Elevated plasma phenylalanine predicts mortality in critical patients with heart failure.
Previous studies found a relationship between elevated phenylalanine levels and poor cardiovascular outcomes. Potential strategies are available to manipulate phenylalanine metabolism. This study investigated whether increased phenylalanine predicted mortality in critical patients with either acute heart failure (HF) or acute on chronic HF, and its correlation with inflammation and immune cytokines. This study recruited 152 subjects, including 115 patients with HF admitted for critical conditions and 37 normal controls. We measured left ventricular ejection fraction (LVEF), plasma concentrations of phenylalanine, C-reactive protein, albumin, pre-albumin, transferrin, and pro-inflammatory and immune cytokines. Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), and maximal vasoactive-inotropic scores (VISmax ) were calculated. Patients were followed up until death or a maximum of 1 year. The primary endpoint was all-cause death. Of the 115 patients, 37 (32.2%) were admitted owing to acute HF, and 78 (67.8%) were admitted owing to acute on chronic HF; 64 (55.7%) had ST elevation/non-ST elevation myocardial infarction. An LVEF measured during the hospitalization of <40%, 40-50%, and ≥50% was noted in 51 (44.3%), 15 (13.1%), and 49 (42.6%) patients, respectively. During 1 year follow-up, 51 (44.3%) patients died. Death was associated with higher APACHE II, SOFA, and VISmax scores; higher levels of C-reactive protein and phenylalanine; higher incidence of atrial fibrillation and use of inotropic agents; lower cholesterol, albumin, pre-albumin, and transferrin levels; and significant changes in pro-inflammatory and immune cytokines. Phenylalanine levels demonstrated an area under the receiver operating characteristic curve of 0.80 for mortality, with an optimal cut-off value set at 112 μM. Phenylalanine ≥ 112 μM was associated with a higher mortality rate than was phenylalanine < 112 μM (80.5% vs. 24.3%, P < 0.001) [hazard ratio = 5.07 (2.83-9.05), P < 0.001]. The Kaplan-Meier curves revealed that phenylalanine ≥ 112 μM was associated with a lower accumulative survival rate (log rank = 36.9, P < 0.001). Higher phenylalanine levels were correlated with higher APACHE II and SOFA scores, higher C-reactive protein levels and incidence of using inotropic agents, and changes in cytokines suggestive of immunosuppression, but lower levels of pre-albumin and transferrin. Further multivariable analysis showed that phenylalanine ≥ 112 μM predicted death over 1 year independently of age, APACHE II and SOFA scores, atrial fibrillation, C-reactive protein, cholesterol, pre-albumin, transferrin, and interleukin-8 and interleukin-10. Elevated phenylalanine levels predicted mortality in critical patients, phenotypically predominantly presenting with HF, independently of traditional prognostic factors and cytokines associated with inflammation and immunity.


Different dynamics of CD4+ and CD8+ T cell responses during and after acute lymphocytic choriomeningitis virus infection.
We fit a mathematical model to data characterizing the primary cellular immune response to lymphocytic choriomeningitis virus. The data enumerate the specific CD8(+) T cell response to six MHC class I-restricted epitopes and the specific CD4(+) T cell responses to two MHC class II-restricted epitopes. The peak of the response occurs around day 8 for CD8(+) T cells and around day 9 for CD4(+) T cells. By fitting a model to the data, we characterize the kinetic differences between CD4(+) and CD8(+) T cell responses and among the immunodominant and subdominant responses to the various epitopes. CD8(+) T cell responses have faster kinetics in almost every aspect of the response. For CD8(+) and CD4(+) T cells, the doubling time during the initial expansion phase is 8 and 11 h, respectively. The half-life during the contraction phase following the peak of the response is 41 h and 3 days, respectively. CD4(+) responses are even slower because their contraction phase appears to be biphasic, approaching a 35-day half-life 8 days after the peak of the response. The half-life during the memory phase is 500 days for the CD4(+) T cell responses and appears to be lifelong for the six CD8(+) T cell responses. Comparing the responses between the various epitopes, we find that immunodominant responses have an earlier and/or larger recruitment of precursors cells before the expansion phase and/or have a faster proliferation rate during the expansion phase.


4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism.
SSADH deficiency, a rare inborn error of human metabolism, disrupts the normal metabolism of the inhibitory neurotransmitter GABA. In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Clinical and bio-chemical findings in patients are contrasted with existing neuropharmacologic data on GHB in animals and men. We conclude that GHB contributes to the pathogenesis of SSADH deficiency; whether this effect is mediated by GHB, by GABA following metabolic interconversion, or via synergistic mechanisms by both compounds, remains to be determined. An animal model of SSADH deficiency should further define the role of GHB in the pathogenesis of SSADH deficiency, and provide a useful vehicle for the evaluation of new therapeutic intervention.


Simultaneous Determination of Nine Active Compounds of the Traditional Chinese Medicinal Prescription Shaoyao-Gancao-Tang and Analysis of the Relationship between Therapeutical Effect and Compatibility of Medicines.
A simple and sensitive HPLC-DAD detection method was established for the simultaneous determination of nine compounds including oxypaeoniflorin, albiflorin, paeoniflorin, benzoylpaeoniflorin, glycyrrhizic acid, liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin in the Traditional Chinese Medicinal Prescription Shaoyao-Gancao-Tang (SGT) and we analyze the relationship between therapeutical effect and compatibility of medicines by using an Agilent extend-C18 column at a flow rate of 1 mL/min. The column temperature was maintained at 30°C and the detection wavelength was set at 230 nm for oxypaeoniflorin, albiflorin, paeoniflorin, benzoylpaeoniflorin, and glycyrrhizic acid; 276 nm for liquiritin and liquiritigenin; 360 nm for isoliquiritin and isoliquiritigenin. The total contents of the nine compounds in SGT varied from 4.65 to 20.06 mg/mL. The results of this study showed that the content of chemical compounds of Traditional Chinese Medicinal Prescription is mainly influenced by the dosage and compatibility of medicines and the therapeutical effect of Traditional Chinese Medicinal prescription is mainly influenced by the dosage and compatibility of medicines. The method could be suitable for quality control of SGT with bioactive multicompounds.


Systematic Analysis of Pharmaceutical Preparations of Chondroitin Sulfate Combined with Glucosamine.
Glycosaminoglycans are carbohydrate-based compounds widely employed as nutraceuticals or prescribed drugs. Oral formulations of chondroitin sulfate combined with glucosamine sulfate have been increasingly used to treat the symptoms of osteoarthritis and osteoarthrosis. The chondroitin sulfate of these combinations can be obtained from shark or bovine cartilages and hence presents differences regarding the proportions of 4- and 6-sulfated N-acetyl β-d-galactosamine units. Herein, we proposed a systematic protocol to assess pharmaceutical batches of this combination drug. Chemical analyses on the amounts of chondroitin sulfate and glucosamine in the batches were in accordance with those declared by the manufacturers. Anion-exchange chromatography has proven more effective than electrophoresis to determine the type of chondroitin sulfate present in the combinations and to detect the presence of keratan sulfate, a common contaminant found in batches prepared with shark chondroitin sulfate. 1D NMR spectra revealed the presence of non-sulfated instead of sulfated glucosamine in the formulations and thus in disagreement with the claims declared on the label. Moreover, 1D and 2D NMR analyses allowed a precise determination on the chemical structures of the chondroitin sulfate present in the formulations. The set of analytical tools suggested here could be useful as guidelines to improve the quality of this medication.


[BIOMECHANICAL SUBSTANTIATION OF ONE-AXIS DEFORMITY OF ADIPOSE-CUTANEOUS FLAPS OF TEMPORAL AND ZYGOMATIC AREAS WHILE PERFORMANCE OF UPPER RHYTIDOPLASTY].
The urgency of the problem of determining the biomechanical features adipose-cutaneous grafts due to a significant increase in the frequency of performing cosmetic surgery and the lack of a unified concept for such interventions. In 32 women aged 35 to 65 years, which will eliminate the excess soft tissues in the implementation ritidectomy and other surgical interventions, isolated patches of adipose-cutaneous flaps to determine the mechanisms of its plastic deformation. Based on the analysis of biomechanical research targeted the optimal stretching the boundaries of adipose-cutaneous flaps zygomatic--to (0.45 ± 0.021) cm and temporal--by (0.0165 ± 0.002) cm refer to areas that allowed to perform surgery with preservation of natural topographoanatomic relations persons in the performance of the upper ritidectomy.


Merging Carbonyl Addition with Photocatalysis.
The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents β-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.


European multicentre pilot survey to assess vitamin D status in rheumatoid arthritis patients and early development of a new Patient Reported Outcome questionnaire (D-PRO).
To collect data on vitamin D (25(OH)D) serum levels in a large number of rheumatoid arthritis (RA) patients from different European countries, to investigate their relation with disease activity, disability, quality of life, and possibly to construct a new Patient Reported Outcome (PRO) questionnaire in order to self-estimate if they are at risk for vitamin D insufficiency/deficiency-related clinical implications (D-PRO). This was a European League Against Rheumatism (EULAR) supported cross-sectional study (project No CLI064) which involved 625 RA patients (mean age 55±11years, mean disease duration 11±9years), 276 age and sex matched healthy subjects, and rheumatologists working in academic institutions or hospital centres, as well as PARE organizations (patient representatives) from 13 European countries. Serum samples for 25(OH)D level measurement were collected during winter time and analyzed in a central laboratory using chemiluminescence immunoassay (DiaSorin). Patient past medical history was recorded. RA patients were provided with three questionnaires: the Rheumatoid Arthritis Impact Diseases score (RAID), the Health Assessment Questionnaire (HAQ), and the new D-PRO questionnaire at the time of 25(OH)D serum sampling. D-PRO questionnaire consisted of three domains, Symptom Risk Score (SRS), Habitus Risk Score (HRS) and Global Risk Score (SRS+HRS=GRS), constructed with items possibly related to vitamin D deficiency. D-PRO was correlated with both clinical and PRO scores. DAS28-CRP was also evaluated. Statistical analysis was performed by non parametric tests. Mean serum concentration of 25(OH)D in RA patients (17.62±9.76ng/ml) was found significantly lower if compared to the levels obtained in matched controls (18.95±9.45ng/ml) (p=0.01), with statistically significant differences among several European countries. Negative correlations were found between 25(OH)D serum levels and DAS28-CRP (p<0.001), RAID (p=0.05) and HAQ (p=0.04) scores in the RA patients group. Negative correlations were also found in the cohort of enrolled RA patients between 25(OH)D serum concentrations and SRS (p=0.04), HRS (p=0.02) and GRS (p=0.02) domains of the D-PRO questionnaire. This first multicentre European survey add new evidences that vitamin D insufficiency/deficiency is frequent in RA patients with statistically significant differences among several countries. Vitamin D serum concentrations seem to correlate negatively and significantly with the D-PRO Global Risk Score, clinimetric indexes for quality of life, disease activity and disability in present cohort of RA European patients.


(1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-Bisfunctionalized 3- and 4-PEG: Synthesis and Photophysical Studies.
Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.


Sound Insulation in a Hollow Pipe with Subwavelength Thickness.
Suppression of the transmission of undesired sound in ducts is a fundamental issue with wide applications in a great variety of scenarios. Yet the conventional ways of duct noise control have to rely on mismatched impedance or viscous dissipation, leading the ducts to have ventilation capability weakened by inserted absorbers or a thick shell to accommodate bulky resonators. Here we present a mechanism for insulating sound transmission in a hollow pipe with subwavelength thickness, by directly reversing its propagating direction via anomalous reflection at the flat inner boundary with well-designed phase profile. A metamaterial-based implementation is demonstrated both in simulation and in experiment, verifying the theoretical prediction on high-efficient sound insulation at the desired frequencies by the resulting device, which has a shell as thin as 1/8 wavelength and an entirely open passage that maintains the continuity of the background medium. We have also investigated the potential of our scheme to work in broadband by simply cascading different metamaterial unit cells. Without the defects of blocked path and bulky size of existing sound insulators, we envision our design will open new route to sound insulation in ducts and have deep implication in practical applications such as designs of ventilation fans and vehicle silencers.


Reirradiation for Recurrent Scalp Angiosarcoma: Dosimetric Advantage of PBT over VMAT and EBT.
Reirradiation in the scalp area can be challenging given the proximity to organs at risk (OARs), such as the eye and brain. Our aim is to evaluate the dosimetric differences of volumetric modulated arc therapy (VMAT) and electron beam therapy (EBT) compared with 3-dimensional proton beam therapy (PBT). We evaluated a patient with recurrent angiosarcoma of the left temporal scalp after prior surgical resections and radiation therapy to 60 Gy in 30 fractions who needed reirradiation. We generated VMAT, EBT, and PBT plans using the Pinnacle Treatment Planning System (TPS). Both VMAT and EBT plans used a skin bolus, whereas no bolus was used for the proton plan. Doses to the OARs, including cochlea, eyes, lens, lacrimal glands, optic nerves, optic chiasm, pituitary gland, and underlying brain, were compared. The reirradiation treatment dose was 60 Gy(RBE). Target volume coverage was comparable in all plans. Compared with VMAT and EBT, the PBT plan showed reductions in mean and maximum doses to all OARs. Without the use of protons, several OARs would have exceeded dose tolerance utilizing VMAT or electrons. Dose reduction of up to 100% was achieved for central and contralateral OARs. Compared with VMAT and EBT, PBT resulted in dose reductions to all OARs, while maintaining excellent target coverage. PBT showed a significant advantage in treating superficially located skin cancers, such as angiosarcoma, without the need for a bolus. PBT can be considered in the upfront treatment and certainly in the reirradiation setting.


[Evaluation of Anterior Segment Parameters of Hyperopia of School-aged Children Using Anterior Segment Optical Coherence Tomography].
The aim of this study was to investigate the feasibility of anterior segment optical coherence tomography to assess the anterior segment morphology of hyperopia in school-aged children. 320 eyes of 160 school-aged children, 6-12 years of age, were examined with anterior segment optical coherence tomography and were divided into four groups according to the cycloplegic spherical equivalence of refractive error. The mentioned four groups were: emmetropia group, low hyperopia group, moderate hyperopia group and high hyperopia group. The measurements of central corneal thickness, anterior chamber depth, angle opening distance, trabecular iris space area and scleral angle were compared in pairs among objects in the four groups. The results showed that high hyperopia and moderate hyperopia had shallower anterior chamber depth and narrower anterior chamber angle compared to those in emmetropia group. The study also showed that anterior segment optical coherence tomography as a non-contact technology could become a new technology for accessing the anterior segment morphology of hyperopia in school-aged children.


Laminin fragments conjugated with perlecan's growth factor-binding domain differentiate human induced pluripotent stem cells into skin-derived precursor cells.
Deriving stem cells to regenerate full-thickness human skin is important for treating skin disorders without invasive surgical procedures. Our previous protocol to differentiate human induced pluripotent stem cells (iPSCs) into skin-derived precursor cells (SKPs) as a source of dermal stem cells employs mouse fibroblasts as feeder cells and is therefore unsuitable for clinical use. Herein, we report a feeder-free method for differentiating iPSCs into SKPs by customising culture substrates. We immunohistochemically screened for laminins expressed in dermal papillae (DP) and explored the conditions for inducing the differentiation of iPSCs into SKPs on recombinant laminin E8 (LM-E8) fragments with or without conjugation to domain I of perlecan (PDI), which binds to growth factors through heparan sulphate chains. Several LM-E8 fragments, including those of LM111, 121, 332, 421, 511, and 521, supported iPSC differentiation into SKPs without PDI conjugation. However, the SKP yield was significantly enhanced on PDI-conjugated LM-E8 fragments. SKPs induced on PDI-conjugated LM111-E8 fragments retained the gene expression patterns characteristic of SKPs, as well as the ability to differentiate into adipocytes, osteocytes, and Schwann cells. Thus, PDI-conjugated LM-E8 fragments are promising agents for inducing iPSC differentiation into SKPs in clinical settings.


Genome-wide association mapping and Identification of candidate genes for fatty acid composition in Brassica napus L. using SNP markers.
B. napus (oilseed) is an important source of edible vegetable oil, and its nutritional and economic value is determined by its fatty acid composition and content. Using the Brassica 60 K SNP array, we performed a genome-wide association study of fatty acid composition in a population of 520 genetically diverse oilseed accessions. Using the PCA + K model in TASSEL 5.2.1, we identified 62 genomic regions that were significantly associated with the composition of seven fatty acids, and five consensus regions that mapped to the A2, A8, A9, C1, and C3 chromosomes, respectively, of the Brassica napus Darmor-bzh genome. We then identified 24 orthologs of the functional candidate genes involved in fatty acid biosynthesis, excluding BnaA.FAE1 and BnaC.FAE1 on the A8 and C3 homologous genome blocks, which are known to have critical roles in the fatty acid biosynthesis pathway, and potential orthologs of these genes (e.g., LACS9, KCR1, FAB1, LPAT4, KCS17, CER4, TT16, and ACBP5). Our results demonstrate the power of association mapping in identifying genes of interest in B. napus and provide insight into the genetic basis of fatty acid biosynthesis in B. napus. Furthermore, our findings may facilitate marker-based breeding efforts aimed at improving fatty acid composition and quality in B. napus.


Multifunctional LUV liposomes decorated for BBB and amyloid targeting - B. In vivo brain targeting potential in wild-type and APP/PS1 mice.
Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140-148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain/liver+spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies.


Dexamethasone acts as a negative regulator of epidermal growth factor receptor synthesis in fetal rat lung cells.
125I-Epidermal growth factor (EGF) binding capacity in fetal rat lung cells is decreased by approximately 50% following 24-h dexamethasone treatment. Ligand binding assays identified an average of 30,000 receptors per cell in untreated FRL cells, while analysis of dexamethasone treated cells showed a decrease to about 16,000 receptors per cell. No substantial changes in receptor affinities were detected. Immunoprecipitation of 35S-methionine-labeled EGF receptor protein demonstrated a 50% decrease in total EGF receptor protein after 24-h dexamethasone treatment. Brief pulse labeling with 35S-methionine showed that the reduction in total EGF receptor protein content was due to a decrease in EGF receptor synthesis. Receptor synthesis declined about 25% after 1 h of dexamethasone treatment and at 3 h, EGF receptor synthesis was maximally decreased to nearly 50% that of cells not exposed to dexamethasone. Dexamethasone treatment was also effective in reducing EGF receptor synthesis in cells pretreated with retinoic acid, an agent which enhances receptor synthesis. These data are the first to document a dexamethasone-induced decrease in EGF receptor synthesis. Furthermore, these findings may provide a plausible mechanism by which dexamethasone could regulate EGF responsiveness.


Effect of alcohol on glucose tolerance in normal and noninsulin-dependent diabetic subjects.
Oral glucose tolerance tests were conducted in 10 noninsulin-dependent diabetic and 14 healthy control subjects with a 75-g glucose load. The tests were repeated 1 week later with 43 g of ethanol mixed with the glucose. Blood samples were analyzed for ethanol, glucose, insulin, C-peptide, and glucagon levels. The blood ethanol peak was nearly equal in diabetic and control subjects (mean +/- SEM values of 55 +/- 8 and 48 +/- 6 mg/dl 45 min after ethanol ingestion). Ethanol did not affect glucose tolerance in either of the study groups. Mean +/- SEM values of the sum of the increment above the baseline glucose level were 659 +/- 48 vs. 675 +/- 76 mg/dl with or without ethanol in diabetics and 227 +/- 35 vs. 244 +/- 36 mg/dl in control subjects. The plasma insulin and C-peptide responses to glucose were delayed in diabetic patients compared to controls but were not affected by ethanol. In vitro, ethanol, at a concentration of 100 mg/dl or greater, significantly decreased insulin binding to erythrocytes in a dose-related manner. Scatchard analysis of competitive insulin binding to erythrocytes indicated that ethanol reduced insulin binding affinity (1.6 +/- 0.5 vs. 4.2 +/- 0.8 x 10(8)/M), but not binding capacity (4.5 +/- 2.4 vs. 4.4 +/- 1.7 nM, with and without ethanol, respectively).


Etiology analysis of nonspecific chronic cough in children of 5 years and younger.
This study aims to analyze the etiology of nonspecific chronic cough in children of 5 years and younger, in order to improve the diagnostic and treatment levels of pediatricians for nonspecific chronic cough in young children.The clinical data of 85 cases of children of 5 years old and below, who suffered from nonspecific chronic cough between the period of January 2015 and August 2016 were retrospectively analyzed.The etiology distribution of 85 cases of children with nonspecific chronic cough were as follows: 27 cases had cough variant asthma (31.8%), 32 cases had upper airway cough syndrome (37.6%), 16 cases had cough after infection (18.8%), 3 cases had gastroesophageal reflux cough (3.5%), 2 cases had allergic cough (2.4%), and 5 cases had unknown causes of cough (5.9%).The main composition ratio of the etiology of chronic cough in children of 5 years old and below is as follows (in sequence): upper airway cough syndrome, cough variant asthma, and post infection cough.


The effects of sensory denervation on the responses of the rabbit eye to prostaglandin E1, bradykinin and substance P.
1 Six to eight days after diathermic destruction of the fifth cranial nerve in the rabbit, the ocular hypertensive and miotic responses to intracameral administration of capsaicin, bradykinin, and prostaglandin E1 were greatly reduced or completely abolished. The response to substance P was not abolished. 2 A response could still be obtained to chemical irritants 36 h after coagulation of the nerve and it is deduced that manifestation of the response is dependent upon functional sensory nerve terminals, and is independent of central connections. 3 It is suggested that prostaglandin E1 and bradykinin act directly upon the sensory nerve endings and that propagation of the response is augmented by axon reflex. 4 In view of the ability of substance P to induce miosis in the denervated eyes, it is presumed that its actions are not mediated via sensory nerves. 5 It is considered possible that the mediator(s) released from sensory nerve endings after chemical irritation or antidromic stimulation may act in the same way as substance P with regard to the miotic effect. 6 Synthetic substance P will only produce ocular hypertension in doses which induce a maximal miotic response. This may either be a question of access or a partial resemblance to the endogenous mediator.


[Immunotherapy for brain tumors: obstacles and perspectives].
Glioblastomas are highly aggressive tumors. Their prognosis remain poor despite standard therapies combining surgery, radiation and temozolomide based chemotherapy. Among innovating strategies, there is a major interest for immunotherapy. During the past 3 decades, there has been a general scepticism concerning the efficacy of this approach. But the latest achievements, such as immune checkpoint inhibitors in solid tumors, and adoptive cell therapy in hematologic malignancies, have radically changed the face of the field and have already an impact on the daily practice. To which extent these advances have an impact for brain tumors also? This article aims to present the principal clinical applications of the various immune therapies currently under investigation in neurooncology and give an insight on the future perspectives in the field.


Herbaspirillum piri sp. nov., isolated from bark of a pear tree.
A Gram-stain-negative, aerobic, motile bacterial strain, shQ-4T, was isolated from a pear tree in Henan Province, China. The strain grew at 10-41 °C, at pH 4.0-8.0 and in the presence of 1-3 % (w/v) NaCl. It shared highest 16S rRNA gene sequence similarity (96.66 %) with Herbaspirillum chlorophenolicum CPW301T. The phylogenetic tree based on 16S rRNA gene sequences showed that strain shQ-4T formed a distinct branch next to reference species in the genus Herbaspirillum. The profile of major polar lipids of strain shQ-4T contained phosphatidylethanolamine (PE), diphosphatidylglycerol (DPG), phosphatidylglycerol (PG) and an unidentified aminophospholipid (APL). The major respiratory quinone was Q-8. The major fatty acids of this strain were C16 : 0, summed feature 3 (C16 : 1ω6c/C16 : 1ω7c), C17 : 0 cyclo and C18 : 0. Strain shQ-4T is considered to represent a novel species of the genus Herbaspirillum, with the proposed name Herbaspirillum piri sp. nov. The type strain is shQ-4T (=CFCC 14641T=KCTC 52804T).


Correlation between salivary and serum anti-desmoglein 1 and 3 antibody titres using ELISA and between anti-desmoglein levels and disease severity in pemphigus vulgaris.
ELISA for anti-desmoglein antibodies (Dsg) is commonly used for diagnosis and assessment of treatment response in pemphigus vulgaris (PV). The present study was conducted to assess the relationship between salivary and serum Dsg1 and Dsg3 levels, and whether salivary Dsg1 and Dsg3 levels correlate with clinical disease severity of oral mucosal lesions in PV. In total 43, patients with PV with predominantly mucosal involvement were recruited. Both serum and salivary samples were collected from the cases, and salivary samples were also collected from five controls. There was a statistically significant correlation between serum and salivary Dsg1 levels and between serum and salivary Dsg3 levels. There was no correlation between serum or salivary Dsg1 and Dsg3 levels with the objective component of the oral mucosal Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Serum Dsg1 levels significantly correlated with cutaneous ABSIS, but there was no correlation between cutaneous ABSIS and either salivary Dsg1, salivary Dsg3 or serum Dsg3. As salivary Dsg titres correlate with serum levels, saliva can serve as a simple and noninvasive alternative to serum for Dsg ELISA.


Developing a genetic approach to target cyanobacterial producers of heterocyte glycolipids in the environment.
Heterocytous cyanobacteria are important players in the carbon and nitrogen cycle. They can fix dinitrogen by using heterocytes, specialized cells containing the oxygen-sensitive nitrogenase enzyme surrounded by a thick polysaccharide and glycolipid layer which prevents oxygen diffusion and nitrogenase inactivation. Heterocyte glycolipids can be used to detect the presence of heterocytous cyanobacteria in present-day and past environments, providing insight into the functioning of the studied ecosystems. However, due to their good preservation throughout time, heterocyte glycolipids are not ideal to detect and study living communities, instead methods based on DNA are preferred. Currently cyanobacteria can be detected using untargeted genomic approaches such as metagenomics, or they can be specifically targeted by, for example, the use of primers that preferentially amplify their 16S rRNA gene or their nifH gene in the case of nitrogen fixing cyanobacteria. However, since not all cyanobacterial nitrogen fixers are heterocytous, there is currently no fast gene-based method to specifically detect and distinguish heterocytous cyanobacteria. Here, we developed a PCR-based method to specifically detect heterocytous cyanobacteria by designing primers targeting the gene (hglT) encoding the enzyme responsible for the last step in the biosynthesis of heterocyte glycolipid (i.e., a glycosyltransferase). We designed several primer sets using the publicly available sequences of 23 heterocytous cyanobacteria, after testing them on DNA extracts of 21 heterocyte-forming and 7 non-heterocyte forming freshwater cyanobacteria. The best primer set was chosen and successfully used to confirm the presence of heterocytous cyanobacteria in a marine environmental sample.


Apoptosis in a unicellular eukaryote (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell death in the control of cell proliferation, differentiation and survival.
The origin of programmed cell death (PCD) has been linked to the emergence of multicellular organisms. Trypanosoma cruzi, a member of one of the earliest diverging eukaryotes, is a protozoan unicellular parasite that undergoes three major differentiation changes and requires two different hosts. We report that the in vitro differentiation of the proliferating epimastigote stage into the G0/G1 arrested trypomastigote stage is associated with massive epimastigote death that shows the cytoplasmic and nuclear morphological features and DNA fragmentation pattern of apoptosis, the most frequent phenotype of PCD in multicellular organisms. Apoptosis could be accelerated or prevented by modifying culture conditions or cell density, indicating that extracellular signals influenced the epimastigote decision between life and death. Epimastigotes responded to complement-mediated immunological agression by undergoing apoptosis, while undergoing necrosis in response to nonphysiological saponin-mediated damage. PCD may participate into the optimal adaptation of T. cruzi to its different hosts, and the avoidance of a local competition between a G0/G1 arrested stage and its proliferating progenitor. The existence of a regulated cell death programme inducing an apoptotic phenotype in a unicellular eukaryote provides a paradigm for a widespread role for PCD in the control of cell survival, which extends beyond the evolutionary constraints that may be specific to multicellular organisms and raises the question of the origin and nature of the genes involved. Another implication is that PCD induction could represent a target for therapeutic strategies against unicellular pathogens.


The effect of psychological distress on self-care intention and behaviour in young adults with type 1 diabetes.
An extended theory of planned behaviour including psychological distress was used to predict blood glucose monitoring in young adults with type 1 diabetes. Participants completed two surveys, a week apart (n = 167). Attitudes and perceived behavioural control were significantly associated with intention but subjective norm was not. Intention predicted blood glucose monitoring at T2. Higher scores in psychological distress significantly predicted poorer blood glucose monitoring at T2 but did not moderate the intention-behaviour relationship. Findings demonstrate some concerns with the theory of planned behaviour to predict self-care behaviour, yet highlight the importance of addressing psychological distress in diabetes self-management.


Uvula Abscess in a Newborn Infant.
Abscesses can be found in several places in the oral cavity, most commonly occurring in peritonsillar and periodontal regions. In this report, the authors described a uvula abscess in a 1-month-old term newborn who was brought to the pediatric outpatient clinic with the complaints of difficulty in sucking-swallowing and refusal to suck at the breast. To the best of the authors' knowledge this is the first report of a uvula abscess in the literature.


Cone-Beam Computed Tomography Study of Mandibular Condylar Morphology.
The purpose of this study was to evaluate the morphology of mandibular condyle using cone-beam computed tomography (CBCT) on coronal sections in a South-Eastern Anatolian population. A total of 1820 joints in 910 subjects with age range of 18 to 86 years were examined retrospectively on CBCT images. The mandibular condylar morphology was examined in right and left sides on coronal sections and classified as convex, round, flat, and angled. In addition, condyle morphology was assessed according to age, gender, edentulism, Angle's classification. The study sample contained CBCT scans of 910 patients (50.3% female, 49.7% male) with a mean age of 42.31 ± 15.74. Condylar morphologies were analyzed as convex in 40.5%, angled in 34.3%, flat in 15.5%, round in 9.6% of the cases. Condyle shape was found statistically related to group age, gender, edentulism (P <0.05). The findings suggest that mandibular condyle shape is associated with age, gender, and edentulism. CBCT may be considered as an appropriate imaging method for detection of condyle alterations of temporomandibular joints and it could provide early diagnosis of temporomandibular joint disorder.


Characteristics of the Development of the Maxillae and Vomer in Patients With Bilateral Cleft Lip and Palate.
The aim of this study was to investigate the anatomical features of the maxillae and vomer in patients with bilateral cleft lip and palate (BCLP). Craniofacial measurements of 24 adult BCLP patients (GB) and 32 normal adult controls (GN) were carried out. We measured the width and length of the maxillae, their relative positions with respect to the coronal plane passing through the basion, and the volume, length, cross-sectional area, and mean width of the vomer. Between-group differences were assessed using independent-sample t tests. Finite element models (FEMs) were used to explore the bite forces acting on the bone by evaluating the distribution of stress and bone displacement. The mean vomer volume and width were significantly larger in the GB group than in the GN group (P = 0.000), whereas the length was significantly shorter (P = 0.000). The anterior maxillary length (A1-P3M⊥CP) was significantly larger in the GB group (P = 0.013), whereas the posterior maxillary length (P3M-P6M⊥CP) and overall maxillary length (A1-P6M⊥CP) at the dental level were significantly reduced (P < 0.01). In the BCLP FEM analysis, the maximum displacement was on the left premaxillary edge (0.2 mm), and high Mises stresses were found in the superior region of the vomer (22.4 Mpa), high tensile stresses in the inferior region (14.3 Mpa), and significant compressive stresses in the superior region (-24.7 Mpa). In summary, for BCLP patients, forward growth of the maxillae and vomer was inhibited during maxillary development, and the vomer was thicker and its volume was increased compared with the vomer in normal subjects.


Comparative study of renal cell carcinoma by CGH, multicolor-FISH and conventional cytogenic banding analysis.
Using different cytogenetic techniques in combination is crucial to studying the high complexity of genetic rearrangements in tumor cells. The 8 clear cell (cc) and 5 papillary (p) renal cell carcinomas (RCC) were analyzed using multicolor fluorescence in situ hybridization (multicolor-FISH), conventional Giemsa banding (G-banding) and comparative genomic hybridization (CGH) analysis. CGH analysis was carried out with DNA from frozen tissue sections and short-term cultures of primary tumors. Using CGH analysis, both tissue sections and cell cultures of ccRCC showed the typical chromosomal changes such as the loss of 3p, 4q, 6q, 8p, 9q, 14 and a gain of 5q and 7. Most imbalances detected by CGH in cell culture could be deciphered by multicolor-FISH and G-banding analysis as unbalanced trans-locations t(3;6)(p11.1;p11.1), t(8;14)(p11.1;q11.1), t(3;5) (p14;q21-22), t(1;15)(p11;q11.1), t(3;15)(p11;q11.1)t(8;17) (p11.1;q11.1), t(8;17)(q22;p11.1). Only one balanced trans-location t(9;18)(q34;q11.1) was shown in ccRCC. CGH of papillary RCC displayed mostly gains of whole chromosomes 7, 12, 16 and 17 and a loss of chromosome Y. There was 1 papillary RCC that displayed a partial gain of chromosome 7, showing an unbalanced translocation t(7;11)(q11.1;q25). The balanced translocations t(2;9)(q11.1;q34) and t(7;15) (q22 approximately 31;q21-22) were registered in pRCC. The combined analysis of RCC by different methods allowed a more accurate characterization of the complex karyotypes of tumor tissue, and offered a comprehensive description of given tumors.


Successful implementation of the National Institutes of Health Stroke Scale on a stroke/neurovascular unit.
The National Institutes of Health Stroke Scale (NIHSS) is accepted as the definitive clinical examination to assess stroke severity. This project examined barriers to implementation and NIHSS use by registered nurses on a stroke/neurovascular Unit. Staff members were surveyed to determine nurse-perceived barriers to the routine use of the NIHSS. Survey results were used to create interventions including staff education, emphasis on NIHSS assessment during interdisciplinary rounds, and use of pocket cards. When the survey was redistributed 9 months later to verify results of the quality improvement initiative and guide further interventions, NIHSS assessment had increased from 12% to 69%. NIHSS scores have been linked to an existing outcomes database to monitor acute stroke treatment and inpatient management outcomes.


Etiopathogenesis of dermatitis herpetiformis.
Dermatitis herpetiformis is a rare chronic, autoimmune bullous disease linked to gluten sensitivity with intense pruritus and characteristic skin eruptions. Etiopathogenesis is complex and not fully understood. It is currently considered to be a specific cutaneous manifestation of celiac disease. Genetic, environmental and immunological factors influence both conditions. Exposure to gluten is the starting point of an inflammatory cascade leading to the formation of circulating IgA antibodies against tissue transglutaminase and skin immune IgA deposition followed by skin lesions. Binding of the immune complex deposits of IgA transglutaminases and epidermal antibodies with enzymes in the papillary dermis stimulates complement activation, neutrophil influx, proinflammatory cytokine release and overproduction of matrix metalloproteinases. We have collected current knowledge of the pathogenesis of dermatitis herpetiformis.


Characterization of label-retaining cells in the epidermis of a human skin equivalent.
The human skin equivalent (HSE) is an in vitro reconstructed model that resembles skin morphologically and biochemically. The HSE is formed by overlaying a fibroblast-populated collagen matrix with a suspension of epidermal cells. Basal keratinocytes attach to the dermal equivalent via a newly formed basement membrane and multiply to form a stratified, differentiated epidermis. The aim of the studies described here was to characterize the basal cells of the HSE in terms of their cell cycling potential. The experiments utilized long-term labelling of the cells with tritiated thymidine ([3H]dT), followed by irradiation with ultraviolet light. [3H]dT incorporation was analysed via routine autoradiography. Irradiation with 100 J/m2 UV light increased the number of labelled basal cells by 58% over the control, the maximal stimulation observed. Decreased numbers of labelled basal cells were observed at doses of UV light greater than 100 J/m2. The maximal number of labelled basal cells was observed on day 14 and decreased over time; the number of labelled suprabasal cells increased concomitantly. Label-retaining cells (12%) persisted in the stratum basale of control HSEs after 32 days in culture. Labelled cells were observed in the apical layers of the stratum granulosum of control HSEs after 22 days in culture. These data suggest that the stratum basale of the HSE contains a population of slow-cycling cells whose characteristics resemble a subpopulation of slowly cycling cells found in normal human skin.


p53 expression in ovarian borderline tumors and stage I carcinomas.
Seventy-nine ovarian serous and mucinous borderline tumors, 36 stage I carcinomas and 39 stage II-IV carcinomas were studied for p53 protein accumulation with monoclonal antibody PAb1801.p53 protein was expressed in 14% of borderline tumors, 36% of stage I carcinomas, and 64% of higher stage carcinomas. All immunopositive carcinomas accumulated p53 protein in the primary tumor, and 95% of them showed concordance in staining among different tissue blocks. A difference in frequency of p53 protein accumulation between stage I and higher stage serous carcinomas was not statistically significant. p53 positivity was associated with microinvasion, microcarcinoma and coexistent carcinoma in mucinous borderline tumors (P = .025). An association between p53 protein expression and poor tumor differentiation in Stage I carcinomas as statistically significant (P = .03). p53 positivity was observed in a poorly differentiated endometrioid carcinoma as well as in adjacent benign endometriotic tissue. These results suggest that p53 abnormalities may be early events in ovarian cancer, possibly contributing to malignant transformation of some borderline tumors, endometriosis and other carcinoma precursors.


Is nitric oxide involved in the regulation of the rat testicular vasculature?
Using immunohistochemistry, endothelial nitric oxide synthase (NOS), and neuronal NOS were localized in the endothelium of rat testicular arteries and in Leydig cells, respectively. NADPH-diaphorase activity, indicating NOS activity, however, was present only in endothelial cells. In order to examine the role of nitric oxide (NO) in the regulation of rat testicular vasculature, intact and hCG-pretreated (50-100 IU hCG given s.c. 6 h earlier) animals were given injections of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), 10 mg/kg i.v.). In all rats this resulted in a major increase in blood pressure. In intact, unstimulated animals, testicular vascular resistance was unaffected, and testicular blood flow consequently increased. In hCG-treated animals, in contrast, vascular resistance increased in an hCG dose-related way. L-NAME treatment also increased the hCG-induced accumulation of polymorphonuclear leukocytes in testicular venules. Treatment with N(G)-nitro-D-arginine methyl ester (D-NAME, 10 mg/kg i.v.), an inactive isomer of L-NAME, had no effect on the testicular vasculature. The study suggests that NO plays only a limited role in the regulation of testicular blood flow under basal conditions. After hCG treatment, however, NOS activity appears to be increased (increased endothelial NADPH-diaphorase staining), suggesting that NO in this situation is of importance to increase blood flow and to inhibit leukocyte accumulation.


Artificial neural networks in neutron dosimetry.
An artificial neural network (ANN) has been designed to obtain neutron doses using only the count rates of a Bonner spheres spectrometer (BSS). Ambient, personal and effective neutron doses were included. One hundred and eighty-one neutron spectra were utilised to calculate the Bonner count rates and the neutron doses. The spectra were transformed from lethargy to energy distribution and were re-binned to 31 energy groups using the MCNP 4C code. Re-binned spectra, UTA4 response matrix and fluence-to-dose coefficients were used to calculate the count rates in the BSS and the doses. Count rates were used as input and the respective doses were used as output during neural network training. Training and testing were carried out in the MATLAB environment. The impact of uncertainties in BSS count rates upon the dose quantities calculated with the ANN was investigated by modifying by +/-5% the BSS count rates used in the training set. The use of ANNs in neutron dosimetry is an alternative procedure that overcomes the drawbacks associated with this ill-conditioned problem.


Automatic characterization of neointimal tissue by intravascular optical coherence tomography.
Intravascular optical coherence tomography (IVOCT) is rapidly becoming the method of choice for assessing vessel healing after stent implantation due to its unique axial resolution <20 μm. The amount of neointimal coverage is an important parameter. In addition, the characterization of neointimal tissue maturity is also of importance for an accurate analysis, especially in the case of drug-eluting and bioresorbable stent devices. Previous studies indicated that well-organized mature neointimal tissue appears as a high-intensity, smooth, and homogeneous region in IVOCT images, while lower-intensity signal areas might correspond to immature tissue mainly composed of acellular material. A new method for automatic neointimal tissue characterization, based on statistical texture analysis and a supervised classification technique, is presented. Algorithm training and validation were obtained through the use of 53 IVOCT images supported by histology data from atherosclerotic New Zealand White rabbits. A pixel-wise classification accuracy of 87% and a two-dimensional region-based analysis accuracy of 92% (with sensitivity and specificity of 91% and 93%, respectively) were found, suggesting that a reliable automatic characterization of neointimal tissue was achieved. This may potentially expand the clinical value of IVOCT in assessing the completeness of stent healing and speed up the current analysis methodologies (which are, due to their time- and energy-consuming character, not suitable for application in large clinical trials and clinical practice), potentially allowing for a wider use of IVOCT technology.


iNKT cell production of GM-CSF controls Mycobacterium tuberculosis.
Invariant natural killer T (iNKT) cells are activated during infection, but how they limit microbial growth is unknown in most cases. We investigated how iNKT cells suppress intracellular Mycobacterium tuberculosis (Mtb) replication. When co-cultured with infected macrophages, iNKT cell activation, as measured by CD25 upregulation and IFNγ production, was primarily driven by IL-12 and IL-18. In contrast, iNKT cell control of Mtb growth was CD1d-dependent, and did not require IL-12, IL-18, or IFNγ. This demonstrated that conventional activation markers did not correlate with iNKT cell effector function during Mtb infection. iNKT cell control of Mtb replication was also independent of TNF and cell-mediated cytotoxicity. By dissociating cytokine-driven activation and CD1d-restricted effector function, we uncovered a novel mediator of iNKT cell antimicrobial activity: GM-CSF. iNKT cells produced GM-CSF in vitro and in vivo in a CD1d-dependent manner during Mtb infection, and GM-CSF was both necessary and sufficient to control Mtb growth. Here, we have identified GM-CSF production as a novel iNKT cell antimicrobial effector function and uncovered a potential role for GM-CSF in T cell immunity against Mtb.


Recognizing species diversity among large-bodied hominoids: a simulation test using missing data finite mixture analysis.
A persistent problem in paleoanthropology is the recognition of intra- vs. inter-specific differences within fossil samples. Exacerbating this situation is the often fragmentary nature of the fossils themselves, thus precluding rote applications of many multivariate approaches designed for complete case analyses. In this paper we apply finite mixture analysis to samples of large-bodied hominoids to test this procedure's efficacy in clustering individuals by species without a priori knowledge of group membership. In addition, we stochastically remove individual specimens and measurements, simulating small, incomplete fossil samples, and re-apply the finite mixture procedure to test how often it correctly assigns these "fragmentary" specimens. Finite mixture analysis can be highly accurate, even when confronted with small sample sizes and missing data. For example, a combination of 124 chimpanzees and humans are correctly identified in one analysis, and the accuracy drops only 2% to become 98% when the total sample size is reduced to 16 and missing data patterns are applied. In comparisons to better known methods that have been used to recognize groups in the fossil record, such as k-means, the benefits of finite mixture analysis are readily apparent. First, k-means is unable to accommodate missing data, an obvious deficiency when investigating the fossil record. Second, in direct comparisons of their ability to accurately assign "unknowns" to taxa, finite mixture performed at least as well as, and often better than, k-means in our analyses. A potential test that can be used to identify species in the fossil record, derived from comparisons of results generated from a general vs. a restricted (isometry-corrected) finite mixture analysis, is presented.


Efficacy and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in Japanese patients with atrial fibrillation – meta-analysis.
Non-vitamin K antagonist oral anticoagulants (NOAC) have been developed as alternatives to warfarin. Until recently, the latter was the standard oral anticoagulant for patients with non-valvular atrial fibrillation (NVAF). The efficacy and safety of NOAC in Japanese patients with NVAF has been investigated in small trials or subgroups from global randomized control trials (RCT). We conducted a systematic review and meta-analysis of RCT, to compare the efficacy and safety of NOAC to those of warfarin in Japanese patients with NVAF. Published research was systematically searched for RCT that compared NOAC to warfarin in Japanese patients with NVAF. Random-effects models were used to pool efficacy and safety data across RCT. Three studies, involving 1,940 patients, were identified. Patients randomized to NOAC had a decreased risk for stroke and systemic thromboembolism (relative risk [RR], 0.45; 95% CI: 0.24-0.85), with a non-significant trend for lower major bleeding (RR, 0.66; 95% CI: 0.29-1.47), intracranial bleeding (RR, 0.46; 95% CI: 0.18-1.16) and gastrointestinal bleeding (RR, 0.52; 95% CI: 0.25-1.08). NOAC are more efficacious than warfarin for the prevention of stroke and systemic embolism in Japanese patients with NVAF. The present findings offer clinicians a more comprehensive picture of NOAC as a therapeutic option to reduce the risk of stroke in Japanese NVAF patients.


Expression of aquaporin 9 in the adult rat epididymal epithelium is modulated by androgens.
Reabsorption of fluid and solutes across the epithelium lining the male excurrent duct is important for adequate sperm maturation, concentration, and storage. Water channels contribute to water movement across epithelia in many tissues. Aquaporin 9 (AQP9) is abundantly expressed in the apical membrane of principal cells that line the epididymis, and in reabsorptive and secretory epithelial cells of the male reproductive tract. In this study we show that the nonsteroidal antiandrogen flutamide, given to adult rats at a dose of 50 mg x kg(-1) x day(-1) for 2 wk via osmotic minipumps significantly decreased the amount of AQP9 in the epididymis. This down-regulation was observed by immunofluorescence of cryostat tissue sections and by Western blotting of epididymal brush border membrane preparations. In addition, castrated adult rats showed lower levels of epididymal AQP9 compared with adult controls, whereas systemic testosterone treatment of castrated adult rats induced a recovery of the expression of AQP9 to control levels. These data indicate that the expression of AQP9, a likely candidate for apical transepithelial fluid and solute transport in several regions of the male reproductive tract, is modulated by androgens in the adult rat epididymis.


Clinical effects of high frequency hyperthermia-assisted irinotecan chemotherapy on patients with middle and advanced colorectal cancer and its safety assessment.
Clinical effects of high frequency hyperthermia-assisted irinotecan chemotherapy on patients with middle and advanced colorectal cancer and its safety assessment were investigated. A retrospective analysis was performed on the medical records of 103 patients with middle and advanced colorectal cancer treated in Cancer Center of Guangzhou Medical University from May 2011 to June 2015, including 48 patients receiving irinotecan plus conventional treatment (irinotecan group) and 55 patients receiving high frequency hyperthermia-assisted irinotecan plus conventional treatment (combination group). The treatment effects, severity and incidence of adverse reactions, quality of life and 3-year survival rates of patients were analyzed and compared between the two groups. After 4 courses of treatment, there were statistically significant differences in the proportions of patients with partial remission and objective remission, with those in combination group higher than those in irinotecan group (both P<0.05). After 4 courses of treatment, no patient died. After 4 courses of treatment, those that increased in different degrees (all P<0.05), compared with those in combination group were significantly higher than those in irinotecan group (all P<0.05). The 1-, 2- and 3-year survival rates of patients in irinotecan group were 31.25% (15 cases), 22.92% (11 cases) and 12.50% (6 cases), respectively. Those in combination group were 58.18% (32 cases), 29.09% (16 cases) and 16.36% (9 cases), respectively. The results of K-M survival curve analysis showed that there was no statistically significant difference in survival rate between the two groups of patients (P=0.050). High frequency hyperthermia-assisted chemotherapy for patients with middle and advanced colorectal cancer can effectively improve its treatment effects and patients' quality of life, with better treatment safety, worthy of clinical promotion.


Small head circumference is associated with less education in persons at risk for Alzheimer disease in later life.
Studies suggest that individuals who are at increased risk for Alzheimer disease (AD) in late life differ on measures of cognition, linguistic performance, and brain metabolism in earlier adult life compared with those with lower risk of this illness. The present study was undertaken to determine whether smaller head circumference (HC), a predictor of AD in late life, could influence educational attainment earlier in life, specifically among individuals at increased risk for AD. Data from the Nun Study, a longitudinal clinicopathologic study of dementia, were analyzed using logistic regression to assess the association between HC and attainment of less than a bachelor's degree. Modification of this association was studied by comparing those with and without evidence of increased AD risk, including possession of apolipoprotein E (APOE)-epsilon 4 alleles, occurrence of dementia before death, and satisfaction of AD neuropathologic criteria at autopsy. Small HC was associated with lower educational attainment in those carrying an APOE-epsilon 4 allele [odds ratio (OR)=6.27, 1.21 to 32.48], those who became demented (OR=3.23, 1.27 to 8.21), and those who fulfilled AD neuropathologic criteria (OR=5.03, 1.29 to 19.66), but not in those without these characteristics. These findings suggest that small HC limits educational attainment only among individuals who have greater risk of AD owing to their APOE genotype or who are destined to develop this illness later in life.


Differential contribution of the immunoreceptor tyrosine-based inhibitory motifs of human leukocyte-associated Ig-like receptor-1 to inhibitory function and phosphatase recruitment.
Leukocyte-associated Ig-like receptor (LAIR)-1 is an inhibitory receptor expressed on most human leukocytes. It contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic tail and recruits phosphatases upon phosphorylation. Here we show that both ITIM are required for full inhibition of cellular responses and optimal phosphatase recruitment. Mutation of the C-terminal ITIM still allows partial inhibition of the cytotoxic activity of the NK-like YT.2C2 cells, while mutation of the N-terminal ITIM completely abolishes this inhibitory activity. In contrast, in rat basophilic leukemia (RBL) cells, both mutants of LAIR-1 are partially effective. This is reflected in phosphorylation of these mutants in the different cell types upon pervanadate treatment. However, in both YT.2C2 cells and RBL cells, only the mutant containing the N-terminal ITIM recruits Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2), while the mutant containing the C-terminal ITIM does not. In RBL cells the mutant containing only the N-terminal ITIM also binds SHP-1, although to a lesser extent than wild-type LAIR-1. We find that in Jurkat T cells Lck is required for the association of SHP-1 with LAIR-1. Co-expression with Lck in 293T cells leads to phosphorylation of both wild-type LAIR-1 and the mutant containing only the N-terminal ITIM, while the mutant lacking this ITIM is not phosphorylated. These results indicate that Lck, or another Src family kinase, is essential for the consecutive phosphorylation of the N- and C-terminal ITIM. Our data imply that the N-terminal ITIM is dominant in LAIR-1 signaling, but that both ITIM contribute to an optimal inhibitory function.


Aortic arch aneurysm. A sentinel of extensive aortic disease requiring subtotal and total aortic replacement.
Aneurysm of the thoracic aorta is a serious form of disease because it may be extensive or associated with a more distant aneurysm. This manifestation occurs in about one-third of the cases. The actuarial 5-year survival of nontreated patients is only 13% with many patients dying from aortic rupture. The 5-year survival of our patients with aneurysm of the descending thoracic aorta treated by graft replacement is 58% with the two most common causes of late death being myocardial infarction and rupture of another aortic aneurysm. Effective treatment consists of initial total aortic examination, continued follow-up examination, and total replacement of disease. Aneurysmal disease that involves the entire aortic arch is especially prone to extensive involvement because it is due to diffuse aortic dissection or medial degenerative disease in most cases. The latter is most common, being present in 63 of our 81 patients requiring total arch replacement. The disease was extensive in all cases with degenerative medial disease and required extensive graft replacement. In fact, the entire thoracic aorta was involved in ten, the entire thoracic aorta and substantial segments of abdominal aorta in ten, and the entire aorta in 12 patients. Most of these patients were women (84%) over 65 years of age (63%) or older, ten (37%) were over 70 years. Associated pulmonary disease was frequent, aortic valvular insufficiency was present in 12 (38%), and symptoms were present in most. Treatment consisted of removing the disease when possible in stages, the arch in one and the remaining disease in another with the sequence and interval depending upon indications and condition of the patient. A total of 53 operations were performed in these 32 patients, the arch replaced in 29, the descending thoracic aorta in eight, and the thoracoabdominal aortic segment in 16 patients. All of the disease was replaced in 21, including the entire aorta in eight and incompletely replaced in 11 patients. Sixteen (76%) of the former are still alive 4 months to 6 1/3 years. Six (55%) of those in whom operation was limited to replacement of the symptomatic aortic segment because of limited risk are still alive. Of the ten deaths occurring during the study period, four (40%) and perhaps five (50%) were due to natural rupture of unresected disease which indicates its progressive nature and suggests the need for aggressive surgical treatment.


Long-term care financing: options for the future.
The aging of the baby boomers will have an enormous impact on the future of long-term care costs. This article projects the magnitude of that impact, discusses sources of financing, and considers the cost and feasibility of three options for financing future long-term care services. The authors investigate the alternatives of increasing personal savings, raising payroll taxes and expanding employer-sponsored private long-term care insurance coverage, respectively.


Aflatoxin biosynthesis control produced by Aspergillus flavus in layer hens feed during storage period of six months.
Aflatoxins (AFTs) are a group of closely related toxins that are produced by different fungus species. Food and feed contamination with AFT is a worldwide health-related problem. As a result of fungal attack, the food and feed resulted in a principal socioeconomic loss and toxins produced in feed and food items harm the humans and animals in different ways. The anti-aflatoxigenic effect Psidium guajava, Ficus benghalensis, Gardenia radicans, Punica granatum and Ziziphus jujuba leaves were evaluated against aflatoxins (AFTs), produced by Aspergillus flavus in layer feed during storage. Among the investigated medicinal plant leaves, P. granatum showed highly promising anti-aflatoxigenic activity and completely inhibited the AFTs (B1 and B2) production over storage period without compromising the nutritive quality of feed (ash, protein, fat, fiber, Fe, Ca, P and K contents). Leaves of F. benghalensis and Z. jujuba were also effective however, higher concentration (15%) inhibited the AFTs production up to 99% and also maintained nutritive quality of feed. G. radicans was found least effective in controlling the AFTs production. Results revealed that all plant leaves were effective in controlling AFTs production in layer feed over the storage period of six months and these plants are potential candidate to replace the fungicides used to protect feed and other agricultural commodities from AFTs production during storage.


Determination of the thermodegradation of deoxyArbutin in aqueous solution by high performance liquid chromatography.
Tyrosinase is the key and rate-limiting enzyme responsible for the conversion of tyrosine into melanin. Competitive inhibition of tyrosinase enzymatic activity results in decreased or absent melanin synthesis by melanocytes in human skin. DeoxyArbutin (4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol), a novel skin whitening agent, was synthesized through the removal of hydroxyl groups from the glucose side-chain of arbutin. DeoxyArbutin not only shows greater inhibition of tyrosinase activity but is also safer than hydroquinone and arbutin. Hence, deoxyArbutin is a potential skin whitening agent for cosmetics and depigmenting drugs; however, stability of this compound under some conditions remains a problem. The lack of stability poses developmental and practical difficulties for the use of deoxyArbutin in cosmetics and medicines. Improving the thermostability of deoxyArbutin is an important issue for its development. In this research, we established an analytical procedure to verify the amount of deoxyArbutin in solutions using a high performance liquid chromatographic (HPLC) method. The results indicate that this novel skin whitening agent is a thermolabile compound in aqueous solutions. Additionally, the rate constant for thermodegradation (k) and the half-life (t(1/2)) of deoxyArbutin were determined and can be used to understand the thermodegradation kinetics of deoxyArbutin. This information can aid in the application of deoxyArbutin for many future uses.


Persistent Pain After Cardiac Surgery: Prevention and Management.
Persistent postoperative pain (PPP) after cardiac surgery is a significant complication that negatively affects patient quality of life and increases health care system burden. However, there are no standards or guidelines to inform how to mitigate these effects. Therefore, in this review, we will discuss strategies to prevent and manage PPP after cardiac surgery. Adequate perioperative analgesia may prove instrumental in the prevention of PPP. Although opioids have historically been the primary analgesic approach to cardiac surgery, an opioid-sparing strategy may prove advantageous in reducing side effects, avoiding secondary hyperalgesia, and decreasing risk of PPP. Implementing a multimodal analgesic plan using alternative medications and regional anesthetic techniques may offer superior efficacy while reducing adverse effects.


Prevalence and pattern of mental health problems.
Three hundred and forty eight children of age group 5-15 years were studied. A reporting questionnaire was administered to the parents and then affected children were examined in detail by history, physical examination and mental status examination. Fifty out of 348 children were having mental health problems. Male and first born children were affected more. Common problems observed were poor scholastic performance, enuresis, hyperkinetic syndrome, speech disorders and sleep disorders. In males, poor scholastic performance, hyperkinetic syndrome and temper tantrums were common while in females enuresis, speech disorders and hysterical symptoms were more frequent. Among the adverse perinatal factors of etiological importance low birth weight, difficult deliveries, birth injuries, delayed cry, neonatal jaundice and convulsions were common. Predominant psychosocial stress factors were quarrels between parents, separated parents, deaths of parents, siblings or relatives and chronic illness in the family.


Anthropometric indices of adolescents who at birth were full-term long and/or overweight for gestational age.
Measurements of adolescents who at birth were large (long and/or heavy) for gestational age are scant. To determine the correlation between birth length and weight in female and male neonates born long and/or overweight for gestational age, with their height and weight at age 17. We reviewed the records of the Rabin Medical Center for birth data of 96 full-term neonates born long and overweight for gestational age (FT-lo,ow), 33 full-term neonates born long but with normal weight for gestational age (FT-lo,nw), 148 full-term neonates born overweight but with normal length for gestational age (FT-nl,ow), and 401 full-term neonates born with normal birth length and weight (FT-nl,nw). Neonates of both genders born long and overweight at birth (FT-lo,ow) were taller and heavier at age 17 years than those born FT-nl,nw: females 167.8 +/- 5.1 cm and 64.6 +/- 10.3 kg vs. 162.6 +/- 5.5 cm and 59.3 +/- 11.1 kg (P < 0.001 for height and P = 0.026 for weight); and males 182.4 +/- 8.1 cm and 80.6 +/- 20.4 kg vs. 174.5 +/- 6.2 cm and 67.4 +/- 12.3 kg (P < 0.001). The correlations between birth length and height at age 17 for both genders were statistically significant (P < 0.001), as were those between birth weight and the weight and body mass index (BMI) at age 17 for both genders (P < 0.001). There was no correlation between birth length and weight or BMI at age 17. Full-term neonates of both genders born large for gestational age become tall adolescents and weigh more at age 17 than children with a normal birth length and weight.


The neural representation of interaural time differences in gerbils is transformed from midbrain to cortex.
Interaural time differences (ITDs) are the dominant cue for the localization of low-frequency sounds. While much is known about the processing of ITDs in the auditory brainstem and midbrain, there have been relatively few studies of ITD processing in auditory cortex. In this study, we compared the neural representation of ITDs in the inferior colliculus (IC) and primary auditory cortex (A1) of gerbils. Our IC results were largely consistent with previous studies, with most cells responding maximally to ITDs that correspond to the contralateral edge of the physiological range. In A1, however, we found that preferred ITDs were distributed evenly throughout the physiological range without any contralateral bias. This difference in the distribution of preferred ITDs in IC and A1 had a major impact on the coding of ITDs at the population level: while a labeled-line decoder that considered the tuning of individual cells performed well on both IC and A1 responses, a two-channel decoder based on the overall activity in each hemisphere performed poorly on A1 responses relative to either labeled-line decoding of A1 responses or two-channel decoding of IC responses. These results suggest that the neural representation of ITDs in gerbils is transformed from IC to A1 and have important implications for how spatial location may be combined with other acoustic features for the analysis of complex auditory scenes.


A Series of COVID-19 Cases With Findings in the Gastrointestinal and Hepatobiliary System.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide. Most of the infected patients present with respiratory symptoms and acute lung damage. Here, we present three cases of patients with COVID-19 disease whose main clinical manifestations are gastrointestinal symptoms. In our first case, we present a COVID-19 patient with histologic findings associated with ischemic necrosis of the small bowel. In the second and third cases, we demonstrate acute cholecystitis and histology showing microvascular thrombosis. These three cases highlight the ischemic and thrombotic changes seen in the setting of COVID-19 infection without classic respiratory symptoms, with resulting severe gastrointestinal and hepatobiliary disease requiring surgical management. Although the bile or stool viral load was not tested in these patients, the small intestine and gallbladder were infected with SARS-CoV-2, most likely via the epithelial angiotensin-converting enzyme 2 (ACE2) receptor.


Genetic landscape of ultra-stable chronic lymphocytic leukemia patients.
Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile. Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis. WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients. The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.


Papillary thyroid carcinoma in one of identical twin patients with Pendred syndrome.
Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Several cases of Pendred syndrome with follicular thyroid carcinomas were reported previously. Here we report identical twin patients with Pendred syndrome, who had thyroid tumors with distinct histopathological findings. 34-year-old identical twins with congenital deafness and goiter were referred to our hospital with complaint of neck discomfort. The genetic testing showed that these twin patients were compound heterozygotes carrying the same two mutations in the Pendred's syndrome (PDS / SLC26A4) gene (c2168A > G and ins2110GCTGG), which confirmed the diagnoses of Pendred syndrome. They underwent thyroidectomy. Histological examination of the thyroid tumors resected from these twin patients revealed follicular variant of papillary thyroid carcinoma, and diffuse and nodular goiter without any evidence of malignancy, respectively. To our knowledge, the former is the first case of follicular variant of papillary thyroid carcinoma in Pendred Syndrome.


Effect of anaerobiosis on staphylococcal nuclease production.
Five strains of Staphylococcus aureus were examined quantitatively for the production of nuclease under aerobic and anaerobic conditions. Hydrolysis of deoxyribonucleic acid and ribonucleic acid was detected by measuring the release of acidsoluble nucleotides spectrophotometrically. We found that the enzyme was produced anaerobically, as well as aerobically, and that anaerobiosis had no effect on production of this enzyme when other conditions, such as pH, were held constant.


Vision analysis and refractive status of youths in a juvenile detention home population.
Clinical optometric findings of 633 juvenile dentention youths were statistically evaluated and compared to data from the general population. The youths had a higher referral rate of refractive errors, organic problems, and muscle in balances than the general population. Female youths exhibited a higher incidence and greater severity of myopia than males at all ages. Referral rate for astigmatism among the youths was higher than the general population although the dioptric power was in agreement with previous studies.


[Exenteration: a retrospective study].
To review all cases of orbit exenteration performed at the Orbit Sector, Ophthalmology Department - Federal University of São Paulo, from 1998 to 2003. We reviewed conditions leading to orbital exenteration in 21 patients at the Orbit Sector of Unifesp-EPM from August 1998 to May 2003. Data regarding sex, age, race, primary lesion site, visual acuity at the moment of diagnosis, previous surgeries related to the exenteration, type of performed surgery, histopathologic diagnosis, postoperative complications and use of adjuvant treatment were collected. 21 patient charts were retrospectively analyzed. Ages ranged from 5 to 91 years (mean of 58.5 years). Of these, 12 were male and 9 were female, most of them Caucasian. All lesions that led to exenteration were malignant neoplasias; however, none were metastatic. Lesions originated from eyelids in twelve patients, from bulbar conjunctiva in six and from the orbit in three. Cases were also classified as squamous cell carcinoma (eleven cases), basal cell carcinoma (four cases), sebaceous gland carcinoma (two cases), rhabdomyosarcoma (two cases), mucoepidermoid carcinoma (one case) and adnexal microcistic carcinoma (one case). Visual acuity at the moment of diagnosis ranged from 20/40 to no light perception. Only six patients had been submitted to previous surgeries related to the exenteration. After surgery, three patients suffered graft necrosis, one presented ethmoidal sinus fistula to the orbit and one presented orbital socket shrinkage. Six patients needed postoperative radiotherapy and two had been previously submitted to chemotherapy. Most patients analyzed in our study presented lesions that are usually small in the beginning; however, they can disseminate to the orbit in the absence of adequate treatment.


Feshbach resonance induced shock waves in Bose-Einstein condensates.
We propose a method for generating shock waves in Bose-Einstein condensates by rapidly increasing the value of the nonlinear coefficient using Feshbach resonances. We show that in a cigar-shaped condensate there exist primary (transverse) and secondary (longitudinal) shock waves. We analyze how the shocks are generated in multidimensional scenarios and describe the related phenomenology.


Synthesis and mechanical evaluation of Sr-doped calcium-zirconium-silicate (baghdadite) and its impact on osteoblast cell proliferation and ALP activity.
For the first time the successful preparation of Sr doped baghdadite (Ca3-x Sr x ZrSi2O9 x = 0.1 and 0.75) is shown. Sr-doped as well as pure baghdadite are prepared via a versatile solid-state synthesis and conventional sintering at 1400 °C. XRD measurements and crystal structure refinements reveal that a substitution of Ca atoms with Sr and a high purity (>99%) is achieved. The physical, mechanical, and biological properties of these novel bioceramics are presented in relation to the dopant concentration. Incorporating Sr into the baghdadite crystal caused only minor changes to the grain size and the mechanical properties. The characteristic strength ranges from 145 to 168 MPa and a Weibull modulus of 4.9 to 9.2 is observed. Other mechanical properties like fracture toughness and hardness vary from 1.23 ± 0.07 MPam(0.5) to 1.31 ± 0.12 MPam(0.5) and 7.3 ± 0.6 GPa to 8.0 ± 0.7 GPa, respectively. The in vitro cellular response of human osteoblasts showed an increase in the cell proliferation and a significantly higher alkaline phosphatase (ALP) activity with an increase in the Sr content. From the improved biological properties and the suitable mechanical performance we conclude that this material is a highly promising candidate for bone replacement material and bioactive implant coatings.


Canine neurological diseases in a referral hospital population between 1989 and 2000 in Switzerland.
To merge clinical information from partly overlapping medical record databases of the Small Animal Teaching Hospital of the Vetsuisse Faculty, University of Berne. To describe the frequencies and localisations of neurological diseases in dogs, as well as their age, gender, breed and geographical distributions. In this retrospective study, a new database, with specific variables and a diagnosis key list 'VITAMIN D', was created and defined. A total of 4497 dogs (average of 375 per year) with a well-documented neurological disease were included in the study. A key list for the diagnoses was developed and applied to either the presumptive or the clinical and neurohistopathological diagnosis, with a serial number, a code for localisation and a code for differential diagnoses. Approximately 1159 dogs (26 per cent) had a neurohistopathological diagnosis confirmed, 1431 (32 per cent) had a clinical diagnosis confirmed and 1491 (33 per cent) had a presumptive diagnosis. The most frequent breeds were mixed-breed dogs (577 of 4497, 13 per cent), followed by German shepherd dogs (466 of 4497, 10 per cent). The most common localisations were the forebrain (908 of 4497, 20 per cent) and the spinal cord at the thoracolumbar area (840 of 4497, 19 per cent). Most dogs were diagnosed with degenerative diseases (38 per cent), followed by inflammatory/infectious diseases (14 per cent). The highest number of submissions originated from geographic regions around the referral hospital and from regions with higher human population densities. By defining closed-list fields and allocating all data to the corresponding fields, a standardised database that can be used for further studies was generated. The analysis of this study gives examples of the possible uses of a standardised database.


Arene-ruthenium complexes with salicyloxazolines: diastereoselective synthesis, configurational stability and applications as asymmetric catalysts for Diels-Alder reactions.
Reaction of the dimers [RuCl2(eta6-arene)]2 (arene = benzene, p-cymene, mesitylene) with salicyloxazolines in the presence of NaOMe gives complexes [RuCl(R-saloxaz)(arene)] (1-5) which have been fully characterised. Complexes [RuL(iPr-saloxaz)(mes)]Y (L = py, 2-Mepy, 4-Mepy; PPh3; Y- = SbF6 or BPh4) 6-9 were prepared by treating the chloride 2a with ligand L and NaY (Y- = SbF6 or BPh4) in methanol at reflux. Halide complexes [RuX(iPr-saloxaz)(mes)](X = Br, 10; X = I, 11) were synthesised by treating 2a with AgSbF6 then with 1.2 equivalents of KBr or NaI, the methyl complex [RuMe(iPr-saloxaz)(mes)] 12 was synthesised from 2a by reaction with MeLi. Five complexes, [RuCl(iPr-saloxaz)(mes)] 2a, [RuCl(tBu-saloxaz)(p-cymene)] 3b, [RuCl(Ph-saloxaz)(mes)] 5a, [Ru(4-Mepy)(iPr-saloxaz)(mes)][SbF6] 7, and [Ru(PPh3)(iPr-saloxaz)(mes)][SbF6] 9, have been characterised by X-ray crystallography. Treatment of complexes 1-5 with AgSbF6 gives cationic species which are enantioselective catalysts for the Diels-Alder reaction of acroleins with cyclopentadiene, the effect of substituents on enantioselectivity has been examined.


Can Self-Locking Cages Offer the Same Clinical Outcomes as Anterior Cage-with-Plate Fixation for 3-Level Anterior Cervical Discectomy and Fusion (ACDF) in Mid-Term Follow-Up?
BACKGROUND Self-locking stand-alone cages (MC+) and cage-with-pate fixation system are 2 different surgical methods used in anterior cervical discectomy and fusion (ACDF), but few systematic comparative studies comparing the 2 methods in treating multilevel cervical spondylotic myelopathy (MCSM) have been published. MATERIAL AND METHODS Sixty-two patients with MCSM who underwent multilevel ACDF were enrolled and completed at least a 3-year postoperative follow-up. The operative time, intra-operative blood loss, and clinical and radiological results were compared between the MC+ self-locking cages group and the cage-with-plate fixation group. Clinical parameters, including VAS for neck pain, Japanese Orthopedic Association (JOA) score, and neck disabled index (NDI), were evaluated. Surgical results according to Odom's criteria and postoperative dysphagia status, C5 nerve root palsy, and loosening of the instrumentation were recorded. Postoperative radiological results, including fusion rates, fusion segmental Cobb's angle (FSC), cervical lordosis, fusion segmental height (FSH), cage subsidence, and adjacent segment degeneration, were assessed. RESULTS The VAS score, JOA score, and NDI score were significantly improved in both groups. However, the patients in the cage-with-plate group were more likely to have neck pain at the last follow-up. The cervical lordosis, FSC, and FSH showed significant correction immediately after surgery. The loss of the cervical lordosis and FSH were higher in the MC+ group. CONCLUSIONS We found that use of MC+ cages is safe and effective in treating MCSM, but for patients who require strong postoperative stabilization and maintaining the cervical alignment better, the cage-with-plate fixation may best.


Extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy for cervical cancer with para-aortic lymph nodes metastasis.
This study was conducted to evaluate the efficacy and toxicity of extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy in patients with cervical cancer with positive para-aortic lymph nodes (PALN). From September 2007 to December 2014, a total of 59 patients who had cervical cancer with para-aortic lymph node metastasis were treated with concurrent chemoradiotherapy at our institution. A dose of 45-50.4 Gy in 25-28 fractions with extended-field intensity-modulated radiation therapy was prescribed to planning target volume, and a dose of 30-36 Gy in 5-6 fractions was prescribed to Point A with high-dose-rate brachytherapy. A concurrent first-line cisplatin-based chemotherapy regimen was used. The median duration of follow-up was 32.1 months (range, 3.2-103.7 months). The 2- and 3-year overall survival, disease-free survival and local control rates were 69.0 and 52.8%, 45.0 and 41.3% and 83.4 and 81.0%, respectively. Distant metastasis was the major pattern of treatment failure, which occurred in 26 patients (44.1%). The incidence of Grade 3 or greater acute hematologic, gastrointestinal and genitourinary toxicity was 50.9, 1.7 and 3.4%, respectively. Only one patient had both Grade 3 late gastrointestinal and genitourinary toxicity. The study found that extended-field intensity-modulated radiation therapy combined with concurrent chemotherapy was safe and effective in patients who had cervical cancer with positive PALN.


Characterization of solid and liquid sorbent materials for biogas purification by using a new volumetric screening instrument.
With the increasing utilization of biogas as an energy source the need for new materials and methods to purify and clean the corresponding gas mixtures is rising. In this regard, the application of ad- or absorptive gas purification methods has increased significantly over the last years. For fast and economic evaluation of the potential of different sorbent materials, a new volumetric screening instrument has been developed. First the measuring method and the new instrument design will be described. This instrument allows ad- and absorption, as well as desorption measurements in a technically relevant, wide pressure, and temperature range. It was used for the characterization of common sorbent materials such as activated carbons and zeolite molecular sieves. Additionally, new substances like metal-organic frameworks and ionic liquids were analyzed. Thereby the sorption of CO(2), CH(4), N(2), and H(2) was measured. The obtained data allow the direct comparison of the sorption properties of the different materials, the results of which will be presented in the second part of the paper.


Outcomes of a hybrid approach of percutaneous coronary intervention followed by minimally invasive aortic valve replacement.
In patients requiring coronary revascularization and aortic valve replacement, a combined approach of percutaneous coronary intervention followed by minimally invasive aortic valve replacement may be a viable treatment strategy. The outcomes of 123 consecutive patients with significant coronary artery and aortic valve disease, who underwent percutaneous coronary intervention followed by elective minimally invasive aortic valve replacement between February 2009 and April 2014, were retrospectively evaluated. The cohort consisted of 80 males and 43 females, with a mean age of 75.7±8.1 years. Drug-eluting stents were used in 69.9% of the patients, and 64.2% were on dual anti-platelet therapy at the time of aortic valve replacement. Within a median of 39 days (IQR 21-64), 83.7% of the patients underwent primary and 16.3% underwent re-operative minimally invasive aortic valve replacement. Post-operatively, there was 1 (0.8%) cerebrovascular accident, 1 patient (0.8%) required a re-operation due to bleeding, and 2 (1.6%) developed acute kidney injury. Thirty-day mortality occurred in 2 (1.6%) patients. Follow-up was available for all of the patients, and at a mean follow-up period of 14.3±12.5 months, 4 (3.3%) had an acute coronary syndrome, and 1 (0.8%) required a repeat target vessel revascularization. The actuarial survival rate at 1- and 3-year was 92.7% and 89.4%, respectively. In a select group of patients with coronary artery and aortic valve disease, a combined approach of percutaneous coronary intervention followed by minimally invasive aortic valve replacement can be safely performed with excellent short-term and midterm outcomes.


Perforator Branch Flaps.
Modern microsurgical reconstruction aims to achieve functional and satisfactory esthetic outcome and the primary thinning procedure results in one-stage reconstruction. However, current techniques are lacking preoperative knowledge of the peripheral perforator in the adipose layer. We hypothesized that the combination of the knowledge of microvasculature and visualization of such small vessels in the adipose layer by Color Doppler ultrasonography (CDU) will make the dissection of these vessels with simultaneous flap thinning of the perforator branch flap technique feasible and provide consistent results in variety of flaps. Retrospective chart review of consecutive cases in which perforator branch flap technique was used from 2011 to 2019 was conducted. Entire course of branch of the perforator in the adipose layer were traced up to the dermis by CDU, and marked on the skin surface. Based on CDU finding, perforator branches were dissected in the adipose layer simultaneously with the primary thinning of the skin flap. Thirty perforator branch flaps in 28 cases were elevated. Courses of the perforator branches detected by CDU accurately corresponded to surgical findings in all cases. There was no total flap loss in any of the cases and partial necrosis in one case. In five flaps, a secondary debulking procedure was needed. The combination of knowledge of microvasculature with CDU guidance has made the perforator branch technique possible and allowed to safely transfer the skin flap from various body areas to the defect, thereby, achieving "like with like" reconstruction in one-stage.


Cancer Cell Membrane Wrapped Nanoparticles for the Delivery of a Bcl-2 Inhibitor to Triple-Negative Breast Cancer.
Overexpression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) is correlated with poor survival outcomes in triple-negative breast cancer (TNBC), making Bcl-2 inhibition a promising strategy to treat this aggressive disease. Unfortunately, Bcl-2 inhibitors developed to date have limited clinical success against solid tumors, owing to poor bioavailability, insufficient tumor delivery, and off-target toxicity. To circumvent these problems, we loaded the Bcl-2 inhibitor ABT-737 in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) that were wrapped with phospholipid membranes derived from 4T1 murine mammary cancer cells, which mimic the growth and metastasis of human TNBC. We show that the biomimetic cancer cell membrane coating enabled the NPs to preferentially target 4T1 TNBC cells over noncancerous mammary epithelial cells in vitro and significantly increased NP accumulation in orthotopic 4T1 tumors in mice after intravenous injection by over 2-fold compared to poly(ethylene glycol)-poly(lactide-co-glycolic) (PEG-PLGA) copolymer NPs. Congruently, the ABT-737 loaded, cancer cell membrane-wrapped PLGA NPs (ABT CCNPs) induced higher levels of apoptosis in TNBC cells in vitro than ABT-737 delivered freely or in PEG-PLGA NPs. When tested in a syngeneic spontaneous metastasis model, the ABT CCNPs significantly increased apoptosis (evidenced by elevated active caspase-3 and decreased Bcl-2 staining) and decreased proliferation (denoted by reduced Ki67 staining) throughout tumors compared with saline or ABT-loaded PEG-PLGA NP controls. Moreover, the ABT CCNPs did not alter animal weight or blood composition, suggesting that the specificity afforded by the TNBC cell membrane coating mitigated the off-target adverse effects typically associated with ABT-737. Despite these promising results, the low dose of ABT CCNPs administered only modestly reduced primary tumor growth and metastatic nodule formation in the lungs relative to controls. We posit that increasing the dose of ABT CCNPs, altering the treatment schedule, or encapsulating a more potent Bcl-2 inhibitor may yield more robust effects on tumor growth and metastasis. With further development, drug-loaded biomimetic NPs may safely treat solid tumors such as TNBC that are characterized by Bcl-2 overexpression.