Troglitazone has a reducing effect on thromboxane production.
Effects of troglitazone, an antidiabetic thiazolidinedione that enhances insulin sensitivity, on thromboxane (TX) production were assessed in human erythroleukemia (HEL) cells and human platelets. Measurement of TX was performed by using the gas chromatography/selected ion monitoring (GC/SIM) method. We found that troglitazone reduced the TX production from HEL cells and human platelets. Furthermore, troglitazone also reduced arachidonic acid (AA)-induced TX production from HEL cell and thrombin-induced TX release from platelets. In addition, we compared the effect of troglitazone with that of alpha-tocopherol and BRL 49653. Other thiazolidinedione compound BRL 49653 had effects similar to troglitazone, but alpha-tocopherol had no effect on TX production. Our findings suggest that the thiazolidinedione group had an antithrombotic effect and was beneficial in preventing vascular complications often observed in diabetes mellitus.


A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells.
The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity. Human T cells were transduced to express the PR1/HLA-A2-specific CAR (h8F4-CAR-T cells) containing the scFv of h8F4 fused to the intracellular signaling endo-domain of CD3 zeta chain through the transmembrane and intracellular costimulatory domain of CD28. Adult human normal peripheral blood (PB) T cells were efficiently transduced with the h8F4-CAR construct and predominantly displayed an effector memory phenotype with a minor population (12%) of central memory cells in vitro. Umbilical cord blood (UCB) T cells could also be efficiently transduced with the h8F4-CAR. The PB and UCB-derived h8F4-CAR-T cells specifically recognized the PR1/HLA-A2 complex and were capable of killing leukemia cell lines and primary AML blasts in an HLA-A2-dependent manner. Human adult PB and UCB-derived T cells expressing a CAR derived from the TCR-like 8F4 antibody rapidly and efficiently kill AML in vitro. Our data could lead to a new treatment paradigm for AML in which targeting leukemia stem cells could transfer long-term immunity to protect against relapse.


Functional gene expression of oil-degrading bacteria resistant to hexadecane toxicity.
Contamination with oil poses a threat to the environment and to human health worldwide. Biological methodologies have proved to be economical, versatile and efficient for the remediation of pollutants. In this paper, a highly efficient oil-degrading bacterial strain USTB-2 was isolated from an oil production well of Dagang oil field in Tianjin, China. The 16S rRNA sequence of USTB-2 showed 100% similarity with that of Bacillus subtilis BSn5. Hexadecane is one of the most important components in petroleum. The half inhibitory ratio (IC₅₀) of hexadecane inhibited organisms, determined by microcalorimetry, was lower in USTB-2 than in B. BSn5. The results indicate that the strain USTB-2 degrades hexadecane to make it less toxic compared with the normal strain. RT-PCR was used to evaluate the expression of oil-degrading enzymes, specifically 4-hydroxyphenylacetate 3-monooxygenase genes (HPMO). A sharp increase in the expression of HPMO genes was observed for USTB-2, while the expression of HPMO genes in reference strain B. BSn5 remained relatively stable. These methods can be used to study the metabolic potential of microorganisms for in situ oil decontamination.


Radiographic risk factors for intracranial hemorrhage in patients with left ventricular assist devices.
Intracranial hemorrhage (ICH) in patients with left ventricular assist devices (LVAD) is a devastating complication. Demographic risk factors for ICH in LVAD patients are defined, however anatomic predispositions to ICH are unknown. We sought to interrogate intracranial radiographic risk factors for ICH in LVAD patients. We reviewed 440 patients who received an LVAD from 2008-2021. We selected patients with CT scans of the head either before or after LVAD placement, but typically within 5 years. 288 patients (21 ICH, 267 Control) with imaging were included. A detailed chart review was performed on demographics, radiographic features, and management. The incidence of ICH in our total cohort was 8.6% (38/440). The presence of pump thrombosis (p=0.001), driveline infection (p=0.034), other hemorrhage (p=0.001), or previous placement of a cardio-defibrillator (p=.003) was associated with increased risk for ICH. An analysis of imaging revealed that the presence of a mass (p=0.006), vascular pathology (p=0.001), and microangiopathy (p=0.04) was significantly associated with ICH in LVAD patients. These radiographic features were validated with a multivariate logistic regression which confirmed presence of a mass (aOR 332.1, 95% CI: 14.7-7485.1, p<0.001), vascular pathology (aOR 69.7, 95% CI: 1.8-2658.8, p=0.022), and microangiopathy (aOR 6.5, 95% CI: 1.1-37.6, p=0.035) were independently associated with ICH. Radiographic evidence of microangiopathy, intracranial mass, and vascular pathology are independent risk factors for ICH which are readily identified by imaging. We advocate that CT imaging be used to further stratify patients at highest risk of ICH during treatment with an LVAD.


Enhancing the Anti-angiogenic Effect of Bevacizumab with ACE Inhibition on mCRC.
Angiotensin 2 has been shown to promote angiogenesis through multiple pathways. Reduction of angiotensin 2 production by angiotensin-converting enzyme inhibitors (ACEi) could enhance the antiangiogenic effect of bevacizumab and lead to improved survival. Data from metastatic colorectal cancer (mCRC) patients treated with bevacizumab in our hospital were retrospectively collected. Patients were divided into groups taking ACEi or angiotensin receptor blockers (ARB) or neither. We performed survival analysis and COX proportional hazard modelling and calculated the hazard ratio (HR). Multivariate analyses were performed to measure the impact of factors affecting survival, and subgroup analyses were performed for patients younger than 65 years. We enrolled 133 patients who received bevacizumab therapy. Eighty patients were male, and 53 were female. Twenty-three patients received ACEi treatment, and 34 patients received ARB. The median age was 58 years. Progression-free survival was higher in the ACEi group than in the ARB group or in the group receiving neither (7.66 vs. 5.98 vs. 5.0 months; p < 0.01), corresponding to a HR of 0.44 for the ACEi group (95% CI 0.26-0.74). Overall survival was not significantly longer in the ACEi group than in the ARB group or in the group receiving neither (22.0 vs. 23.5 vs. 19.7 months; p = 0.30), HR 0.66 (95% CI 0.38-1.2). In a subgroup analysis, overall survival was higher in patients younger than 65 years in the ACEi group (45.0 vs. 16.2 months; p = 0.02). In the final analysis, ACEi use in patients treated with bevacizumab resulted in prolonged progression-free survival, but this did not affect overall survival. Because our study is the first to look at the enhancement of the effect of bevacizumab by ACEi treatment and ACEi receiving patients are older, it would be useful to confirm our results by randomized trials.


Protein comparative sequence analysis and computer modeling.
A problem frequently encountered by the biological scientist is the identification of a previously unknown gene or protein sequence, where there are few or no clues as to the biochemical function, ligand specificity, gene regulation, protein-protein interactions, tissue specificity, cellular localization, developmental phase of activity, or biological role. Through the process of bioinformatics there are now many approaches for predicting answers to at least some of these questions, often then allowing the design of more insightful experiments to characterize more definitively the new protein.


Pseudoaneurysm associated with multiple osteochondromatosis.
The authors present a case of a 12-year-old boy with a known family history of multiple hereditary exostoses who presented with knee swelling. Physical examination and subsequent workup revealed a pseudoaneurysm associated with an osteochondroma. We present this interesting case and review the literature.


Cross-species transcriptomic signatures identify mechanisms related to species sensitivity and common responses to nanomaterials.
Physico-chemical characteristics of engineered nanomaterials are known to be important in determining the impact on organisms but effects are equally dependent upon the characteristics of the organism exposed. Species sensitivity may vary by orders of magnitude, which could be due to differences in the type or magnitude of the biochemical response, exposure or uptake of nanomaterials. Synthesizing conclusions across studies and species is difficult as multiple species are not often included in a study, and differences in batches of nanomaterials, the exposure duration and media across experiments confound comparisons. Here three model species, Danio rerio, Daphnia magna and Chironomus riparius, that differ in sensitivity to lithium cobalt oxide nanosheets are found to differ in immune-response, iron-sulfur protein and central nervous system pathways, among others. Nanomaterial uptake and dissolution does not fully explain cross-species differences. This comparison provides insight into how biomolecular responses across species relate to the varying sensitivity to nanomaterials.


Retrospective analysis of spinal missile injuries.
One hundred six patients with spinal missile injury from war zones were admitted to our department from 1994 to 2000. Functional recovery and complications in surgical and conservative treatment groups were evaluated. Sixty-five were treated surgically, of whom 55 (84%) had incomplete injuries (Frankel scores B, C, and D). In the conservative group, 28 (68%) had incomplete injuries. A total of 81 patients (53 in the surgical group, 28 in the conservative group) could be monitored for functional recovery. In the surgical group, 34 (64%) showed improvement, 15 (28%) were unchanged, and four (7%) worsened. In the conservative group, 17 (60%) improved, nine (32%) remained unchanged, and two (7%) worsened. Cerebrospinal fluid fistula was observed in ten patients, seven of them in the surgically treated group. Five of seven meningitides were seen in the surgically treated group. Surgical intervention is not essential for spinal gunshot injury; however, it may be beneficial for patients with CSF fistula, infectious and compressing foreign bodies in the injury site, instability, and rapid neurological deterioration.


B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity.
Small, soluble metabolites not only are essential intermediates in intracellular biochemical processes, but can also influence neighbouring cells when released into the extracellular milieu1-3. Here we identify the metabolite and neurotransmitter GABA as a candidate signalling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages that secrete interleukin-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA-generating enzyme GAD67 enhances anti-tumour responses. Our study reveals that, in addition to cytokines and membrane proteins, small metabolites derived from B-lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.


Birth weight and gestation influence striatal morphology and motor response in normal six-year-old boys.
The relation between fetal growth and attention deficit hyperactivity disorder (ADHD) cuts across the normal range of birth weights suggesting that subtle variations in fetal development may influence brain and cognitive function. We investigated the relation of ADHD-related endophenotypes, such as the striatum morphology, motor response and inhibition, with birth weight and gestational age in healthy children. 157 Six-year-old boys born at term (37 to 41 weeks) within the normal range for birth weight (2500 to 4630 g) underwent magnetic resonance imaging (MRI) and performed the stop signal task. Linear regression was used to examine effects of birth weight, gestational age, and their interaction on striatal volumes and shapes as well as motor response and inhibition. Interactive effects of birth weight and gestational age, even within the normal range, predicted caudate volumes and shapes. Boys with relatively low birth weight and shorter gestation had smaller caudate volumes, reflected by shape contraction in the middle body, and in addition performed worst in motor response, reflected by mean reaction time and its variability. Our results supported the idea that prenatal influences on neurocognitive and brain development are not limited to the extreme range, but occur across the entire population. Variations in brain structure and cognitive endophenotypes associated with childhood ADHD psychopathology are sensitive to subtle prenatal influences, which provides guidance for intervention research to improve mental health of children.


Nck1 and Grb2 localization patterns can distinguish invadopodia from podosomes.
Invadopodia are matrix-degrading ventral cell surface structures formed in invasive carcinoma cells. Podosomes are matrix-degrading structures formed in normal cell types including macrophages, endothelial cells, and smooth muscle cells that are believed to be related to invadopodia in function. Both invadopodia and podosomes are enriched in proteins that regulate actin polymerization including proteins involved in N-WASp/WASp-dependent Arp2/3-complex activation. However, it is unclear whether invadopodia and podosomes use distinct mediators for N-WASp/WASp-dependent Arp2/3-complex activation. We investigated the localization patterns of the upstream N-WASp/WASp activators Nck1 and Grb2 in invadopodia of metastatic mammary carcinoma cells, podosomes formed in macrophages, and degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells. We provide evidence that Nck1 specifically localizes to invadopodia, but not to podosomes formed in macrophages or degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells. In contrast, Grb2 specifically localizes to degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells, but not invadopodia or podosomes formed in macrophages. These findings suggest that distinct upstream activators are responsible for N-WASp/WASp activation in invadopodia and podosomes, and that all these ventral cell surface degradative structures have distinguishing molecular as well as structural characteristics. These patterns of Nck1 and Grb2 localization, identified in our study, can be used to sub-classify ventral cell surface degradative structures.


Osteoarthritis in veterans undergoing bariatric surgery is associated with decreased excess weight loss: 5-year outcomes.
Obesity exacerbates pre-existing musculoskeletal disease and joint pain. This may limit physical activity in obese individuals. We sought to identify the disease burden and impact of osteoarthritis of the lumbar back, hip, knee, and ankle in veterans undergoing bariatric surgery. Veterans Affairs medical center. Retrospective review of a prospective bariatric database of operations performed at a single Veterans Affairs medical center. Patients with osteoarthritis of the lumbar spine, hip, knee, or ankle were identified and diagnosis confirmed by electronic health record review of prior radiographic reports. Analysis was performed using χ2 test for continuous variables. Student's t test and one-way analysis of variance were used to compare qualitative variables. Of 254 bariatric surgical patients, 83.9% had preoperative musculoskeletal pain before bariatric surgery and 59.1% had a confirmed diagnosis of osteoarthritis of the lumbar spine, hips, knees, and/or ankles. Follow-up rate was 97.4%, 85.4%, and 82.6% at 1, 3, and 5 years respectively. Of patients with osteoarthritis, 58.6% had knee involvement and 46% had multiple sites involved. In the cohort without osteoarthritis, percent excess body mass index loss was 66.9% at 1 year versus 58.5% in the cohort with osteoarthritis (P = .009), 66.1% versus 51.9% (P = .001) at 3 years, and 64.3% versus 50.1% (P = .002) after 5 years. Percent total weight loss was 28.4% versus 25.2%, 28.0% versus 22.8%, and 27.1% versus 22.4%, respectively, at 1, 3, and 5 years. Osteoarthritis is common among veterans undergoing bariatric surgery. It is associated with significantly less weight loss compared to veterans who do not have osteoarthritis, up to 5 years after bariatric surgery.


The Anti-fibrotic Effects and Mechanisms of MicroRNA-486-5p in Pulmonary Fibrosis.
To identify microRNAs (miRNAs, miRs) with potential roles in lung fibrogenesis, we performed genome-wide profiling of miRNA expression in lung tissues from a silica-induced mouse model of pulmonary fibrosis using microarrays. Seventeen miRNAs were selected for validation via qRT-PCR based on the fold changes between the silica and the control group. The dysregulation of five miRNAs, including miR-21, miR-455, miR-151-3p, miR-486-5p and miR-3107, were confirmed by qRT-PCRs in silica-induced mouse model of pulmonary fibrosis and were also confirmed in a bleomycin (BLM)-induced mouse lung fibrosis. Notably, miR-486-5p levels were decreased in the serum samples of patients with silicosis, as well as in the lung tissues of patients with silicosis and idiopathic pulmonary fibrosis (IPF). In addition, as determined by luciferase assays and Western blotting, SMAD2, a crucial mediator of pulmonary fibrosis, was identified to be one of target genes of miR-486-5p. To test the potential therapeutic significance of this miRNA, we overexpressed miR-486-5p in animal models. At day 28, miR-486-5p expression significantly decreased both the distribution and severity of lung lesions compared with the silica group (P < 0.01). In addition, miR-486-5p had a similar effect in the BLM group (P < 0.001). These results indicate that miR-486-5p may inhibit fibrosis.


Ultrasound-guided aspiration of dominant follicles (≥25 mm) followed by luteinization and progesterone production during the estrous cycle in mares.
The present study was designed to evaluate luteinization rates subsequent to aspiration of dominant follicles (≥25 mm) in the absence of a functional CL (progesterone <1 ng/mL) and characterize the temporal changes in plasma concentrations of progesterone following aspiration-induced luteinization during the estrous cycle in mares. A total of 29 estrous cycles involving 15 mares in a cross-over design were randomly assigned to five groups: 1) ASP-F≥25 mm (n = 6; follicle aspiration 25-29 mm), 2) ASP-F≥30 mm (n = 6; follicle aspiration 30-34 mm), 3) ASP-F≥35 mm (n = 6; follicle aspiration 35-40 mm), 4) ASP-F≥40 (n = 6; follicle aspiration ≥40), and 5) Control (n = 5; spontaneous ovulation or no follicle aspiration). Subsequent to ovulation (Day 0), PGF was administered to all groups on Day 5, blood samples were collected daily and aspiration of the dominant follicle was done using ultrasound-guided transvaginal follicle needle puncture. Among the follicle aspirations groups 25-29, 30-34, 35-39, and ≥40 mm, the luteinization rates were not different (P > 0.05) at 83, 67, 83, and 100%, respectively. Correspondingly, progesterone concentrations increased (>2 ng/mL) by approximately 6, 7, 5, and 4 d after aspiration, respectively, which were delayed (P < 0.05) in the 25-29 and 30-34 mm follicle aspiration groups compared to 2 d after ovulation in the control group. Thereafter, progesterone reached maximal concentrations (10-11 ng/mL) as averaged over all aspiration groups but were lower (P < 0.05) compared to the mean maximal concentration (18 ng/mL) in the control group. Subsequently, there was a decrease in progesterone concentrations (<2 ng/mL) in response to luteolysis, which was delayed (P < 0.05) in the aspiration groups over Days 16-20 compared to Day 15 in the control group. Despite this discrepancy, the mean length of the interovulatory intervals were not different (P > 0.05) among groups on Day 23. Thus, the present study provided novel information that the luteinization rate is relatively high (83%) and consistent following aspiration of dominant follicles (≥25 mm) in the absence of a functional CL and that the increase in progesterone reaches sustainable progestational concentrations (≥2 ng/mL) in accord with the length of the estrous cycle that may potentially support development and maintenance of early pregnancy in recipient mares involved in an embryo transfer program.


Image registration reveals central lens thickness minimally increases during accommodation.
To evaluate anterior chamber depth, central crystalline lens thickness and lens curvature during accommodation. California Retina Associates, El Centro, CA, USA. Healthy volunteer, prospective, clinical research swept-source optical coherence biometric image registration study of accommodation. Ten subjects (4 females and 6 males) with an average age of 22.5 years (range: 20-26 years) participated in the study. A 45° beam splitter attached to a Zeiss IOLMaster 700 (Carl Zeiss Meditec Inc., Jena, Germany) biometer enabled simultaneous imaging of the cornea, anterior chamber, entire central crystalline lens and fovea in the dilated right eyes of subjects before, and during focus on a target 11 cm from the cornea. Images with superimposable foveal images, obtained before and during accommodation, that met all of the predetermined alignment criteria were selected for comparison. This registration requirement assured that changes in anterior chamber depth and central lens thickness could be accurately and reliably measured. The lens radii of curvatures were measured with a pixel stick circle. Images from only 3 of 10 subjects met the predetermined criteria for registration. Mean anterior chamber depth decreased, -67 μm (range: -0.40 to -110 μm), and mean central lens thickness increased, 117 μm (range: 100-130 μm). The lens surfaces steepened, anterior greater than posterior, while the lens, itself, did not move or shift its position as appeared from the lack of movement of the lens nucleus, during 7.8 diopters of accommodation, (range: 6.6-9.7 diopters). Image registration, with stable invariant references for image correspondence, reveals that during accommodation a large increase in lens surface curvatures is associated with only a small increase in central lens thickness and no change in lens position.


The fate of the three subunits of major histocompatibility complex class I molecules.
At the surface of the murine T lymphoma cell line RMA-S, the expression of "empty" class I molecules can be dramatically enhanced by culture at 26 degrees C. These class I molecules are unstable following transfer to 37 degrees C unless they are loaded with exogenously added peptides. Class I heterodimers that have failed to bind peptide ("empty" class I molecules) dissociate and the class I heavy chains are degraded. Internalization, if it precedes breakdown, would be the rate-limiting step. Radioiodinated peptides (VSV NP 8-mer or Sendai NP 9-mer) dissociate from the class I molecules in the absence of exogenous peptide or beta 2 microglobulin and appear in the medium. Release of the iodinated peptides does not result in a reduction in the quantity of stable assembled class I molecules. This paradox may be explained by a more rapid off-rate for radioiodinated peptides, when compared with their unlabeled counterparts, which constitute about 99% of the total in our radiolabeled preparations. In the medium the peptide is rapidly modified by serum- and cell-derived proteases. The short half-life of empty class I molecules and of free ligand would effectively preclude sensitization of innocent bystanders for lysis by cytotoxic T lymphocytes.


Addressing activation of WNT beta-catenin pathway in diverse landscape of endometrial carcinogenesis.
The WNT-beta-catenin pathway (WP) is one of the major oncogenic pathways in solid tumors. Wnt beta-catenin pathway plays a unique role in a wide range of endometrial dysfunctions, from embryo implantation failure to severe pathogenic changes like endometriosis and endometrial cancer. Although abnormal activation of the pathway has long been known to be associated with endometrial tumorigenesis, the pathway's exact mode of involvement remains to be understood. As more evidence has been presented in favor of a crucial role of the WP in solid tumors, including endometrial cancer, anti-WP drugs are currently being tested to manage the disease. Aggressive tumor cells are nurtured by the tumor microenvironment (TME). The genetic alterations within tumor cells are the primary driving force to activate the extra-tumoral micro-environment. TME (a) provides metabolic support for the proliferation of tumor cells, (b) orchestrates immune-evasion, (c) initiates mechanistic signaling for several metastasis-associated phenotypes, and (d) supports cellular events for the development of drug resistance. To get metabolic as well as immune support from the tumor microenvironment, tumor cells cross-talk with components of the TME, most critically to the cancer-associated fibroblasts. Thus it is expected that the tumor-TME cross-talk throughout the process of tumorigenesis and metastasis is one of the characteristic features of an aggressive tumor. Here we review the WP's mechanistic involvement as a common culprit (Un Colpevole Comune) in endometrial tumor cells and endometrial cancer-associated fibroblast (CAF). In this review, we have attempted to discuss the activation of the WP in the genesis and progression of endometrial cancers, including endometrial tumor biology, tumor microenvironment, cancer-associated fibroblasts, and wnt-beta catenin genetic alteration. We interrogated the available literature on the various aspects of endometrial carcinogenesis leading to the pathway's activation. We examined how genetic alterations in WP directly influence tumor cell signaling to bring out different tumor cell phenotypes, and present palpable evidence to envision a role of WP inhibitors in the future management of the disease.


Bridging the theory--practice gap in the ITU with in-service education.
The use of an education programme within a busy intensive therapy unit has proved to be highly successful in providing a framework for learning for those taking up an appointment in the unit with no previous experience of intensive therapy. The creation of a supportive learning environment was vital for it to work, promoted by enthusiastic and motivated staff and led by a full-time education coordinator. New course members were allocated to teams and provided with a 4-week supernumerary status to work alongside the education coordinator or mentors who acted as role models. This provided an opportunity for junior nurses to build confidence in newly acquired skills and knowledge. Resources for learning included a room designated for teaching equipped with visual teaching and learning aids. It has been shown that a large percentage of the nurses who have completed the education programme have gone on to undertake the English National Board Course 100 or other related courses. The education programme has been effective in bridging the theory-practice gap and ultimately achieving excellence in patient care.


BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology.
Bispecific T-Cell Engagers (BiTEs) are effective at inducing remission in hematologic cancers, but their use in solid tumors has been challenging due to their extreme potency and on-target, off-tumor toxicities in healthy tissue. Their deployment against solid tumors is further complicated by insufficient drug penetration, a hostile tumor microenvironment, and immune escape. To address these challenges, we developed targeted nanocarriers that can deliver in vitro-transcribed mRNA encoding BiTEs to host myeloid cells - a cell type that is actively recruited into the tumor microenvironment. We demonstrate in an immunocompetent mouse model of ovarian cancer, that infusion of these nanoparticles directs BiTE expression to tumor sites, which reshapes the microenvironment from suppressive to permissive and triggers disease regression without systemic toxicity. In contrast, conventional injections of recombinant BiTE protein at doses required to achieve anti-tumor activity, induced systemic inflammatory responses and severe tissue damage in all treated animals. Implemented in the clinic, this in situ gene therapy could enable physicians - with a single therapeutic - to safely target tumor antigen that would otherwise not be druggable due to the risks of on-target toxicity and, at the same time, reset the tumor milieu to boost key mediators of antitumor immune responses.


Irradiance and temperature effects on photosynthesis of tussock tundra Sphagnum mosses from the foothills of the Philip Smith Mountains, Alaska.
Photosynthetic characteristics of three species of Sphagnum common in the foothills of the Brooks Range on the North Slope of Alaska were investigated. Generally, light-saturated rates of net photosynthesis decreased in the order S. squarrosum, S. angustifolium, and S. warnstorfii when plants were grown under common growth chamber conditions. For field-grown S. angustifolium, average light compensation point at 10°C was 37 μmol m-2s-1 photosynthetic photon flux density (PPFD), and light saturation occurred between 250 and 500 μmol m-2 s-1. At 20°C, compensation point increased to 127 μmol m-2s-1 and the PPFD required for light saturation increased to approximately 500 μmol m-2s-1, while maximum rates of CO2 uptake increased only slightly. Light response curves of chamber-grown plants exhibited substantially lower compensation points and higher light-saturated rates of CO2 assimilation than field-grown material, due perhaps to a higher percentage of green, photosynthetically competent tissue. All three species exhibited broad responses to temperature, with optima near 20°C, and maintained at least 75% of maximum assimilation between approx. 13° and 30°C. Rates at 5°C were approx. 50% of maximum. Studies of the microclimate of Sphagnum at the field research site suggest that CO2 uptake should occur at near light-saturated rates during the day in open tussock tundra but that PPFD may often be limiting under Salix and Betula canopies in a water track drainage. Simulations using a simple model provided a seasonal estimate of 0.78 g dry weight (DW) of S. angustifolium produced from each initial g of photosynthetic tissue under willow canopies, assuming no water limitations. Although the simulation model suggests that production would be 66% higher in open tussock tundra, S. angustifolium is rarely found in this potentially more stressful habitat. To explain the relative abundance of Sphagnum in shaded water track areas as compared to open tussock tundra, we postulate that the vascular plant canopies provide protection from adverse effects of high temperatures, excess irradiance and reduced water availability. Under conditions of normal water availability, removal of the vascular plant cover did not affect the tissue water content of S. squarrosum, but resulted in a strong decrease in photosynthetic capacity, accompanied by chlorophyll bleaching. These results suggest that photoinhibition may limit production under certain conditions.


Evaluating macular and optic nerve changes during Ramadan fasting by optical coherence tomography angiography-a prospective before-and-after study.
During Ramadan, millions of Muslims fast from sunrise to sunset. Fasting influences the hormonal system, sympathetic activity, blood circulation, and metabolic pathways. Because of these changes, we employed optical coherence tomography angiography (OCTA) to investigate the effects of fasting on the macula and optic nerve. In this prospective before-and-after study, both eyes of 45 participants were examined. Vascular characteristics of the macula and optic nerve head were evaluated in the morning and evening, once before Ramadan and once on the 20th day of Ramadan. Compared to the non-fasting condition, fasting significantly reduced inner parafoveal retinal thickness in both eyes and total foveal retinal thickness in the left eye in the morning and evening. Fasting in the morning also considerably reduced inner foveal retinal thickness in both eyes and total parafoveal retinal thickness in the right eye. Fasting significantly reduced central choroidal flow (1 mm) in both eyes in the evening (all p-values are < 0.05). In the morning, there were significant increases in the foveal avascular zone (FAZ) area (p-value = 0.006) and deep parafoveal vascular density in the left eye (p-value = 0.001). Fasting alters both the macular characteristics and the optic nerve head, as seen in OCTA, although it did not affect participants' vision. However, further research is needed before reaching a broad conclusion.


Isolation, characterization and docking studies of 2,3-dihydroxybiphenyl 1,2-dioxygenase from an activated sludge metagenome.
A 2,3-dihydroxybiphenyl-1,2-dioxygenase gene (designated as bphC_meta) was identified in activated sludge metagenome by PCR. This gene shared 99% sequence identity with BphC from Burkholderia xenovorans LB400. The enzyme was purified from recombinant Escherichia coli with a subunit molecular mass of 32 ± 1 kDa. It was optimally active at pH 9.0 and 40°C, using 2,3-dihydroxybiphenyl as a substrate. Activity toward substituted catechols was: 2,3-dihydroxybiphenyl > 3-methylcatechol > catechol > 4-chlorocatechol (4-methylcatechol). The prediction made by molecular docking was consistent with the kinetic experimental data, and further explained the substrate preference of BphC_meta. The present study could pave the way for the improved understanding and application of BphCs derived from metagenomes.


The ascending tectofugal visual system in amniotes: new insights.
Ascending tectal axons carrying visual information constitute a fiber pathway linking the mesencephalon with the dorsal thalamus and then with a number of telencephalic centers. The sauropsidian nucleus rotundus and its mammalian homologue(s) occupy a central position in this pathway. The aim of this study was analyzing the rotundic connections in reptiles and birds in relation with comparable connections in mammals, by using biotinylated dextran amines and the lipophilic carbocyanine dye DiI as tracing molecules. In general, rotundic connections in reptiles and birds are quite similar, especially with regards to pretectal and tectal afferences; as a novel finding, we describe varicose fibers arising from nucleus rotundus that reached the developing chick striatum. In addition, this study described the dorsal claustrum as a novel telencephalic target for the suprageniculate nucleus in mammals. Overall, telencephalic projections from the posterior/intralaminar complex of the mammalian thalamus can be compared with the telencephalic projections of the reptilian nucleus rotundus. With the exception of the isocortical connections, the mouse suprageniculate nucleus shares a number of afferent and efferent connections with the sauropsidian nucleus rotundus. Especially significant were the suprageniculate fibers reaching the striatum and then following to reach pallial derivatives such as the lateral amygdala (ventral pallium) and the dorsal claustrum (lateral pallium). These connections can be compared with the rotundic fibers reaching the ventromedial part of the anterior dorsal ventricular ridge in reptiles/entopallium in birds (ventral pallium) and the dorsolateral part of the anterior dorsal ventricular ridge in reptiles (lateral pallium), and probably the mesopallium in birds.


Bovine allergic pneumonitis: an acute outbreak associated with mouldy hay.
An outbreak of acute bovine atypical interstitial pneumonia is reported in association with feeding mouldy hay. Results of serological investigation and of provocation challenge indicated a hypersensitivity pneumonitis due to allergens of Micropolyspora faeni. Macroscopic and microscopic pulmonary changes were predominantly those of oedema and emphysema. These lesions were contrasted with more chronic changes reported in allergic pneumonitis of housed cattle.


Frozen Block Tissue Staining for Eye Structure of Zebrafish Embryo.
Histology is a technique used to study the morphology of cell structures by cutting samples into thin sections. Histological cross-section and staining are the techniques needed to visualize the morphology of cell tissues. A suitable tissue staining experiment was created to observe changes in the retinal layer in zebrafish embryos. Zebrafish have a human-like visual system, retina, and eye structures. Due to the small size of zebrafish and undeveloped bones in the embryonic stage, the resistance through cross-section is inevitably small. Here, we present optimized protocol changes in eye tissue of zebrafish using frozen blocks.


Pseudosarcomatous cystadenocarcinoma of the liver.
A case of papillary cystadenocarcinoma with spindle (pseudosarcomatous) metaplasia of the liver is described in a 64-year-old woman. This tumor was solitary, multiloculated, and had a fibrous pseudocapsule. It was composed of undifferentiated malignant epithelial cells, which lined cystic spaces, with sarcomatous cells underneath. Immunohistochemical studies showed no detectable alpha-fetoprotein in the tumor; keratin was present in epithelial and spindle tumor cells, and alpha 1-antitrypsin was present in cytoplasm of many tumor cells. Intracytoplasmic periodic acid--Schiff-positive, diastase-resistant globules, some of them reactive for alpha 1-antitrypsin, were seen. A primary liver tumor with this histology has not been described previously in the literature.


"The COVID-19 outbreak"-An empirical phenomenological study on perceptions and psychosocial considerations surrounding the immediate incorporation of final-year Spanish nursing and medical students into the health system.
The COVID-19 pandemic has caused an unprecedented health crisis worldwide, with the numbers of infections and deaths worldwide multiplying alarmingly in a matter of weeks. Accordingly, governments have been forced to take drastic actions such as the confinement of the population and the suspension of face-to-face teaching. In Spain, due to the collapse of the health system the government has been forced to take a series of important measures such as requesting the voluntary incorporation of final-year nursing and medical students into the health system. The objective of the present work is to study, using a phenomenological qualitative approach, the perceptions of students in this exceptional actual situation. A total of 62 interviews were carried out with final-year nursing and medicine students from Jaime I University (Spain), with 85% reporting having voluntarily joined the health system for ethical and moral reasons. Results from the inductive analysis of the descriptions highlighted two main categories and a total of five sub-categories. The main feelings collected regarding mood were negative, represented by uncertainty, nervousness, and fear. This study provides a description of the perceptions of final-year nursing and medical students with respect to their immediate incorporation into a health system aggravated by a global crisis.


Can Bioactive Lipids Augment Anti-cancer Action of Immunotherapy and Prevent Cytokine Storm?
It is desired to selectively kill tumor cells with little or no action on normal cells. Current treatment options are associated with significant side effects including therapy with immune check point inhibitors (ICI). ICI therapy induced side effects are due to excess production of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). At the same time, production of appropriate amounts of IL-6 and TNF-α are needed to eliminate tumor cells. Hence, methods are needed that can selectively eliminate tumor cells and tone down the side effects of cytokine storm. Studies showed that IL-6 and TNF-α activate phospholipases to induce the release of polyunsaturated fatty acids (PUFAs) from the cell membrane phospholipid pool. PUFAs form precursors to pro- and anti-inflammatory eicosanoids and are capable of suppressing IL-6 and TNF-α excess production. PUFAs are endowed with capacity to selectively kill tumor cells by augmenting free radical generation and accumulation of toxic lipid peroxides in tumor but not normal cells. NK cells, TILs (tumor infiltrating cells) and γδ T cells release toxic granules (also called as cytolytic granules) that contain unsaturated fatty acids localized between the granule delimiting membrane and the granule core. Thus, lipids are a universal component of cytolytic granules and play an important role in their cytotoxic actions. Based on this evidence, it is suggested that a combination of ICI/TILs and PUFAs may form a novel method of eliminating cancer with few side effects.


Polymeric grape-seed procyanidins, but not monomeric catechins and oligomeric procyanidins, impair degranulation and membrane ruffling in RBL-2H3 cells.
Grape-seed proanthocyanidins (GSPs) are catechin polymers that are predicted to form helices in their global minimum-energy conformation and to have a mean degree of polymerization of seven (mDP = 7). The highly polymerized GSP-H fraction (mDP = 10) was found to impair degranulation in RBL-2H3 cells after stimulation with an antigen (Ag) and treatment with the Ca-ATPase inhibitor thapsigargin (Tg). In addition, GSP-H affected actin cytoskeleton and inhibited membrane ruffling in these cells, resulting in the suppression of exocytosis. By contrast, monomeric epicatechin, the dimeric procyanidins PA-1, PA-2, and PB-2, and the oligomerized GSP-L (mDP = 3) had no effect on membrane ruffling and degranulation. These findings indicate that the molecular size and length of GSP-H are needed for the inhibition of membrane ruffling and degranulation in RBL-2H3 mast-cell lines.


Punch above one's weight--or going to confession through the past.
Last decades overweight and obesity dominate the lifestyle scene and became a public health challenge. From a historic perspective all aspects we nowadays consider important are already covered like for instance the interaction between human genotype and environment. History encourages us to stimulate moderation but also helps in restoring human dignity, not stigmatizing but putting overweight in perspective within the human context. Clinical interesting side issues like D.I.S.H., the obesity paradox and advantage in survival are put on the stage.


RiskSOAP: Introducing and applying a methodology of risk self-awareness in road tunnel safety.
Complex socio-technical systems, such as road tunnels, can be designed and developed with more or less elements that can either positively or negatively affect the capability of their agents to recognise imminent threats or vulnerabilities that possibly lead to accidents. This capability is called risk Situation Awareness (SA) provision. Having as a motive the introduction of better tools for designing and developing systems that are self-aware of their vulnerabilities and react to prevent accidents and losses, this paper introduces the Risk Situation Awareness Provision (RiskSOAP) methodology to the field of road tunnel safety, as a means to measure this capability in this kind of systems. The main objective is to test the soundness and the applicability of RiskSOAP to infrastructure, which is advanced in terms of technology, human integration, and minimum number of safety requirements imposed by international bodies. RiskSOAP is applied to a specific road tunnel in Greece and the accompanying indicator is calculated twice, once for the tunnel design as defined by updated European safety standards and once for the 'as-is' tunnel composition, which complies with the necessary safety requirements, but calls for enhancing safety according to what EU and PIARC further suggest. The derived values indicate the extent to which each tunnel version is capable of comprehending its threats and vulnerabilities based on its elements. The former tunnel version seems to be more enhanced both in terms of it risk awareness capability and safety as well. Another interesting finding is that despite the advanced tunnel safety specifications, there is still room for enriching the safe design and maintenance of the road tunnel.


Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer.
We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.


Prevalence and correlates of hormonal therapy among Israeli women in the post-WHI era.
Following the results of recent randomized controlled trials on the risks and benefits of the long-term use of hormonal therapy (HT), practice guidelines regarding HT use have been revised. The aim of the study is to assess the prevalence and the correlates of HT use in Israel in 2003. This is a cross-sectional study, conducted on a representative sample of the general population in Israel aged 21 years and over. The study questionnaire is based on the European Health Interview Survey (EUROHIS) project, aimed to develop uniform study tools, to enable international comparisons. The current module of the survey focused on women's health, and telephone interviews were conducted with 1396 women by trained interviewers in the year 2003. Out of a total of 1396 participants, 535 were defined as peri- or postmenopausal (38%). Of them, 9.9% were currently using HT (11.7% and 2.9% among the Jewish and Arab participants, respectively), and their mean age (S.D.) was 57.7 (6.5) years. Mean duration of HT use was 8.0 (5.5) years. Treatment of menopausal symptoms was the most common reason for HT use (69.2%). Significant correlates of HT use were age, being secular and having seen a gynecologist in the previous 12 months. Current HT use rates reported are lower than those reported 3 years ago for Israeli women. Awareness of both physicians and patients to the WHI results (2002), may have accounted for this trend, at least partially.


Curved membrane structures induced by native lipids in giant vesicles.
Native lipids in cell-membrane support crucial functions like intercell communication via their ability to deform into curved membrane structures. Cell membrane mimicking Giant unilamellar vesicles (GUV) is imperative in understanding native lipid's role in membrane transformation however remains challenging to assemble. We construct two giant vesicle models mimicking bacterial inner-membrane (IM) and outer-membrane (OM) under physiological conditions using single-step gel-assisted lipid swelling. IM vesicles composed of native bacterial lipids undergo small-scale membrane remodeling into bud and short-nanotube structures. In contrast, OM vesicles asymmetrically assembled from Lipopolysaccharide (LPS) and bacterial lipids underwent global membrane deformation under controlled osmotic stress. Remarkably, highly-curved structures mimicking cell-membrane architectures, including daughter vesicle networks interconnected by necks and nano-tubes ranging from micro to nanoscale, are generated in OM vesicles at osmotic stress comparable to that applied in IM vesicles. Further, we provide a quantitative description of the membrane structures by experimentally determining membrane elastic parameters, i.e., neck curvature and bending rigidity. We can conclude that a larger spontaneous curvature estimated from the neck curvature and softer membranes in OM vesicles is responsible for large-scale deformation compared to IM vesicles. Our findings will help comprehend the shape dynamics of complex native bacterial lipid membranes.


Undifferentiated carcinoma with osteoclast-like giant cells of the ampullary region: Short term survival after pancreaticoduodenectomy.
Undifferentiated carcinomas with osteoclast-like giant cells (UC-OGCs) of the ampullary region are very rare, with only a few cases reported to date. The clinicopathological features, treatment options, and prognosis of UC-OGCs are unclear. This report describes a patient with UC-OGCs of the ampullary region. A 78-year-old male patient was admitted for epigastric pain and fever. Contrast-enhanced computed tomography revealed a 2.6-cm mass at the duodenal papilla. Duodenoscopy revealed a smooth red protruding mass compressing the orifice of the papilla of Vater. Biopsy of the mass showed proliferation of osteoclast-like giant cells. A subtotal stomach-preserving pancreaticoduodenectomy was performed, and the tumor was histologically diagnosed as an UC-OGCs of the ampullary region. Carcinoma in situ was also observed, spreading from the tumor at the terminal segment of the common bile duct to the common hepatic duct, with carcinoma cells at the surgical margin of the common hepatic duct. One year after surgery, the patient is alive and without tumor recurrence. UC-OGCs of the ampullary region is very rare neoplasm containing osteoclast-like giant cells and mononuclear cells. Osteoclast-like giant cells may originate from reactive mesenchymal cells and carcinoma in situ may spread to the common hepatic duct. Surgery including pancreaticoduodenectomy may be a treatment option for resectable tumors, whereas gemcitabine may be a treatment option for unresectable tumors. Carcinoma in situ may spread quite far (5cm) to the common hepatic duct, making it desirable to intraoperatively confirm negative bile duct margins by rapid pathologic diagnosis.


Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers.
Apolipoprotein E epsilon4 is a major genetic risk factor for Alzheimer's disease, but the neurobiological basis for this risk is unknown. We used diffusion tensor imaging to measure diffusion anisotropy in the parahippocampal gyrus white matter in healthy elderly apolipoprotein E epsilon4 carriers and noncarriers. We also measured volumes of the lateral ventricles and temporal horns as proxies of cerebral atrophy. The epsilon4 carriers (n=14) showed significantly lower fractional anisotropy and higher radial diffusivity in the parahippocampal white matter 15 mm below the anterior commissure-posterior commissure plane than noncarriers (n=15). No group differences in ventricular volumes were found, nor were diffusion tensor imaging measures modulated by ventricular volumes. Diffusion tensor imaging may be sufficiently sensitive to detect preclinical brain changes related to Alzheimer's disease.


PAH dynamics in roadside environments: Influence on the consistency of diagnostic ratio values and ecosystem contamination assessments.
Roadside contamination (of air, soils and organisms) by polycyclic aromatic hydrocarbons (PAHs) was examined in an arable field and a mature forest (central France). Measured contents accounted for minute fractions of the cumulative vehicular exhaust emissions. The fate of vehicular PAHs was affected by many factors, including: atmospheric load dispersal, deposition on soils and vegetation, incorporation into water and organic matter cycles, and accumulation in species. Given these empirical results, we evaluated the consistency of a set of well-known diagnostic ratios. This effort has revealed that: i) most diagnostic ratio values vary considerably across roadside samples, including exhaust emissions; and ii) the first few meters from the carriageway or the road verge/forest interface or remote areas where surface water accumulates actually define turning or inflection points in the ratio profiles. These variations constitute a major obstacle to delimitating the extent of roadside contamination due to PAHs, in addition to raising questions over the applicability of ratios routinely used to designate sources. New ratios, namely (Flt+BkF)/(Pyr+BbF) and (Flt+BkF+BghiP)/Σ10PAH, have been specifically developed to address this challenge. The higher consistencies exhibited among environmental compartments as well as between surface soil and exhaust emissions still yield differentiated values relative to several industrial sources.


A pH-sensitive hyaluronic acid prodrug modified with lactoferrin for glioma dual-targeted treatment.
Gliomas are the most common and lethal type of primary malignant brain tumor. But the existence of blood brain barrier (BBB) and blood-tumor barrier (BTB) hinder drug from reaching the tumor site. To address this problem, we developed a novel prodrug (Lf-HA-DOX) by conjugating hyaluronic acid with doxorubicin (HA-DOX) by an acid-labile hydrazone linkage, which is released in an acidic environment and accumulates in tumor tissues. Lactoferrin (Lf) was coupled for transporting across the BBB. In vitro, the release of DOX from Lf-HA-DOX was pH-dependent. At lower pH (5.0 and 6.0), the release of DOX was much quicker than that at pH7.4. In the cellular uptake studies, flow cytometry analyses and confocal laser scanning microscopy results showed significantly enhanced cellular uptake of Lf-HA-DOX and HA-DOX in C6 cells compared to DOX. In BALB/C mice bearing C6 glioma, enhanced accumulation of Lf-HA-DOX in the glioma was observed by real time fluorescence image. Correspondingly, glioma-bearing mice treated with Lf-HA-DOX displayed the longest median survival time, which was 2-fold longer than that of saline group. In conclusion, Lf-HA-DOX was able to significantly increase drug delivery to the glioma, which might provide a promising strategy for antiglioma therapy.


Occipital Nerve Stimulation in Chronic Migraine: The Relationship Between Perceived Sensory Quality, Perceived Sensory Location, and Clinical Efficacy-A Prospective, Observational, Non-Interventional Study.
Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy. Thirty-two subjects (21.9% male, mean age 45.77 years) suffering from chronic migraine refractory to other treatment and therefore treated with ONS were included in this study. We used a computer-based imaging method for mapping the ONS-induced perceived sensory location, the perceived spatial sensory field size, as well as the perceived sensory quality in a long-term course over 21 months in weekly time intervals. Additionally, the effect of ONS on the migraine headache was documented weekly by the participants using a verbal rating scale. Over the observation period, a total of 808 individual weekly data sets were recorded and a potential relationship between ONS-induced perceptions and headache parameters could be analyzed. We found that 48.9% of stimulation intervals were reported as effective by patients. Women displayed a significantly higher responder rate than men. The reported effectiveness did not differ depending on age, the average number of migraine days per month, the MIDAS score, or the duration of the migraine disorder prior to ONS treatment. Implantation with trial period led to significantly lower responder rates than without the trial period. The most frequently perceived sensory quality of "tingling" was found significantly more frequently in non-responders than in responders. Responders displayed significantly lower pleasantness scores for their reported perceptions than non-responders. Sensations that were spatially perceived above the line connecting the external acoustic meati with the external occipital protuberance (MOP line) led to patients reporting a positive clinical effect significantly more frequently than sensations spatially perceived below the MOP line. Spatially small fields of sensory perception were correlated with a higher responder rate than those covering broader areas. The ONS-induced sensory location, the size of the spatial sensory field, as well as the sensory quality are significantly correlated with the reported clinical effectiveness. The results suggest that besides surgical technique, the individual and continuous programming of the stimulation parameters is clinically relevant in increasing the therapeutic effectiveness.


Capturing snapshots of APE1 processing DNA damage.
DNA apurinic-apyrimidinic (AP) sites are prevalent noncoding threats to genomic stability and are processed by AP endonuclease 1 (APE1). APE1 incises the AP-site phosphodiester backbone, generating a DNA-repair intermediate that is potentially cytotoxic. The molecular events of the incision reaction remain elusive, owing in part to limited structural information. We report multiple high-resolution human APE1-DNA structures that divulge new features of the APE1 reaction, including the metal-binding site, the nucleophile and the arginine clamps that mediate product release. We also report APE1-DNA structures with a T-G mismatch 5' to the AP site, representing a clustered lesion occurring in methylated CpG dinucleotides. These structures reveal that APE1 molds the T-G mismatch into a unique Watson-Crick-like geometry that distorts the active site, thus reducing incision. These snapshots provide mechanistic clarity for APE1 while affording a rational framework to manipulate biological responses to DNA damage.


Instrumental Robots.
Advances in artificial intelligence research allow us to build fairly sophisticated agents: robots and computer programs capable of acting and deciding on their own (in some sense). These systems raise questions about who is responsible when something goes wrong-when such systems harm or kill humans. In a recent paper, Sven Nyholm has suggested that, because current AI will likely possess what we might call "supervised agency", the theory of responsibility for individual agency is the wrong place to look for an answer to the question of responsibility. Instead, or so argues Nyholm, because supervised agency is a form of collaborative agency-of acting together-the right place to look is the theory of collaborative responsibility-responsibility in cases of acting together. This paper concedes that current AI will possess supervised agency, but argues that it is nevertheless wrong to think of the relevant human-AI interactions as a form of collaborative agency and, hence, that responsibility in cases of collaborative agency is not the right place to look for the responsibility-grounding relation in human-AI interactions. It also suggests that the right place to look for this responsibility-grounding relation in human-AI interactions is the use of certain sorts of agents as instruments.


The impact of primary healthcare reform on equity of utilization of services in the province of Quebec: a 2003-2010 follow-up.
In 2003, the Quebec government made important changes in its primary healthcare (PHC) system. This reform included the creation of new models of PHC, Family Medicine Groups (e.g. multidisciplinary health teams with extended opening hours and enrolment of patients) and Network Clinics (clinics providing access to investigation and specialist services). Considering that equity is one of the guiding principles of the Quebec health system, our objectives are to assess the impact of the PHC reform on equity by examining the association between socio-economic status (SES) and utilization of healthcare services between 2003 and 2010; and to determine how the organizational model of PHC facilities impacts utilization of services according to SES. We held population surveys in 2005 (n = 9206) and 2010 (n = 9180) in the two most populated regions of Quebec province, relating to utilization and experience of care during the preceding two years, as well as organizational surveys of all PHC facilities. We performed multiple logistical regression analyses comparing levels of SES for different utilization variables, controlling for morbidity and perceived health; we repeated the analyses, this time including type of PHC facility (older vs newer models). Compared with the lowest SES, highest SES is associated with less emergency room visits (OR 0.80) and higher likelihood of at least one visit to a PHC facility (OR 2.17), but lower likelihood of frequent visits to PHC (OR 0.69), and higher affiliation to a family doctor (OR 2.04). Differences remained stable between the 2005 and 2010 samples except for likelihood of visit to PHC source which deteriorated for the lowest SES. Greater improvement in affiliation to family doctor was seen for the lowest SES in older models of PHC organizations, but a deterioration was seen for that same group in newer models. Differences favoring the rich in affiliation to family doctor and likelihood of visit to PHC facility likely represent inequities in access to PHC which remained stable or deteriorated after the reform. New models of PHC organizations do not appear to have improved equity. We believe that an equity-focused approach is needed in order to address persisting inequities.


Clinical significance of intra-nodal naevi in sentinel node biopsies for malignant melanoma.
Intra-nodal naevi (INN) identified during assessment of a sentinel lymph node for melanoma are not an uncommon finding. Little is known about their clinical significance. Patients with INN are treated as sentinel node biopsy (SNB) negative currently. Our aim was to assess the significance of INN in patients who undergo SNB for melanoma. 353 melanoma patients who underwent a SNB between November 1999 and June 2012 were retrospectively analysed from a prospectively collected database. The patients were divided into SNB negative, INN, isolated tumour cells (ITC) and SNB positive groups. Outcome measures of nodal recurrence, distal recurrence and survival were used to assess the differences between the groups. 203 patients were SNB negative, 103 were positive of which 13 had ITC, 47 had INN (13%). Overall median follow up was 2.3 years (range 0.1-14.1 years). Our data demonstrated a statistically significant survival benefit for patients who had an INN compared to the SNB positive and ITC group. INN patients also had significantly better nodal and regional recurrence compared to SNB positive patients. There was no difference between INN and SNB negative patients. We have clinically demonstrated that patients with INN on SNB can be adequately treated as SNB negative patients.


Real-world emission characteristics and inventory of volatile organic compounds originating from construction and agricultural machinery.
Volatile organic compound (VOC) emissions originating from nonroad mobile sources constitute an important but uncertain source of secondary organic aerosols (SOAs) and ozone (O3). In this study, we investigated the emission factors (EFs) of 120 individual VOC species for 40 machines via gas chromatography-mass spectrometry/flame ionization detection and high-performance liquid chromatography. The results showed that the diesel-based VOC EF for the tested machines was 4.18 ± 2.55 (average ± standard deviation) g/kg fuel, dominated by alkanes (38.20 % ± 18.08 %) and oxygenated VOCs (OVOCs; 30.94 % ± 15.71 %). The machine type, rated power, emission standards, and operating conditions affected the emissions of VOCs and their components, and this effect maybe mostly depends on the fuel combustion efficiency. The VOC species were primarily distributed in the C1-C2 and C4-C6 (based on the carbon number) and B4-B6 (based on the saturated vapor concentration) intervals. Furthermore, the estimated formation potential (FP) values of SOAs and O3 from VOCs were 21.02 ± 15.57 mg/kg fuel and 15.96 ± 11.87 g/kg fuel, respectively. VOC control based on the SOA formation potential (SOAFP) and ozone formation potential (OFP) could be more effective in the mitigation of fine particulate matter (PM2.5) and O3 pollution because the top 5 species ranked by percentage contribution accounted for 83.09 % ± 9.59 % and 51.78 % ± 14.38 % of the estimated SOAFP and OFP, respectively. Finally, the emission estimates showed that the VOC emissions originating from construction and agricultural machinery in China (2020) reached 64.05 and 95.24 Gg, respectively. We provide species-specific VOC EFs and detailed emission characteristics to facilitate a comprehensive understanding of gas emissions originating from nonroad mobile sources and an update of emission inventories and atmospheric chemistry models.


A Review on Hexachloro-1,3-butadiene (HCBD): Sources, Occurrence, Toxicity and Transformation.
Hexachloro-1,3-butadiene (HCBD) is a persistent organic pollutant listed in Annex A and C of the Stockholm Convention. This review summarized the sources, occurrence, toxicity, and transformation of HCBD in the environment. HCBD had no natural sources, and anthropogenic sources made it frequently detected in environmental medium, generally at µg L- 1 and µg kg- 1 in water and soil (or organism) samples, respectively. HCBD posed reproductive, genetic, and potentially carcinogenic toxicity to organisms, threatening human health and the ecosystem. Upon biodegradation, photodegradation and physicochemical degradation processes, HCBD can be degraded to a different extent. Nevertheless, further studies should be focused on the potential emission sources and the impact of HCBD on human health and the environment. Additionally, exploring removal technologies based on advanced oxidation and reduction are recommended.


Blood pressure, intraerythrocyte content, and transmembrane fluxes of sodium during normal and high salt intake in subjects with and without a family history of hypertension: evidence against a sodium transport inhibitor.
Seventeen young normotensive men with a family history of hypertension in two generations (H) and 15 age-matched control subjects (C) were studied with respect to blood pressure (BP), intraerythrocyte sodium content (IeNa), sodium influx, and rate of sodium efflux. The investigations were done during normal salt intake and after 4 weeks of ordinary intake plus 12 g NaCl daily. BP did not increase significantly in either of the two groups during increased salt intake. During normal salt intake H had a significantly (p less than 0.01) higher IeNa (9.5 +/- 1.5 mmol/L) compared with C (8.2 +/- 1.4 mmol/L). During high salt intake IeNa in H decreased significantly to 8.1 +/- 1.2 mmol/L, the difference from C (7.6 +/- 1.2 mmol/L) not being significant. While the Na influx was similar in the two groups, the rate constant for Na efflux was significantly lower during normal salt intake in H (0.23 +/- 0.08 vs 0.29 +/- 0.1 h-1, p less than 0.05). Salt intake increased the efflux rate constant significantly in H (0.28 +/- 0.08 h-1, p less than 0.05), while it did not change significantly in C (0.32 +/- 0.08 h-1) compared with the value for normal salt intake. Our results suggest that young men with a hereditary predisposition to hypertension have a higher IeNa secondary to a lower rate of Na efflux, while a normal Na influx indicates normal cell permeability to Na. The findings in H during high Na intake--a decreased IeNa and an increased efflux rate of Na--do not favor the existence of a sodium transport inhibitor, in subjects predisposed to hypertension, increasing during high salt intake and volume expansion and acting through inhibition of the Na efflux.


Relating sensory profiles of canned amaranth (Amaranthus cruentus), cleome (Cleome gynandra), cowpea (Vigna unguiculata) and Swiss chard (Beta vulgaris) leaves to consumer acceptance.
The younger generation of South Africans generally do not consume traditional meals prepared using African green leafy vegetables, primarily because they are regarded as bitter, "poverty" foods. Canning of these vegetables could create value-added products that can be sold in the commercial market. Descriptive sensory evaluation and consumer acceptance testing with young females were used to assess the potential of such products. The sensory attributes of amaranth, cleome and cowpea leaves canned in brine and in a cream sauce were described using 21 attributes grouped by aroma, taste, texture/mouthfeel and aftertaste. Amaranth and Swiss chard products were described as sweet with a popcorn-like aroma. Cleome products were described as bitter, sour, pungent, chemical-tasting, astringent, sandy with a metallic mouthfeel and strong aftertaste. Cowpea products were described as having woody and tobacco aromas as well as a chewy and cohesive texture. Among the products canned with a cream sauce, young female consumers preferred amaranth and Swiss chard; cowpea was less liked, while cleome was least liked. Canned amaranth leaves have potential as a commercial product that may be well liked by young consumers. The cowpea leaves product has consumer potential, but the formulation needs revision, while canned cleome leaves need further research work. © 2017 Society of Chemical Industry.


The rapid and sensitive enumeration of antibody-secreting cells using immunogold/silver staining (SIG-blot assay).
A simple and robust method has been developed for the enumeration of antibody-secreting cells. Secretion is assessed on the surface of 96-well microtitre plates using immunogold/silver staining techniques. The method is sufficiently straightforward to allow, for the first time, assessment of secretory cells in the clinical laboratory. This approach has great potential for enumerating cells that secrete other products, such as the interleukins.


Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi.
p27Kip1 that regulates the G1/S transition of cell cycle and inhibits Rho A signaling is frequently lost in several cancers leading to the deregulation of cell growth and cell motility. Mitogen-activated protein kinases (MAPK) regulate the export of p27Kip1 from nucleus to cytoplasm, followed by the degradation with proteases. Skp-2, a subunit of an SCF ubiquitin-protein ligase complex responsible for the ubiquitination of p27Kip1, is upregulated frequently in several cancers, leading to the decrease of p27Kip1. We applied human immunodeficiency virus (HIV) lentivirus-mediated RNA interference (RNAi) to melanoma cells with the BRAF mutation (V599E) and overexpressed Skp-2 and found that the simultaneous suppression of these activated oncogenes resulted in the effective inhibition of in vitro cell growth and invasive ability of melanoma cells accompanied by the additional increase of p27Kip1. Our results suggest that gene therapy against melanoma with the enhanced MAPK and ubiquitin-proteasomal pathways could be a specific and effective therapeutic strategy for cancers.


Estimating the number of New Zealand children with a physical disability.
To estimate the number of New Zealand children who have a physical disability, and to describe this group in relation to sex, age, ethnic group and severity. We used data collected by Statistics New Zealand's Household Disability Survey 2001. Within the estimated 90 000 children aged 0-14 years with a disability as described in Disability Counts 2001, we identified a subgroup using information on the use of equipment suggestive of mobility disability, the numbers estimated to be in receipt of or in need of physiotherapy and/or occupational therapy, and the small number needing ramps or similar modifications. An estimated 14 500 children had a physical disability. This equates to an estimated 1.7% of the New Zealand population of children aged 0-14 years. Fifty-seven per cent were boys. An estimated 9600 were New Zealand-European, 3800 Maori and 600 Samoan. Approximately half were of moderate severity as defined by Statistics New Zealand. An estimated 9500 had a multiple disability. The rate is somewhat higher than in studies from countries where only locomotor disability is described, but similar to rates where other types of disability such as dexterity disability are included. This may reflect the fact that within our group are children who in other countries would have been described as having a dexterity or a self-help disability. It would be useful if future New Zealand data collection could attempt to separate these subgroups in order to allow better forward planning of health, education and family support services.


Bovine milk exosomes affected proliferation of macrophages under hypoxia.
Exosomes are extracellular vesicles implicated in cell-to-cell communication. The objective was to investigate the effect of exosomes in macrophages under hypoxia. Exosomes were isolated from skim milk using differential centrifugation and was characterized by particle size and exosomal markers TSG101, CD81, and ALIX. The effect of exosomes on macrophages under hypoxia was investigated by assessing proliferation, cytokine and reactive oxygen species (ROS) production, and cell cycle. Exosomes treatment increased the cell viability under hypoxia while ROS production was significantly reduced. The production of TNF-α was not affected by hypoxia alone but increased in a dose-dependent manner in cells treated with exosomes under hypoxic condition. Hypoxia arrested cells in the G0/G1 phase whereas exosome treatment reduced the cell in this phase. Our study found that bovine milk exosomes affect the proliferation of macrophages under hypoxia and are able to reverse the adverse effects of hypoxia on cell viability.


Syringaldehyde ameliorates mouse arthritis by inhibiting dendritic cell maturation and proinflammatory cytokine secretion.
Syringaldehyde (SD), a kind of flavonoid polyphenolic small molecule compound, has the antioxidant and anti-inflammatory properties. But it is unknown whether SD has properties on the treatment of rheumatoid arthritis (RA) by modulating dendritic cells (DCs). We explored the effect of SD on the maturation of DCs in vitro and in vivo. The results showed that SD significantly down-regulated the expression of CD86, CD40 and MHC II, decreased the secretion of TNF-α, IL-6, IL-12p40 and IL-23, and increased IL-10 secretion and antigen phagocytosis in vitro induced by lipopolysaccharides in a dose-dependent manner through reducing the activation of MAPK/NF-κB signaling pathways. SD also significantly inhibited the expression of CD86, CD40 and MHC II on DCs in vivo. Moreover, SD suppressed the expression of CCR7 and the in vivo migration of DCs. In arthritis mouse models induced by λ-carrageenan and complete Freund's adjuvant, SD significantly alleviated paw and joint oedema, reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 and increased the level of IL-10 in serum. Interestingly, SD significantly decreased the numbers of type I helper T cells (Th1), Th2, Th17 and Th17/Th1-like (CD4+IFN-γ+IL-17A+), but increased the numbers of regulatory T cells (Tregs) in spleens of mice. Importantly, the numbers of CD11c+IL-23+ and CD11c+IL-6+ cells were negatively correlated with the numbers of Th17 and Th17/Th1-like. These results suggested that SD ameliorated mouse arthritis through inhibiting the differentiation of Th1, Th17 and Th17/Th1-like and promoting the generation of Tregs via regulation of DC maturation.


Characterization of cord blood interleukin 10 on aflatoxinB1-exposed patients with gestational diabetes.
Interleukin 10 (IL10) refers to a pleiotropic cytokine exerted immunoregulation. Aflatoxin B1 (AFB1) is a strong carcinogen, marked by causing immunosuppression. We determined the possible association between cord blood IL10 and AFB1-exposed patients with gestational diabetes (GD). Cord blood samples from non-GD adults (n = 3) and GD patients (n = 3) were harvested for determining representative serological parameters by use of biochemical assays and enzyme linked immunosorbent assay (ELISA) tests. As results, GD patients showed no statistical comparable clinical data (hepatic function, lipids metabolism, immune cell count) to those in controls or references. Interestingly, cord blood contents of AFB1 in GD patients were significantly increased when compared to those in non-GD controls, characterized with visibly increased cord blood IL10. Preliminary clinical data reveal that IL10 may function as a biomarker for immunoregulation in AFB1-exposed GD patients.


A study of the proliferative response of rabbit T cells using the BrdU-Hoechst method.
Con-A- and PHA-induced proliferation of cells from rabbit thymus, spleen and mesenteric lymph node was studied with the DNA-fluorescent probe 33258 Hoechst. The fluorescence of this probe is quenched when 5-bromo-2'-deoxy-uridine is incorporated into nascent DNA during the S phase. Fluorescence decreased with increasing content of newly formed DNA per cell. Proliferation kinetics and the number of Con-A- and PHA-reactive cells (C+ and P+ cells) were determined cytofluorometrically . Lymphocytes from control and dexamethasone (DX)-treated animals start their proliferation early: after 42 hr about 25% of the control and the majority of the DX-resistant cells finished their second cell division. Small numbers of C+ (12.0%) and P+ (3.5%) cells were found in control thymus, while these percentages were enhanced in DX thymus: 32.5 and 27.0% respectively; 50% of the spleen T cells in control and DX animals are C+ or P+ and 75% of the lymph-node T cells are C+ (after DX 45%) and 50% are P+ (after DX also 50%). It is concluded that in thymus and lymph nodes, a steroid sensitive (Ss) C+P-, and in lymph nodes a Ss C+P+ cell pool is present. A mitogen non-proliferative cell pool (C-P-) is present in control and DX thymus.


Ménétrier disease in a child of 18 months: diagnosis by ultrasonography.
We present an 18-month-old infant with Ménétrier disease diagnosed by ultrasonography. The sonographic changes are illustrated and the possibility of early diagnosis of this disorder is suggested.


Dental profile of a community of recovering drug addicts: Biomedical aspects. Retrospective cohort study.
to obtain a biomedical oral profile of a community of adult drug addicts in treatment by analysing their dental health, with a view to determining whether the state of their oral health could be attributed primarily to their lifestyle and the direct consequences of drug abuse on their overall condition, rather than to the effects of the drugs used. The study was conducted under the terms of an agreement between the Complutense University of Madrid's (UCM) Odontology Faculty and the City of Madrid's Substance Abuse Institute. Seventy drug addicts and 34 control group subjects were examined. The study assessed oral hygiene habits, systemic pathology, type of drugs used and the duration of use, oral pathology, oral health indices, risk of caries based on saliva tests, oral candidiasis and periodontal microbiology. Statistically significant differences (p<0.05) were found between the test and control groups for practically all the variables analysed. In the drug users group, dental hygiene was wanting, systemic and oral pathology prevailed and the decayed/missing/filled teeth or surface (DMFT/S) indices denoted very poor buccodental health. The saliva tests showed a substantial risk of caries and candidiasis rates were high. By contrast, with a single exception, the microbiological studies detected no statistically significant difference between drug users and control groups periodontal flora. Drug-dependent patients had poor oral health and a significant increase in oral pathology, essentially caries and periodontal disease. Their risk of caries was high and the presence of candidiasis was representative of their poor general and oral health. Drug users' poor buccodental condition was more closely related to lifestyle than to drug abuse itself.


The CHRNA5-A3-B4 gene cluster in nicotine addiction.
Nicotine addiction (NA) is a common and devastating disease, such that the annual number of deaths (world-wide) from tobacco-related diseases will double from 5 million in the year 2000 to 10 million in 2020. Nicotine is the only substance in tobacco which animals and humans will self-administer. NA, as a lifetime diagnosis, has been assessed in various approaches, including the concept of cigarettes per day (CPD). Other assessments of NA are somewhat more comprehensive, such as the Fagerstrom Test for Nicotine Dependence or the American Psychiatric Association's Diagnostic and Statistical Manual (fourth edition) diagnosis of nicotine dependence. These different measures have moderate agreement with one another. Twin, family and adoption studies have shown that these different assessments of NA have substantial heritability (that fraction of risk attributable to genetic factors). The heritability of NA has been estimated at 50-75%, depending on the definition and the population under study. DNA-based studies of NA have been somewhat successful in identifying a common haplotype, which increases risk for NA among European-origin populations. This haplotype explains a small amount of variance, accounting for ∼1 CPD, and it includes the α5 and the α3 nicotinic receptor subunit genes (CHRNA5 and CHRNA3). The review will focus on this implicated region. In this risk region, there is a common (among European-origin people) mis-sense single-nucleotide polymorphism in the CHRNA5 gene (D398N), which changes a conserved amino acid from aspartic acid to asparagine. The risk allele (398N) confers decreased calcium permeability and more extensive desensitization, according to in vitro cellular studies, raising the possibility that a positive allosteric modulator of the (α4β2)(2)α5 type of nicotinic receptor might have therapeutic potential in NA. There are other genetic influences on NA in this region, apart from the mis-sense variant, and additional biological experiments must be done to understand them.


Acyl-CoA oxidase activity and peroxisomal fatty acid oxidation in rat tissues.
Acyl-CoA oxidase, the first enzyme of the peroxisomal beta-oxidation, was proved to be rate-limiting for this process in homogenates of rat liver, kidney, adrenal gland, heart and skeletal muscle. Acyl-CoA oxidase activity, based on H2O2-dependent leuko-dichlorofluorescein oxidation in tissue extract, was compared with radiochemically assayed peroxisomal beta-oxidation rates. Dichlorofluorescein production was a valid measure of peroxisomal fatty acid oxidation only in liver and kidney, but not in adrenal gland, heart or skeletal muscle. Production of 14C-labeled acid-soluble products from 1-14C-labeled fatty acids in the presence of antimycin-rotenone appears to be a more accurate and sensitive estimate of peroxisomal beta-oxidation than the acyl-CoA oxidase activity on base of H2O2 production. Chain-length specificity of acyl-CoA oxidase changed with the acyl-CoA concentrations used. Below 80 microM, palmitoyl-CoA showed the highest activity of the measured substrates in rat liver extract. No indications were obtained for the presence in rat liver of more forms of acyl-CoA oxidase with different chain-length specificity.


Round Window Insertion in Veria Technique of Cochlear Implantation: An Essential Modification.
Cochlear implants have been done using various surgical approaches. The classical posterior tympanotomy approach has been practiced by majority of surgeons worldwide. An alternative approach is the transcanal Veria approach. This is non mastoidectomy approach where the electrode is threaded via a transcanal tunnel into the cochleostomy site. Majority of "Veria" surgeons are inserting the cochlear electrodes via a cochleostomy. This article focuses on round window insertion of cochlear electrode which has been proven to be a "softer "technique of electrode insertions and finds its role in preservation of residual hearing. Out of 115 cochlear implants done at AIIMS Patna between May 2014-May 2018, using the Veria approach, 52 patients have now been done using the round window insertion. Veria approach is a non-mastoidectomy technique where a special perforator is used to drill a trans canal tunnel which lodges the cochlear electrodes. All kind of implants were used and round window insertion was possible with different kind of electrodes. Out of 52 implants, 24 were MEDEL Sonata with straight electrode and flex soft electrode, 21 were Advanced Bionics Precurved 1 J electrode, 2 were (CI 24 REST) Cochlear devices standard straight array and 5 were Neurelec standard straight array devices. Insertion was uneventful in all the cases and intra op telemetry results were satisfactory post insertion. Round window insertion has now become routine for cochlear implants especially in cases where we have to preserve residual hearing. Veria approach earlier was considered to be only a "cochleostomy" approach but our successful insertion via the round window using the Veria technique is a landmark modification and alleviates any such limitation which was associated with this technique before.


Lipid biosynthesis and deposition in genetically lean and fat chickens. Comparative in vivo studies with 14C acetate.
Following intravenous administration of 14C-acetate to genetically lean or fat chickens, the radioactivity in their liver, plasma, striated muscle and abdominal adipose tissue lipids and that in the breathed out CO2 were studied in function of time. As compared to the lean ones, the fat chickens showed a higher labelling of their triglyceride fatty acids in the plasma and adipose tissue, but not in the liver. Thus a higher rate of triglyceride secretion from the liver would be responsible for the higher abdominal fat weight in the fat line chickens.


Single-operator cholangioscopy for the treatment of concomitant gallbladder stones and secondary common bile duct stones.
This study aims to assess the clinical validity and safety of single-operator cholangioscopy system (SOCS) for the treatment of concomitant gallbladder stones and secondary common bile duct (CBD) stones. This retrospective study included 10 consecutive patients who had small-sized stones (< 1 cm) in both the gallbladder and CBD; the patients underwent SOCS treatment from June 2016 to December 2016. The clinical validity of this minimally invasive surgery was determined by the operation success rate, stone removal rate, postoperative hospital stay, hospitalization cost, and contrast images before and after the operation. The clinical safety was evaluated by perioperative complications and outcomes, gallbladder stone recurrence, and gallbladder contractility function. Both the technique success rate and the stone removal rate when using SOCS was 100%. There were no serious complications that occurred during the operation; three patients developed acute cholecystitis, and four patients underwent hyperamylasemia after the surgery. The average postoperative hospital stay was 5.8 ± 1.32 days, and the average hospitalization cost was 7466 ± 566.1 dollars. In the follow-up period, which ranged from 3 to 8 months, there was no stone residuals or recurrences in the gallbladder and CBD, and no patient showed a recurrence of biliary colic. In addition, the gallbladder contractility function was proven to be normal within 3 to 6 months after the operation. SOCS could successfully manage concomitant gallbladder stones and secondary CBD stones and precisely protect normal biliary function.


Assessment of an immunoassay for interferon-alpha in cerebrospinal fluid as a diagnostic aid in infections of the central nervous system.
A highly sensitive and specific immunoradiometric assay, based upon a monoclonal antibody, was used to measure interferon-alpha (IFN-alpha) in the cerebrospinal fluid (CSF) of patients with central nervous system infections and in controls with non-infectious neurological disorders. IFN-alpha was detected in all 21 patients with viral meningitis but in only one of four patients with non-viral aseptic meningitis. It was also present in the CSF of three of four patients with herpes encephalitis and five of seven patients with acute bacterial meningitis. By contrast, IFN-alpha was present in the CSF in low concentrations in only five (7%) of 71 neurological controls. This rapid test is positive in viral meningitis and may help in distinguishing viral infection from other causes of aseptic meningitis. It is usually negative in non-infective disorders but will not distinguish between viral and bacterial infections.


Post-translational modification of spectrin induced by excitatory amino acids in cultured cerebellar granule cells.
We have utilized primary cultures from rat cerebellum, 95% enriched in granule cells, to investigate the expression of proteins of the cortical cytoskeleton and of the synaptic vesicles and the relationship between excitatory amino acid receptors activation and calcium dependent proteolysis of fodrin. Exposure of neuronal cell cultures to N-methyl-D-aspartate (NMDA) in the absence of Mg(2+) and in the presence of glycine causes the appearance of 150 kDa proteolytic fragment (s) of-fodrin as detected by immunoblots. The effect of NMDA on fodrin proteolysis is inhibited by the NMDA antagonist 2-amino-5-phosphonovalerate (APV), by 3 mM Mg(2+), by calpain I inhibitor and by the omission of extracellular calcium. The kainate, at the same concentration of NMDA, is less effective and no degradation of fodrin is observed after exposure of cerebellar neurons to quisqualate. These findings suggest that calcium/calpain I-dependent fodrin proteolysis is selectively associated to the functional activation of NMDA receptors.


[Effect of stimulation of dopamine and histamine receptors on spontaneous lymphocyte adhesion in vitro].
With the help of spontaneous lymphocyte adhesion test the influence of dopamine and histamine on the adhesion of peripheral blood lymphocytes has been studied in healthy donors. It was shown that dopamine enhanced spontaneous lymphocyte adhesion, with the optimal concentrations of the substance for the realization of a stimulating effect being 10(-4)-10(-6) M. The effect of the enhancement was pharmacologically specific, as it was completely blocked by dopamine receptor-blocker--haloperidol. It was demonstrated that low concentrations of histamine (10(-7)-10(-8) M) enhanced, while higher concentrations (10(-6)-10(-3) M) inhibited lymphocyte adhesion. Dimedrol, but not cimetidine abolished the enhancement of spontaneous lymphocyte adhesion, while the adhesion inhibition was blocked by cimetidine, but not dimedrol. Thus, the revealed histaminergic enhancement and inhibition of spontaneous lymphocyte adhesion is mediated through the influence of histamine on H1- and H2-receptors, respectively.


The suppression of mitogen responses associated with resistance to experimental autoimmune encephalomyelitis requires adherent and T cells.
Resistance to experimental autoimmune encephalomyelitis (EAE) in Hartley guinea pigs has previously been reported to be associated with disease-specific antigen-induced suppression of mitogen responses in vitro. The present studies were initiated to investigate the requirement for different cell populations in this suppression. Intact and adherent-cell-depleted cultures of spleen cells from experimental and control animals were incubated with myelin basic protein (MBP), the major antigen of EAE, with the T-cell mitogen concanavalin A (Con A) alone or with Con A in the presence of MBP. In agreement with previous studies, MBP-induced suppression of the Con A response was observed only in cultures derived from resistant animals. In addition, it was observed that this suppression was abrogated by depletion of adherent cells. When cells from resistant and susceptible animals were mixed, suppression occurred only in the presence of nonadherent cells from resistant guinea pigs. Adherent cells from either resistant or susceptible animals functioned equally well. Cultures of purified E-rosette-forming cells (E+) from resistant animals (i.e., T cells) showed no suppression. Similarly, cells from these same animals which were depleted of E+ cells (i.e., non-T cells) did not demonstrate suppression in vitro. Upon reconstitution of spleen cell populations from resistant guinea pigs by mixing E+ and E- cells, suppression was restored. These experiments show that this model of suppression in vitro requires adherent cells as well as T cells and suggests that antigen-induced suppression of mitogen responses is dependent upon a cell-mediated immunologic mechanism.


Surgical management of intra-abdominal cystic lymphangioma. Report of 20 cases.
Cystic lymphangioma (CL) is a benign rare malformation of lymphatic vessels. Its discovery in adults is rare. Although it can affect any organ, the common forms found in adults are mesenteric and/or retroperitoneal CL. This article was designed to study the epidemiological, diagnostic difficulties, and therapeutic principles of intra-abdominal cystic lymphangioma in adults. We report a retrospective study from January 1998 to September 2010 concerning 20 patients who underwent surgical removal of a CL. We were interested in discovering the clinical, biological, and radiological characteristics of CL. The localization, size, and number of cysts have been reported, as well as the surgical intervention used and the postoperative immediate and late complications. The median age was 46 years. Abdominal pain was the main symptom and was found in 15 patients (75%). Physical examination revealed an abdominal mass in 12 patients (60%). In four patients (20%), the cystic lymphangioma was incidental. Abdominal ultrasound and abdominal CT scan helped to highlight 22 cystic masses. CL diagnosis was established preoperatively in 13 patients (65%). Six patients (30%) were operated with a diagnosis other than CL. The diagnosis was made intraoperatively in one case (5%). Only two patients (10%) were operated on in emergency: one due to an infected CL and the other was CL complicated with intracystic hemorrhage. A laparotomy in 13 cases (65%) was the surgical approach used, whereas 7 cases (35%) benefited from a laparoscopy. No conversion was noted. The majority of the patients, 18 cases (90%), received a total cystectomy. Only two patients (10%) had recurrences of which only one was reoperated. The diagnosis of CL often is facilitated by means of modern imaging; however, other diagnoses may be discussed, particularly hydatid disease endemic areas. If symptomatic lesions or complications arise, complete surgical excision, when possible without major sacrifice, seems to be the best therapeutic option to reduce the risk of recurrence.


Bacterial toxins as tools for mucosal vaccination.
Several studies have demonstrated that the biological properties of secreted bacterial toxins could be harnessed for the induction of mucosal and systemic immunity following application at epithelial surfaces. Although the properties and potential application of several of these toxins will be discussed in this review, special focus will be placed on Pseudomonas aeruginosa exotoxin A (PE). A non-toxic form of PE (ntPE) into which antigenic epitopes can be integrated appears to be a particularly promising vaccination tool, which is able to cross the polarized epithelia of the gastrointestinal, respiratory and reproductive tracts and selectively target macrophages and dendritic cells.