=0.003, respectively) and binary logistic regression analysis (odds ratio [OR]: 2.95 [95% confidence interval: 1.07-8.15], p=0.036 and OR: 4.28 [95% confidence interval: 1.55-11.77], p=0.005, respectively). Total/mature cataract and the presence of any postoperative complication adversely affected the final BCVA. Having a congenital cataract and intraoperative anterior hyaloid membrane rupture increased the risk of complications.


Managed care at the bedside: how do we look in the moral mirror?
Managed care per se is a morally neutral concept; however, as practiced today, it raises serious ethical issues at the clinical, managerial, and social levels. This essay focuses on the ethical issues that arise at the bedside, looking first at the ethical conflicts faced by the physician who is charged with responsibility for care of the patient and then turning to the way in which managed care exacts costs that are measured not in dollars but in compromises in the caring dimensions of the patient-physician relationship.


[Historical background of researches in headache].
In seventeenth century, Thomas Willis pointed out the source of headache is distention of the vessels nearly identical with Wolf's twentieth century vascular hypothesis of migraine. The concept of the pathophysiology in migraine swung to neural cause by Edward Liveing (1873). The research evidence for special role of serotonin was revealed by modern approach and the mechanism of migraine was presented in trigeminovascular system. The development of the basic science leads to new treatments in headache clinic.


Higher order assembly: folding the chromosome.
The linear molecules of DNA that constitute a eukaryotic genome have to be carefully organised within the nucleus to be able to correctly direct gene expression. Microscopy and chromosome capture methods have revealed a hierarchical organisation into territories, domains and subdomains that ensure the accessibility of expressed genes and eventually chromatin loops that serve to bring gene enhancers into proximity of their target promoters. A rapidly growing number of genome-wide datasets and their analyses have given detailed information into the conformation of the entire genome, allowing evolutionary insights, observations of genome rearrangements during development and the identification of new gene-to-disease associations. The field is now progressing into using computational models of genome dynamics to investigate the mechanisms that shape genome structure, placing increasing importance on the role of chromatin associated proteins for this process.


Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery.
There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment.


Guidewire deflector system removal of catheter foreign body retained in the right heart for six months.
A case of successful removal of a catheter foreign body retained in the right atrium for 6 months is presented. The hooked catheter approach was used to retrieve the catheter from the right atrium. Due to the hook configuration of the retrievers, the catheter had to be surgically excised from the common femoral vein. Subsequently a system was developed and used successfully in other cases which eliminates the need for performance of a further surgical procedure to remove successfully the catheter or retrieval device.


Influenza vaccination levels among persons aged > or =65 years and among persons aged 18-64 years with high-risk conditions--United States, 2003.
Influenza vaccination is an effective tool for preventing hospitalization and death among persons aged > or =65 years and among persons aged 18-64 years with medical conditions that increase the risk for influenza-related complications. Two national health objectives for 2010 are to increase influenza vaccination coverage to 90% among persons aged > or =65 years and to 60% among persons aged 18-64 years who have one or more high-risk conditions (objectives 14-29a and 14-29c, respectively). To determine influenza vaccination coverage among persons in both targeted groups, CDC analyzed data from the 2003 National Health Interview Survey (NHIS). This report summarizes the results of that analysis, which determined that influenza vaccination coverage among persons aged > or =65 years and persons aged 18-64 years with high-risk conditions remains substantially below 2010 target levels. In addition, racial/ethnic disparities in coverage levels persist in both targeted populations. To improve overall influenza vaccination coverage and reduce racial/ethnic disparities, combinations of evidence-based effective interventions should be implemented, and the influenza vaccine supply should be stabilized.


Reliability of Ayurvedic Diagnosis for Knee Osteoarthritis Patients: A Nested Diagnostic Study Within a Randomized Controlled Trial.
Background: Ayurveda is a traditional Indian system of medicine. The customized Ayurvedic approach consists of a combination of several diagnostic procedures and subsequent individualized therapeutic interventions. Evaluation of inter-rater reliability (IRR) of Ayurvedic diagnoses has rarely been performed. The aim of this study was to evaluate IRR of Ayurvedic diagnosis for patients with knee osteoarthritis. Methods: A diagnostic reliability study of 30 patients and 4 Ayurvedic experts was nested in a randomized controlled trial. Patients were diagnosed in a sequential order by all experts utilizing a semistructured patient history form. A nominal group technique as consensus procedure was performed to reach agreement on the items to be diagnosed. An IRR analysis using Fleiss' and Cohen's kappa statistics was performed to determine a chance-corrected measure of agreement among raters. Results: One hundred and twenty different ratings and 30 consensus ratings were performed and analyzed. While high percentages of agreement for main diagnostic entities and the final Ayurveda diagnosis (95% consensus agreement on main diagnosis) could be observed, this was not reflected in the corresponding kappa values, which largely yielded fair-to-poor inter-rater agreement kappas for central diagnostic aspects such as prakriti and agni (κ values between 0 and 0.4). Notably, agreement on disease-related entities was better than that on constitutional entities. Conclusions: This is the first diagnostic study embedded in a clinical trial on patients with knee osteoarthritis utilizing a multimodality whole systems approach. Results showed a contrast between the high agreement of the consented final diagnosis and disagreement on certain diagnostic details. Future diagnostic studies should have larger sample sizes and a methodology more tailored to the specificities of traditional whole systems of medicine. Equal emphasis will need to be placed on all core diagnostic components of Ayurveda, both constitutional and disease specific, using detailed structured history taking forms.


Plasmacytoid dendritic cells, a role in neoplastic prevention and progression.
Plasmacytoid dendritic cells (pDCs) are multifunctional bone-marrow-derived immune cells that are key players in bridging the innate and adaptive immune systems. Activation of pDCs through toll-like receptor agonists has proven to be an effective treatment for some neoplastic disorders. In this mini-review, we will explore the fascinating contribution of pDCs to neoplastic pathology and discuss their potential utilization in cancer immunotherapy. Current research suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of tumour-derived cells lines. They are also reported to display tolerogenic function with the ability to suppress T-cell proliferation, analogous to regulatory T cells. In this capacity, they are critical in the suppression of autoimmunity but can be exploited by tumour cells to circumvent the expansion of tumour-specific T cells, thereby allowing tumours to persist. Several forms of skin cancer are successfully treated with the topical drug Imiquimod, which activates pDCs through toll-like receptor 7 engagement. Additionally, pDC-based anticancer vaccines have shown encouraging results for the treatment of melanoma in early trials. Future studies regarding the contributions of pDCs to malignancy will likely afford many opportunities for immunotherapy strategies.


Models Matter, So Does Training: An Empirical Study of CNNs for Optical Flow Estimation.
We investigate two crucial and closely-related aspects of CNNs for optical flow estimation: models and training. First, we design a compact but effective CNN model, called PWC-Net, according to simple and well-established principles: pyramidal processing, warping, and cost volume processing. PWC-Net is 17 times smaller in size, 2 times faster in inference, and 11 percent more accurate on Sintel final than the recent FlowNet2 model. It is the winning entry in the optical flow competition of the robust vision challenge. Next, we experimentally analyze the sources of our performance gains. In particular, we use the same training procedure for PWC-Net to retrain FlowNetC, a sub-network of FlowNet2. The retrained FlowNetC is 56 percent more accurate on Sintel final than the previously trained one and even 5 percent more accurate than the FlowNet2 model. We further improve the training procedure and increase the accuracy of PWC-Net on Sintel by 10 percent and on KITTI 2012 and 2015 by 20 percent. Our newly trained model parameters and training protocols are available on https://github.com/NVlabs/PWC-Net.


Evaluation of Occupational Therapy and Music Therapy Co-Treatment in the Neonatal Intensive Care Unit.
To examine co-treatment with music therapy and occupational therapy with infants in the neonatal intensive care unit (NICU). A quasi-experimental design was used to study the effect of standard care occupational therapy (SCOT) vs co-treatment with music therapy (Co-Tx) on behavioral state and physiologic measures. 46 participants were enrolled in the study. Interventions were implemented in approximately 20-minute sessions. Physiologic measures, heart rate (HR) and oxygen saturation (SpO2), were collected using Sickbay. Behavioral measures were collected using The Face, Legs, Activity, Cry, and Consolability (FLACC) Pain Assessment Tool. Mean heartrates during Co-Tx (161.3 ± 15.4 BPM) did not differ significantly compared to SCOT (161.8 ± 15.7 BPM). In unadjusted comparisons, mean SpO2 levels were significantly higher during Co-Tx than SCOT (95.48 ± 3.43% vs. 95.12 ± 3.71%, p = 0.046). There was a significant decrease in pre- to post-test FLACC scores for Co-Tx when compared to SCOT (decrease of 0.97 ± 1.96 vs. 0.61 ± 1.65, p = 0.023). In adjusted comparisons, there were no statistically significant differences in physiological outcomes. Co-treatment with music therapy may create a more stable and regulated environment for NICU infants. Further research is recommended on music therapy co-treatment with rehabilitative therapies.


Short-chain fatty acids increase expression and secretion of stromal cell-derived factor-1 in mouse and human pre-adipocytes.
Stromal cell-derived factor-1 (SDF-1) is expressed in pre-adipocytes but its role is unknown. We investigated butyrate (a histone deacetylase inhibitor--HDACi) and other short-chain fatty acids (SCFA) in the regulation of SDF-1. We further investigated whether effects of SCFA were signalled through G protein-coupled receptors FFA2 and FFA3. SDF-1 mRNA expression and protein secretion were studied in 3T3-L1 cells and human pre-adipocytes. SDF-1 was abundant, with mRNA and protein levels increased by butyrate. This was replicated with acetate and propionate, but not with trichostatin or valproate. Trichostatin inhibited SDF-1 secretion. Pertussis toxin blocked stimulation by butyrate. The order of potency of SCFA in stimulating SDF-1 (C3 > C4 > C2) is consistent with action through FFA3. Silencing the FFA3 gene abolished butyrate-stimulated SDF-1 expression and secretion. FFA3 was expressed in both pre-adipocytes and adipocytes, while FFA2 was expressed in adipocytes only. SDF-1 expression was low in murine macrophage J774.2 cells, while the SDF-1 receptor CXCR4 was absent from 3T3-L1 cells but abundant in J774.2 macrophages. In human pre-adipocytes, FFA3 was also expressed and SCFA increased SDF-1 secretion. SDF-1 and CXCR4 may mediate the interaction between adipose stromal cells and macrophages. Effects of SCFA are mediated through FFA3, but not histone deacetylase inhibition.


Immune Response to Exercise During Growth.
Two papers were selected for this commentary. The first paper (Citation 1) suggests that a 10-week, moderate-intensity exercise program performed early after allogeneic hematopoietic stem cell transplantation is feasible in this fragile population, and might improve cell cytotoxicity by redistributing subpopulations of NK cells. This study adds to the growing evidence that enhancing immune cell surveillance (e.g., NK cells) in response to exercise could benefit cancer patients. The second paper (Citation 2) studied neutrophil-related mediators of oxidative stress and inflammatory cytokines in response to exercise in children compared with adults. The authors found age/maturation-related differences in these responses. The paper provides a valuable introduction to the current knowledge of maturational changes in immune mediators' response to exercise. Data about leukocyte function in response to exercise in healthy children and in children with clinical conditions is scant. The need for prospective large scale pediatric clinical exercise studies is clear. Molecular approaches to understand the mechanisms through which physical activity can improve health will help to shape guidelines that optimize the mode, frequency, intensity, and duration of the training intervention.


A Pilot Screening of Agro-Food Waste Products as Sources of Nutraceutical Formulations to Improve Simulated Postprandial Glycaemia and Insulinaemia in Healthy Subjects.
The control of glucose homeostasis is the main goal for both the prevention and management of diabetes and pre-diabetes. Numerous drugs are available, despite their side effects. This is constantly leading people to be inclined to natural alternative treatments. Evidence indicates antioxidant-based nutraceuticals as an optimal tool for the glycaemic control. Currently, a great interest has been focused on the valorisation of agro-food by-products as sources of bioactive compounds including polyphenols. In this sense, we tested the efficacy of novel nutraceutical products based on polyphenolic extract from nectarines (NecP), tomato peels (TP), and olive leaves (EOL) on glycaemic and insulinemic responses. The three formulations contained, respectively, 0.007 mg abscisic acid (ABA)/g, 0.5 mg carotenoids/g, and 150 mg oleuropein/g. Twenty healthy subjects consumed a regular glucose solution (RG) or a treatment beverage (TB) obtained by mixing RG with the individual formulations (TB NecP, TB EOL, and TB TP), separately, and on different days. All three formulations significantly lowered the 30 min glucose plasma peak (p < 0.05 for all); similarly, NecP and TP also significantly lowered the 30 min insulin plasma peak (p < 0.05 for all). These results may lead to the hypothesis of a formulation of a multi-component nutraceutical with a synergistic efficacy for the glycaemic control.


[Assessment of adaptive mechanisms to obturators of the upper jaw according to the data of electronic axiography and cone-beam computer tomography].
Was to assess the adaptation of patients to obturator at different periods of adaptation using objective digital methods of analysis: axiography, cone-beam computer tomography, digital facial scans, and intraoral scanning. The study comprised 17 patients with postoperative defects of the upper jaw at different periods of removable obturators usage. In 88.2% of the subjects limited mouth opening and displacement of the mandible to the healthy side was detected. Contracture as a complication can develop in the later stages of rehabilitation. A long-term rehabilitation of patients is recommended using simulators and special gymnastic exercises in order to prevent extra-articular contracture.


Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study.
Patient preference is an important factor when choosing an inhaler device for asthma or chronic obstructive pulmonary disease (COPD). To identify characteristics of patients with asthma or COPD who prefer a once-daily controller medication regimen. This retrospective observational study used electronic patient records and linked outcomes from patient-completed questionnaires in a primary care database. We compared the characteristics of patients indicating a preference for once-daily therapy with those who were unsure or indicating no preference. Of 3,731 patients with asthma, 2,174 (58%) were women; the mean age was 46 years (range 2-94). Of 2,138 patients with COPD, 980 (46%) were women; the mean age was 70 years (range 35-98). Approximately half of the patients in each cohort indicated once-daily preference, one-quarter were unsure, and one-quarter did not prefer once-daily therapy. In patients with asthma or COPD, the preference for once-daily controller medication was significantly associated with poor adherence and higher concerns about medication. In asthma, good control and low self-perceived controller medication need were associated with once-daily preference. By contrast, in COPD, a high self-perceived need for controller medication was associated with once-daily preference. There was no significant relationship between once-daily preference and age, sex, disease severity, or exacerbation history. Understanding patient preferences may help prescribers to individualise therapy better for asthma and COPD.


Higher Prevalence of Diabetes in Pontine Infarction than in Other Posterior Circulation Strokes.
Pontine infarction is the major subtype of posterior circulation stroke, and diabetes is more common in pontine infarction patients than in anterior circulation stroke patients. Whether the prevalence of diabetes remains homogenous within the posterior circulation stroke population is unclear. The present study is aimed at investigating the prevalence of diabetes in pontine infarction and comparing it to other subtypes of posterior circulation stroke. We conducted a multicenter case-control study. Patients with posterior circulation stroke were screened. The subjects were divided into pontine infarction and nonpontine infarction groups. From November 1, 2018, to February 28, 2021, a total of 6145 stroke patients were screened and 2627 patients had posterior circulation strokes. After excluding cardioembolic stroke, as well as its other determined and undetermined causes, 1549 patients with 754 pontine infarctions were included in the analysis. The prevalence of diabetes in the pontine infarction group was higher than that in the nonpontine infarction group (42.7% vs. 31.4%, P < 0.05). After adjusting for confounding factors, diabetes was an independent risk factor for pontine infarction (OR 1.63, 95% CI 1.27-2.09, P < 0.05). For small vessel occlusion, diabetes was also more common in the pontine infarction group (43.2% vs. 30.0%, P < 0.05). Multivariate analysis also showed that diabetes was an independent risk factor for pontine infarction (OR 1.80, 95% CI 1.32-2.46, P < 0.05). In comparison with the nonpontine infarction subtype of posterior circulation stroke, patients with pontine infarction had a higher prevalence of diabetes, and diabetes was an independent risk factor for pontine infarction.