Proline is required for the stimulation of DNA synthesis in hepatocyte cultures by EGF.
Epidermal growth factor (EGF) has been shown to stimulate DNA synthesis in rat parenchymal hepatocytes both in vivo in vitro. We report here that this response in vitro is dependent on the amino acids present in the media. Of all the amino acids, proline has the strongest effect. The response to EGF is absent without proline and none of the other amino acids can substitute for it. Added proline (1 mM) to the media caused the labeling index to increase from 11% to 55% in the presence of 50 ng/ml EGF and insulin. In the presence of proline, small additional increases of the EGF effect on DNA synthesis were stimulated by phenylalanine and tyrosine.


Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors.
γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer's disease, neuropathic pain, and depression. One possibility to enhance GABA levels in the synaptic cleft is to inhibit mGAT1, one of the four known plasma membrane bound GABA transporters, which is considered the most important GABA transporter subtype, being in charge of the removal of GABA from the synaptic cleft after a neuronal impulse. Lipophilic derivatives of nipecotic acid like Tiagabine (Gabitril®), an approved drug used in add-on therapy of epilepsy, are known to inhibit uptake of mGAT1 with high subtype selectivity and affinity. We synthesized new N-substituted nipecotic acid derivatives with a vinyl ether spacer and an unsymmetrical bis-aromatic residue, which carries fluorine substituents at various positions of the aromatic ring-system. The new compounds were characterized with respect to their potency and subtype selectivity as mGAT1 inhibitors.


HLD-NAC design and evaluation of a fully dilutable lecithin-linker SMEDDS for ibuprofen.
Lecithin-linker microemulsions have been previously proposed as a platform for designing a fully dilutable self-microemulsifying drug delivery system (SMEDDS). This SMEDDS formulation, composed of ethyl caprate (oil), lecithin (Le), glycerol monooleate (lipophilic linker, LL) and polyglycerol caprylate (hydrophilic linker, HL), produced a ternary phase diagram (TPD) that had a fully dilutable path suitable for oral drug delivery. However, introducing ibuprofen as an active pharmaceutical ingredient (API) resulted in TPD phase boundaries that eliminated the fully dilutable path. The purpose of this work was to understand the origin of the changes in the TPD, use that understanding to restore the fully dilutable path with an ibuprofen-loaded SMEDDS, and finally to evaluate the absorption of ibuprofen in vivo. The effect of ibuprofen on the HLD (hydrophilic-lipophilic difference, interpreted as normalized net interfacial curvature) of the system was evaluated via a polar oil model, showing that ibuprofen played a surfactant-like role, having a characteristic curvature (Cc) value of +5 (highly hydrophobic). The net-average curvature (NAC) framework used the HLD calculated with Le, LL, HL and ibuprofen Cc to generate TPDs in ibuprofen lecithin-linker systems. The HLD-NAC simulations show that restoring full dilutability required a highly hydrophilic linker (HL-) with a Cc of -5 or more negative. The fully dilutable path was restored after introducing a hexaglycerol caprylate as HL- (Cc = -6). Plasma concentration profiles obtained with this ibuprofen-loaded SMEDDS showed a more than three-fold increase in the area under the curve (AUC) of rat plasma concentration profiles compared to the same 25 mg/kg ibuprofen dose in suspension.


Genetic variations of bone marrow mesenchymal stromal cells derived from acute leukemia and myelodysplastic syndrome by targeted deep sequencing.
Bone marrow mesenchymal stromal cells (MSCs), which support proliferation and differentiation of hematopoietic stem cells, may play a crucial role in the pathogenesis of myeloid neoplasms. To determine whether MSCs in myeloid neoplasms harbor distinct somatic mutations that may affect their function, we used a targeted gene sequencing panel containing 50 myeloid neoplasm-associated genes with coverage of ≥500. We compared the genetic alterations between MSCs and bone marrow hematopoietic (BM) cells from patients with acute leukemia (n=5) or myelodysplastic syndrome (MDS, n=5). Non-synonymous somatic mutations, such as DNMT3A-R882H and FLT3-D835Y, were only detected in BM cells with high allelic frequency. We found several non-synonymous genetic variants overlapping BM cells and MSCs, including TP53 and ASXL1, partially owing to the heterogenous cell fraction of MSC samples and lineage fidelity. We also found MSC-specific genetic variants with very low allelic frequency (7% to 8%), such as NF1-G2114D and NF1-G140. Further studies in large cohorts are needed to clarify the molecular properties of MSCs including age-related genetic alterations by targeted deep sequencing.


Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C90 H48 PAH.
Herein, we have synthesized an enantiomerically pure propeller-shaped PAH, C90 H48 , possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two-photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single-crystal X-ray diffraction analysis.


Isolation of an esterase-producing Trichosporon brassicae and its catalytic performance in kinetic resolution of ketoprofen.
A yeast strain CGMCC 0574, identified as Trichosporon brassicae, was selected from 92 strains for its high (S) selectivity in the hydrolysis of ketoprofen ethyl ester. The effective strains of the microorganisms were isolated from soil samples with the ester as the sole carbon source. The ethyl ester proved to be the best substrate for resolution of ketoprofen among several ketoprofen esters examined. The resting cells of CGMCC 0574 could catalyze the hydrolysis of ketoprofen ethyl ester with an enantiomeric ratio of 44.9, giving (S)-ketoprofen an enantiomeric excess of 91.5% at 42% conversion.


Residual mitral regurgitation in patients with left ventricular assist device support - An INTERMACS analysis.
Left ventricular assist device (LVAD) placement frequently leads to a reduction in the severity of functional mitral regurgitation (MR). However, a significant number of LVAD supported patients have residual MR. We sought to assess the impact of residual MR in LVAD patient outcomes. Patients in the INTERMACS registry who received a continuous flow LVAD between 2006 and 2017 without a prior mitral valve repair were included for analysis. Residual MR was defined as moderate or severe MR within the first 3 months device support. Baseline characteristics, echocardiographic and hemodynamic variables, and clinical outcomes were comparatively analyzed between those with or without residual MR. A total of 8,364 patients were included in the study, of which 18.8% demonstrated residual MR. Younger age, female gender, and non-ischemic heart failure were predictors of residual MR, as were increased LVEDD, RV dysfunction, severe baseline MR or TR, and elevated right heart pressures. Concomitant mitral valve repair reduced the risk of residual MR. Those with residual MR demonstrated worse LV remodeling, more right ventricular dysfunction, and higher right heart pressures at almost all time points analyzed. Residual MR was associated with increased risk of right heart failure and renal failure, and a trend toward increased mortality on LVAD support. Residual MR is associated with worse clinical outcomes on LVAD support. Strategies to minimize MR including medical and device optimization as well as valve repair should be considered in LVAD patients with residual MR.


Cyclooxygenase inhibition reveals synergistic action of vasoconstrictors on mesangial cell growth.
Since endogenous vasoconstrictors promote mesangial cell growth and increase the biosynthesis of antiproliferative prostaglandins, the effects of cyclooxygenase inhibition on mesangial cell proliferation should be strongly dependent on the prevailing levels of neuroendocrine vasoconstrictors. We compared the effects of indomethacin (10(-6) M), a cyclooxygenase inhibitor, on [3H]thymidine incorporation by cultured rat mesangial cells in the presence of various combinations of angiotensin II (10(-10) M), [Arg8]vasopressin (10(-11) M), (-)-norepinephrine (10(-8) M) and endothelin-1 (10(-11) M). Indomethacin did not enhance [3H]thymidine incorporation in cells treated with each individual vasoconstrictor, or in cells treated with two-way combinations with the exception of modestly increased [3H]thymidine incorporation in cells treated with angiotensin II + (-)-norepinephrine or [Arg8]vasopressin + (-)-norepinephrine. In contrast, in cells treated with any three-way or the four-way combination, indomethacin markedly increased [3H]thymidine incorporation. Importantly, a highly significant interaction (P<0.0001) was observed for thymidine incorporation between the number of vasoconstrictors present and indomethacin treatment, thus demonstrating that cyclooxygenase inhibition reveals a synergistic action of vasoconstrictors on the DNA synthesis in mesangial cells.


Molecular cloning and expression analysis of PDR1-like gene in ginseng subjected to salt and cold stresses or hormonal treatment.
The plant pleiotropic drug resistance (PDR) family of ATP-binding cassette (ABC) transporters is potentially involved in diverse biological processes. Currently, little is known about their actual physiological functions. A Panax ginseng PDR transporter gene (PgPDR1) was cloned and the cDNA has an open reading frame of 4344 bp. The deduced amino acid sequence contained the characteristic domains of PDR transporters: Walker A, Walker B, and ABC signature. Genomic DNA hybridization analysis indicated that one copy of PgPDR1 gene was present in P. ginseng. Subcellular localization showed that PgPDR1-GFP fusion protein was specifically localized in the cell membrane. Promoter region analysis revealed the presence of cis-acting elements, some of which are putatively involved in response to hormone, light and stress. To understand the functional roles of PgPDR1, we investigated the expression patterns of PgPDR1 in different tissues and under various conditions. Quantitative real-time PCR (qRT-PCR) and Western blotting analysis showed that PgPDR1 was expressed at a high level in the roots and leaves compared to seeds and stems. The expression of PgPDR1 was up-regulated by salicylic acid (SA) or chilling, down-regulated by ABA, and regulated differently at transcript and protein levels by MeJA. These results suggest that PgPDR1 might be involved in responding to environmental stresses and hormones.


A pilot case series using qualitative and quantitative methods: biological, psychological and social outcome in severe and enduring eating disorder (anorexia nervosa).
We explore the level of disability and quality of life in participants with severe and enduring eating disorder (anorexia nervosa). We use qualitative and quantitative methods to assess in detail eleven participants with a 10-year history of anorexia nervosa. Outcomes for quality of life are compared with those of a sample of primary care patients with moderate-severe depression. Outcomes for living skills are compared with a standardized community sample of patients with schizophrenia. Despite scoring highly for communication skills and levels of responsibility, participants were as impaired as the sample of patients with schizophrenia for self-care and social contact. Participants were severely depressed and scores for quality of life mirrored those of the primary care population. Qualitative data illustrate intrapersonal and interpersonal avoidance leading to self-neglect and social isolation despite social skills. Quality of life and living skills are as impaired as those of other severe and enduring mental illnesses.


Using whole exome sequencing to identify susceptibility genes associated with nonsyndromic cleft lip with or without cleft palate.
Cleft lip and palate is a common congenital birth defect in humans. Its incidence rate in China is as high as 1.82%, and is now a frequent deformity observed among the Chinese population; moreover, it varies across regions. Although the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has been widely investigated, the results are inconsistent. The specific genes and mechanisms responsible for NSCL/P have not been fully understood. Whole exome sequencing (WES) is a new strategy for studying pathogenic genes. WES studies on NSCL/P have not been conducted in East China. Therefore, the aim of this study was to screen candidate genes of NSCL/P in East China using WES and analyze the temporal and spatial expressions of the candidate genes during embryonic palatal development. WES was performed in 30 children with NSCL/P from East China to screen candidate genes. A bioinformatics analysis was performed using commercially available software. Variants detected by WES were validated by immunohistochemistry and western blotting. After WES, 506,144 single-nucleotide variant sites were found. The results of database comparison, functional analysis, and mass spectrometry revealed that only the laminin alpha 5 (LAMA5) gene (site: rs145192286) was associated with NSCL/P. Immunohistochemistry results showed that LAMA5 expression in the medial edge epithelium changed with formation, lifting, and contact during palatogenesis. Almost no LAMA5 expression was detected in the palatal mesenchyme or after palatal fusion. Western blotting and immunohistochemistry results showed consistent trends. In conclusion, the WES results shows that the mutation at the site (rs145192286) of LAMA5 is associated with NSCL/P. The temporal and spatial expressions of LAMA5 during palatal development further demonstrate the involvement of this gene. Therefore, we speculate that LAMA5 is a new candidate pathogenic gene of NSCL/P. The identification of new pathogenic genes would help elucidate the pathogenesis of NSCL/P and provide a scientific basis for the prenatal diagnosis, prevention, and treatment of NSCL/P.


Near-field resonance at far-field-induced transparency in diffractive arrays of plasmonic nanorods.
We numerically demonstrate that a periodic array of metallic nanorods sustains a maximum near-field enhancement and a far field (FF)-induced transparency at the same energy and in-plane momentum. The coupling of bright and dark plasmonic lattice resonances, and electromagnetic retardation along the nanorod length, are responsible for this effect. A standing wave with a quadrupolar field distribution is formed, giving rise to a collective suppression of FF scattering and simultaneously enhanced local fields.


Epistemic trust and unchanging personal narratives.
Focusing on imagination and the social context in the generation of conviction narratives, we propose that these elements are dynamically related to one another, and crucially that it is the nature of this relationship that determines individuals' level of epistemic openness and capacity to respond adaptively to update their narratives in a way that increases the possibility of more successful decision-making.


Antibody-induced botulinum toxin therapy failure: can it be overcome by increased botulinum toxin doses?
In some patients treated with botulinum toxin type A (BT) therapy failure occurs due to the formation of antibodies against BT (BT-AB). We investigated whether increased BT doses can overcome this form of therapy failure. Eight patients with cervical dystonia, secondary BT therapy failure and evidence of BT-AB formation in the mouse diaphragm bioassay received BT test doses (Dysport, Ipsen Ltd., Maidenhead, Berks, UK) into one of their sternocleidomastoid muscles. Test doses were increased in three steps at 3-month intervals and their effect on the amplitude of the electromyographic activity of the sternocleidomastoid muscle under maximal isometric activation (M-EMG) was measured and compared to a control group. In step 1 (200 or 300 MU) the M-EMG reduction was 12 +/- 13% compared to 85 +/- 10% (200 MU) and 83 +/- 9% (300 MU) in the control group. In step 2 (400, 600 or 800 MU) the M-EMG reduction was 25 +/- 21% compared to 78 +/- 7% (400 MU) in the control group. In step 3 (1,600 or 1,800 MU) the M-EMG reduction was 24 plus minus 10%. Side effects were not observed in any of the patients studied. In 1 patient with partial secondary BT therapy failure, with a low BT-AB titre (0.0015 U/ml) and with a moderately pathological M-EMG reduction of 40% with 200 MU a normal M-EMG reduction of 71% could be regained with 800 MU. In three subsequent therapeutic injection series with quadrupled BT doses in all target muscles the original therapy outcome could be regained and maintained. Side effects or increasing BT-AB titres were not observed. Even massively increased BT doses cannot overcome BT-AB-induced complete secondary therapy failure. However, in patients with partial secondary therapy failure, low BT-AB titres and a moderately pathological M-EMG reduction, increased BT doses might regain and maintain normal BT efficacy without induction of side effects or increasing BT-AB titres.


Standards of practice for superficial femoral and popliteal artery angioplasty and stenting.
This is a Standards of Practice document endorsed by CIRSE. The authors performed a literature review and provide recommendations and quality improvement guidelines based on the most recent and highest level of evidence available to date on the field of Superficial Femoral and Popliteal Artery Angioplasty and Stenting. Standards for the use of basic and more advanced endovascular techniques in the femoropopliteal arteries are reported and relevant aspects of case selection, imaging, follow-up, and overall patient management are presented to guide endovascular practice in Europe.


Role of early radiotherapy in the treatment of supratentorial WHO Grade II astrocytomas: long-term results of 97 patients.
To determine principal prognostic factors and the effect of timing of radiotherapy (RT) on disease-specific survival (DSS) and progression-free survival (PFS) in WHO Grade II astrocytomas. Histologic slides of 166 consecutive patients with the original tissue diagnosis of low-grade, non-pilocytic astrocytoma were reviewed. One-hundred and six were selected where two additional certified neuropathologist agreed on the grading of WHO Grade II astrocytoma. In 97 out of 106 cases follow-up informations were available. Early postoperative RT was given to 36 out of 97 patients (37%). The two groups of patients (early vs. delayed RT) were well balanced in respect to extent of surgery and other main clinical prognostic factors. Median follow-up of surviving patients was 79 months. The 5- and 10-year PFS was 52.2% and 30.7% with early RT and 39.5% and 12.4% with delayed RT (p = 0.0388). In respect to DSS, there was no significant difference in the 5- and 10-year actuarial survival rate according to the timing of RT (60.5% and 26.5% vs. 66.6% and 23.7%; p = 0.7545). Age (p = 0.0145) and extent of surgery (p = 0.0473) were significant prognostic variables in respect to DSS. Subdividing the irradiated group based on the extent of surgery, early RT in the subtotal group significantly improved 5-year PFS (60.0% vs. 12.4%; p = 0.0036) and DSS (66.7% vs. 49.8%; p = 0.0389). However, postoperative RT had no influence on PFS (p = 0.6812) and DSS (p = 0.3987) in the group with extensive resection. Early postoperative RT in subtotally resected, Grade II astrocytomas significantly improves both progression-free and disease-specific survival. Early RT does not benefit patients with extensive resection, RT should be withheld in these patients until progression.


Structurally based epitope analysis of major histocompatibility complex class I-related chain A (MICA) antibody specificity patterns.
Recent studies have suggested a clinical significance to the detection of anti-major histocompatibility complex class I-related chain A (MICA) antibodies in transplantation. We have developed an eplet-based version of the HLAMatchmaker algorithm to assess the epitope specificity of these antibodies. Molecular viewing of the MICA structure and the determination of amino acid sequence differences between MICA alleles has yielded a repertoire of 38 potentially immunogenic MICA eplets. These eplets are based on the functional epitope structure that considers a configuration of amino acids within a 3-Angstrom radius of an antibody-accessible polymorphic residue on the molecular surface. In this study MICA-reactive sera were screened in Luminex assays with single MICA allele panels and analyzed with HLAMatchmaker. We identified reactivity patterns that correspond to eplet-specific antibodies to identify of unacceptable MICA mismatches including those alleles that have not been tested with the serum. In conclusion, HLAMatchmaker is a useful algorithm to analyze the reactivity patterns of anti-MICA antibodies and the determination of MICA mismatch acceptability at the structural level.


Identification of motoneurons innervating the tensor tympani and tensor veli palatini muscles in the cat.
The somatotopic arrangement of the motoneurons associated with the two non-masticatory muscles innervated by the trigeminal motor nerve, tensor tympani (TT) and tensor veli palatini (TVP), was determined in the cat using retrograde transport of horseradish peroxidase. The motoneurons of the TT are distinct and separate, ventral and ventral-lateral to the rostral two-thirds of the trigeminal motor nucleus. The cells are smaller than those of the motor nucleus and constitute a parvocellular division. Based on functional and morphological criteria, TT motoneurons may be considered as an accessory trigeminal nucleus. The somatotopic arrangement of TVP motoneurons has been described for the first time. These motoneurons are located in the rostral two-thirds of the ventromedial division of the cat trigeminal motor nucleus. The location of motoneurons associated with TT and TVP does not fit the parcellation of the cat trigeminal motor nucleus as described by previous investigators. The motoneurons of these muscles can now be assigned to areas either within (TVP) or adjacent to (TT) the rostral two-thirds of the motor nucleus.


Identification, characterization, and expression analysis of a serotonin receptor involved in the reproductive process of the Pacific abalone, Haliotis discus hannai.
Serotonin receptor (5-HT) is a biogenic amine acting as a neurotransmitter and neuromodulator that mediates various aspects of reproduction and gametogenesis. The full-length nucleotide sequence of Haliotis discus hannai encodes a protein of 417 amino acids with a predicted molecular mass of 46.54 kDa and isoelectric point of 8.94. The structural profile of 5-HTHdh displayed key features of G protein-coupled receptors, including seven hydrophobic transmembrane domains, putative N-linked glycosylation sites, and several phosphorylation consensus motifs. It shares the highest homology of its amino acid sequence with the 5-HT receptor from Haliotis asinina, and to lesser extent of human 5-HT receptor. The cloned sequence possesses two cysteine residues (Cys-115 and Cys-193), which are likely to form a disulfide bond. Phylogenetic comparison with other known 5-HT receptor genes revealed that the 5-HTHdh is most closely related to the 5-HTHa receptor. The three-dimensional structure of the 5-HTHdh showed multiple alpha helices which is separated by a helix-loop-helix (HLH) structure. Quantitative PCR demonstrated that the receptor mRNA was predominantly expressed in the pleuropedal ganglion. Significant differences in the transcriptional activity of the 5-HTHdh gene were observed in the ovary at the ripening stage. An exclusive expression was detected in pleuropedal ganglion, testis, and ovary at higher effective accumulative temperature (1000 °C). In situ hybridization showed that the 5-HTHdh expressing neurosecretory cells were distributed in the cortex of the pleuropedal ganglion. Our results suggest that 5-HTHdh synthesized in the neural ganglia may be involved in oocyte maturation and spawning of H. discus hannai.


NPL secondary standard radionuclide calibrator. Syringe calibration factors for radionuclides used in nuclear medicine. National Physical Laboratory.
The measurement of the activity of a radiopharmaceutical administration to a patient is normally achieved via the use of a radionuclide calibrator. Although these radionuclides are normally measured initially in a standard glass vial, an aliquot of the solution is then usually withdrawn into a syringe prior to the administration. Both for general quality assurance good practice and for additional guarantees for patient safety, a confirmatory measurement of the syringe is almost obligatory Because of the different geometries and elemental compositions between plastic syringes and glass vials, the calibration factors for syringes may well be significantly different from those for the glass containers. The magnitude of these differences depends on the energies of the emitted photons. A variety of syringes typically used in hospital administrations, and covering a range of volumes and manufacturers, were obtained. The results obtained were compared to those for glass vials and show the large errors that can be produced by ignoring these differences in container format.


Natural convective non-Newtonian nanofluid flow in a wavy-shaped enclosure with a heated elliptic obstacle.
A numerical investigation has been carried out in a wavy-shaped enclosure with an elliptical inner cylinder to find out the effect of an inclined magnetic field and a non-Newtonian nanofluid on fluid flow and heat transfer. Here, the dynamic viscosity and thermal conductivity of the nanofluid are also taken into account. These properties change with the temperature and nanoparticle volume fraction. The vertical walls of the enclosure are modeled through complex wavy geometries and are kept at a constant cold temperature. The inner elliptical cylinder is deemed to be heated and the horizontal walls are considered adiabatic. Temperature difference between the wavy walls and the hot cylinder leads to natural convective circulation flow inside the enclosure. The dimensionless set of the governing equations and associated boundary conditions are numerically simulated using the COMSOL Multiphysics software, which is based on finite element methods. Numerical analysis has been scrutinized for varying Rayleigh number (Ra), Hartmann number (Ha), magnetic field inclination angle (γ), rotation angle of the inner cylinder (ω), power-law index (n), and nanoparticle volume fraction (ϕ). The findings demonstrate that the solid volumetric concentration of nanoparticles diminishes the fluid movement at greater values of φ. The heat transfer rate decreases for larger nanoparticle volume fractions. The flow strength increases with an increasing Rayleigh number resulting in a best possible heat transfer. A higher Hartmann number diminishes the fluid flow but converse behavior is exhibited for magnetic field inclination angle (γ). The average Nusselt number (Nuavg) values are maximum for γ = 90°. The power-law index plays a significant role on the heat transfer rate, and results show that the shear-thinning liquid augments the average Nusselt number.


Ubiquitin-proteasome system as a target for anticancer treatment-an update.
As the ubiquitin-proteasome system (UPS) regulates almost every biological process, the dysregulation or aberrant expression of the UPS components causes many pathological disorders, including cancers. To find a novel target for anticancer therapy, the UPS has been an active area of research since the FDA's first approval of a proteasome inhibitor bortezomib in 2003 for treating multiple myeloma (MM). Here, we summarize newly described UPS components, including E3 ubiquitin ligases, deubiquitinases (DUBs), and immunoproteasome, whose malfunction leads to tumorigenesis and whose inhibitors have been investigated in clinical trials as anticancer therapy since 2020. We explain the mechanism and effects of several inhibitors in depth to better comprehend the advantages of targeting UPS components for cancer treatment. In addition, we describe attempts to overcome resistance and limited efficacy of some launched proteasome inhibitors, as well as an emerging PROTAC-based tool targeting UPS components for anticancer therapy.


Electronic, magnetic and optical properties of Cu, Ag, Au-doped Si clusters.
The structural, optical and magnetic properties of Cu, Ag, Au-doped Si7 Clusters have been systematically investigated using density functional theory calculations. The global optimized structures of Cu, Ag, Au-doped Si clusters are predicted to have a lower HOMO-LUMO gap and higher magnetic moment. M-doping (M = Cu, Ag, Au) in Si cluster widens a range of adsorption wavelength, especially Au-doping. The characteristics in electronic density of states (DOSs) show that C5v-Si6Cu has a big asymmetrical spin-up and spin-down. The average atomic moment is 0.428 mμB per atom for the Si6Cu cluster with C5v symmetry, while the average paramagnetic moment is 0.143 mμB per atom for other M-doped (M = Cu, Ag, Au) Si7 clusters.


Chronic polyarthritis as isolated manifestation of toxocariasis.
Human toxocariasis is a parasitic zoonosis mainly caused by Toxocara canis or Toxocara cati and is acquired by ingestion of the parasite's embryonated eggs. Arthralgia and/or arthritis were reported in up to 17% of the cases, generally with acute duration (less than 6 weeks). However, to our knowledge, chronic polyarthritis, as the isolated presentation of Toxocara infection, was not reported. One of the 5809 patients that was followed up at our service (0.017%) had chronic polyarthritis as the single manifestation of toxocariasis and was described herein. A 3-year-old girl was referred to our service with severe painful chronic polyarthritis for a period longer than 10 weeks and morning stiffness of 30min. Dog contact exposure history in the recreational areas of neighborhood was reported. Her exams showed high levels of eosinophils in peripheral blood (29%), bone marrow aspirate revealed marked eosinophilia (32%) and Toxocara enzyme-linked immunosorbent assay (Elisa) was positive (1:1280). She was treated with paracetamol (40mg/kg/day) and thiabendazole (25mg/kg/day) for 10 days, and all manifestations reduced. After eight months of follow-up, she was on clinical and laboratorial remission. In conclusion, we described a case of chronic polyarthritis, as isolated manifestation of toxocariasis, mimicking juvenile idiopathic arthritis and leukemia. Importantly, this zoonosis should be considered in patients with arthritis and eosinophilia.


Snake venom three-finger toxins and their potential in drug development targeting cardiovascular diseases.
Cardiovascular diseases such as coronary and peripheral artery diseases, venous thrombosis, stroke, hypertension, and heart failure are enormous burden to health and economy globally. Snake venoms have been the sources of discovery of successful therapeutics targeting cardiovascular diseases. For example, the first-in-class angiotensin-converting enzyme inhibitor captopril was designed largely based on bradykinin-potentiating peptides from Bothrops jararaca venom. In the recent years, sensitive and high throughput approaches drive discovery and cataloging of new snake venom toxins. As one of the largest class of snake venom toxin, there are now>700 sequences of three-finger toxins (3FTxs) available, many of which are yet to be studied. While the function of 3FTxs are normally associated with neurotoxicity, increasingly more 3FTxs have been characterized to have pharmacological effects on cardiovascular systems. Here we focus on this family of snake venom toxins and their potential in developing therapeutics against cardiovascular diseases.


Risk factors of first recurrence of Clostridioides difficile infection.
Clostridioides difficile infection (CDI) often recurs. Approximately 25% of patients have recurrences after the initial treatment, and patients who have relapsed once are more likely to relapse. We aimed to identify the risk factors for initial CDI recurrence. We performed a retrospective survey of patient backgrounds and treatment-related factors. Risk factors were analyzed using single and multiple logistic regression analyses. A total of 134 patients were included in the study. Prophylactic probiotic use and nasogastric tube feeding were independent risk factors for the initial recurrence of CDI. Patients using prophylactic probiotics had significantly higher recurrence rates than those not using prophylactic probiotics. Prophylactic probiotic use and nasogastric tube placement may be risk factors for the initial recurrence of CDI. It is noteworthy that CDI that occurs during the use of prophylactic probiotics may be prone to recurrence.


Optimal, Early Postoperative Management of Cardiac Transplant and Durable Left Ventricular Assist Recipients.
Summarize developments in the early postoperative care of patients undergoing cardiac transplantation or left ventricular assist device implantation. Provide a practical approach with personal insights to highly complex patients at risk for prolonged hospitalization. Advancements in technology allow for percutaneous mechanical circulatory support of both the right and left ventricles either isolated or combined via subclavian and neck vessels. Since the adult heart allocation system has been changed to reduce waitlist mortality, the use of temporary mechanical circulatory support has increased. This has influenced preoperative optimization by enabling ambulation and majorly changed postoperative strategy. New doors have been opened for a multidisciplinary approach to facilitate rapid weaning of inotropic medications, limitation of sedation, early liberation from mechanical ventilation, and mobilization. Individualized percutaneous mechanical circulatory support offers new possibilities for the early postoperative management of highly complex patients undergoing cardiac transplantation or durable left ventricular assist device implantation.


A study on the effects of inhibition of prostaglandin biosynthesis with flunixin meglumine and later administration of prostaglandin F2 alpha on the intraluminal pressure variations in the isthmus of the oviduct in unrestrained gilts.
Three gilts were each equipped with 2 ultra-miniature pressure sensors, placed at 2 different points along the same isthmus of the oviduct. Following base recordings of isthmic intraluminal pressure, the gilts were treated with 2.2 mg flunixin meglumine (FM) per kg body weight. After FM treatment, the peripheral plasma levels of 15-ketodihydro-PGF2 alpha, the major metabolite of prostaglandin F2 alpha (PGF2 alpha), decreased within 30 min. The frequency of the phasic pressure fluctuations in the isthmus of the oviduct decreased after FM treatment. Exogenous administration of PGF2 alpha increased the peripheral plasma levels of 15-ketodihydro-PGF2 alpha. When administered at a dose of 0.1 mg, PGF2 alpha produced an increase in the frequency of the phasic pressure fluctuations in the oviductal isthmus. When the PGF2 alpha dose was increased to 0.5 mg, a marked increase in the base and total pressures was seen in addition to the increase in the frequency of the phasic pressure fluctuations.


Serum Bactericidal Activity Levels Monitor to Guide Intravenous Dalbavancin Chronic Suppressive Therapy of Inoperable Staphylococcal Prosthetic Valve Endocarditis: A Case Report.
Here we describe a case of a methicillin-resistant coagulase-negative staphylococci prosthetic valve endocarditis in a patient considered not eligible for valve replacement due to high perioperative mortality risk and who did not tolerate oral antibiotic treatment. Under these circumstances, intravenous long-term chronic suppressive antibiotic therapy with dalbavancin, scheduling the doses using the serum bactericidal activity titers, proved to be safe and effective.


The inflammatory response in candidal chorioamnionitis.
Fetal infection with Candida organisms has not commonly been reported. Umbilical cords and placentas from 23 cases of chorioamnionitis collected over a nine-year period were examined by electron microscopy and immunoperoxidase staining. Gross features, especially of the umbilical cord, were distinctive and included the pale yellow plaques pathognomonic of candidal funisitis. Histopathologically, the lesions were found to be focal and subamniotic and were often embedded in a "fibrinoid" exudate and surrounded by inflammatory cells. In some cases the exudate and inflammatory cells were deposited in dense bands. Immunoperoxidase staining showed the lesions to contain IgG, IgM, and IgA, which probably originated in dense-staining plasmacytoid and immunoblastic cells in the inflammatory infiltrates. Additional findings in two fetal cases of giant cell pneumonitis suggested that the fetus can mount a brisk inflammatory and immune response to Candida organisms as early as 18 weeks' gestation and that mucosal exposure to this antigen can result in production of IgA by the lung.


Rabbit cerebellar slice analysis of long-term depression and its role in classical conditioning.
Cerebellar long-term depression (LTD) has been proposed as a mechanism underlying classical conditioning of the rabbit nictitating membrane/eyelid response (NMR). However, LTD has only been obtained reliably when (1) cerebellar slices are bathed in GABA antagonists which abolish disynaptic inhibitory post synaptic potentials, and (2) the temporal sequence of stimulation used in slice or intact preparations is the opposite of that used in classical conditioning. Based on intradendritic Purkinje cell recordings obtained from rabbit cerebellar slices, we report that stimulation of climbing fibers and then parallel fibers in the presence of the GABA antagonist, bicuculline, produced significant depression of parallel fiber excitatory post synaptic potential (epsp) amplitude that continued to increase for at least 20 min after stimulation. However, application of the same stimulation protocol without GABA antagonists produced a brief depression of parallel fiber epsps that disappeared within minutes. Activation of parallel fibers and then climbing fibers in an order opposite to the LTD-producing sequence (i.e. a classical conditioning-like order) produced a brief depression that dissipated quickly. Stimulation of parallel fibers alone produced a small, slowly developing potentiation, but stimulation of parallel fibers during depolarization-induced local dendritic calcium spikes produced significant depression almost immediately which then declined slowly to more modest levels. Finally, stimulation of parallel fibers at frequencies used in in vivo parallel fiber-climbing fiber stimulation experiments (e.g. 100 Hz) produced an immediate and profound long-lasting epsp depression. The depression occurred, however, whether parallel and climbing fibers were stimulated separately (unpaired) or in a classical conditioning-like protocol (paired) where parallel fiber stimulation coterminated with climbing fiber stimulation (10 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)


Cerebrovascular β-dystroglycan immunoreactivity in vertebrates: not detected in anurans and in the teleosts Ostariophysi and Euteleostei.
The aim of the present paper was to check for the presence of cerebrovascular dystroglycan in vertebrates, because dystroglycan, which is localized in the vascular astroglial end-feet, has a pivotal function in glio-vascular connections. In mammalian brains, the immunoreactivity of β-dystroglycan subunit delineates the vessels. The results of the present study demonstrate similar patterns in other vertebrates, except for anurans and the teleost groups Ostariophysi and Euteleostei. In this study, we investigated 1 or 2 representative species of the main groups of Chondrichthyes, teleost and non-teleost ray-finned fishes, urodeles, anurans, and reptiles. We also investigated 5 mammalian and 3 bird species. Animals were obtained from breeders or fishermen. The presence of β-dystroglycan was investigated immunohistochemically in free-floating sections. Pre-embedding electron microscopical immunohistochemistry on Heterodontus japonicus shark brains demonstrated that in Elasmobranchii, β-dystroglycan is also localized in the perivascular glial end-feet despite the different construction of their blood-brain barrier. The results indicated that the cerebrovascular β-dystroglycan immunoreactivity disappeared separately in anurans, and in teleosts, in the latter group before its division to Ostariophysi and Euteleostei. Immunohistochemistry in muscles and western blots from brain homogenates, however, detected the presence of β-dystroglycan, even in anurans and all teleosts. A possible explanation is that in the glial end-feet, β-dystroglycan is masked in these animals, or disappeared during adaptation to the freshwater habitat.


Report cards don't make the grade with physicians or consumers.
Not popular with physicians or consumer, but they help with quality improvement initiatives.


A comparative differential scanning calorimetry study of the effects of cholesterol and various oxysterols on the thermotropic phase behavior of dipalmitoylphosphatidylcholine bilayer membranes.
We have carried out a comparative differential scanning calorimetric (DSC) study of the effects of cholesterol (C) and the eight most physiologically relevant oxysterols on the thermotropic phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. The structures of these oxysterols differ from that of C by the presence of additional hydroxyl, keto or epoxy groups on the steroid ring system or by the presence of a hydroxyl group in the alkyl side chain. In general, the progressive incorporation of these oxysterols reduces the temperature, cooperativity and enthalpy of the pretransition of DPPC to a greater extent than C, indicating that their presence thermally destabilizes and disorders the gel states of DPPC bilayers to a greater extent than C. Similarly, the incorporation of these oxysterols either increases the temperature of the broad component of the main phase transition to a smaller extent than C or actually decreases it. Again, this indicates that the presence of these compounds is less effective at thermally stabilizing and ordering the sterol-rich domains of DPPC bilayers than is C itself. Moreover, the incorporation of these oxysterols decrease the cooperativity and enthalpy of the main phase transition of DPPC to a smaller extent than C, indicating that they are somewhat less miscible in fluid DPPC bilayers than is C. Particularly notable in this regard is 25-hydroxycholesterol, which exhibits a markedly reduced miscibility in both gel and fluid DPPC bilayers compared to C itself. In general, the effectiveness of these oxysterols in stabilizing and ordering DPPC bilayers decreases as their rate of interbilayer exchange and the polarity of the oxysterol increases. We close by providing a tentative molecular explanation for the results of our DSC studies and of those of previous biophysical studies of the effects of various oxysterol on lipid bilayer model membranes.


[Sleep habits and starting time to school in Brazilian children].
This study investigated the sleep habits in Brazilian children according to age, gender and starting time to school. We investigated 2,482 scholars aged 7 to 10 years. We compared sleep habits, gender, and starting time to school (morning and afternoon). Sixty-one per cent of the children presented sleep rituals before sleep. Milk drinking before sleep was more frequent among seven years old children. We found a progressive reduction with age in keeping the lights on. Girls used to leave an object to bed more than boys did. Children that studied in the morning presented reduced total sleep time, sleep earlier, and nap more frequently than children that studied in the afternoon. Starting time to school deeply influences sleep habits in Brazilian children from São Paulo City, in whom bed-time rituals are highly prevalent.


AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.
Congenital generalized lipodystrophy is an autosomal recessive disorder characterized by marked paucity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. We report several different mutations of the gene (AGPAT2) encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 in 20 affected individuals from 11 pedigrees of diverse ethnicities showing linkage to chromosome 9q34. The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. AGPAT2 mRNA is highly expressed in adipose tissue. We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes.


The de novo design of median molecules within a property range of interest.
In this paper an application is presented of the median molecule workflow to the de novo design of novel molecular entities with a property profile of interest. Median molecules are structures that are optimised to be similar to a set of existing molecules of interest as an approach for lead exploration and hopping. An overview of this workflow is provided together with an example of an instance using the similarity to camphor and menthol as objectives. The methodology of the experiments is defined and the workflow is applied to designing novel molecules for two physical property datasets: mean molecular polarisability and aqueous solubility. This paper concludes with a discussion of the characteristics of this method.


Why is autophagy important in human diseases?
The process of macroautophagy (referred to hereafter as autophagy), is generally characterized by the prominent formation of autophagic vesicles in the cytoplasm. In the past decades, studies of autophagy have been vastly expanded. As an essential process to maintain cellular homeostasis and functions, autophagy is responsible for the lysosome-mediated degradation of damaged proteins and organelles, and thus misregulation of autophagy can result in a variety of pathological conditions in human beings. Although our understanding of regulatory pathways that control autophagy is still limited, an increasing number of studies have shed light on the importance of autophagy in a wide range of physiological processes and human diseases. The goal of the reviews in the current issue is to provide a general overview of current knowledge on autophagy. The machinery and regulation of autophagy were outlined with special attention to its role in diabetes, neurodegenerative disorders, infectious diseases and cancer.


From Veld to Coast: Towards an Understanding of the Diverse Landscapes' Uses by Past Foragers in Southern Africa.
In this brief contribution, we outline the aims of a collection entitled "From veld to coast: towards an understanding of the diverse landscapes' uses by past foragers in southern Africa," and we define its chronological, geographic and thematic framework.


Predictors of infectious foci on FDG PET/CT in Staphylococcus aureus bacteremia.
We looked for predicting factors for the detection of infectious foci on 18F-fluorodeoxyglucose-positron emission tomography in combination with computed tomography (FDG PET/CT) among patients with Staphylococcus aureus bacteremia (SAB) who participated in an interventional study that was conducted at Rambam Health Care Campus, between July 1, 2015 and February 1, 2019. The primary outcome was an infectious focus detected by FDG PET/CT. Independent predictors for detection of focal infection were identified using univariate followed by a logistic regression multivariate analysis. We included 149 patients with 151 separate episodes of SAB who underwent FDG-PET/CT. Focal infections were detected in 107 patients (70.8%). Independent predictors for focal infection detection were community acquisition of bacteremia with odds ratio (OR) 3.03 [95% confidence interval (CI) 1.04-8.77], p-0.042 and C reactive protein (CRP) with OR 1.09 [95% CI 1.04-1.14], p < 0.001. Primary bacteremia was inversely associated with focal infection detection with OR 0.27 [0.10-0.69], p = 0.007, as were the pre-scan blood glucose levels OR 0.9 [0.98-0.99], p-0.004. The latter stayed significant in the subgroup of patients with diabetes mellitus. To conclude, patients with community-acquired bacteremia or high CRP levels should be carefully investigated for focal infection. Patients who present with primary bacteremia seem to be at low risk for focal infection.


The Effect of Visual Function on the Batting Performance of Professional Baseball Players.
This report evaluates the role of the combined visual abilities of acuity, contrast sensitivity and presentation time on plate discipline and baseball batting performance. A visual function test (EVTS) was performed on 585 professional baseball players. The results were compared to several common plate-discipline measures. The EVTS test provides a single measure combining target size, contrast and presentation time. Correlations (statistically significant) were found between this measure and several plate discipline metrics (InzoneSwingPct, inzoneFbSwingPct, ChasePct, FbChasePct, BBperPa). Years of major league service did not appear to be related to visual ability. When comparing the best and worst 20% groups based on visual ability, statistically significant improvements ranging from 11.6% in BBperPa to 3.5% in inzoneSwingPct were noted in the better visual function group. Effect sizes ranged from 0.278 to 0.387. These results demonstrate the relationship between basic visual function and batting performance. These are the first results, on a large group at the professional level, to demonstrate this relationship statistically. These results may aid player selection, indicating that batters with better visual function are more likely to be successful when batting and more productive for their team.


Licit and Illicit Substance Use by Adolescent E-Cigarette Users Compared with Conventional Cigarette Smokers, Dual Users, and Nonusers.
Compare the lifetime prevalence of eight forms of substance use (alcohol, drunkenness, oral tobacco, snuff, sleeping pills/tranquilizers, sniffed glue, marijuana, and amphetamine) among adolescent e-cigarette (EC) users, conventional cigarette (CC) smokers, dual users, and nonusers. We analyzed population-level school-survey data collected from 10th-grade students (aged 15-16 years) in February 2015 in Iceland (N = 3,477; response rate, 84.4%). Smoking rates were similar for both sexes. Around 17% had used ECs and almost 8% had used ECs and not combustible tobacco, 5%-6% had smoked CCs but not ECs, around 9% were dual users. EC-only users were significantly more likely than nonusers to have used the eight substances investigated in the study but were less likely to have used these substances than CC smokers and dual users. The four groups assessed in this study appear to form a sequential risk gradient to the use of other substances.


Impact of CVOTs in primary and secondary prevention of kidney disease.
Type 2 diabetes mellitus is the leading cause of end stage renal disease worldwide. Diabetic kidney disease, whose main clinical manifestations are albuminuria and decline of glomerular filtration rate, affects up to 40% of patients. Sodium Glucose cotransporter-2 inhibitors (SGLT2-is) and Glucagon-like peptide-1 receptor agonists (GLP-1ras) are new classes of anti-hyperglycemic drugs which have demonstrated to improve renal outcome. Renal benefits of both SGLT2-is and GLP-1ras are acknowledged from data of large randomized phase III clinical trials conducted to assess their cardiovascular safety. In this review, we will focus on renal results of major cardiovascular outcome trials, and we will describe direct and indirect mechanisms through which they confer renal protection.


Detection and quantification of poly-ADP-ribosylated cellular proteins of spleen and liver tissues of mice in vivo by slot and Western blot immunoprobing using polyclonal antibody against mouse ADP-ribose polymer.
Poly-ADP-ribosylation (PAR) of cellular proteins has been shown to have decisive roles in diverse cellular functions including carcinogenesis. There are indications that metabolic level of poly-ADP-ribosylated cellular proteins might indicate carcinogenesis and, therefore, could be potentially used in cancer screening program. Keeping in mind the limitations of currently available assays of cellular PAR, a new assay is being reported that measures the metabolic level of poly-ADP-ribosylated cellular proteins. The ELISA based slot and Western blot immunoassay used polyclonal antibody against natural, heterogeneous ADP-ribose polymers. It could be successfully employed to qualitatively and quantitatively assay metabolic levels of poly-ADP-ribosylated proteins of spleen and liver tissues of normal mice or mice exposed to dimethylnitrosamine for up to 8 weeks; potentially PAR of cellular proteins could be assayed in any tissue or biopsy. Implications of the results in cancer screening program have been discussed.


Prostaglandin E1 infusion fails to prevent hyperoxic lung injury in adult rabbits.
Arachidonic acid (AA) metabolites may be important mediators in the hyperoxic lung injury process. We have previously demonstrated, in an adult model of hyperoxic lung injury, that bronchoalveolar lavage (BAL) fluid levels of AA metabolites of the cyclooxygenase pathway increase before evidence of overt injury. Nonselective inhibition with indomethacin or dexamethasone failed to ameliorate the injury process, possibly because production of prostaglandin I2 (PGI2) was suppressed. In this study, we attempted to ameliorate hyperoxic lung injury using an infusion of prostaglandin E1 (PGE1), since PGE1 has some of the potentially protective effects of PGI2. Thirty-two adult rabbits were exposed to greater than 95% oxygen; eight served as controls and 24 received PGE1 infusion (five, nine, and ten received 0.1, 0.06, and 0.03 micrograms/kg.min, respectively). At the end of the 65-h exposure period, BAL of the left lung was performed; the right was saved for light microscopy. PGE1 infusion at the 0.06 and 0.03-micrograms/kg.min doses resulted in significantly fewer polymorphonuclear leukocytes (PMN) in BAL fluid (p less than .05). However, PGE1 infusion did not significantly ameliorate the lung injury process. In summary, although PGE1 infusion inhibited the influx of PMN into the lung, treatment did not result in any significant amelioration of the hyperoxic lung injury process.


Pan-cancer population pharmacokinetics and exposure-safety and -efficacy analyses of atezolizumab in patients with high tumor mutational burden.
We retrospectively investigated the pharmacokinetics and exposure-efficacy/safety relationships of single-agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan-tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two-compartment intravenous-infusion population-pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high- and low-tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6-NE) months vs 15.9 (12.5-20.5) months for patients with high-tTMB vs low-tTMB tumors, respectively. A flat exposure-efficacy relationship was seen for ORR in patients with high-tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure-safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high-tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200-mg, every 3-week regimen in a tumor-agnostic high-tTMB population.


Magnetic resonance imaging of nonmetallic orbital foreign bodies.
We studied a cadaver head model in which we inserted three orbital foreign bodies. We chose these foreign bodies because of their similarity to substances found in orbital trauma. Teflon and Lucite were used to represent synthetic materials, and dry pine was chosen as a type of organic material. Lucite is similar in radiographic density to plastics used in interior trim for automobiles and spectacle frames. While both orbital ultrasound and plain skull films failed to detect the foreign bodies consistently, both computed tomography and magnetic resonance imaging detected and localized the foreign bodies relatively well. Computed tomography was better in delineating shape and characterizing composition.


Growth of the conjunctival fornix and orbital margin in term and premature infants.
Knowledge of the growth of the neonatal conjunctival fornix and anterior orbit will aid development of neonatal prosthetic conformers and conjunctival sensors for oxygen determinations, as well as help define orbital malformation syndromes. These data are not available in any prospective series in the literature. The authors studied 55 premature and term neonates and determined horizontal and vertical dimensions of the conjunctival fornix and orbital margin and palpebral fissure width. Each of the ocular parameters had statistically significant correlation coefficients in relation to weight and gestational age (P less than 0.05). Linear regression analysis showed significant relationships which predict conjunctival fornix, orbital margin, and palpebral fissure dimensions from body weight (P less than 0.05). Statistically significant correlation coefficients and linear regression relationships were found for horizontal, but not vertical, diameter measurements of the conjunctival fornix in relation to orbital margin and palpebral fissure dimensions (P less than 0.01).


Appearance of enkephalin-immunoreactivity in rat adrenal medulla following treatment with nicotinic antagonists or reserpine.
Various neuroendocrine factors known to be important in the regulation of adrenal catecholamine biosynthesis were investigated for possible effects on enkephalin-like immunoreactivity (Enk-IR) in the adrenal medulla of the rat. In normal rats, the adrenal chromaffin cells were not stained for either methionine (met-) or leucine (leu-) Enk-IR. Staining for Enk-IR appeared in many chromaffin cells following denervation of the adrenal or treatment of rats with the nicotinic receptor antagonists chlorisondamine or pempidine. These observations suggest that splanchnic nerve activity normally depresses the levels of enkephalin-like peptides in chromaffin cells through a trans-synaptic mechanism involving acetylcholine release and nicotinic receptor stimulation. Paradoxically, treatment with reserpine also increased Enk-IR in chromaffin cells. However, this increase did not appear to result from the well known effect of reserpine to increase presynaptic nerve firing and tyrosine hydroxylase (TOH) activity, since no increase in Enk-IR was observed following treatment with phenoxybenzamine or 6-hydroxydopamine, drugs which also increase TOH activity through trans-synaptic mechanisms. The reserpine effect also did not appear to be mediated by a stress-induced increase in glucocorticoid hormones since glucocorticoid therapy alone did not increase adrenal Enk-IR. It is suggested that the increase in adrenal Enk-IR following reserpine may result from a direct action of reserpine on chromaffin cells.


Bone marrow-impregnated collagen matrix for wound healing: experimental evaluation in a microcirculatory model of angiogenesis, and clinical experience.
This study aims to investigate the effect of collagen matrix impregnated with bone marrow on wound healing angiogenesis in an effective microcirculatory model and to describe our clinical experience. We used a skinfold chamber of original design which visualises microcirculation following wound creation on the dorsal skin of the mouse to establish an in vivo experimental model to estimate angiogenesis. Animals were divided into two groups: a bone marrow group (n = 6) in which bone marrow-impregnated collagen matrix was applied to the wound; and a control group (n = 7), in which collagen immersed in saline was applied, and functional capillary density was quantified during the repair process. The increase rate in functional capillary density during wound healing significantly increased in the bone marrow group on days 3, 5 and 7 after creation of the wound but no significant difference was detected on day 10. A patient with a chronic leg ulcer that had not responded to conventional therapy for 1 year was treated with autogenous bone marrow-impregnated collagen matrix and successful wound closure was obtained. The present study suggested that collagen matrix impregnated with bone marrow significantly promoted the repair process, especially in the early stage. The features of the treatment, including the possible use of a patient's own cells, simple method, immediate application without any processing procedure and preservation of the inclusive potentiality of bone marrow suspension, offer significant advantages in terms of the anticipated routine clinical use.


Modified fibula free flap harvesting technique for prevention of heterotopic pedicle ossification.
Pedicle ossification is thought to arise from the residual perieosteum left along the pedicle during the fibula free flap (FFF) harvesting. Pedicle ossification in head and neck reconstruction can cause trismus, pain on mastication/turning the neck, or neck swelling. Two patients reported in this article developed severe trismus within 6 months after mandibular reconstruction with FFF. CT scans revealed ossification along the vascular pedicle interfering with mouth opening. Both patients underwent surgical debridement of the heterotopic bone. Surgical debridement of the heterotopic bone led to the resolution of trismus in both patients with pedicle ossification. Pedicle ossification is a complication of FFF that can be effectively managed by removal of heterotopic bone. However, it is best prevented at the time of initial surgery. In this article, a new modified FFF harvesting technique is introduced to prevent pedicle ossification and reduce the ischemia time.


Bone scintigraphy of vascularized bone transfer in maxillofacial surgery.
Postoperative assessment of the viability of seven vascularized bone transfers was done in seven patients by means of radionuclide imaging within the first postoperative week. The results of a positive bone scan correlated with an uncomplicated union, with no frank failures. The two negative results both led to total failure, necessitating removal of the transferred bone. Radionuclide imaging in the first postoperative week after vascularized bone transfer appears to be a useful assessment of the anastomotic patency and the viability of the revascularized bone grafts.


Sensitive biosensor for p53 DNA sequence based on the photothermal effect of gold nanoparticles and the signal amplification of locked nucleic acid functionalized DNA walkers using a thermometer as readout.
A convenient photothermal biosensor was constructed for p53 DNA sequence detection based on the high discrimination capability of locked nucleic acid and high efficiency of signal amplification strategy of DNA walkers and difference photothermal effect between aggregated and dispersed gold nanoparticles (AuNPs). The presence of target activated the DNA walkers via the high affinity between target and complementary locked nucleic acid in the probe strand, resulting in the hybridization of the walker strand and substrate strand to form a specific enzyme recognition site. Under the cleavage of the endonuclease, single-stranded DNA (ssDNA) was released to the solution. Then the walker strand bound to a new substrate strand, and the next round of cleavage was triggered. The released ssDNA enhanced the stability of AuNPs against salt-induced aggregation. Given difference photothermal effects of the aggregated AuNPs and dispersed AuNPs under the near-infrared laser, the change of the temperature was detected by a common thermometer easily, which had a linear relationship with the target concentration in the range of 2.0-120.0 pM, the detection limit was 1.4 pM (S/N = 3). The proposed photothermal assay has been applied to detect p53 DNA sequence spiked complex samples with satisfying results.


Effects of butyrate on active sodium and chloride transport in rat and rabbit distal colon.
Short chain fatty acids, particularly butyrate, stimulate electroneutral NaCl absorption from the colon. Their effect in colonic epithelia lacking basal electroneutral NaCl absorption is unknown. Butyrate is also reported to inhibit active Cl- secretion in the colon. The present studies were undertaken to investigate the inter-relationships between the effects of butyrate on active Na+ and Cl- transport in the colon. Studies were carried out in rabbit distal colon (known to have predominant electrogenic Na+ absorption), rat distal colon (characterised by electroneutral Na+ absorption), and hyperaldosteronaemic rat distal colon (characterised by electrogenic Na+ absorption). The effect of cholera toxin (CT) was also noted. Potential difference, short-circuit current (I(SC)) and fluxes of Na+ and Cl- were measured in stripped mucosa under voltage-clamp conditions. Butyrate stimulated electroneutral Na+ and Cl- absorption in distal colon of normal and salt-depleted rats, and stimulated Na+ absorption in rabbit distal colon. Amiloride (10(-4) M) or CT did not inhibit this process. In rabbit distal colon, stimulation of Na+ absorption by butyrate was not dependent on the presence of Cl- in the medium. Butyrate significantly decreased conductance, decreased flux of sodium from serosa to mucosa (particularly in rabbit distal colon), and decreased I(SC). Net Cl- secretion, induced by CT, was completely inhibited by butyrate. Stimulation of Na+ absorption was independent of exposure to CT. Bumetanide reversed net Cl- secretion to net absorption, but did not alter Na+ or Cl- fluxes in tissues exposed to butyrate. Thus butyrate stimulates active Na+ absorption in colonic epithelia, with or without expression of basal Na+-H+ exchange. Independently, butyrate inhibits active Cl- secretion induced by cAMP in these epithelia.


Toxicity assessment of simulated urban runoff containing polycyclic musks and cadmium in Carassius auratus using oxidative stress biomarkers.
The objective of this study was to assess potential toxic effects of simulated urban runoff on Carassius auratus using oxidative stress biomarkers. The activity of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and the content of malondialdehyde (MDA) in the liver of C. auratus were analyzed after a 7-, 14- and 21-day exposure to simulated urban runoff containing galaxolide (HHCB) and cadmium (Cd). The results showed that the activity of antioxidant enzymes and the content of MDA increased significantly exposed to the simulated urban runoff containing HHCB alone or mixture of HHCB and Cd. The activity of the investigated enzymes and the content of MDA then returned to the blank level over a longer period of exposure. The oxidative stress could be obviously caused in the liver of C. auratus under the experimental conditions. This could provide useful information for toxic risk assessment of urban runoff.


Decreased lipoprotein clearance is responsible for increased cholesterol in LDL receptor knockout mice with streptozotocin-induced diabetes.
Patients with diabetes often have dyslipidemia and increased postprandial lipidmia. Induction of diabetes in LDL receptor (Ldlr(-/-)) knockout mice also leads to marked dyslipidemia. The reasons for this are unclear. We placed Ldlr(-/-) and heterozygous LDL receptor knockout (Ldlr(+/-)) mice on a high-cholesterol (0.15%) diet, induced diabetes with streptozotocin (STZ), and assessed reasons for differences in plasma cholesterol. STZ-induced diabetic Ldlr(-/-) mice had plasma cholesterol levels more than double those of nondiabetic controls. Fast-performance liquid chromatography and ultracentrifugation showed an increase in both VLDL and LDL. Plasma VLDL became more cholesterol enriched, and both VLDL and LDL had a greater content of apolipoprotein (apo)E. In LDL the ratio of apoB48 to apoB100 was increased. ApoB production, assessed using [(35)S]methionine labeling in Triton WR1339-treated mice, was not increased in fasting STZ-induced diabetic mice. Similarly, postprandial lipoprotein production was not increased. Reduction of cholesterol in the diet to normalize the amount of cholesterol intake by the control and STZ-induced diabetic animals reduced plasma cholesterol levels in STZ-induced diabetic mice, but plasma cholesterol was still markedly elevated compared with nondiabetic controls. LDL from STZ-induced diabetic mice was cleared from the plasma and trapped more rapidly by livers of control mice. STZ treatment reduced liver expression of the proteoglycan sulfation enzyme, heparan sulfate N-deacetylase/N-sulfotrasferase-1, an effect that was reproduced in cultured hepatocytyes by a high glucose-containing medium. STZ-induced diabetic, cholesterol-fed mice developed hyperlipidemia due to a non-LDL receptor defect in clearance of circulating apoB-containing lipoproteins.


Predictors of long-term clinical response in patients with non-radiographic axial spondyloarthritis receiving certolizumab pegol.
Identification of predictive clinical factors of long-term treatment response may contribute to improved management of non-radiographic axSpA (nr-axSpA) patients. This analysis aims to identify whether any baseline characteristics or Week 12 clinical outcomes in nr-axSpA patients with elevated C-reactive protein (CRP) and/or sacroiliitis on magnetic resonance imaging (MRI) enrolled in the C-axSpAnd study are predictive of achieving clinical response after 1 year of certolizumab pegol (CZP). C-axSpAnd (NCT02552212) was a phase 3, multicentre study, including a 52-Week double-blind, placebo-controlled period. Enrolled patients were randomised to CZP 200 mg Q2W or placebo. Predictors of Week 12 (CZP group only) and Week 52 clinical response were identified using a multivariate stepwise logistic regression analysis. Response variables included Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI), Assessment of SpondyloArthritis International Society 40% response (ASAS40), Bath Ankylosing Spondylitis Disease Activity Index 50% response (BASDAI50) and ASDAS inactive disease (ASDAS-ID). Predictive factors assessed included demographic and baseline characteristics and clinical outcomes at Week 12. A p-value <0.05 was required for forward selection into the model and p ≥0.1 for backward elimination. Missing data or values collected after switching to open-label treatment were accounted for using non-responder imputation. Sensitivity analyses accounted for patients with changes in non-biologic background medication. Of 317 enrolled patients, 159 and 158 were randomised to CZP and placebo, respectively. Younger age and male sex were identified as predictors of Week 12 response across all assessed efficacy outcomes in CZP-treated patients. Consistent predictors of Week 52 response, measured by ASDAS-MI, ASAS40 and BASDAI50, included human leukocyte antigen (HLA)-B27 positivity and sacroiliitis on MRI at baseline. MRI positivity was also predictive of achieving ASDAS-ID at Week 52. Sensitivity analyses were generally consistent with the primary analysis. In placebo-treated patients, no meaningful predictors of Week 52 response were identified. In this 52-Week, placebo-controlled study in nr-axSpA patients with elevated CRP and/or active sacroiliitis on MRI at baseline, MRI sacroiliitis and HLA-B27 positivity, but not elevated CRP or responses at Week 12, were predictive of long-term clinical response to CZP. Findings may support rheumatologists to identify patients suitable for TNFi treatment. ClinicalTrials.gov, NCT02552212 . Registered on 15 September 2015.


Comparative study of three herbal formulations against dengue vectors Aedes aegypti.
The efficacy of three formulations (i.e., natural lavender crude, essential oil, and gel) extracted from Lavender angustifolia was tested against vectors of the epidemic dengue virus, Aedesaegypti, to evaluate their larvicidal activity effect. The ethanolic extract of the lavender crude was prepared using a rotary evaporator, while the other extracts, such as essential oil and gel, were obtained from iHerb, a supplier of medicinal herbs in the US. The mortality rate of larvae was evaluated 24 h after exposure. Larvicidal activity of the lavender crude was 91% mortality at 150 ppm, 94% for essential oil at a concentration of 3000 ppm, and 97% for lavender gel at a 1000 ppm. Natural lavender crude was one of the most promising extracts tested against Ae.aegypti larvae, with lethal concentrations at LC50 and LC90 of 76.4 and 174.5 ppm post-treatment. The essential oil had the least effect on mosquito larvae, with LC50 and LC90 reaching 1814.8 and 3381.9 ppm, respectively. The lavender gel was moderately effective against Ae. aegypti larvae, with LC50 and LC90 values reaching 416.3 and 987.7 ppm after exposure. The occurrence of morphological abnormalities in the larvae treated with the three compounds, in turn, resulted in an incomplete life cycle. Therefore, our results indicated that natural lavender crude displayed the highest larvicidal activity against larvae, followed by gel and essential oil. Thus, this study concluded that lavender crude is an effective, eco-friendly compound that can be used as an alternative to chemical products to control vector-borne epidemic diseases.


Radiosensitivity and sublethal damage repair in human umbilical cord vein endothelial cells.
The assessment of the comparative radiosensitivity of different parenchymal cells is potentially of great importance in clinical radiotherapy. Previous studies from various laboratories using vessel regeneration techniques have demonstrated that endothelial cells are quite radioresistant, having a Do in excess of 250 rads. The present studies were undertaken to investigate the radiosensitivity of human endothelial cells obtained from umbilical cord veins (HEC) using "colony formation" as an endpoint, and to evaluate their ability to repair sublethal radiation damage (SLD). The endothelial origin of the cells in the surviving colonies was demonstrated by their positive staining for factor VIII antigen. The survival curve for HEC has a Do of about 165 rads, with a moderate initial shoulder. Dose fractionation studies demonstrate a moderate capability to repair SLD, comparable to other human cells studied including fibroblasts and other normal diploid cells in vitro. These studies indicate that HEC, being a terminally differentiated cell type with various differentiated markers, may prove useful in radiobiological and radiocarcinogenesis studies.


R-R variations, a test of autonomic dysfunction.
Beat-to-beat variation of the heart rate was studied as a test of autonomic function. Recordings were made during quiet breathing, deep breathing and tilting from supine to upright position. The heart rate variations were expressed as a % of mean R-R interval. In order to establish normal criteria, the influence of age, wakefulness and intra-individual variations was studied in healthy volunteers. A negative correlation with age was found for all measured parameters. Patients with diabetic polyneuropathy differed from age-matched controls. Patients with symptoms of autonomic failure showed smaller variations than those without such symptoms.


Radiotherapy and radiosurgery for tumors of the central nervous system.
In this article, the application of radiotherapy, alone and in combination with surgery and chemotherapy, in the treatment of metastases to the brain (the most common malignant brain lesion), primary malignant gliomas (the most common malignant primary brain tumor), and metastases to the osseous spine is reviewed. Brain metastases may be treated with surgical resection, whole-brain radiotherapy, stereotactic radiosurgery, or some combination of these treatments. The optimum treatment of brain metastases is a matter of controversy, and patient and disease factors favoring one approach over another are presented.


Neutrophil intrinsic and extrinsic regulation of NETosis in health and disease.
Neutrophil extracellular traps (NETs) evolved to protect the host against microbial infections and are formed by a web-like structure of DNA that is decorated with antimicrobial effectors. Due to their potent inflammatory functions, NETs also cause tissue damage and can favor and/or aggravate inflammatory diseases. This multipronged activity of NETs requires that the induction, release, and degradation of NETs are tightly regulated. Here we describe the key pathways that are intrinsic to neutrophils and regulate NETosis, and we review the most recent findings on how neutrophil extrinsic factors participate in the formation of NETs. In particular, we emphasize how bystander cells contribute to modifying the capacity of neutrophils to undergo NETosis. Finally, we discuss how these neutrophil extrinsic processes can be harnessed to protect the host against the excessive inflammation elicited by uncontrolled NET release.


Aortic valve cusp vessel density: relationship with tissue thickness.
The presence of a microvasculature within aortic cusps implies that tissue oxygen requirements exceed the amount deliverable by diffusion from the tissue surfaces alone. For the design of a successful tissue-engineered valve replacement, the effect of diffusion distance (tissue thickness) on oxygen delivery must be considered. We therefore examined in normal aortic valve cusps the relationship between the presence of microvessels and the tissue thickness. Thirty porcine aortic valve cusps were excised and examined after cusp microvessels were pressure filled with a carbon particle solution. Cusp images were captured for stereographic vessel density analysis, and cusp thickness was determined with a radiographic technique. Histologic cross-sections were evaluated to determine vessel depth from the cusp surface. Cusp basal regions measured 0.69 to 0.86 mm in thickness, significantly thicker (P =.001) than the rest of the cusp, which measured 0.36 to 0.48 mm. In general a vascular bed was present when cusp thickness exceeded 0.5 mm, with a median value of 5.16 vessels/mm(3). From published values of arterial wall oxygen consumption and diffusivity, we predicted that the probable maximum oxygen diffusion distance for valve tissue would be about 0.2 mm. This was consistent with our physical findings, which implies that central tissue anoxia is avoided by the capillary bed. An avascular tissue-engineered valve metabolically similar to an aortic valve should therefore not exceed a thickness of approximately 0.40 mm.


Administration of recombinant Reishi immunomodulatory protein (rLZ-8) diet enhances innate immune responses and elicits protection against nervous necrosis virus in grouper Epinephelus coioides.
Nervous necrosis virus (NNV) infection during larvae and juvenile stage in grouper (Epinephelus coioides) has caused severe economic losses in the aquaculture industry in Asia. The aims of this study were to evaluate the influence of recombinant Reishi protein, rLZ-8, on the innate immune responses and the viral resisting ability in fish. Groupers were fed with rLZ-8 supplemented diet (1.25-37.5 mg (rLZ-8)/kg(diet)), and the cytokine gene expression, innate immune responses, and survival rate after NNV challenge were examined. The fish fed with rLZ-8 diet showed 6- to 11-fold upregulated TNF-α and IL-1β gene expression, along with significant increased respiratory burst and phagocytic activity. Moreover, feeding the fish with 37.5 mg/kg rLZ-8 diet elicited significant improvement in post viral challenge survival rate (85.7%). These discoveries indicated that rLZ-8 could be utilized as an ant-pathogen immunostimulant, and provided a new candidate to fight against NNV infection in fish.


Ambulatory blood pressure monitoring and cardiovascular reactivity testing for the evaluation of the role of psychosocial factors and prognosis in hypertensive patients.
This article reviews the contributions of laboratory-based reactivity testing and ambulatory blood pressure monitoring in the evaluation of the role of psychosocial factors in hypertension. Reactivity testing is ideally suited for evaluating individual differences in susceptibility to the acute effects of stressors but cannot resolve the question regarding whether stressors in everyday life contribute to a sustained elevation of pressure. Although several associations between increased reactivity and hypertension have been demonstrated, they do not necessarily imply a primary role for behavioral factors. Ambulatory monitoring is ideally suited for studying the effects of everyday stressors and has shown that blood pressure may increase as a result of occupational stress. On the grounds that hypertension results from an interaction of genetic and environmental factors, it is argued that both techniques have their place and that the role of psychosocial factors can best be demonstrated by prospective studies of persons exposed to different levels of stress.


The effect of calcitriol on high mobility group box 1 expression in periodontal ligament cells during orthodontic tooth movement in rats.
High mobility group box 1 (HMGB1) is a late inflammatory cytokine that plays an important role in periodontal tissue remodeling during orthodontic tooth movement. Calcitriol (1,25-dihydroxyvitamin D3 [1α,25 (OH)2D3]) is a systemic calcium-regulating hormone shown to downregulate expression of multiple proinflammatory cytokines in human periodontal ligament cells in response to orthodontic force. The purpose of this study was to investigate the effect of 1α,25(OH)2D3 on the expression of HMGB1 in periodontal ligament (PDL) cells during orthodontic tooth movement. Seven-week-old male Wistar rats were used for experimentation. Tooth movement was assessed using a nickel-titanium coil spring to apply mechanical loading to the tooth for 5 days. This was followed by administration of either 1α,25(OH)2D3 or normal saline by gavage every other day for up to 28 days. Immunohistochemistry was used to analyze the expression of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and HMGB1. After discontinuation of orthodontic force, expression of the early inflammatory cytokines IL-6 and TNF-α were time-dependently reduced in the 1α,25(OH)2D3 group compared with the control group at each time point. Similarly, expression of HMGB1 was decreased over time in both the 1α,25(OH)2D3 and normal saline groups, and 1α,25(OH)2D3 administration enhanced this decline. These findings indicate that administration of 1α,25(OH)2D3 might provide a favorable microenvironment for orthodontic tooth movement by downregulating expression of HMGB1 in PDL cells.


Haematological disorders and lung alveolar macrophage function following total parenteral nutrition in rats.
Alterations in haematological parameters have been reported both clinically and experimentally following administration of total parenteral nutrition (TPN). Fat emulsions also affect function of the mononuclear phagocytic system. We have examined haematological parameters and pulmonary alveolar macrophages in rats fed intravenously with the individual components of TPN; a 20 % fat emulsion (Intralipid) and an amino acid solution (Vamin-Glucos), for 1, 3 and 7 days as a continuous infusion. The control groups were given saline infusion for the same periods of time. Haemoglobin, haematocrit, red blood cells, leukocytes, leukocyte superoxide anion production, leukocyte distribution, platelets and platelet aggregation were measured. Lung lavage fluid was examined for alveolar macrophage concentration and procoagulant activity of macrophages. Several of the animals in the experimental groups developed superior caval vein thrombosis. Both experimental groups developed anaemia after 7 days of infusion. Thrombocytopaenia occurred in both experimental groups after 3 and 7 days of infusion. Platelet aggregation decreased already after 1 day of infusion. We did not observe any alteration in counts, distribution in peripheral blood, or superoxide production of leukocytes. The concentration of alveolar macrophages in the lung lavage fluid increased in the experimental groups. The tissue factor activity of the alveolar macrophages increased in the group receiving Intralipid. Our observations are consistent with a granulomatous inflammation reaction.


Influence of an internal trifluoromethyl group on the rhodium(II)-catalyzed reactions of vinyldiazocarbonyl compounds.
Incorporation of a trifluoromethyl group into the structure of 4-(alkoxycarbonyl)vinyldiazocarbonyl compounds greatly decreases the tendency of the carbenoid intermediates formed during Rh(II)-catalyzed reactions to undergo intermolecular processes. Instead, they are prone to experience intramolecular [1,5]- and [1,3]-electrocyclizations to produce reactive cyclopropenes and furans, and these are capable of further transformations.


Extrahepatic bile duct cancer and smoking, beverage consumption, past medical history, and oral-contraceptive use.
Information on potential causal factors in 67 patients with histologically confirmed cancer of the extrahepatic bile ducts was compared with that from 273 patients with other cancers. The control group did not include subjects with tobacco- or alcohol-related cancers. The study subjects were interviewed at 11 large hospitals in eastern Massachusetts and Rhode Island between 1975 and 1979. Among the patients with extrahepatic bile duct cancer, the male-female ratio was 1.5. The use of cigarettes was associated with decreased risk of extrahepatic bile duct cancer. The use of alcohol and coffee was not related to risk of extrahepatic bile duct cancer. Fewer patients than controls reported tea consumption. A statistically significant association between the use of oral contraceptives and extrahepatic bile duct cancer was observed among women under 60 years of age. Patients reported significantly higher frequencies of history of ulcerative colitis or diseases of the gallbladder.


Effect of submucosal injection of dexamethasone after third molar surgery: a meta-analysis of randomized controlled trials.
The aim of this meta-analysis was to analyse the effectiveness of submucosal injection of dexamethasone to control the postoperative signs and symptoms resulting from impacted third molar surgery. An electronic search was conducted, without restriction on date or language, in the PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases until June 2015 . The eligibility criteria included non-randomized or randomized clinical trials in humans. After the search and selection process, eight articles were included. The fixed-effects or random-effects model, depending on heterogeneity, was built on the inverse-variance method used. The estimations of intervention were expressed as the mean difference (MD) in millimetres. The results of this meta-analysis suggest that the submucosal injection of dexamethasone presents a reduction in the postoperative signs and symptoms resulting from impacted third molar surgery, especially those associated with oedema and pain. In relation to trismus, the meta-analysis showed no statistically significant difference between dexamethasone and the placebo solution.


A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation.
The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin β subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin β tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin β subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in αIIbβ3 integrin activation, but not for kindlin binding to integrin β tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well β-integrin tails contribute to the ability of kindlins to activate integrins.


Cell Profiling Based on Sugar-Chain-Cell Binding Interaction and Its Application to Typing and Quality Verification of Cells.
Developing methods to determine cell type and cell state has been a significant challenge in the field of cancer diagnosis as well as in typing and quality verification for cultured cells. Herein, we report a cell profiling method based on binding interactions between cell-surface sugar-chain-binding proteins and sugar-chain-immobilized fluorescent nanoparticles (SFNPs), together with a method for cell typing and cell quality verification. Binding profiles of cells against sugar chains were analyzed by performing flow cytometry analysis with SFNPs. Discrimination analysis based on binding profiles could classify cell type and evaluate the quality of cultured cells. By applying our method to differentiated cells originating from conventional cell lines and also to mouse embryotic stem cells, we could detect the cells before and after differentiation. Our method can be utilized not only for the biofunctional analysis of cells but also for diagnosis of cancer cells and quality verification of cultured cells.


Relationship Between Ultraprocessed Food Intake and Cardiovascular Health Among U.S. Adolescents: Results From the National Health and Nutrition Examination Survey 2007-2018.
Studies of the association between ultraprocessed foods (UPF) and cardiovascular disease risk factors have been mainly focused on the adult population. This study examined the association between usual percentage of calories (%kcal) from UPF and the American Heart Association's seven cardiovascular health (CVH) metrics among U.S. adolescents aged 12-19 years. We used data from the National Health and Nutrition Examination Survey 2007-2018 (n = 5,565). The NOVA food system was used to classify UPF according to the extent and purpose of food processing. Each CVH metric was given a score of 0, 1, or 2 (poor, intermediate, or ideal health, respectively). Scores of six metrics were summed (excluding diet) to categorize CVH as low (0-7), moderate (8-10), or high (11-12). The National Cancer Institute's methods were used to estimate usual %kcal from UPF. Multivariable linear regression and multinomial logistic regression were used to evaluate the association between UPF and CVH. Among youth, 12.1% had low CVH, 56.3% moderate, and 31.6% high. The mean usual %kcal from UPF was 65.7%. Every 5% increase in calories from UPF was associated with .13 points lower CVH scores (p < .001). Comparing Q2, Q3, and Q4 to Q1 of UPF intake, the adjusted odds ratios for low versus high CVH were 1.43 (95% confidence interval 1.16-1.76), 1.86 (1.29-2.66), and 2.59 (1.49-4.55), respectively. The pattern of association was largely consistent across subgroups. U.S. adolescents consume about two thirds of daily calorie from UPF. There was a graded inverse association between %kcal from UPF and CVH score.


Fatigue in multiple-car fatal accidents.
In a re-examination of 334 fatal multiple car accidents, without any reasonable explanation besides possible intoxication, 205 drivers were found responsible for the accident. Twenty-one of these accidents happened between midnight and 0600 h and 11 of the drivers were found to be intoxicated with a blood/alcohol content (BAC) of more than 0.080%. The remaining 184 accidents took place during the rest of the day and 55 drivers were intoxicated. By comparing this apparent over-representation of intoxicated drivers in night-time accidents with that of a control group of no less than 15,923 drivers, it was possible to convert this over-representation into an under-representation. This decline in accidents while under influence seems to indicate another human accident factor specific to night-time traffic. It is concluded that fatigue is an overlooked but most obvious cause of otherwise unexplainable accidents in the night-time traffic.


Comparison of the healing and revascularization of onlayed autologous and lyophilized allogeneic rib grafts to the edentulous maxilla.
The healing and revascularization of onlayed autologous and lyophilized allogeneic rib grafts to the edentulous maxilla in the Macaca fascicularis monkey were studied using clinical, histologic, and microangiographic methods at varying intervals of up to eight months. Results indicated that healing and revascularization were similar but resorption of the allografts occurred approximately three months later than resorption of the autografts. Both grafting systems appeared to have minimal osteogenic potential. Osteoinduction and the final bony augmentation obtained were less than were seen with comparable autologous and allogeneic interpositional grafts.


One-year water-ageing of calcium phosphate composite containing nano-silver and quaternary ammonium to inhibit biofilms.
Dental composites are commonly used restorative materials; however, secondary caries due to biofilm acids remains a major problem. The objectives of this study were (1) to develop a composite containing quaternary ammonium dimethacrylate (QADM), nanoparticles of silver (NAg), and nanoparticles of amorphous calcium phosphate (NACP), and (2) to conduct the first investigation of the mechanical properties, biofilm response and acid production vs water-ageing time from 1 day to 12 months. A 4 × 5 design was utilized, with four composites (NACP-QADM composite, NACP-NAg composite, NACP-QADM-NAg composite, and a commercial control composite), and five water-ageing time periods (1 day, and 3, 6, 9, and 12 months). After each water-ageing period, the mechanical properties of the resins were measured in a three-point flexure, and antibacterial properties were tested via a dental plaque biofilm model using human saliva as an inoculum. After 12 months of water-ageing, NACP-QADM-NAg had a flexural strength and elastic modulus matching those of the commercial control (P>0.1). Incorporation of QADM or NAg into the NACP composite greatly reduced biofilm viability, metabolic activity and acid production. A composite containing both QADM and NAg possessed a stronger antibacterial capability than one with QADM or NAg alone (P<0.05). The anti-biofilm activity was maintained after 12 months of water-ageing and showed no significant decrease with increasing time (P>0.1). In conclusion, the NACP-QADM-NAg composite decreased biofilm viability and lactic acid production, while matching the load-bearing capability of a commercial composite. There was no decrease in its antibacterial properties after 1 year of water-ageing. The durable antibacterial and mechanical properties indicate that NACP-QADM-NAg composites may be useful in dental restorations to combat caries.