Exposure to Mycobacterium avium induces low-level protection from Mycobacterium bovis infection but compromises diagnosis of disease in cattle.
We assessed the effect of exposure to Mycobacterium avium on the development of immune responses and the pathogenesis of disease observed following Mycobacterium bovis challenge. A degree of protection against M. bovis was observed in calves which were pre-exposed to M. avium as assessed by the extent of lesions and bacterial load compared to the M. bovis alone group. The immune response following M. bovis challenge in cattle previously inoculated with M. avium was biased towards antigens (PPD) present in M. avium, whereas the response following M. bovis alone was biased towards antigens present in M. bovis, indicating an imprinting of memory to avian antigens on T lymphocytes. A consequence of the memory to M. avium antigens was failure to diagnose M. bovis infection by the skin test or the IFN(gamma) assay in some of the animals which had lesions of tuberculosis at necropsy. The use of M. bovis specific antigens ESAT-6 and CFP-10 increased IFN(gamma) test specificity in animals previously exposed to M. avium but the responses to these antigens were lower than those observed in animals exposed to M. bovis alone. The implication is that responses to M. avium, although providing some immunity, may mask diagnosis of M. bovis infection, even when specific antigens are employed, potentially contributing to disease transmission in the field.


Set-up errors in head and neck cancer patients treated with intensity modulated radiation therapy: Quantitative comparison between three-dimensional cone-beam CT and two-dimensional kilovoltage images.
To compare the patient set-up error detection capabilities of three-dimensional cone beam computed tomography (3D-CBCT) and two-dimensional orthogonal kilovoltage (2D-kV) techniques. 3D-CBCT and 2D-kV projections were acquired on 29 head-and-neck (H&N) patients undergoing Intensity Modulated Radiotherapy (IMRT) on the first day of treatment (time 0) and after the delivery of 40 Gy and 50 Gy. Set-up correction vectors were analyzed after fully automatic image registration as well as after revision by radiation oncologists. The dosimetric effects of the different sensitivities of the two image guidance techniques were assessed. A statistically significant correlation among detected set-up deviations by the two techniques was found along anatomical axes (0.60 < ρ < 0.72, p < 0.0001); no correlation was found for table rotation (p = 0.41). No evidence of statistically significant differences between the indications provided along the course of the treatment was found; this was also the case when full automatic versus manually refined correction vectors were compared. The dosimetric effects analysis revealed slight statistically significant differences in the median values of the maximum relative dose to mandible, spinal cord and its 5 mm Planning Organ at Risk Volume (0.95%, 0.6% and 2.45%, respectively), with higher values (p < 0.01) observed when 2D-kV corrections were applied. A similar sensitivity to linear set-up errors was observed for 2D-kV and 3D-CBCT image guidance techniques in our H&N patient cohort. Higher rotational deviations around the table vertical axis were detected by the 3D-CBCT with respect to the 2D-kV method, leading to a consistent better sparing of organs at risk.


Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.
An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167.


Redesign, synthesis and functional expression of the 6-deoxyerythronolide B polyketide synthase gene cluster.
A generic design of Type I polyketide synthase genes has been reported in which modules, and domains within modules, are flanked by sets of unique restriction sites that are repeated in every module [1]. Using the universal design, we synthesized the six-module DEBS gene cluster optimized for codon usage in E. coli, and cloned the three open reading frames into three compatible expression vectors. With one correctable exception, the amino acid substitutions required for restriction site placements were compatible with polyketide production. When expressed in E. coli the codon-optimized synthetic gene cluster produced significantly more protein than did the wild-type sequence. Indeed, for optimal polyketide production, PKS expression had to be down-regulated by promoter attenuation to achieve balance with expression of the accessory proteins needed to support polyketide biosynthesis.


In vivo assessment of the placental anatomy and perfusion in a mouse model of intrauterine inflammation.
Magnetic resonance imaging (MRI) provides useful markers to examine placental function. MRI features of placental injury due to intrauterine inflammation-a common risk during pregnancy, are not well known. To investigate the capability of structural MRI and intravoxel incoherent motion (IVIM) imaging in examining acute placental injury in a mouse model of intrauterine inflammation, as well as gestation-dependent placental changes. Prospective study. Pregnant CD1 mice were scanned on embryonic day 15 (E15, n = 40 placentas from six dams) and E17. On E17, mice were subjected to intrauterine injury by exposure to lipopolysaccharide (LPS, n = 25 placentas from three dams) or sham injury (n = 25 placentas from three dams). In vivo MRI was performed on an 11.7T Bruker scanner, using a fast spin-echo sequence and a diffusion-weighted echo-planar imaging (EPI) sequence. T2 -weighted MRI was acquired to evaluate placental volume. IVIM imaging was performed in a restricted field-of-view using 15 b-values from 10-800 s/mm2 , based on which, the pseudodiffusion fraction (f), pseudodiffusion coefficient (D*), and tissue water coefficient (D) were estimated with a two-step fitting procedure. Two-way analysis of variance (ANOVA) was used to evaluate the group differences. The placental volume increased by ∼21% from E15 to E17 (P < 0.01), and a 15% volume loss was observed at 6 hours after LPS exposure (P < 0.01). IVIM parameters (f, D*, and f·D*) were similar between the E15 and E17 sham groups (P > 0.05), which was significantly reduced in the LPS-exposed placentas compared to the shams (P < 0.001). D values decreased from E15 to E17 (P < 0.05), which were further reduced after LPS exposure (P < 0.05). Changes in placental area and vascular density were histologically identified in the LPS-exposed group, along with gestation-dependent changes. Our results suggested structural MRI and IVIM measurements are potential markers for detecting acute placental injury after intrauterine inflammation. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1260-1267.


Functional characterization of novel melanocortin-3 receptor mutations identified from obese subjects.
It is controversial whether mutation in the melancortin-3 receptor (MC3R) gene is a cause for monogenic obesity in humans. Three novel mutations in the MC3R, A293T, I335S, and X361S, were identified from morbidly obese subjects. We investigated whether these mutations caused loss-of-function and the molecular defects if any. Ligand binding, signaling, and cell surface expression of the mutant MC3Rs were studied. I335S resulted in a complete loss of ligand binding and signaling due to intracellular retention. A293T and X361S MC3Rs had normal ligand binding and signaling as wild type MC3R. Co-expression studies showed that the mutants did not affect wild type MC3R signaling. Hence the I335S variant previously identified from obese patients is not expressed at the cell surface when expressed in vitro, suggesting that it might contribute to obesity in carriers of this variant. Whether A293T and X361S cause obesity remains to be investigated. Additional mutations at I335 showed that I335, part of the highly conserved N/DPxxY motif, was critical for multiple aspects of the MC3R function, including cell surface expression, ligand binding, and signaling.


Role of interleukin-32 in the mechanism of chronic inflammation in IgG4-related disease and as a predictive biomarker for drug-free remission.
In immunoglobulin (Ig) G4-related disease (IgG4-RD), the mechanism of chronic inflammation and predictive factors for drug-free remission is still unclear. To examine the issues, we focused on tuberculosis, a chronic infection, and on the role of interleukin (IL)-32. We examined the positive rate of QuantiFERON TB-2G (QFT-2G) in 126 patients with IgG4-RD, and compared with the rate in the general population. Furthermore, specimens of submandibular glands from the maintenance treatment group and drug-free group of IgG4-RD and specimens of small salivary glands from primary Sjögren's syndrome (SS) were stained with anti-IL-32 antibody and anti-protease-activated receptor 2 antibody, and the number of positive cells was compared between these groups. The positive rate of QFT-2G was 19.8% in IgG4-RD patients, which is higher than in the general population. The expression of IL-32 and PAR2 in the submandibular glands of the maintenance treatment group of IgG4-RD was significantly greater than that of the drug-free remission group and SS patients. This study indicates the possibility that IL-32 is associated with chronic inflammation and that it can be a predictive factor for drug-free remission in IgG4-RD.


Both the resistance training session and the static stretching after exercise does not affect the pectoralis major stiffness of well-trained men.
Previous evidence suggests the intense resistance training session can increase the muscle hardness, while stretching protocols with high intensity and volume can decrease it. However, it remains unknown the effects of an exercise and a less intensive stretching maneuver on muscle stiffness of well-trained men. Herein we (i) analyze the acute effects of heavy bench press exercise on the pectoralis major muscle shear modulus of well-trained men and (ii) assess the effectiveness of a 1-min stretching maneuver applied on this muscle after the exercise using shear wave elastography. Fourteen participants performed three sets of bench press from 8 to 13 repetitions maximum. Immediately after the exercise, their right shoulder was passively stretched for 1 min (stretched side) while their left arm stayed relaxed along the side of the body (control side). Elastographic images were acquired for the pectoralis major mid-region of both sides before the exercise, immediately after the intervention and after 5 min of rest. Our results revealed that both the bench press exercise and the static stretching does not affect the pectoralis major shear modulus of well-trained men. Conversely, the shear modulus significantly decreased at 5 min after intervention with respect to immediately after, for both the stretched (from 5.52 to 4.29 kPa) and the control sides (from 5.87 to 4.56 kPa). Therefore, both resistance training session and 1-min static stretching were not sufficient to significantly change the pectoralis major muscle stiffness of well-trained men.


Nutritional Support of the Critically Ill Small Animal Patient.
Over the past couple of decades, a component of veterinary critical care was simply to ensure that nutritional support formed some part of the treatment plan. Great emphasis was made on early placement of feeding tubes in critically ill veterinary patients to facilitate enteral feeding. Progress has been made on techniques for nutritional provision, establishing feasibility of nutritional interventions in various patient populations and establishing that nutritional support does have an important role in veterinary critical care. Some refinement of appropriate caloric targets in critically ill animals has decreased complications relating to overfeeding, but further work is required to establish optimal feeding regimes.


Dietary supplementation of Ocimum gratissimum improves growth performance and immune response in broilers under high ambient temperature.
Ocimum gratissimum (OG) was found to have immunity boosting effect on Taiwan country chickens and broiler chickens raised in moderate ambient temperature in previous studies, and the current study investigates its potential on the growth performance, blood traits, intestinal traits, and immune responses in Ross 308 broilers raised in high ambient temperature which can induce mild heat-stress (26 to 33 ˚C, average 30 ˚C). Two hundred 1-d-old male/female chicks were randomly assigned to a control group, three OG (1 g/kg, 3 g/kg, and 5 g/kg)/basal diet groups, and one Amoxicillin group. Data collected during the experiment indicated that the weight gain increase of 1742 g/bird to 1815 g/bird comparing control to 5 g/kg OG supplementation was statistically significant. In addition, the production efficiency factor was also noticeably increased by OG, particularly in the 5 g/kg group, and the uric acid levels were decreased in the 3 and 5 g/kg OG groups (from 4.26 to 2.91 and 2.90 mg/dL, respectively), indicating heat-stress alleviation was observed. Several areas of the carcass saw desirable growth changes, including the increase of breast muscle ratio observed in the 5 g/kg OG group, an overall decrease in abdominal fat in all OG groups, as well as dimensional changes in several areas of the digestive system. Lastly, the hemaglutination, hemaglutination inhibition, and phytohemaglutinin tests indicated elevated immuno-response in all OG groups. In conclusion, OG has exhibited the ability to alleviate symptoms of mild heat-stress, leading to improvement of the digestive organ development and increase of carcass mass and mean weight gain for birds, and we find OG to be a potentially beneficial feed supplement for poultry raising in high ambient temperature conditions.


Use of filter paper stored dried blood for measurement of triglycerides.
Adaptation of assays on dried blood has advantages of ease of collection, transportation, minimal invasiveness and requirement of small volume. A method for extraction and estimation of triglyceride from blood spots dried on filter paper (Whatman no. 3) has been developed. A single dried blood spot containing 10 muL blood was used. Triglyceride was efficiently extracted in methanol from blood dried on filter paper by incubation at 37 degrees C for two hours with gentle shaking. For the estimation, a commercially available enzymatic method was used. Blood spot assays showed mean intra and inter assay coefficient of variance of 6.0% and 7.4% respectively. A comparison of paired whole blood spots and plasma samples (n = 75, day 0) gave an intraclass correlation of 0.96. The recovery was 99.6%. The dried blood triglyceride concentrations were stable for one month when the filter discs were stored at room temperature (16-28 degrees C). Storage of filters at 4 degrees C extended the stability and triglycerides could be quantitatively recovered after 3 months of storage.


Sellar Lesions/Pathology.
The sellar region is a tiny anatomic compartment in which many lesions and developmental diseases can be found. If pituitary adenomas represent most of the sellar mass, it is important to recognize other pathologic conditions before any surgical procedure, because the optimal treatment may differ considerably from one lesion to another. A careful clinical evaluation followed by neuroimaging studies and an endocrinologic and ophtalmologic workup will lead, in most cases, to a diagnosis with near certainty. This article provides an overview of sellar diseases with emphasis on their most useful characteristics for clinical practice.


Annual replacement of the tillers of Agropyron desertorum following grazing.
The annual replacement of tillers of Agropyron desertorum (Fisch. ex Link) Schult., a grazing-tolerant, Eurasian tussock grass, was examined in the field following cattle grazing. Heavy grazing before internode (culm) elongation seldom affected tiller replacement. Heavy grazing during or after internode elongation, which elevates apical meristems, increased overwinter mortality of fall-produced tillers and reduced the number and heights of these replacement tillers. Unexpectedly, tussocks grazed twice within the spring growing season tended to have lower overwinter tiller mortality, greater tiller replacement, and larger replacement tillers than tussocks grazed only once in late spring. These responses of twice-grazed tussocks, however, were still less than those of ungrazed tussocks or tussocks grazed moderately in early spring. The presence of ungrazed tillers on partially grazed tussoks did not increase the replacement of associated grazed tillers relative to tillers on uniformly grazed plants. This result indicates that resource sharing among tillers, if present, is short-lived or ecologically unimportant in this species. Although A. desertorum is considered grazing-tolerant, tiller replacement on heavily grazed tussocks, particularly those grazed during or after internode elongation when apical meristems were removed, was usually inadequate for tussock maintenance. These observations at the tiller (ramet) level of organization in individual tussocks (genet) may explain the often noted reduction in stand (population) longevity with consistent heavy grazing.


Chalcopyrite concentrate leaching with biologically produced ferric sulphate.
Biological ferric iron production was combined with ferric sulphate leaching of chalcopyrite concentrate and the effects of pH, Fe3+, temperature and solids concentration on the leaching were studied. The copper leaching rates were similar at pH of 1.0-1.8 and in the presence of 7-90 g L-1 Fe3+ despite massive iron precipitation with 90 g L-1 Fe3+. Increase of the leaching temperature from 50 degrees C to 86 degrees C and solids concentration from 1% to 10% increased the copper leaching rate. Increase in solids concentration from 1% to 10% decreased the copper yields from 80% to 40%. Stepwise addition of ferric iron did not improve the copper yields. CuFeS2, Ag and Cu1.96S potentials indicated the formation of a passivating layer, which consisted of jarosite and sulphur precipitates and which was responsible for the decreased leaching rates.


Subretinal hemorrhage masquerading as a hemorrhagic choroidal detachment in a case of nonaccidental trauma.
Retinal hemorrhages are the most commonly reported ocular findings in nonaccidental trauma in children. Other reported ocular findings include perimacular folds, traumatic retinoschisis, choroidal hemorrhages, and retinal detachments. We report the clinical and pathologic findings in a case of a 10-month-old boy who sustained nonaccidental trauma and whose clinical presentation was characteristic of a hemorrhagic choroidal detachment. Postmortem examination revealed a large subretinal hemorrhage, with no evidence of choroidal hemorrhage.


Bilateral congenital hypoplasia of the carpal scaphoid bone.
A case of bilateral congenital scaphoid hypoplasia, with wasting of the thenar muscles and absence of certain muscles of the forearm is presented. The patient had additional congenital disorders of the vertebrae, skull and elbow.


Capillary-venous hematocrit differences in newborn infants. I. Relationship to blood volume, peripheral blood flow, and acid base parameters.
Venous and capillary hematocrit, acid base values, and circulatory parameters were measured simultaneously in 92 newborn infants within six hours of birth. Gestational age ranged from 26 to 41 weeks. The capillary/venous hematocrit ratio (Hctc/Hctv) was greater than 1.00 in 89 infants. We found significant inverse correlations between Hctc/Hctv and several parameters, such as pH (r = -0.82), standard bicarbonate (r = -0.73), systolic blood pressure (r = -0.51), and peripheral blood flow (r = -0.70). Most of the infants with a Hctc/Hctv of 1.20 and above had red cell mass values of less than 35 ml/kg. However, blood volume apparently did not influence the Hctc/Hctv. Gestational age appeared to affect Hctc/Hctv only before 30 weeks, when compared with the Hctc/Hctv of term infants. Our results indicate that disturbed circulation, and in particular, disturbed microcirculation is involved in the development of high Hctc/Hctv ratios. We strongly advise that hematocrits obtained by skin prick from a sick newborn infant should not be relied on as they may give misleading information on oxygen carrying capacity to vital organs.


A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors.
Positively selected CD34(+) hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO(+) HLA-DR(+), whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA(+) naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of gammadelta T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.


Applying the consolidated framework for implementation research to evaluate the community rapid intervention service.
Developed in 2019, the Community Rapid Intervention Service (CRIS) is a community intervention service aiming to prevent hospital admissions. CRIS provides a response within two hours to patients with sub-acute medical needs in their usual place of residence. This evaluation aimed to identify challenges and facilitators to implementation of the service, with a view to informing future service development, optimising patient care and disseminating learning to other areas looking to implement similar services. This study used the Consolidated Framework for Implementation Research (CFIR) as an evaluation framework. We conducted semi-structured interviews with local healthcare system leaders, clinicians that worked within the CRIS, and clinicians who interfaced with the CRIS. The CFIR was used to guide data collection and analysis. Two Community of Practice (CoP) meetings were held to gather stakeholders' perspectives of the evaluation. Three key themes were identified from the analysis of 13 interviews: contextual factors influencing implementation, service identity and navigating complexity. Contextual factors such the influence of the Covid 19 pandemic upon health services and the expansion of the CRIS were discussed by participants. The adaptability of the service was deemed both a facilitator and challenge of implementation. Ways to build-on and improve the existing CRIS model were suggested. This evaluation has shown that the CRIS may need to be redefined with clarity provided as to how the service interfaces with other urgent and planned care offered in acute, primary, community and social services. Structuring the evaluation around the CFIR was helpful in identifying facilitators and challenges that influenced the implementation of the CRIS.


Cholinergic somata and terminals in the rat substantia nigra: an immunocytochemical study with optical and electron microscopic techniques.
The topographical distribution, histochemical characteristics, and anatomical relationships of the cellular elements containing choline acetyltransferase (ChAT) immunoreactivity, demonstrated with specific monoclonal antibodies to ChAT following the unlabelled antibody peroxidase-antiperoxidase (PAP) procedure at the optical and electron microscopic levels, were investigated in the rat substantia nigra (SN). Scarce, large (20-30 microns in maximum soma extent) cholinergic cell bodies and processes were found within the boundaries of the SN, in the borders of the pars compacta and pars reticulata, principally at caudal levels. Occasionally, cholinergic neurons were also found at intermediate levels of the SN, in the borders of the pars reticulata and pars lateralis. Cytologically, these large cells resembled ChAT-positive neurons localized in other areas of the central nervous system (CNS) of the rat--for example, the pontomesencephalotegmental (PMT) cholinergic complex (Ch5-Ch6) and the nucleus basalis of Meynert (nbM) (Ch4). Histochemically, ChAT-positive cells in the SN were characterized by their ability to utilize the reduced cofactor nicotinamide adenine dinucleotide phosphate (NADPH). Identified ChAT-positive neurons in the light microscope were subsequently studied in the electron microscope. All cholinergic neurons in the SN share essentially the same ultrastructural characteristics. The copious cytoplasm was rich in organelles with large lipofuscin granules. The synaptic input onto cell bodies and their dendrites was studied in serial sections. Synaptic contacts onto the perikarya and proximal dendrites were sparse and of asymmetric type. Both symmetric and asymmetric synaptic specializations onto ChAT-positive distal dendrites were detected. Asymmetric synaptic contacts onto cell bodies and dendrites were often defined by the presence of subjunctional dense bodies associated with the postsynaptic membrane. The pattern of the synaptic input to these cells differs strikingly from that onto unlabelled neighboring neurons. The perikarya and dendrites of the latter were characteristically covered with synaptic boutons. Scarce immunoreactive terminals in asymmetric synaptic contact with unlabelled dendritic profiles were also detected in portions of SN compacta with no ChAT-positive cells. Extranigrally located ChAT-positive cells of the PMT cholinergic complex were also examined in the electron microscope for comparison purposes. These cells exhibited, on the basis of their morphology and synaptic input pattern, very similar characteristics to those shown by SN cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


LKB1 up-regulation inhibits hypothalamic inflammation and attenuates diet-induced obesity in mice.
Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus. The inflammatory pathway of the hypothalamus is activated during obesity, and inhibition of activation of the inflammatory pathway can partially reverse obesity. Therefore, exploring new targets for inhibiting hypothalamic inflammation will provide new ideas for the prevention and treatment of obesity. Liver kinase B1 (LKB1), a serine/threonine kinase, is a tumor suppressor and metabolic regulator. Recent studies have shown that LKB1 has a certain anti-inflammatory effect. However, a role of LKB1 in the regulation of hypothalamic inflammation remains unclear. Therefore, we examined whether LKB1 overexpression in the hypothalamus could weaken the hypothalamic inflammation and inhibit the development of obesity. LKB1 overexpressing adeno-associated virus (AAV) particles were injected stereotactically into the third ventricle (3 V) of C57BL/6 mice fed with HFD. We assessed changes in body mass and adiposity, food intake, hypothalamic inflammatory markers, and energy and glucose metabolism. LKB1 up-regulation in hypothalamus attenuated diet-induced hypothalamic inflammation, reduced food intake and body weight gain. In addition, the overexpression of hypothalamic LKB1 increased the insulin sensitivity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum lipid levels. Hypothalamic LKB1 up-regulation attenuates hypothalamic inflammation, and protects against hypothalamic inflammation induced damage to melanocortin system, resulting in lower food intake and lower fat mass accumulation, which consequently protects mice from the development of obesity. Our data suggest LKB1 as a novel negative regulator of hypothalamic inflammation, and also a potentially important target for treating other inflammatory diseases.


Interactions of smoking with rs833061 polymorphism on the risk of non-alcoholic fat liver disease in Hubei Han population: a preliminary case-control study.
Vascular endothelial growth factor (VEGF) has biological actions on energy homeostasis, inflammation and insulin resistance. The present study aimed to investigate the association between VEGF -460 T/C (rs833061), and +936 C/T (rs3025039) polymorphism and risk of non-alcohol fatty liver disease (NAFLD) in Hubei Han population and to further explore the interactions of smoking with rs833061 and rs3025039. 341 healthy controls and 246 cases were recruited. Two variants, rs833061 and rs3025039, were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The unconditional logistic regression (ULR) was performed to assess the association of the two variants with risk of NAFLD. Gene-environment interactions on the risk of NAFLD were preliminarily explored by generalized multifactor dimensionality reduction (GMDR) and further confirmed by ULR methods. After adjusting for covariates, increased risk of NAFLD was observed in patients carrying CT/CC genotypes in rs833061 and rs3025039 (ORa=1.80, 95% confidence interval (CI): 1.51, 2.36, Pa =0.000; ORa=1.89, 95% CI: 1.41, 2.82, Pa =0.000, respectively). Interaction of smoking with rs833061 was found by GMDR, with maximum prediction accuracy (67.91%) and a maximum cross-validation consistency (10/10). ULR method confirmed that, smoking-positive patients with genotype CT/CC had 4.93 times risk of NAFLD compared to smoking-negative participants with genotype TT (ORadd (a)=4.93, 95% CI: 2.91, 8.54, P add (a)=0.000), which further confirmed synergistic effects. The results indicated that both rs833061 and rs3025039 are associated with NAFLD risk. Furthermore, rs833061 is likely to have an interaction with smoking, and they have synergistic effects on risk of NAFLD in Hubei Han population.


Indole-based melatonin analogues: Synthetic approaches and biological activity.
Melatonin is a natural hormone primarily released by the pineal gland that regulates the sleep-wake cycles. The diverse biological applications of melatonin, together with the need to develop new melatoninergic ligands, have stimulated the preparation of a wide range of melatonin derivatives. Here, all the synthetic approaches to indole-based melatonin analogues as well as their biological applications are reviewed. The modifications which have been performed on the melatonin's indole ring and the effects of these modifications on the biological activities have been analysed, detailing the binding affinity of the derivatives for melatonin receptors.


Dichorionic triplets following frozen-thawed poor-stage embryo transfer: a report of two cases and a review.
We describe two cases of dichorionic triplet pregnancy after a frozen-thawed poor-stage embryo transfer. A 39-year-old and a 41-year-old woman underwent ART treatment. The first patient underwent intracytoplasmic sperm injection (ICSI) at 34 years of age, and two frozen-thawed poor-stage embryos were transferred at 39 years of age with assisted hatching, resulting in a trichorionic triamniotic triplet pregnancy. The second patient underwent ICSI, and two poor-grade blastocysts were transferred followed by assisted hatching, resulting in a dichorionic triamniotic triplet pregnancy. In the first case, the heartbeat of one monozygotic twin fetus had stopped on day 48 post-transfer (9 weeks 2 days), resulting in a dichorionic diamniotic twin pregnancy. A healthy boy and girl were delivered by elective caesarean section at 36 weeks, 5-days gestation. In the second case, the patient underwent selective reduction of the monochorionic twins, resulting in a single pregnancy that was vaginally delivered without any problems at 38 weeks 0-days gestation. Numerous factors may be associated with the development of a monochorionic pregnancy; however, controversies still remain. The present morphological grading for embryos is insufficient for inhibiting the development of a monochorionic pregnancy.


MiR-134 functions as a regulator of cell proliferation, apoptosis, and migration involving lung septation.
MicroRNAs (miRNAs) are 21-25 nt long non-coding RNA that modulate various biological processes, including developmental timing via regulating the expression of their target genes. One critical determinant of normal postnatal lung architecture is septation, and there are many miRNAs involved in the development process. miR-134 is reported as a powerful inducer of pluripotent stem cell differentiation, and we have found that miR-134 is strongly downregulated during mice lung septation (from postnatal Day 2 to postnatal Day 21). Further cell function experiments have revealed that over-expression of miR-134 in A549 and Calu-3 cells can promote cell proliferation and inhibit cell apoptosis and migration abilities in vitro, and the down-expression of miR-134 in cells can act in the opposite way, which indicate that miR-134 is associated with lung septation. This study provides a basis for further investigation of its function in lung development.


Alcohol induced pancreatitis: social and surgical aspects.
During the period 1977-1985, 38 patients with alcohol related pancreatitis (37 men, 1 woman) were referred to a specific pancreatic follow-up clinic; their mean age was 42.4 years (range 20-69 years). At initial presentation 14 patients were unemployed (37 per cent) and 11 worked as unskilled labourers (29 per cent). Twenty-seven patients (71 per cent) required more than one hospital admission. Surgery was indicated in 14 patients (37 per cent): 4 diagnostic laparotomy, 3 cholecystectomy, 3 drainage of pancreatic pseudocyst and 1 pancreatic abscess, 3 biliary bypass and 4 pancreatic resection. Four patients required more than one operative procedure. Five deaths occurred during the study period: one following biliary bypass, one following total pancreatectomy and three not directly related to pancreatitis. Follow-up attendance rates at 1, 3 and 5 years were 76, 47 and 34 per cent respectively. Alcohol induced pancreatitis in Teesside, UK, is a disease of young adult males of lower socio-economic status with a recurring pattern leading to repeated hospital admissions and an unexpectedly high incidence of surgery. The study demonstrates the problem of ascertaining data related to long term follow-up in a condition where, despite intensive efforts, patient compliance is poor.


Pharmacology of L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpro pan oic acid); a potent, selective thromboxane/prostaglandin endoperoxide antagonist.
L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) has been studied in vitro on the guinea-pig tracheal chain, pulmonary artery and thoracic aorta ring and shown to be a potent, competitive antagonist of contractions induced by the prostaglandin endoperoxide analogue, U-44069 (pA2 values 8.0, 8.4 and 8.0 respectively). Selectivity on the guinea-pig trachea was indicated by non-competitive antagonism of contractions induced by prostaglandin D2 and minimal activity against contractions induced by leukotriene D4, prostaglandin F2 alpha, serotonin, histamine and acetylcholine. L-655,240 was a potent inhibitor of the aggregation of washed human platelets induced by U-44069 (IC50 value 7 X 10(-9) M) and inhibited aggregation of human platelet rich plasma induced by U-44069, U-46619, thromboxane A2 and collagen but not ADP or platelet activating factor. In vivo i.v. L-655,240 administered to guinea-pigs inhibited bronchoconstriction induced by i.v. U-44069 and arachidonic acid (ED50 values 0.09 and 0.23 mg kg-1) but not histamine, acetylcholine or serotonin. When administered to rhesus monkeys (3 and 10 mg/kg p.o.), L-655,240 inhibited ex vivo platelet aggregation induced by U-44069 but not ADP. It is concluded that L-655,240 is a potent, selective, orally active thromboxane/prostaglandin endoperoxide antagonist.


Reproductive toxicity of vinclozolin in the fathead minnow: confirming an anti-androgenic mode of action.
The objective of the present study was to characterize responses of the reproductive endocrine system of the fathead minnow (Pimephales promelas) to the fungicide vinclozolin (VZ), using a 21-d reproduction assay, and a shorter-term (approximately two weeks) test in which fish were cotreated with the VZ (a putative anti-androgen) and the androgen 17beta-trenbolone (TB). Effects on fecundity, gonadal histology, secondary sexual characteristics, reproductive hormones, and relative abundance of androgen receptor (AR) and 11beta-hydroxysteroid dehydrogenase (11betaHSD) mRNA transcripts were evaluated in one or both of these studies. Fecundity of VZ-exposed fish was decreased in a concentration-dependent manner in the 21-d test, culminating in complete reproductive failure at a concentration of 700 microg/L. Exposure to VZ decreased expression of male secondary sexual characteristics -- an effect typical of anti-androgens. The finding that exposure of females to TB-induced expression of prominent, male-like tubercles, which could be effectively blocked with VZ, provides powerful evidence of the anti-androgenic activity of VZ in vivo. In the two experiments VZ produced several responses possibly indicative of compensation or adaptation of the fish to the anti-androgen, including increases in gonad weight, AR and 11 betaHSD mRNA transcript abundance, and ex vivo gonadal production of testosterone and 11-ketotestosterone. Overall, our results demonstrate that the model anti-androgen VZ, which also is an environmental contaminant, impairs reproductive success of fathead minnows and elicits endocrine responses consistent with an anti-androgenic mode of action.


Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment.
Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2(+) monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti-cancer treatments.


Quantum information theoretic approach to the mind-brain problem.
The brain is composed of electrically excitable neuronal networks regulated by the activity of voltage-gated ion channels. Further portraying the molecular composition of the brain, however, will not reveal anything remotely reminiscent of a feeling, a sensation or a conscious experience. In classical physics, addressing the mind-brain problem is a formidable task because no physical mechanism is able to explain how the brain generates the unobservable, inner psychological world of conscious experiences and how in turn those conscious experiences steer the underlying brain processes toward desired behavior. Yet, this setback does not establish that consciousness is non-physical. Modern quantum physics affirms the interplay between two types of physical entities in Hilbert space: unobservable quantum states, which are vectors describing what exists in the physical world, and quantum observables, which are operators describing what can be observed in quantum measurements. Quantum no-go theorems further provide a framework for studying quantum brain dynamics, which has to be governed by a physically admissible Hamiltonian. Comprising consciousness of unobservable quantum information integrated in quantum brain states explains the origin of the inner privacy of conscious experiences and revisits the dynamic timescale of conscious processes to picosecond conformational transitions of neural biomolecules. The observable brain is then an objective construction created from classical bits of information, which are bound by Holevo's theorem, and obtained through the measurement of quantum brain observables. Thus, quantum information theory clarifies the distinction between the unobservable mind and the observable brain, and supports a solid physical foundation for consciousness research.


Phosphorylase activity as a histochemical marker of specialized tissue of heart.
Phosphorylase activity has been investigated histochemically under controlled conditions in the specialized tissue and the general myocardium of goat heart using glucose-1-phosphate as the substrate. It has been observed that the phosphorylase content of the nodal and conducting tissue is very high as compared to the general myocardium. The phosphorylase content of the cardiac neural elements is also high. Since the connective tissue which surrounds the nodal and conducting tissue has almost no phosphorylase activity, the nodal and conducting tissue is sharply demarcated by the histochemical reaction for phosphorylase. This reaction can, therefore, be used as a specific and expedient method for the localization of specialized tissue as an exploratory and confirmatory test.


Employment, economy and care in Sweden by the year 2000.
Within the context of the future study 'Care in Society' an analysis has been made concerning the relationships between employment, economy and care. The changed economic outlook for Sweden creates problems for employment as well as for the public care systems. Employment in the future will be influenced by: --the growing labour force; --the changing structure of the labour market; --the expansion of the public care systems; --working hours per week and life. It is argued that shorter working hours--besides positive effects on employment--also will create more favourable conditions for the informal care sector--care in the family and voluntary care. A conscription system for care might be a solution to the problems of care and employment in the future.


Adrenergic regulation of immune cell function and inflammation.
The sympathetic nervous system integrates the functions of multiple organ systems by regulating their autonomic physiological activities. The immune system is regulated both locally and systemically by the neurotransmitters epinephrine and norepinephrine secreted by the adrenal gland and local sympathetic neurons. Immune cells respond by activation of adrenergic receptors, primarily the β2-adrenergic receptor, which signal through heterotrimeric G-proteins. Depending upon the cell type, adrenergic signaling regulates a variety of functions in immune cells ranging from cellular migration to cytokine secretion. Furthermore, due to the diurnal oscillation of systemic norepinephrine levels, various immune functions follow a circadian rhythmic pattern. This review will highlight recent advances in our understanding of how the sympathetic nervous system regulates both innate and adaptive immune functions and how this regulation is linked to circadian rhythms.


[Responses by neuropaediatricians to a palliative care questionnaire].
Up to 70% of children currently treated by Palliative Care Units in Europe are neurological patients. Our objective is to assess the knowledge, interest and involvement in Paediatric Palliative Care (PPC) among Spanish paediatric neurologists. We contacted 297 Neuropaediatricians by and attached a 10-question multiple choice test. This questionnaire was related to the level of knowledge of PPC, identification of patients requiring this specific care, involvement of a paediatric neurologist, use of local palliative resources, and formal training in this subject. Participation rate was 32% (96/297). Around 90% knew the definition of PPC, could identify patients with a short-term survival prognosis, and had treated children who eventually died due to their illnesses. A "non resuscitation order" had been written by 61% of them at least once; 77% considered the patient́s home as the preferred location of death (if receiving appropriate care), 9% preferred the hospital, and 14% had no preference for any of these options. Just over half (52%) had contacted local PC resources, and 61% had referred or would refer patients to be seen periodically by both services (PC and Paediatric Neurology). More than half (55%) consider themselves not trained enough to deal with these children, and 80% would like to increase their knowledge about PPC. The paediatric neurologists surveyed frequently deal with children who suffer from incurable diseases. Their level of involvement with these patients is high. However, there is an overwhelming necessity and desire to receive more training to support these children and their families.


A malignant mixed gonadal stromal tumor of the testis with heterologous components and i(12p) in one of its metastases.
A malignant mixed gonadal stromal tumor with mesenchymal heterologous elements of the testis is presented. This entity has been described in the ovary, but not hitherto in the testis. Karyotyping and ploidy measurement was done of the primary tumor and of an inguinal and lung metastases. The DNA ploidy and modal chromosome numbers were in agreement with each other in all samples. The most significant cytogenetic finding was the presence of the metacentric germ cell tumor marker i(12p) in an inguinal metastasis. This marker has been demonstrated in testicular and ovarian germ cell tumors and in a mixed Müllerian tumor, which raises the question of a possible relationship between the pluripotency of these tumors and the presence of i(12p).


Pathogen safety of Beriate®.
Plasma-derived factor VIII (FVIII) concentrates have been used successfully to treat haemophilia A since the late 1960s. To ensure the pathogen safety of the plasma-derived FVIII concentrate, Beriate(®) (formerly Beriate(®) P), donors of blood/plasma are carefully selected and all donations are screened for hepatitis B virus surface antigen (HBsAg), antibodies against HIV types 1 and 2 (HIV-1/HIV-2) and hepatitis C virus (HCV), and genomic material of hepatitis A virus (HAV), hepatitis B virus (HBV), HCV, and for high titres of parvovirus B19 (B19V). As additional quality control, plasma pools for fractionation are only released for further processing when non-reactivity has been demonstrated in serological and genome amplification assays. The manufacturing process for Beriate(®) comprises dedicated virus reduction steps such as pasteurization and the recently introduced virus filtration step, resulting in effective inactivation of various enveloped and non-enveloped viruses and effective removal of viruses and prion material larger than the mean pore size of the virus filter (19 nm). The effectiveness of these production steps has been demonstrated in virus and prion validation studies using a range of different viruses and prion preparations. The multiple precautionary measures inherent to the overall production process for Beriate(®) (and its predecessor Beriate(®) P) are reflected in an excellent safety record documented during 20 years of clinical use with no proven record of virus transmission, even before the introduction of the virus filtration step. Continued improvement of safety measures according to scientific knowledge and regulatory guidance maintains and even enhances the excellent safety profile of Beriate(®).


Secretory expression and characterization of insulin in Pichia pastoris.
The yeasts Pichia pastoris and Saccharomyces cerevisiae have similar overall features regarding the secretory expression of insulin. The S. cerevisiae mating factor alpha (alpha-factor) prepro-leader facilitated the secretion of an insulin precursor, but not proinsulin expressed in P. pastoris. Synthetic prepro-leaders developed for the secretory expression of the insulin precursor in S. cerevisiae also facilitated the secretion of the insulin precursor expressed in P. pastoris. In contrast with S. cerevisiae, only insulin precursor and no unprocessed hyperglycosylated alpha-factor pro-leader/insulin precursor fusion protein was secreted from P. pastoris. A spacer peptide in the fusion protein increased the fermentation yield of the insulin precursor in P. pastoris. A synthetic prepro-leader, but not an alpha-factor prepro-leader lacking N-glycosylation sites, facilitated the secretion of the insulin precursor in P. pastoris. P. pastoris has a capacity for secretory expression of the insulin precursor that is equal to or better than that of S. cerevisiae. Peptide mapping and MS indicated a structure of the insulin precursor expressed in P. pastoris identical with that of human insulin.


On the chemical nature of the blood borne cardiotoxic material released from the feline small bowel in regional shock.
The cardiotoxic material released into blood from the feline small intestine during a 2 or 3 h regional shock period (inflow pressure to the small intestine 30--35 mmHg during a continuous activation of the regional sympathetic vasoconstrictor fibres at 6 Hz) has been analyzed with regard to three properties: 1. molecular mass determined by molecular filtrations; 2. solubility in a nonpolar solvent (ether); 3. heat stability by heating plasma to 80 degrees C for 30 min. The results obtained suggest that the cardiotoxic material consists of at least two heat stable fractions. One is water soluble with a molecular mass between 500 and 1 000 d and the other is lipid soluble with an unknown molecular mass.


Simulated microgravity potentiates generation of reactive oxygen species in cells.
Microgravity (MG) and space radiation are two major environmental factors of space environment. Ionizing radiation generates reactive oxygen species (ROS) which plays a key role in radiation-induced DNA damage. Interestingly, simulated microgravity (SMG) also increases ROS production in various cell types. Thus, it is important to detect whether SMG could potentiate ROS production induced by genotoxins including radiation, especially at a minimal level not sufficient to induce detectable ROS. In this study, we treated mouse embryonic stem (MES) cells with H2O2 and SMG for 24 h. The concentration of H2O2 used was within 30 μmol/L at which intracellular ROS was the same as that in untreated cells. Exposure of cells to SMG for 24 h did not induce significantly higher levels of intracellular ROS than that of control cells either. Simultaneous exposure of cells to both SMG- and H2O2-induced ROS and apoptosis in MES cells. Although incubation in medium containing 5 or 30 μmol/L H2O2 induced a small enhancement of DNA double-strand breaks (DSBs), the addition of SMG treatment dramatically increased DSB levels. Taken together, SMG can significantly potentiate the effects of H2O2 at a low concentration that induce a small or negligible change in cells on ROS, apoptosis, and DNA damage. The results were discussed in relation to the combined effects of space radiation and MG on human body in this study.


The association between serum estradiol level and hearing sensitivity in postmenopausal women.
To estimate whether hearing sensitivity in postmenopausal women is associated with serum estradiol level or bone mineral density. Serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and hearing sensitivity were measured in 1830 postmenopausal women. Serum estradiol level was measured by radioimmunoassay, and dual energy x-ray absorptiometry was used to measure bone mineral densities of the lumbar vertebrae and femoral neck. Hearing sensitivity was evaluated by pure tone audiometry. Age, serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and the proportion of women on hormone replacement therapy were analyzed in women with and without hearing loss. On univariate analysis, significant differences were found in mean age, serum estradiol level, bone mineral densities of the lumbar vertebrae and femoral neck, and the proportion of women on hormone replacement therapy between the two groups (mean +/- standard deviation, 59.4 +/- 5.6 versus 56.9 +/- 4.7 years, P <.001; 8.4 +/- 3.8 versus. 9.9 +/- 8.7 pg/mL, P <.001; 0.85 +/- 0.14 versus 0.88 +/- 0.15 g/cm(2), P <.01; 0.65 +/- 0.10 versus 0.68 +/- 0.10 g/cm(2), P <.005; 0.006% versus 0.03%, P <.05, respectively). On multiple logistic regression analysis, significant association was found between age and hearing loss and between serum estradiol level and hearing loss (P <.001, P =.02, respectively). This study suggests that a lower level of serum estradiol possibly impedes hearing sensitivity in postmenopausal women.


Multicenter, Open-Label Study of Long-Term Topiroxostat (FYX-051) Administration in Japanese Hyperuricemic Patients with or Without Gout.
Topiroxostat-a novel selective xanthine oxidoreductase inhibitor-has been reported to reduce serum urate levels. The purpose of this study was to assess the efficacy and safety of long-term topiroxostat administration in Japanese hyperuricemic patients with or without gout. This multicenter, open-label study evaluated the efficacy and safety of long-term twice-daily oral topiroxostat administration in patients with or without gout. The initial topiroxostat dosage was 40-80 mg/day, and the maintenance dosage was 120 mg/day, which was increased to 240 mg/day at 40 mg increments if the serum urate level exceeded 6.0 mg/dL. Serum urate level, which was the primary endpoint, decreased stably over time and showed significant reduction on the final visit (38.44% ± 13.34%) compared with that at the baseline. Both urinary albumin/creatinine ratio and mean blood pressure significantly improved. The overall incidence rate of adverse drug reactions to topiroxostat was 67.8%; on the final visit, the rate of adverse drug reactions was 66.7% with 120 mg/day, 72.2% with 160 mg/day, 53.8% with ≥ 200 mg/day, and 100% with the other dosages. On the final visit, the incidence of gouty arthritis, for which a causal relationship with topiroxostat could not be ruled out, was 4.1% overall, 4.8% with 120 mg/day, 0% with 160 mg/day, and 7.7% with ≥ 200 mg/day. We verified the efficacy and safety of 58-week oral topiroxostat administration at stepwise increments to up to 240 mg/day. JAPIC CTI-101068.


Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.
Approximately 3% of the live-born infants have major dysmorphic features, and about two-thirds of which are observed in the maxillofacial region; however, in many cases, the etiology of the dysmorphic features remains uncertain. Recently, the genome-wide screening of large patient cohorts with congenital disorders has made it possible to discover genomic aberrations corresponding to the pathogenesis. In our analyses of more than 536 cases of clinically undiagnosed multiple congenital anomalies and mental retardation (MR) by microarray-based comparative genomic hybridization, we detected two non-consanguineous unrelated patients with microdeletions at 10p11.23-p12.1, which overlapped for 957 kb, including four protein-coding genes: ARMC4, MPP7, WAC and BAMBI. As the two patients had similar phenotypes; for example, MR and multiple maxillofacial abnormalities including midface retrusion, wide mouth and large tongue, we assessed the phenotypes in detail to define the common features, using quantitative evaluations of the maxillofacial dysmorphism. The concordance of the genetic and phenotypic alterations is a good evidence of a new syndrome. Although an interstitial deletion of 10p is rare, the current study is the first trial to examine precisely the craniofacial characteristics of patients with a heterozygous deletion at 10p11.23-p12.1, and presents good evidence to diagnose potential patients with the same genetic cause.


In vitro modulation of bcl-2 protein expression, drug-induced apoptosis and cytotoxicity by interleukin-10 in chronic lymphocytic leukemia.
Interleukin-10 failed to modify either the percentage of bcl-2+ cells or the number of bcl-2 molecules, or to reduce 2-chlorodeoxyadenosine- and fludarabine-induced apoptosis. The cytokine at 0.1 ng/mL induced an increase of cell survival both in the absence or in the presence of 2-chlorodeoxyadenosine, while no difference was appreciated with fludarabine.


Utility of chromogenic property of 2, 2-dihydroxyindane-1, 3-dione for quantification of Memantine hydrochloride in pure, pharmaceutical preparation and application to uniformity testing.
Accurate, simple, sensitive, and fast spectrophotometric assay was applied for the quantification of certain anti-Alzheimer drug namely; Memantine hydrochloride, in its bulk and pharmaceutical preparation. The described assay has been established on the reaction between the primary amino moiety of the cited drug and 2,2-dihydroxyindane-1,3-dione reagent in N,N'-dimethylformamide medium in boiling water bath. Which give Ruhemann's purple color that can be determined at λmax = 595 nm. Beer's law has been obeyed within drug concentration range from 10-120 μg per milliliter. Detection limit and quantitation limit have been 1.6 & 4.9 μg per milliliter respectively. Developed procedure has been validated in agreement with International Conference of Horizon recommendations and applied successfully for detection of cited drug in bulk, pharmaceutical dosage form and content uniformity testing.


[The synthesis of new photoaffinity probes on the basis of ganglioside GM1].
New photoaffine probes, photoreactive derivatives of ganglioside GM1 bearing a carbene-generating diazocyclopentadien-2-ylcarbonyl group at various distances from the carbohydrate moiety in their molecules, were synthesized.


Preliminary note: vertebral-Doppler sonography in near sudden infant death syndrome (NSIDS).
Using vertebral artery sonography, we investigated the influence of the position of the head on the vertebral artery bloodflow in five children, who were admitted because of NSIDS (near sudden infant death syndrome) episodes. Three out of the five children showed blocking of vertebral bloodflow determined by position of the head. This was not observed in five age-matched controls. Our preliminary observations indicate the value of noninvasive ultrasound Doppler techniques in the diagnostic work in the children with NSIDS. In this way one of the risk factors for SIDS might be identified.


[Severe poisonings in intensive care unit: study of announced substances in 2011].
To treat poisonings, physicians must rapidly make a diagnosis. As of today, exhaustive data on most frequently reported toxics are not available in France. This was a retrospective study of announced substances at patients' admissions in intensive care unit for poisoning in 2011 at Lariboisière hospital. Announced substances were collected from anamnesis reported in patient medical records. Verbatims were harmonized and substances classified in medicinal products and three categories of non-medicinal products (recreational/addictive drugs, others, unknown nature). Three hundred and fifteen patients were included, with 891 announced specified substances corresponding to 198 different verbatims. Most of them (83%) are medicinal products (mainly nervous and cardiovascular system molecules). There were 13% of recreational/addictive substances, 3% of other non-medicinal substances. Of the occurrences, 1.5% represent unknown substances. These substances supposedly used in poisoning should be included in toxicology learning programs. Their dosage should be possibly performed in routine by toxicology laboratories. An ongoing study in a prospective and retrospective manner will become an observatory of the substances involved in poisoning.


Young man with acute pain in the hypogastrium: What is the diagnostic?
Congenital renal anomalies can stay asymptomatic even until adult age and be revealed by occurrence of complications. Clinicians should keep in mind this eventuality, especially in the countries where screening for congenital abnormalities is not adopted. Ultrasound in front of abdominal pain is useful and can sometimes rectify the diagnosis.


Identification of isoliquiritigenin as an activator that stimulates the enzymatic production of glycyrrhetinic acid monoglucuronide.
Glycyrrhetinic acid monoglucuronide (GAMG) is a great value-added and has considerable commercial interest due to its strong pharmacological activities and functional low-calorie sweetener. However GAMG is quite rare in natural plants, and it must be prepared from glycyrrhizin (GL) by hydrolysing one terminal glucuronic acid. β-Glucuronidase is the key enzyme in the biotransformation of GL to GAMG, but its activities need to be enhanced to facilitate the industrial large-scale production of GAMG. In this study, we identified that isoliquiritigenin (ISL), as one of chemical compositions from the total flavonoids glycyrrhiza (TFG), can significantly enhance β-glucuronidase activity in vitro. Measurements using high-performance liquid chromatography (HPLC) showed that the activity of β-glucuronidase could be increased by 2.66-fold via the addition of ISL to a β-glucuronidase solution that contained GL at a 3:10 molar ratio of ISL to GL. ISL was concluded to be an activator because ISL could reduce the Km and Ea of β-glucuronidase reacting with GL. This study sheds new light on the mechanism of β-glucuronidase and helps to make industrial production of GAMG through fermentation feasible.


Molecular basis for herpesvirus entry mediator recognition by the human immune inhibitory receptor CD160 and its relationship to the cosignaling molecules BTLA and LIGHT.
CD160 was recently identified as a T cell coinhibitory molecule that interacts with the herpesvirus entry mediator (HVEM) on antigen-presenting cells to deliver a potent inhibitory signal to CD4(+) T cells. HVEM also binds to the coinhibitory receptor BTLA (B- and T-lymphocyte attenuator) and the costimulatory receptor LIGHT (which is homologous to lymphotoxins, exhibits inducible expression, and competes with the herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14), thus regulating the CD160/BTLA/LIGHT/HVEM signaling pathway. To date, the detailed properties of the formation of these complexes, especially HVEM binding to the newly identified receptor CD160, and the relationship of CD160 with BTLA and LIGHT are still unclear. We performed N-terminal sequencing and a mass spectrometric analysis, which revealed that the extracellular domain of CD160 exists primarily in the monomeric form. The surface plasmon resonance analysis revealed that CD160 binds directly to the cysteine-rich domain 1-3 of HVEM with a similar affinity to, but slower dissociation rate than, that of BTLA. Notably, CD160 competed with BTLA for binding to HVEM; in contrast, LIGHT did not affect HVEM binding to either CD160 or BTLA. The results of a mutagenesis study of HVEM also suggest that the CD160 binding region on HVEM was slightly different from, but overlapped with, the BTLA binding site. Interestingly, an anti-CD160 antibody exhibiting antiangiogenic properties blocked CD160/HVEM binding. These results provide insight into the molecular architecture of the CD160/BTLA/LIGHT/HVEM signaling complex that regulates immune function.


Functional characterisation and product specificity of Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1.
Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1 (Blg32) composed of 284 amino acids with a predicted molecular mass of 31.6 kDa is expressed in Escherichia coli and purified to homogeneity. Herein, Blg32 characteristics, substrates and product specificity as well as structural traits that might be involved in the production of sugar molecules are analysed. This enzyme functions optimally at the temperature of 70 °C, pH value of 8.0 with its catalytic activity strongly enhanced by Mn2+. Remarkably, the purified enzyme is highly stable in high temperature and alkaline conditions. It exhibits the highest activity on laminarin (376.73 U/mg) followed by curdlan and yeast β-glucan. Blg32 activity increased by 62% towards soluble substrate (laminarin) compared to insoluble substrate (curdlan). Hydrolytic products of laminarin were oligosaccharides with degree of polymerisation (DP) of 1 to 5 with the main product being laminaritriose (DP3). This suggests that the active site of Blg32 could recognise up to five glucose units. High concentration of Blg32 mainly produces glucose whilst low concentration of Blg32 yields oligosaccharides with different DP (predominantly DP3). A theoretical structural model of Blg32 was constructed and structural analysis revealed that Trp156 is involved in multiple hydrophobic stacking interactions. The amino acid was predicted to participate in substrate recognition and binding. It was also exhibited that catalytic groove of Blg32 has a narrow angle, thus limiting the substrate binding reaction. All these properties and knowledge of the subsites are suggested to be related to the possible mode of action of how Blg32 produces glucooligosaccharides.


Topographic organization of certain tectal afferent and efferent connections can develop normally in the absence of retinal input.
To test the hypothesis that the topographic organization of the connections of the optic tectum is determined during development by the "retinotopically" ordered input that it receives from the eye, we have mapped certain of the connections of the tectum in chicken embryos and chicks in which both eye rudiments were removed before the outgrowth of optic fibers. Because several of the connections of the tectum are normally organized retinotopically, we should expect, if this hypothesis were correct, that some or all of these connectional patterns would be significantly altered in such "eyeless" chickens. In fact, we have found that the connections formed between the optic tectum and two of the isthmic nuclei, with which it is reciprocally connected, show the same topographic organization in "eyeless" animals as in control chickens raised under the same conditions. This clearly indicates that the topographic organization of the chicken optic tectum is independently specified and is not contingent upon the input that it receives from the retina.


The political presence of persons living with dementia in parliament. A qualitative study into the dementia representation work of German parliamentarians.
Parliamentary representation of persons living with dementia is important because it has the potential to enhance the lives of affected individuals. However, studies that take a closer look at the parliamentarization of dementia are few and far between. Drawing on recent advances in political science representation theory, this paper shows how parliamentary attention to persons living with dementia takes the form of representative claims. An interpretive analysis of 56 parliamentary documents revealed that German parliamentarians voiced what they considered to be the political wants and needs of persons living with dementia in different debates on a broad range of topics. They also created a political presence for persons living with dementia in representative claims about other groups - such as professional carers. Both types of claims were one-dimensional in nature: parliamentarians reduced persons living with dementia to their impairments, rendering them politically visible as vulnerable persons who need to be protected by the same society that their existence is putting a "burden" on. A more multi-dimensional political presence for persons living with dementia is required. In order to improve their dementia representation work, it is important that parliamentarians engage with persons living with dementia and understand how they wish to be engagedin parliament or otherwise.


Frequency of Intravitreal Anti-VEGF Injections and Risk of Death: A Systematic Review with Meta-analysis.
To investigate whether an increasing number of intravitreal anti-VEGF injections is associated with a higher mortality risk. The issue of systemic safety of intravitreal anti-VEGF therapy has been long discussed. Evidence from meta-analyses of randomized studies has shown no increased risk of mortality in the overall population, whereas some warning signals of higher mortality were found in patients with diabetes exposed to intense and prolonged treatment. Concerns have been raised about whether an increasing number of anti-VEGF injections could be associated with a higher mortality. Randomized clinical trials enrolling arms with different intensities of anti-VEGF therapy were searched. The primary outcome measure was the incidence rate ratio (IRR) of death with 95% confidence interval (CI) for receiving 5 injections. The relationship between the number of injections and all-cause mortality was investigated. Separate regression analyses were conducted to investigate this relationship in subgroups of studies with different diseases and drugs. Fifty-two trials were included. Overall mortality rates of 1.02% and 3.36% were recorded at 12 and 24 months, respectively. Univariate regression showed that a larger number of injections was not associated with a significant increase in mortality both at 12 months (IRR, 1.16; 95% CI, 0.87-1.53; P = 0.31) and at 24 months (IRR, 1.05; 95% CI, 0.95-1.15; P = 0.34). According to subgroup analyses, in diabetic macular edema (DME) studies, a higher risk was marginally associated with an increasing number of injections at 24 months (IRR, 1.17; 95% CI, 1.02-1.33; P = 0.03). No significant influence of anti-VEGF treatment intensity on mortality was shown, supporting a message of reassurance over safety concerns of this therapy. Marginal evidence of a higher risk associated with a more intense treatment was found in patients with DME.


A Phase II Trial of Trifluridine/Tipiracil in Combination with Cetuximab Rechallenge in Patients with RAS Wild-Type mCRC Refractory to Prior Anti-EGFR Antibodies: WJOG8916G Trial.
Trifluridine/tipiracil (FTD/TPI) improved the overall survival in patients with metastatic colorectal cancer (mCRC) who had previously received standard chemotherapies; however, the clinical outcomes remain poor. A multicenter phase II study aimed to assess the efficacy and safety of FTD/TPI plus cetuximab rechallenge. Patients with histologically confirmed RAS wild-type mCRC refractory to prior anti-epidermal growth factor receptor (anti-EGFR) antibody were enrolled and treated with FTD/TPI (35 mg/m2 twice daily on days 1-5 and 8-12) plus cetuximab (initially 400 mg/m2, followed by weekly 250 mg/m2) every 4 weeks. The primary endpoint was disease control rate (DCR), expecting a target DCR of 65% and null hypothesis of 45% with 90% power and 10% one-sided alpha error. Gene alterations of RAS, BRAF, EGFR, PIK3CA, ERBB2, and MET in pre-treatment circulating tumor DNA were evaluated using the Guardant360 assay. A total of 56 patients (median age 60 years; left-sided tumors 91%; objective partial or complete response during the prior anti-EGFR therapy 61%) were enrolled. The DCR was 54% (80% confidence interval [CI] 44-63; P = 0.12), with a partial response rate of 3.6%. Median progression-free survival (PFS) was 2.4 months (95% CI 2.1-3.7). In the circulating tumor DNA analysis, patients without any alterations of the six genes (n = 20) demonstrated higher DCR (75% vs. 39%; P = 0.02) and longer PFS (median 4.7 vs. 2.1 months; P < 0.01) than those with any gene alterations (n = 33). The most common grade 3/4 hematologic adverse event was neutropenia (55%). No treatment-related deaths occurred. FTD/TPI plus cetuximab rechallenge did not demonstrate clinically meaningful efficacy in all mCRC patients, but might be beneficial for the molecularly selected population.


Assaying Proliferation Characteristics of Cells Cultured Under Static Versus Periodic Conditions.
Two-dimensional in vitro culture models are widely being employed for assessing a vast variety of biological questions in different scientific fields. Common in vitro culture models are typically maintained under static conditions, where the surrounding culture medium is replaced every few days-typically every 48 to 72 h-with the aim to remove metabolites and to replenish nutrients. Although this approach is sufficient for supporting cellular survival and proliferation, static culture conditions do mostly not reflect the in vivo situation where cells are continuously being perfused by extracellular fluid, and thus, create a less-physiological environment. In order to evaluate whether the proliferation characteristics of cells in 2D culture maintained under static conditions differ from cells kept in a dynamic environment, in this chapter, we provide a protocol for differential analysis of cellular growth under static versus pulsed-perfused conditions, mimicking continuous replacement of extracellular fluid in the physiological environment. The protocol involves long-term life-cell high-content time-lapse imaging of fluorescent cells at 37 °C and ambient CO2 concentration using multi-parametric biochips applicable for microphysiological analysis of cellular vitality. We provide instructions and useful information for (i) the culturing of cells in biochips, (ii) setup of cell-laden biochips for culturing cells under static and pulsed-perfused conditions, (iii) long-term life-cell high-content time-lapse imaging of fluorescent cells in biochips, and (iv) quantification of cellular proliferation from image series generated from imaging of differentially cultured cells.


Lumbar facet joint subchondral bone density in low back pain and asymptomatic subjects.
To report in vivo measurements of lumbar facet joint subchondral bone mineral density used in the description of facet joint loading patterns and to interrogate if low back pain is associated with changes in subchondral bone mineral density. In vivo measurements of lumbar facet joint subchondral bone mineral density (L1/2 to L5/S1) in Hounsfield units were performed on 89 volunteers (56 controls and 33 with low back pain) by computed tomography osteoabsorptiometry at subchondral regions between 1.5 mm and 2.5 mm below the joint surface. The facet surface was divided into five topographic zones: cranial, lateral, caudal, medial, and central. We analyzed 1780 facet joint surfaces. Facets were denser (p < 0.0001) both in superior facets and in low back pain subjects (p < 0.0001). For the entire cohort, the facet center zone subchondral bone mineral density was higher (p < 0.0001) than that of the peripheral zones. The analyses indicate that subchondral bone mineral density is highest in patients with low back pain, the superior facets, and the center zone of the facets. Subchondral bone mineral density is thought to reflect cumulative, long-term distribution of stress acting on a joint. This work shows that higher subchondral bone mineral density values in the center zone indicate predominant stress transmission through the center of the facet joints. Finally, the greater subchondral bone mineral density in patients with low back pain may reflect both increased load bearing by the facets secondary to disc degeneration and misdistribution of loading within the joint.


Characterization of the novel HLA-B*15:269 allele by sequencing-based typing.
HLA-B*15:269 differs from HLA-B*15:63 by two nucleotide substitutions in exon 3.


Paper-based device for separation and cultivation of single microalga.
Single-cell separation is among the most useful techniques in biochemical research, diagnosis and various industrial applications. Microalgae species have great economic importance as industrial raw materials. Microalgae species collected from environment are typically a mixed and heterogeneous population of species that must be isolated and purified for examination and further application. Conventional methods, such as serial dilution and a streaking-plate method, are intensive of labor and inefficient. We developed a paper-based device for separation and cultivation of single microalga. The fabrication was simply conducted with a common laser printer and required only a few minutes without lithographic instruments and clean-room. The driving force of the paper device was simple capillarity without a complicated pump connection that is part of most devices for microfluidics. The open-structure design of the paper device makes it operable with a common laboratory micropipette for sample transfer and manipulation with a naked eye or adaptable to a robotic system with functionality of high-throughput retrieval and analysis. The efficiency of isolating a single cell from mixed microalgae species is seven times as great as with a conventional method involving serial dilution. The paper device can serve also as an incubator for microalgae growth on simply rinsing the paper with a growth medium. Many applications such as highly expressed cell selection and various single-cell analysis would be applicable.


Itraconazole Inhibits Intracellular Cholesterol Trafficking and Decreases Phosphatidylserine Level in Cervical Cancer Cells.
Itraconazole shows anticancer activity in various types of cancer but its underlying mechanism is unclear. We investigated the effect of itraconazole on membrane-associated lipids. To investigate the influences of itraconazole on cholesterol trafficking, cervical cancer CaSki cells were cultured with itraconazole and analyzed by Filipin staining followed by confocal microscopy. Effect on the glycerophospholipid profiles was analyzed by liquid chromatography/mass spectrometry (LC/MS). After itraconazole treatment, Filipin staining revealed cholesterol accumulation in the intracellular compartments, which was similar to the distribution after treatment of U18666A (cholesterol transport inhibitor). LC/MS analysis showed a significant decrease in phosphatidylserine levels and an increase in lysophosphatidylcholine levels in CaSki cells. Itraconazole inhibited cholesterol trafficking and altered the phospholipid composition. Alterations in the cell membrane can potentiate the anticancer activity of itraconazole.


Ectopic Corticotropin-Producing Neuroendocrine Tumor of the Pancreas Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.
A 57-year-old woman diagnosed with ectopic Cushing syndrome was found to have a 111In-octreotide-avid corticotropin-producing pancreatic neuroendocrine tumor with liver metastases. She was treated with 4 induction and 4 maintenance cycles of 177Lu-DOTATATE, which normalized her serum corticotropin levels and dramatically reduced the size of the pancreatic primary and liver metastases.


Longitudinal hippocampal atrophy in hippocampal sclerosis of aging.
Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer's disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.


Neural grafting to ischemic lesions of the adult rat hippocampus.
The purpose of this study was to examine the structural and connective integration of developing hippocampal neurons grafted to ischemic lesions of the adult rat hippocampus. The 4-vessel occlusion model was used to cause transient cerebral ischemia which damages CA1 pyramidal cells in the dorsal hippocampus, but spares nonpyramidal neurons and afferents in the area. One week later, cell suspensions were made from the CA1 region of fetal (E18-20) rats and injected stereotaxically into the lesion. The recipient brains were examined 6 weeks to 6 months later for survival, morphology, and intrinsic and extrinsic connections of the grafts. The methods used included cell stains, histochemical staining for acetylcholinesterase (AChE), immunocytochemical staining for neuropeptides (cholecystokinin (CCK), somatostatin (SS), enkephalin (Enk) and an astrocytic marker, glial fibrillary acidic protein (GFAP), as well as tracing by retrograde axonal transport of fluorochromes and light and electron microscopy of anterograde axonal degeneration. The grafts survived well (80%) and were often quite large. They were well integrated in the lesioned host brain area, contained both pyramidal cells and neuropeptidergic neurons and displayed a near normal GFAP immunoreactivity for astrocytes. The latter contrasted the dense gliosis of the host ischemic lesion. Judged by the AChE staining the grafts were innervated by cholinergic host septohippocampal fibers. Ingrowth of host hippocampal commissural fibers was demonstrated by Fink-Heimer staining for degenerating nerve terminals following acute lesions of the hippocampal commissures. At the ultrastructural level degenerating, electron dense terminals of host commissural origin were found even deep inside the graft neuropil in synaptic contact with mainly dendritic spines. A transplant efferent connection to the host brain was demonstrated by retrograde fluorochrome tracing and consisted of a homotypic projection to more posterior levels of the ipsilateral host CA1 and subiculum. Minor abnormal, efferent projections to the host dentate molecular layer were shown in Timm staining. We conclude that fetal CA1 neurons grafted to one week old ischemic lesions of the dorsal CA1 in adult rats become structurally well incorporated and can establish nerve connections with the host brain.


Ridaifen-SB8, a novel tamoxifen derivative, induces apoptosis via reactive oxygen species-dependent signaling pathway.
Tamoxifen is an anticancer agent widely used for treatment of estrogen receptor (ERα)-positive breast cancer. We previously developed a novel synthesis of tamoxifen and its derivatives, named Ridaifens (RIDs). Some of them, including RID-SB8, exhibited a stronger anticancer activity than tamoxifen in ERα-positive MCF-7 cells while having lost the affinity for ERα, suggesting an ERα-independent anticancer mode of action. In this study, we investigated the underlying mechanism by which RID-SB8 exerts anticancer activity. As expected, anticancer activity of RID-SB8 was not influenced upon knockdown of ERα expression in MCF-7 cells. RID-SB8 exerted similar anticancer effects on thirteen ERα-negative cancer cell lines including human gliosarcoma SF539 cells. In SF539 cells, RID-SB8 triggered loss of mitochondrial membrane potential (ΔΨ(m)) and progression of apoptosis accompanied by activation of caspases and translocation of apoptosis-inducing factor (AIF) to the nucleus. Furthermore, it induced reactive oxygen species (ROS), and a ROS scavenger, N-acetylcysteine (NAC), canceled loss of ΔΨ(m) and progression of apoptosis triggered by RID-SB8. Using fifteen human cancer cell lines, we demonstrated a significant correlation between RID-SB8 concentration required for ROS production and that required for cytotoxic effect across these cell lines, but such correlation was not observed for tamoxifen. Finally, the selective induction of ROS and cytotoxic effect on cancer cells by RID-SB8 were confirmed. From these results, we concluded that RID-SB8 exerts an anticancer effect via a mode of action distinct from tamoxifen, and that RID-SB8 could become a promising anticancer lead compound which selectively induces ROS formation and apoptosis in cancer cells.


Technology Insight: image-guided robotic radiosurgery--a new approach for noninvasive ablation of spinal lesions.
The need for an effective noninvasive tool to ablate spinal lesions reflects the limitations of traditional surgical and radiotherapeutic approaches. Open surgery is invasive and carries a risk of neurological injury and vertebral column dysfunction. Conventional radiotherapy often has poor clinical efficacy and a risk of neurologic complications. Spinal radiosurgery has been developed to overcome these limitations. This technique consists of precise delivery of high-dose radiation to a spinal target. To spare the delicate and radiation-sensitive spinal cord and to avoid potentially devastating neurological complications, it is essential that the radiation dose decreases rapidly outside of the target. This is accomplished by use of advanced, image-guidance technology, treatment planning software, and robotics. Preliminary data indicate that this approach can achieve high rates of tumor control of spinal and paraspinal lesions and durable reduction of associated vertebral pain without neurological complications. Although spinal radiosurgery is not yet widely practiced, the benefits of this new therapeutic approach are likely to encourage its widespread adoption in coming years.


Design and synthesis of novel 5-aminosalicylate (5-ASA)-4-thiazolinone hybrid derivatives with promising antiproliferative activity.
Two privileged pharmacophores were assembled in one molecular frame involving 5-aminosalicylate and 4-thiazolinones that can be found in different stereochemical features. The compounds were fully characterized and evaluated for antiproliferative activity against four human cancer cell lines and some are equipotent to doxorubicin with lower cytotoxicity to normal cells. The most interesting finding relates to compound 10, which shows an IC50 value of 70nM against MCF-7 cells, while the IC50 against human fibroblasts is 10μM. The results of this study indicate that the new compounds are optimal anti-cancer leading compounds and merit further studies to optimize their structure, detect their biotargets and in vivo activity.


[The city-hospital link in the care of severely obese patients].
After the initial weekday hospital stay, a personalized, multidisciplinary care pathway is offered to each patient followed at the specialized obesity center (CSO). This article illustrates the support approach adopted by the CSO at Caen Normandy University Hospital.


Glucocorticoids and hypothalamic obesity.
Recent studies have demonstrated a role for adrenal glucocorticoid hormones in the hyperphagia and obesity which follow lesions of the ventromedial hypothalamus (VMH). Although VMH lesions elevate morning plasma corticosterone levels, it is concluded that this contributes little to the development of obesity. More importantly, animals with VMH lesions appear to be hyperresponsive to very low levels of circulating glucocorticoids. The overeating and obesity are both prevented and reversed by either complete adrenalectomy or complete hypophysectomy (i.e., resulting in plasma corticosterone levels of less than 1.0 microgram/dl) and restored by dosages of glucocorticoids that have no effect on feeding behavior and weight gain in nonlesioned adrenalectomized animals. Mineralocorticoid hormones have no effect on hypothalamic obesity. Judging by the time course of effects on feeding behavior in VMH-damaged mice of a single intracerebroventricular injection of a low dose of glucocorticoid, which has no effect when administered intraperitoneally, it is concluded that glucocorticoids exert their effect centrally in a permissive, rather than a regulatory, manner. Stimulation of the neighboring paraventricular nuclei (PVN) with norepinephrine or neuropeptide Y produces a rapid feeding response which is also abolished by adrenalectomy and restored with administration of glucocorticoids. However, it is unlikely that the PVN is the site at which glucocorticoids exert their effect in animals with VMH lesions, for PVN lesions or knife-cuts, or combination VMH-PVN lesions, also result in hyperphagia and obesity. It is concluded that adrenal glucocorticoid hormones exert their permissive effects on feeding behavior at brain sites other than the medial hypothalamus. The septo-hippocampal complex is suggested as a possible site.


Order stability via Fröhlich condensation in bio, eco, and social systems: The quantum-like approach.
Stability of social and behavioural order in biological, ecological, and social systems is modelled within the formalism of the Fröhlich condensation. The latter is a high temperature analogue of the Bose-Einstein condensation and stability is approached via intensive pumping of energy into a system interacting with a bath. We start with the review of this formalism considering nonequilibrium thermodynamic and quantum frameworks. Although Fröhlich applied this formalism to bio-systems and the physical energy flows (electromagnetic, chemical, vibrational), he pointed out on the possibility to apply it to wider class of systems. We realize this program by using quantum-like modelling in combination with the information approach to biological and social systems, by treating them as information processors and introducing the notion of social energy (with its versions, as, e.g., social and behavioural energy). This formalism is applied to modelling of social stability in the modern open society characterized by powerful flows of information and huge information reservoir based on internet, including the variety of social networks. Then, it is applied to modelling of coherent behaviour in herds and flocks with the illustrative example of wolf packs. The essence of the paper is extracting conditions for the Fröhlich condensation and reformulating them in the purely information framework.


Arthroscopic Repair of Isolated Partial- and Full-Thickness Upper Third Subscapularis Tendon Tears: Minimum 2-Year Outcomes After Single-Anchor Repair and Biceps Tenodesis.
To investigate outcomes of arthroscopic single-anchor repair and biceps tenodesis of partial- and full-thickness tears of the upper third subscapularis (SSC). Thirty-three patients with arthroscopically confirmed isolated SSC tears, Lafosse type I (>50% of the tendon thickness involved), or type II were included. All patients underwent arthroscopic subcoracoid decompression, coracoplasty if the coracohumeral distance was narrowed, biceps tenodesis, and a single-anchor repair of the upper third SSC. No other reconstructive procedures were performed. Subjective evaluations included American Shoulder and Elbow Surgeons, Short-Form 12, Quick Disabilities of the Arm, Shoulder and Hand, Single Assessment Numeric Evaluation, and visual analog scale pain scores preoperatively and at minimum 2 years postoperatively. Thirty-one patients (n = 25 male, n = 6 female) were included in the final collective, because 2 patients refused participation. Minimum 2-year follow-up data were available for 28 of the 31 patients (90.3%). The mean age at the time of surgery was 54.8 (range, 36-71) years. The mean follow-up was 4.1 (range, 2.0-8.0) years. The results of all outcome measures improved significantly postoperatively compared with preoperative scores (P < .05). Patients with single-anchor repair of type II SSC tears (n = 17) had a significantly higher mean postoperative American Shoulder and Elbow Surgeons score (93.7 ± 10.8) than patients with single-anchor repair of type I SSC tears (n = 11; 86.7 ± 10.9; P = .027). Arthroscopic single-anchor repair of upper third SSC tendon tears led to improved function and decreased pain with high patient satisfaction. Outcomes of full-thickness upper third SSC tears were more favorable compared with outcomes of high grade partial-thickness upper third SSC tears. Level IV, retrospective therapeutic case series.


Identifying analytics for high throughput bioprocess development studies.
In recent years, high throughput screening (HTS) studies have been increasingly employed as an integral element of bioprocess development activities. These studies are often limited by an analytical bottleneck; they generate multiple samples for analysis and the available analytical methods cannot always cope with the added analytical burden. A potential solution to this challenge is offered by the deployment of appropriate analytics. This article outlines features of analytical methods that affect their fit to high throughput (HT) applications. These are discussed for a range of analytics frequently used in bioprocess development studies of monoclonal antibodies. It then outlines how these features need to be considered in order to classify analytical methods in terms of their particular application in high throughput scenarios.


Patient values regarding overlapping surgery: Identification of distinct patient subgroups.
To explore patient values associated with their comfort level with surgical trainees and attending surgeon absence from the operating room. Qualitative interviews with general medical patients. We analyzed data from qualitative interviews with patients that included a quantitative rating on a visual analog scale (VAS) of comfort consenting to three surgical scenarios, including overlapping surgery, to identify subgroups of patients based on comfort level. After identifying subgroups, we compared qualitative responses from participants who were generally comfortable with overlapping surgery to those who were uncomfortable to identify themes associated with these perceptions. We identified three subgroups of patients based on the patterns of VAS responses. Participants who were comfortable with overlapping surgery expressed trust in the surgeon and delegation process. Those who were most uncomfortable expressed a strong desire to know who was operating on them, and a desire for control over their surgical process. Subjects uncomfortable with overlapping surgery were also generally not sensitive to tradeoffs (cost, timing). We identified distinct subgroups of patients based on their comfort level with trainee independence and primary attending availability. By examining the predominant values in these subgroups, we identified potential explanations for patient discomfort with attending absence. Strategies to enhance patients' knowledge about the process of surgery and a sense of control over their own care may improve comfort with trainee participation and overlapping surgery. 6 Laryngoscope, 2019.


A comparison of fat absorption in young and old subjects.
Using an oral fat load, it is demonstrated that the pattern of absorption in elderly subjects is significantly different from that found in younger controls. This change may be due to the slower gastric emptying or reduced pancreatic function observed in this study. The possibility of impaired small bowel absorption has not been excluded.


Affinity purified tetanus toxin binds to isolated chromaffin granules and inhibits catecholamine release in digitonin-permeabilized chromaffin cells.
Tetanus toxin, a potent neurotoxin which blocks neurotransmitter release in the CNS, also inhibits Ca2+-induced catecholamine release from digitonin-permeabilized, but not from intact bovine chromaffin cells. In searching for intracellular targets for the toxin we studied the binding of affinity-purified tetanus toxin to bovine adrenal chromaffin granules. Tetanus toxin bound in a neuraminidase-sensitive fashion to intact granules and to isolated granule membranes, as assayed biochemically and visualized by electron microscopic techniques. The binding characteristics of the toxin to chromaffin granule membranes are very similar to the binding of tetanus toxin to brain synaptosomal membranes. We suggest that the toxin-binding site is a glycoconjugate of the G1b type (a polysialoganglioside or a glycoprotein-proteoglycan) which is localized on the cytoplasmic face of the granule membrane and might directly be involved in exocytotic membrane fusion.