Deep-sea corals provide new insight into the ecology, evolution, and the role of plastids in widespread apicomplexan symbionts of anthozoans.
Apicomplexans are the causative agents of major human diseases such as malaria and toxoplasmosis. A novel group of apicomplexans, recently named corallicolids, have been detected in corals inhabiting tropical shallow reefs. These apicomplexans may represent a transitional lifestyle between free-living phototrophs and obligate parasites. To shed light on the evolutionary history of apicomplexans and to investigate their ecology in association with corals, we screened scleractinians, antipatharians, alcyonaceans, and zoantharians from shallow, mesophotic, and deep-sea communities. We detected corallicolid plastids using 16S metabarcoding, sequenced the nuclear 18S rRNA gene of corallicolids from selected samples, assembled and annotated the plastid and mitochondrial genomes from a corallicolid that associates with a deep-sea coral, and screened the metagenomes of four coral species for corallicolids. We detected 23 corallicolid plastotypes that were associated with 14 coral species from three orders and depths down to 1400 m. Individual plastotypes were restricted to coral hosts within a single depth zone and within a single taxonomic order of corals. Some clusters of closely related corallicolids were revealed that associated with closely related coral species. However, the presence of divergent corallicolid lineages that associated with similar coral species and depths suggests that corallicolid/coral relations are flexible over evolutionary timescales and that a large diversity of apicomplexans may remain undiscovered. The corallicolid plastid genome from a deep-sea coral contained four genes involved in chlorophyll biosynthesis: the three genes of the LIPOR complex and acsF. The presence of corallicolid apicomplexans in corals below the photic zone demonstrates that they are not restricted to shallow-water reefs and are more general anthozoan symbionts. The presence of LIPOR genes in the deep-sea corallicolid precludes a role involving photosynthesis and suggests they may be involved in a different function. Thus, these genes may represent another set of genetic tools whose function was adapted from photosynthesis as the ancestors of apicomplexans evolved towards parasitic lifestyles. Video abstract.


Role of calcium, glutamate neurotransmission, and nitric oxide in spreading acidification and depression in the cerebellar cortex.
This study investigated the mechanisms underlying the recently reported fast spreading acidification and transient depression in the cerebellar cortex in vivo. Spreading acidification was evoked by surface stimulation in the rat and mouse cerebellar cortex stained with the pH-sensitive dye neutral red and monitored using epifluorescent imaging. The probability of evoking spreading acidification was dependent on stimulation parameters; greater frequency and/or greater amplitude were more effective. Although activation of the parallel fibers defined the geometry of the spread, their activation alone was not sufficient, because blocking synaptic transmission with low Ca(2+) prevented spreading acidification. Increased postsynaptic excitability was also a major factor. Application of either AMPA or metabotropic glutamate receptor antagonists reduced the likelihood of evoking spreading acidification, but stronger stimulation intensities were still effective. Conversely, superfusion with GABA receptor antagonists decreased the threshold for evoking spreading acidification. Blocking nitric oxide synthase (NOS) increased the threshold for spreading acidification, and nitric oxide donors lowered the threshold. However, spreading acidification could be evoked in neuronal NOS-deficient mice (B6;129S-Nos1(tm1plh)). The depression in cortical excitability that accompanies spreading acidification occurred in the presence of AMPA and metabotropic glutamate receptor antagonists and NOS inhibitors. These findings suggest that spreading acidification is dependent on extracellular Ca(2+) and glutamate neurotransmission with a contribution from both AMPA and metabotropic glutamate receptors and is modulated by nitric oxide. Therefore, spreading acidification involves both presynaptic and postsynaptic mechanisms. We hypothesize that a regenerative process, i.e., a nonpassive process, is operative that uses the cortical architecture to account for the high speed of propagation.


The nuclear DEK interactome supports multi-functionality.
DEK is an oncoprotein that is overexpressed in many forms of cancer and participates in numerous cellular pathways. Of these different pathways, relevant interacting partners and functions of DEK are well described in regard to the regulation of chromatin structure, epigenetic marks, and transcription. Most of this understanding was derived by investigating DNA-binding and chromatin processing capabilities of the oncoprotein. To facilitate the generation of mechanism-driven hypotheses regarding DEK activities in underexplored areas, we have developed the first DEK interactome model using tandem-affinity purification and mass spectrometry. With this approach, we identify IMPDH2, DDX21, and RPL7a as novel DEK binding partners, hinting at new roles for the oncogene in de novo nucleotide biosynthesis and ribosome formation. Additionally, a hydroxyurea-specific interaction with replication protein A (RPA) was observed, suggesting that a DEK-RPA complex may form in response to DNA replication fork stalling. Taken together, these findings highlight diverse activities for DEK across cellular pathways and support a model wherein this molecule performs a plethora of functions.


Cellular rejection in discordant xenografts when hyperacute rejection is prevented: analysis using adoptive and passive transfer.
Hyperacute rejection of discordant xenografts occurs rapidly, precluding cellular infiltration. Thus the role of cellular rejection in discordant xenografts is debated. Using adoptive transfer of sensitized splenocytes and passive transfer of sensitized serum, we evaluated the influence of cellular and humoral elements on cellular infiltration and rejection in the guinea-pig-to-rat discordant xenograft model. Guinea-pig hearts were transplanted into Lewis rats. Pretransplant, rats underwent splenectomy and plasma exchange and were started on daily cobra venom factor injections. Xenografts rejected faster after adoptive (1, 2, 2 and 2 days) or passive (1, 1, 2 and 2 days) transfer than controls (4, 4, 4 and 4 days; p < 0.05). Macrophages and neutrophils were predominant in early prerejection specimens. Over time, cellular infiltrates were dominated by mononuclear cells. Natural killer cells were present in all groups, as were interleukin 2 receptor positive cells. Our data suggest that either sensitized serum or sensitized cells are capable of initiating an accelerated rejection characterized by cellular infiltration. Despite subtle differences, the population of infiltrating cells was similar in each group. Thus, although rejection may be initiated by either cellular or humoral influences, the ultimate result is the same. We have, therefore, established a small animal model to study cellular rejection in discordant xenografts. This model will help evaluate the role of cell subsets and xenoantibodies in xenograft rejection and will help determine the precise relationship between the two when hyperacute rejection is prevented.


The inhibitory effects of vasoactive intestinal polypeptide on the mechanical and electrical activity of canine antral smooth muscle.
1. The inhibitory effects of vasoactive intestinal polypeptide (VIP) on the electrical and mechanical activity of canine antral smooth muscle were investigated. 2. In concentrations ranging from 5 X 10(-9) to 1 X 10(-7) M, VIP decreased the force of spontaneous contractions but had no measurable effect on spontaneous action potential complexes. 3. VIP had no effect on the increase in the amplitude and duration of the plateau potential and on the amplitude of contraction caused by a maximally effective concentration of acetylcholine. 4. VIP caused a significant decrease in the force of contraction caused by ED50 and threshold concentrations of acetylcholine. However, VIP had no measurable effect on the increase in the size of the action potential plateau caused by either concentration of acetylcholine. 5. VIP antagonized the increase in the amplitude of the plateau potential and the force of contraction induced by pentagastrin. It had no consistent effect on the pentagastrin-induced increase in frequency. 6. The data indicate that VIP acts as an inhibitor in this tissue in two distinct ways. It uncouples electromechanical coupling during spontaneous and acetylcholine-induced electrical and mechanical activity, and antagonizes pentagastrin-induced increases in electrical and mechanical activities.


Factors associated with the increased incidence of necrotising enterocolitis in extremely preterm infants in Sweden between two population-based national cohorts (2004-2007 vs 2014-2016).
To investigate potential risk factors behind the increased incidence of necrotising enterocolitis (NEC) in Swedish extremely preterm infants. Registry data from two population-based national cohorts were studied. NEC diagnoses (Bell stage ≥II) were validated against hospital records. All liveborn infants <27 weeks of gestation 2004-2007 (n=704) and 2014-2016 (n=895) in Sweden. NEC incidence. The validation process resulted in a 28% reduction of NEC cases but still confirmed a higher NEC incidence in the later epoch compared with the earlier (73/895 (8.2%) vs 27/704 (3.8%), p=0.001), while the composite of NEC or death was lower (244/895 (27.3%) vs 229/704 (32.5%), p=0.022). In a multivariable Cox regression model, censored for mortality, there was no significant difference in early NEC (0-7 days of life) between epochs (HR=0.9 (95% CI 0.5 to 1.9), p=0.9), but being born in the later epoch remained an independent risk factor for late NEC (>7 days) (HR=2.7 (95% CI 1.5 to 5.0), p=0.001). In propensity score analysis, a significant epoch difference in NEC incidence (12% vs 2.8%, p<0.001) was observed only in the tertile of infants at highest risk of NEC, where the 28-day mortality was lower in the later epoch (35% vs 50%, p=0.001). More NEC cases were diagnosed with intramural gas in the later epoch (33/73 (45.2%) vs 6/26 (23.1%), p=0.047). The increase in NEC incidence between epochs was limited to cases occurring after 7 days of life and was partly explained by increased survival in the most extremely preterm infants. Misclassification of NEC is common.


Effect of secondary preventive therapy on recurrence of tuberculosis in HIV-infected individuals: a systematic review.
Human immunodeficiency virus (HIV)-infected individuals successfully treated for tuberculosis (TB) remain at risk of recurrence of the disease, especially in high TB incidence settings. We performed a systematic review, investigating whether secondary preventive therapy (sPT) with anti-TB drugs (preventive therapy in former TB patients with treatment success) is an effective strategy to prevent recurrence of TB in this patient group. We searched the databases PubMed, Cochrane Library, EMBASE, Web of Science and Google Scholar using the keywords HIV-infections, HIV, human immunodeficiency virus, AIDS, isoniazid, isoniazid preventive therapy (IPT), tuberculosis, TB, recurrence and recurrent disease, resulting in 253 potential publications. We identified eight publications for full text assessment, after which four articles qualified for inclusion in this systematic review. The quality of the included articles was rated using the GRADE system. All but one study were rated as having a high quality. In all included studies, sPT significantly decreased the incidence of recurrent TB in HIV-infected individuals to a substantial degree in comparison to non-treatment or placebo. Relative reductions varied from 55.0% to 82.1%. These data showed that the use of sPT to prevent recurrent TB in HIV-infected individuals was highly beneficial. These findings need to be confirmed in prospective studies with an adequate assessment of the effect of antiretroviral therapy (ART) and the occurrence of drug resistance.


Color Doppler ultrasonography as an alternative tool for postoperative evaluation of collaterals after indirect revascularization surgery in Moyamoya disease.
The cerebral hypoperfusion caused by chronic progressive stenosis or occlusion of intracranial arteries in moyamoya disease can be treated by direct bypass or indirect revascularization procedures. The extent of collaterals from the external carotid artery (ECA) after indirect revascularization surgery is the key point of angiographic follow-up, and the invasiveness of angiography impelled us to investigate the role of ultrasonography in the evaluation of collaterals. We hypothesized that the collaterals shown on angiography might produce corresponding hemodynamic changes in color Doppler ultrasonography. We prospectively recruited moyamoya patients who underwent indirect revascularization surgery and received both preoperative and postoperative angiography and color Doppler ultrasound studies. The collaterals on angiography were graded according to Matsushima method. A total of 21 patients (age, 17 ± 10.2 years) with 24 operated hemispheres were enrolled. Patients who showed better collateral establishment by angiography had higher end-diastolic velocity (EDV), lower resistance index (RI), and larger flow volume in the superficial temporal artery (STA) and ECA (all p < 0.05). In STA, increase of EDV greater than 13.5 cm/sec or reduction of RI greater than 0.19 after operation corresponded to 94% of Matsushima grade A+B. In ECA, post-operative EDV greater than 22 cm/sec or increase of EDV greater than 6.4 cm/sec also corresponded to 94% of Matsushima grade A+B. Our findings revealed potential roles of color Doppler ultrasonography in identifying patients with poor collaterals after indirect revascularization procedures.


Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive.
Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.


Synchrotron-Based Pencil Beam Scanning Nozzle with an Integrated Mini-Ridge Filter: A Dosimetric Study to Optimize Treatment Delivery.
A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter as an integral part of the synchrotron nozzle (IMRF). Dose models with and without IMRF were commissioned in a commercial Treatment planning system (TPS). Dosimetric characteristics in a homogenous water phantom were compared between plans with and without IMRF for a fixed spread-out Bragg peak width of 4 cm with distal ranges varying from 8 to 30 g/cm². Six clinical cases were then used to compare the plan quality between plans. The delivery efficiency was also compared between plans in both the phantom and the clinical cases. The Bragg peak width was increased by 0.18 cm at the lowest energy and by only about 0.04 cm at the highest energy. The IMRF increased the spot size (σ) by up to 0.1 cm at the lowest energy and by only 0.02 cm at the highest energy. For the phantom, the IMRF negligibly affected dose at high energies but increased the lateral penumbra by up to 0.12 cm and the distal penumbra by up to 0.06 cm at low energies. For the clinical cases, the IMRF slightly increased dose to the organs at risk. However, the beam delivery time was reduced from 18.5% to 47.1% for the lung, brain, scalp, and head and neck cases, and dose uniformities of target were improved up to 2.9% for these cases owing to the reduced minimum monitor unit effect. In conclusion, integrating a mini-ridge filter into a synchrotron nozzle is feasible for improving treatment efficiency without significantly sacrificing the plan quality.


Identification of a novel cytochrome P-450 gene from the white rot fungus Phanerochaete chrysosporium.
A gene fragment belonging to the cytochrome P-450 superfamily has been cloned and identified from stationary cultures of the filamentous fungus Phanerochaete chrysosporium by reverse transcriptase (RT)-PCR. A set of degenerate primers homologous to highly conserved regions of known cytochrome P-450 sequences were used for initial RT-PCRs. Individual PCR products were cloned, sequenced, and identified as those belonging to the cytochrome P-450 superfamily based on amino acid sequence homologies and the presence of the highly conserved heme binding region. The nucleotide sequence of a single cDNA clone indicated the presence of an open reading frame encoding a partial cytochrome P-450 protein of 208 amino acids. Comparisons of the deduced amino acid sequence of the partial protein to other known cytochrome P-450 sequences indicate that it is the first member of a new family of cytochrome P-450s, designated CYP63-1A. Northern blot analysis suggests that CYP63-1A is expressed under both nitrogen-rich and nitrogen-deficient culture conditions and thus not under the same regulatory constraints as the well-studied lignin and manganese peroxidases. Western blot analyses using antibodies raised to the heme binding region of CYP63-1A indicate that the protein has a molecular mass of approximately 44,000 Da.


Permeation of the luminal capillary glycocalyx is determined by hyaluronan.
The endothelial cell glycocalyx influences blood flow and presents a selective barrier to movement of macromolecules from plasma to the endothelial surface. In the hamster cremaster microcirculation, FITC-labeled Dextran 70 and larger molecules are excluded from a region extending almost 0.5 micrometer from the endothelial surface into the lumen. Red blood cells under normal flow conditions are excluded from a region extending even farther into the lumen. Examination of cultured endothelial cells has shown that the glycocalyx contains hyaluronan, a glycosaminoglycan which is known to create matrices with molecular sieving properties. To test the hypothesis that hyaluronan might be involved in establishing the permeation properties of the apical surface glycocalyx in vivo, hamster microvessels in the cremaster muscle were visualized using video microscopy. After infusion of one of several FITC-dextrans (70, 145, 580, and 2,000 kDa) via a femoral cannula, microvessels were observed with bright-field and fluorescence microscopy to obtain estimates of the anatomic diameters and the widths of fluorescent dextran columns and of red blood cell columns (means +/- SE). The widths of the red blood cell and dextran exclusion zones were calculated as one-half the difference between the bright-field anatomic diameter and the width of the red blood cell column or dextran column. After 1 h of treatment with active Streptomyces hyaluronidase, there was a significant increase in access of 70- and 145-kDa FITC-dextrans to the space bounded by the apical glycocalyx, but no increase in access of the red blood cells or in the anatomic diameter in capillaries, arterioles, and venules. Hyaluronidase had no effect on access of FITC-Dextrans 580 and 2,000. Infusion of a mixture of hyaluronan and chondroitin sulfate after enzyme treatment reconstituted the glycocalyx, although treatment with either molecule separately had no effect. These results suggest that cell surface hyaluronan plays a role in regulating or establishing permeation of the apical glycocalyx to macromolecules. This finding and our prior observations suggest that hyaluronan and other glycoconjugates are required for assembly of the matrix on the endothelial surface. We hypothesize that hyaluronidase creates a more open matrix, enabling smaller dextran molecules to penetrate deeper into the glycocalyx.


Specialization of mutualistic interaction networks decreases toward tropical latitudes.
Species-rich tropical communities are expected to be more specialized than their temperate counterparts. Several studies have reported increasing biotic specialization toward the tropics, whereas others have not found latitudinal trends once accounting for sampling bias or differences in plant diversity. Thus, the direction of the latitudinal specialization gradient remains contentious. With an unprecedented global data set, we investigated how biotic specialization between plants and animal pollinators or seed dispersers is associated with latitude, past and contemporary climate, and plant diversity. We show that in contrast to expectation, biotic specialization of mutualistic networks is significantly lower at tropical than at temperate latitudes. Specialization was more closely related to contemporary climate than to past climate stability, suggesting that current conditions have a stronger effect on biotic specialization than historical community stability. Biotic specialization decreased with increasing local and regional plant diversity. This suggests that high specialization of mutualistic interactions is a response of pollinators and seed dispersers to low plant diversity. This could explain why the latitudinal specialization gradient is reversed relative to the latitudinal diversity gradient. Low mutualistic network specialization in the tropics suggests higher tolerance against extinctions in tropical than in temperate communities.


MRI Volume Changes of Axillary Lymph Nodes as Predictor of Pathologic Complete Responses to Neoadjuvant Chemotherapy in Breast Cancer.
Longitudinal monitoring of breast tumor volume over the course of chemotherapy is informative of pathologic response. This study aims to determine whether axillary lymph node (aLN) volume by magnetic resonance imaging (MRI) could augment the prediction accuracy of treatment response to neoadjuvant chemotherapy (NAC). Level-2a curated data from the I-SPY-1 TRIAL (2002-2006) were used. Patients had stage 2 or 3 breast cancer. MRI was acquired pre-, during, and post-NAC. A subset with visible aLNs on MRI was identified (N = 132). Prediction of pathologic complete response (PCR) was made using breast tumor volume changes, nodal volume changes, and combined breast tumor and nodal volume changes with sub-stratification with and without large lymph nodes (3 mL or ∼1.79 cm diameter cutoff). Receiver operating characteristic curve analysis was used to quantify prediction performance. The rate of change of aLN and breast tumor volume were informative of pathologic response, with prediction being most informative early in treatment (area under the curve (AUC), 0.57-0.87) compared with later in treatment (AUC, 0.50-0.75). Larger aLN volume was associated with hormone receptor negativity, with the largest nodal volume for triple negative subtypes. Sub-stratification by node size improved predictive performance, with the best predictive model for large nodes having AUC of 0.87. aLN MRI offers clinically relevant information and has the potential to predict treatment response to NAC in patients with breast cancer.


First records raise questions: DNA barcoding of Odonata in the middle of the Mediterranean.
We present the results of the first-ever DNA barcoding study of odonates from the Maltese Islands. In total, 10 morphologically identified species were collected during a two-week long expedition in 2018. Eighty cytochrome c oxidase subunit I (COI) barcodes were obtained from the collected specimens. Intra- and interspecific distances ranged from 0.00% to 2.24% and 0.48% to 17.62%, respectively. Successful species identification based on ascribing a single morphological species to a single Barcode Index Number (BIN) was achieved for eight species (80%). In the case of two species, Ischnura genei and Anax parthenope, BINs were shared with other closely related species. The taxonomic status of I. genei is questionable and the phylogenetic relationship between A. imperator/parthenope is not clear. Further studies involving a series of adult specimens collected in a wide spatial range and nuclear markers are necessary to resolve these cases. Therefore, this dataset serves as an initial DNA barcode reference library for Maltese odonates, within a larger project: Aquatic Macroinvertebrates DNA Barcode Library of Malta.


Evaluation of developing maize microbiomes and associations among nitrogen cyclers and key fungal taxa.
More sustainable approaches to agriculture are urgently needed to protect existing resources and optimize crop yields and to provide food for a growing global human population. More sustainable agricultural practices that utilize plant-microbe relationships across cultivation are urgently needed. The main objectives of this study were to track the prokaryotic and fungal microbiomes associated with key growth stages of developing maize to evaluate the relationships among nitrogen cycling bacteria and major fungal genera including those known to contain arbuscular mycorrhizal fungi and other important taxa. Prokaryotic and fungal microbiomes associated with bulk soils, rhizosphere soils and tissues of developing maize were characterized using Illumina MiSeq sequencing. Similarities in microbiome diversity and abundance were compared to sample metadata to explore the influence of external factors on microbiome development. Correlations among target fungal taxa, bulk bacteria and nitrogen cycling bacteria were determined using non-parametric Spearman correlations. Important maize-associated fungal taxa were detected in all samples across growth stages, with Fusarium, Penicillium and Aspergillus fungi comprising up to 4.21, 4.26 and 0.28% of all fungal genera, respectively. Thirteen statistically significant correlations between nitrogen cycling genera and targeted fungal genera were also identified (rS≥0.70 or rS≤-0.70; P<0.05). This study is the first to note a strong positive association among several nitrifying bacteria and Fusarium (R=0.71; P=0.0046), Aspergillus (R=0.71; P=0.0055) and Cladosporium spcies (R=0.74; P=0.0038), suggesting the levels of soil nitrate, nitrite or nitrification intermediates may have large roles in the proliferation of important maize-associated fungi.


Heterogeneity in lipid composition of the outer membrane and cytoplasmic membrane and cytoplasmic membrane of Pseudomonas BAL-31.
The outer membranes and cytoplasmic membranes of the marine bacterium Pseudomonas BAL-31 were separated by washing the cells three times in 0.5 M NaCl and twice in 0.5 M sucrose. Electron microscopy during the removal of membranes revealed that the outer membranes fragmented in a regular manner to give rise to fairly uniform vesicles measuring approximately 140 nm in diameter. Isolated outer membranes had a buoyant density in sucrose of 1.230 g per cm(3), whereas the cytoplasmic membranes had a density of 1.194 g per cm(3). The removal of the outer membrane during the application of this procedure was monitored by measuring the release of 2-keto-3-deoxyoctulosonic acid and phospholipid. The cells lost 85.5% of their 2-keto-3-deoxyoctulosonic acid and 47.3% of their phospholipid during this treatment. Complete recovery of outer membrane material could be achieved. The removal of 25.5% of the 2-keto-3-deoxyoctulosonic acid and 0.9% of the phospholipid rendered the cells sensitive to lysis with Triton X-100. The phospholipid composition of the outer membrane was calculated to be 78.9% phosphatidylethanolamine and 16.1% phosphatidylglycerol. The phospholipid composition of the cytoplasmic membrane proved to be 71.5% phosphatidylethanolamine and 23.5% phosphatidylglycerol. The fatty acid composition was also found to be quantitatively heterogeneous between the two membranes.


Spike-Triggered Covariance Analysis Reveals Phenomenological Diversity of Contrast Adaptation in the Retina.
When visual contrast changes, retinal ganglion cells adapt by adjusting their sensitivity as well as their temporal filtering characteristics. The latter has classically been described by contrast-induced gain changes that depend on temporal frequency. Here, we explored a new perspective on contrast-induced changes in temporal filtering by using spike-triggered covariance analysis to extract multiple parallel temporal filters for individual ganglion cells. Based on multielectrode-array recordings from ganglion cells in the isolated salamander retina, we found that contrast adaptation of temporal filtering can largely be captured by contrast-invariant sets of filters with contrast-dependent weights. Moreover, differences among the ganglion cells in the filter sets and their contrast-dependent contributions allowed us to phenomenologically distinguish three types of filter changes. The first type is characterized by newly emerging features at higher contrast, which can be reproduced by computational models that contain response-triggered gain-control mechanisms. The second type follows from stronger adaptation in the Off pathway as compared to the On pathway in On-Off-type ganglion cells. Finally, we found that, in a subset of neurons, contrast-induced filter changes are governed by particularly strong spike-timing dynamics, in particular by pronounced stimulus-dependent latency shifts that can be observed in these cells. Together, our results show that the contrast dependence of temporal filtering in retinal ganglion cells has a multifaceted phenomenology and that a multi-filter analysis can provide a useful basis for capturing the underlying signal-processing dynamics.


Response of bacterial communities in Barents Sea sediments in case of a potential CO2 leakage from carbon reservoirs.
Carbon capture and storage sites in Barents Sea shelf are currently in progress as part of climate change mitigation activities. However environmental impacts of a possible CO2 seepage on bacterial community are lacking knowledge. This work addressed potential consequences on bacterial communities from Snøvit region in Barents Sea sediments. Long-term experiment (92 days) was carried out mimicking realistic conditions of pressure (∼30 bars) using the unique hyperbaric chamber (Karl Erik TiTank). The experiment was divided in three stages: i) 21 days of no CO2, ii) 50 days of simulation of carbon dioxide leakage (depletion of pH to 7.0) and iii) 14 days emulating a leakage cessation. Results suggested that bacterial communities can adapt to a CO2 leakage in short term. However, bacteria showed negative effects in terms of activity, community structure, and number of cells after long term CO2 exposure. After CO2 leakage cessation, bacterial communities did not show a significant recovery. These findings highlighted that, even though marine bacteria showed adaptation to the new conditions (acidified environment), in case of a small but continuous CO2 leakage marine bacteria might not be recovered upon pre-exposure status.


Unstable repeat expansion in major psychiatric disorders: two decades on, is dynamic DNA back on the menu?
For a period in the mid-1990s, soon after the discovery of the involvement of trinucleotide repeat expansions in fragile-X syndrome (both A and E), Huntington's disease, myotonic dystrophy, and a number of hereditary ataxias, there was a clear sense that this new disease mechanism might provide answers for psychiatric disorders. Given the then failures to replicate initial genetic linkage findings for schizophrenia (SCZ) and bipolar disorder (BD), a greater emphasis was placed on the role of complex and non-Mendelian mechanisms, and repeat instability appeared to have the potential to provide adequate explanations for numerous apparently non-Mendelian features such as anticipation, incomplete penetrance, sporadic occurrence, and nonconcordance of monozygotic twins. Initial molecular studies using a ligation-based amplification method (repeat expansion detection) appeared to support the involvement of CAG•CTG repeat expansion in SCZ and BD. However, subsequent studies that dissected the large repeats responsible for much of the positive signal showed that there were three main loci where CAG•CTG repeat expansion was occurring (on 13q21.33, 17q21.33-q22, and 18q21.2). None of the expansions at these loci appeared to segregate with SCZ or BD, and research into repeat expansions in psychiatric illness petered out in the early 2000s. The 13q expansion occurs within a noncoding RNA and appears to be associated with spinocerebellar ataxia 8 (SCA8), but with a still unexplained dichotomy in penetrance - either very high or very low. The 17q expansion occurs within an intron of the carbonic anhydrase-like gene, CA10. The 18q expansion is located within an intron of the TCF4 gene. Mutations in TCF4 are a known cause of Pitt-Hopkins syndrome. Also, pertinently, genome-wide association studies have shown a well-replicated association between TCF4 and SCZ. Two decades on, in 2016, it appears to be an appropriate juncture to reflect on what we have learned, and, with the arrival of newer technologies, whether there is any mileage to be made in revisiting the unstable DNA hypothesis for psychiatric illness.


Drinking to cope: a comparison of questionnaire and electronic diary reports.
The purpose of this article is to assess the correspondence between questionnaire reports of dispositional drinking to cope (DTC) and different indices of daily DTC in a sample of nondependent heavy drinkers. Data from electronic diary (ED) records of interpersonal problems, negative affect, coping and drinking were used to examine how questionnaire reports of dispositional DTC corresponded to ED reports of daily DTC and to within-person associations among ED reports of negative affect, interpersonal problems and drinking. In the current study, 98 community-residing heavy drinkers using EDs recorded moods, interpersonal problems, coping attempts, desire to drink and drinking for 21 consecutive days. The findings demonstrate correspondence between questionnaire reports of dispositional DTC and (1) ED reports of daily DTC, (2) intensity of negative mood associated with daily drinking initiation and (3) some between-person differences in within-day prediction of drinking and desire to drink from mood and interpersonal problem ratings. Those reporting higher dispositional DTC were somewhat more likely to drink in response to some negative moods and less likely to drink in response to some positive moods than those reporting relatively lower dispositional DTC, but these findings were mixed. Questionnaire reports of dispositional DTC are at best inconsistently linked to observed within-person associations among daily moods, interpersonal problems and drinking even among heavy drinkers.


Expression of leukotriene biosynthetic enzymes in tonsillar tissue of children with obstructive sleep apnea: a prospective nonrandomized study.
Cysteinyl leukotrienes (CysLTs) potentially promote adenotonsillar hypertrophy in children with obstructive sleep apnea (OSA). Previous studies have identified CysLTs and their receptors in tonsillar tissue from children with OSA. To demonstrate expression of the leukotriene biosynthetic enzymes 5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), leukotriene A(4) hydrolase (LTA(4)H), and leukotriene C(4) synthase (LTC(4)S) in T and B tonsillar lymphocytes from pediatric patients with OSA. It was hypothesized that children with OSA have greater expression of biosynthetic enzymes for CysLTs (5-LO, FLAP, and LTC(4)S) in their tonsillar tissue than do children with recurrent tonsillitis (RT), who were enrolled as controls. This prospective, nonrandomized study was performed at a tertiary care university hospital on 13 children with OSA and adenotonsillar hypertrophy undergoing adenotonsillectomy and 12 children without OSA also undergoing tonsillectomy for RT. Tonsillar tissue from children with OSA or RT was examined for 5-LO, FLAP, LTA(4)H, and LTC(4)S expression under real time-quantitative polymerase chain reaction (RT-qPCR), flow cytometry (FC), and confocal laser scanning microscopy (CM). Expression of biosynthetic enzymes for CysLTs (5-LO, FLAP, and LTC(4)S) was the main outcome measure. Patients with OSA and control patients with RT were compared for numbers of copies of 5-LO, FLAP, and LTC(4)S messenger RNA (by RT-qPCR) in T or B tonsillar lymphocytes and proportions of CD3(+) or CD19(+) tonsillar lymphocytes that expressed 5-LO, FLAP, and LTC(4)S (by FC). Messenger RNA for all 4 enzymes was detected in T and B lymphocytes from both study groups, and expression of all biosynthetic enzymes was demonstrated in participants with OSA and RT by FC. Patients with OSA differed from controls in the proportions (median [10th-90th percentile]) of LTC(4)S(+) CD3(+) T lymphocytes (23.31% [8.64%-50.07%] vs 10.81% [3.48%-23.32%], respectively) (P = .01) and LTC(4)S(+) CD19(+) B lymphocytes (20.66% [14.62%-65.77%] vs 12.53% [2.87%-36.64%], respectively) (P = .01) detected by FC. Immunoreactivity for the 4 enzymes was detected by CM in B lymphocytes of mantle zones and T lymphocytes of extrafollicular areas. Leukotriene biosynthetic enzymes are expressed in tonsillar lymphocytes, and the previously reported detection of CysLTs in tonsillar tissue from children with OSA may be attributed to endogenous synthesis. Enhanced expression of LTC(4)S is a potential target for pharmacologic interventions in OSA.


A self-care, problem-solving and mindfulness intervention for informal caregivers of people with motor neurone disease: A pilot study.
Informal caregivers of people with motor neurone disease (MND) take on an extensive role. Caregivers are at increased risk of experiencing psychological distress and burden, yet, there is a lack of intervention programmes to support them. The aim of this study was to investigate the feasibility and acceptability of a therapeutic group intervention promoting self-care, problem-solving and mindfulness to informal caregivers of people with MND. Pilot study that utilised a one-arm pre- and post-design. Acceptability of the intervention was assessed 2 weeks post intervention with a questionnaire designed specifically for this study. Feasibility was assessed with consent, adherence and reasons for non-participation, refusal and attrition. Participants completed baseline and follow-up (6-week post intervention) questionnaires for psychological morbidity, burden, problem-solving, mindfulness and preparedness. Settings/participants: Caregivers of people with a diagnosis of MND within the past 12 months who were 18 years or older; who could speak, read and write in English and who were attending a progressive neurological diseases clinic were eligible. A total of 13 caregivers participated in one of three group intervention sessions which were focused on self-care, problem-solving and mindfulness. The intervention appeared to be feasible and acceptable. All participants stated that they would recommend the intervention to others. The group format appeared to be highly valued. There was no significant change in measures between pre-intervention and 6 weeks post intervention. This pilot serves as an initial step for examining interventions for MND caregivers, with the hope of identifying effective, efficient and sustainable strategies to best support this group.


Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A.
Cyclosporin G (CsG) is an analogue of cyclosporin A (CsA) with strong immunosuppressive activity. We compared these two drugs in a rat model in which salt depletion promotes irreversible renal interstitial fibrosis with renal dysfunction in animals given CsA for three weeks. When both drugs were given in the same dosage on a weight basis (15 mg/kg/day, subcutaneously), CsA blood levels were higher than CsG (3305 vs. 1824 ng/ml, P < 0.001). This could be explained by a higher CsG clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinary excretion of N-acetyl beta-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had similar GFR and urinary NAG. When CsA dosage was decreased to 7.5 mg/kg blood levels were similar to those found with CsG 15 mg/kg. CsA at this dose caused a reduced GFR (0.29 ml/min/100 g) and an increased urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term in vitro expansion of osteoarthritic human articular chondrocytes do not alter genetic stability: a microsatellite instability analysis.
In this study, we investigated genetic damage acquisition during in vitro culture of human osteoarthritic (OA) chondrocytes to evaluate their safety for use in regenerative medicine clinical applications. In particular, we have addressed the impact of long-term in vitro culture on simple sequence repeat stability, to evaluate the involvement of the mismatch repair system (MMR) in the accumulation of genetic damage. MMR, the main post-replicative correction pathway, has a fundamental role in maintaining genomic stability and can be monitored by assessing microsatellite instability (MSI). MMR activity has been reported to decrease with age not only in vivo, but also in vitro in relationship to culture passages. OA chondrocytes from seven donors were cultured corresponding to 13-29 population doublings. Aliquots of the cells were collected and analyzed for MSI at five DNA loci (CD4, VWA, FES, TPOX, and P53) and for MMR gene expression at each subculture. Genetic stability was confirmed throughout the culture period. MMR genes demonstrated a strong coordination at the transcriptional level among the different components; expression levels were very low, in accordance with the observed genetic stability. The reduced expression of MMR genes might underline no need for increasing DNA repair control in the culture conditions tested, in which no genetic damage was evidenced. These data argue for the safety of chondrocytes for cellular therapies and are encouraging for the potential use of in vitro expanded OA chondrocytes, supporting the extension of autologous cell therapy procedures to degenerative articular diseases.


[Main left coronary artery disease. Aspects of its diagnosis and treatment].
The Left Main Disease (LMD) assumes a special particularity within the coronary pathology, because of its seriousness and of its urgent need of surgical treatment. The lesion is associated mainly with clinical situations of unstable angina, and who's diagnose by non-invasive methods is extremely difficult; among these methods the echocardiography and specially the stress test still remain of most value in this diagnosis. Coronary arteriography remains the standard exam and is indispensable for a positive confirmation of diagnosis. However, the risk involved here is significantly higher than in other coronary pathologies especially if the lesion of LMD is localized in the proximal region or is ostium level. Therefore, in this review, the need of special care is emphasized before, during and after catheterization, in patients with sunpect of LMD or in those in which the diagnosis was placed during the angiographic examination. Finally, it is very important to recognize the most dangerous situations in order to rightly identify those who need urgent surgical treatment.


HLA system. Phenotypic and gene frequencies in celiac and healthy subjects from the same geographical area.
To compare the phenotypic and gene frequencies of the HLA system in celiac and healthy subjects the same geographical area. HLA A, B, C, DR and DQ phenotypic and gene frequencies have been estimated in 38 celiac children and healthy subjects. The HLA typing has been done according to the microlymphocytotoxicity assay. The individual HLA antigen frequencies in each group have been compared by Chi-square test using Yates correction. For each specificity, the strength of association with celiac disease has been estimated by Odds Ratio and 95% confidence limit. The comparative study of both population show increased phenotypic and gene frequencies among celiac patients and significant differences compared with healthy subjects for B8, Cw7, DR3, DR7 and DQ2. On the contrary, Cw4 and DQ1 phenotypic and gene frequencies are significantly increased in the control population. Our findings support the role of HLA antigens as predisposing factors for celiac disease. The presence of Cw4 and DQ1 can be a protective factor against such disease.


Using pharmacists' perceptions in planning changes in pharmacy practice.
Pharmacists' perceptions of and goals for clinical pharmacy services, as well as the proportion of time devoted to clinical services, were studied at one hospital as part of the process for establishing departmental goals. Three methods were used in evaluating pharmacists' perceptions of clinical pharmacy services. The first was a departmental survey. Second, staff members were asked to generate and prioritize a list of goals for clinical pharmacy services; this was done by means of an interactive, small-group process. Finally, a work-sampling study was performed that indirectly measured use of staff pharmacist and technician time. Staff pharmacists perceived that clinical pharmacy services were being provided to individual patients; however, support for these services from upper management was perceived as inadequate. Staff development had the highest priority for the further development of clinical pharmacy services. Only 19.7% of pharmacists' time was devoted to clinical services. Data from all three studies were incorporated into the development of a strategic plan that set forth long-term departmental goals and objectives. The plan includes a statement of commitment to develop management systems to eliminate deficiencies identified in the study. Among the changes in pharmacy operations introduced as a result of the survey were (1) a career-ladder system, (2) new opportunities for staff development, and (3) improved documentation systems. Surveying staff perceptions of existing services, joint goal setting and prioritization, and work-sampling studies formed the basis for the development and implementation of a new model of integrated pharmacy services at this institution.


Defining long-term drivers of pertussis resurgence, and optimal vaccine control strategies.
Pertussis resurgence has been reported from several developed countries with long-standing immunisation programs. Among these, Australia in 2003 discontinued an 18 months (fourth) booster dose in favour of an adolescent (fifth) dose. We developed a model to evaluate determinants of resurgence in Australia and alternative vaccine strategies for mitigation. Novel characteristics of our model included the use of seroepidemiologic data for calibration, and broad investigation of variables relevant to transmission of, and protection against, pertussis. We simulated multiple parameter combinations, retaining those consistent with observed data for subsequent use in predictive models comparing alternative vaccination schedules. Reproducing the early control of pertussis followed by late resurgence observed in Australia required natural immunity to last decades longer than vaccine-acquired immunity, with mean duration exceeding 50 years in almost 90% of simulations. Replacement of the dose at 18 months with an adolescent dose in 2003 resulted in a 40% increase in infections in the age group 18-47 months by 2013. A six dose strategy (2, 4, 6, 18 months, 4 and 15 years) yielded a reduction in infection incidence (pre-school 43%, infants 8%) greater than any alternative strategies considered for timing of five administered doses. Our finding that natural immunity drives long-term trends in pertussis cycles is relevant to a range of pertussis strategies and provides the necessary context in which to consider maternal vaccination. Comparatively short-lived vaccine-acquired immunity requires multiple boosters over the first two decades of life to maximise reduction in infections.


Comparative effectiveness research: decision-based evidence.
In the clinical research context, comparative effectiveness research (CER) refers to the comparison of several health-care interventions administered under real-world conditions to individuals representative of the day-to-day clinical practice target population. We provide a brief history of CER and argue that CER can be used to deliver useful, but currently lacking information. Three study designs that can accomplish this are discussed, and incorporating CER into cost-benefit analyses is examined. The relationships between CER and evidence-based and personalized medicine are also considered, as is the challenge of implementing CER results into routine clinical practice.


Mechanisms of SOCS3 phosphorylation upon interleukin-6 stimulation. Contributions of Src- and receptor-tyrosine kinases.
The suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine signal transduction. SOCS3 is a key negative regulator of interleuking-6 (IL-6) signal transduction. Furthermore, SOCS3 was shown to be phosphorylated upon treatment of cells with IL-2, and this has been reported to regulate its function and half-life. We set out to investigate whether SOCS3 phosphorylation may play a role in IL-6 signaling. Tyrosine-phosphorylated SOCS3 was detected upon treatment of mouse embryonic fibroblasts with IL-6. Interestingly, the observed SOCS3 phosphorylation does not require SOCS3 recruitment to phosphotyrosine (Tyr(P)) 759 of gp130, and the kinetics of SOCS3 phosphorylation do not match the activation kinetics of the Janus kinases. This suggests that other kinases may be involved in SOCS3 phosphorylation. Using Src and Janus kinase inhibitors as well as Src kinase-deficient mouse embryonic fibroblasts, we provide evidence that Src kinases, which we found to be constitutively active in these cells, are involved in the phosphorylation of IL-6-induced SOCS3. In addition, we found that receptor-tyrosine kinases such as platelet-derived growth factor receptor or epidermal growth factor receptor can very potently phosphorylate IL-6-induced SOCS3. Taken together, these results suggest that SOCS3 phosphorylation is not a JAK-mediated phenomenon but is dependent on the activity of other kinases such as Src kinases or receptor-tyrosine kinases, which can either be constitutively active or activated by an additional stimulus.


Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.
Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.


Association between dietary calcium and phosphorus intakes, dietary calcium/phosphorus ratio and bone mass in the Korean population.
Osteoporosis has become a major public health issue. Among various factors affected bone health, not only dietary calcium and phosphorus intakes, but also the dietary calcium/phosphorus ratio could relate to bone health. Therefore, we evaluated whether dietary calcium and phosphorus intakes, and dietary calcium/phosphorus ratio are associated with bone mass in Korean adults ≥ 20 years of age. The analysis used data from the Korean National Health and Nutrition Examination Survey, a cross-sectional survey of Korean civilians, conducted from January to December 2010. A total of 4,935 participants (2,309 men and 2,626 women) were analyzed in this study. Dietary calcium and phosphorus intakes of the participants were estimated using 24-h dietary recall. Bone mass densities for the whole body, femoral neck, and lumbar spine were measured by dual-energy X-ray absorptiometry. Dietary calcium intake and dietary calcium/phosphorus ratio were positively related to bone mass density for femoral neck in men ≥ 50 years of age (p = 0.046 and 0.041, respectively). Dietary calcium intake showed positive associations with bone mass density for whole body in premenopausal women (p = 0.022). Increased calcium intake and high dietary calcium/phosphorus ratio might have favorable effects on bone mass in Korean adults. Additional gender- and age-specific studies are needed to further identify the influence of calcium and phosphorus intakes, and the dietary calcium/phosphorus ratio on bone mass.


Student attitudes toward a web-based interprofessional education package.
The objective of this study was to examine undergraduate health science students' attitudes toward interprofessional learning using a web-based interprofessional education package. A before and after study of student attitudes toward a web-based interprofessional education package was conducted using the 17-item Readiness for Interprofessional Learning Scale (RIPLS). Students completed the RIPLS before and after the educational package. Forty-six students commenced the study with 2 students failing to complete. The group contained mostly females with a mean age of 22.6 yrs. A statistically significant change was found for RIPLS subscale one, "shared learning," p=0.035. This study demonstrated that a web-based interprofessional education package did appear to have an impact on undergraduate students' attitudes toward interprofessional learning.


[Effect of amantadine (1-aminoadamantane) and remantadine (alpha-methyl-1-adamantane methyl amine) hydrochlorides on formation of influenza A viral proteins].
Inhibitory effect of amantadine (I-amino adamantane) and remantadine (alpha-methyl-1-adamantane methylamine) hydrochlorides on reproduction of influenza A virus as well as, in particular, on formation of virus specific proteins was studied in cell culture. These drugs were dissimilar; they resembled each other in the patients of their effect as a function of the course of administration into the cells infected with the virus. Both preparations inhibited the synthesis of virus specific proteins exhibiting distinct effects under conditions of preliminary or immediate administration following the infection. At the same time, the inhibitory properties of remantadine were maintained at the subsequent period after infection; these were not observed in the amantadine treatment.


Density Oscillations Induced by Individual Ultracold Two-Body Collisions.
Access to single-particle momenta provides new means of studying the dynamics of a few interacting particles. In a joint theoretical and experimental effort, we observe and analyze the effects of a finite number of ultracold two-body collisions on the relative and single-particle densities by quenching two ultracold atoms with an initial narrow wave packet into a wide trap with an inverted aspect ratio. The experimentally observed spatial oscillations of the relative density are reproduced by a parameter-free zero-range theory and interpreted in terms of cross-dimensional flux. We theoretically study the long-time dynamics and find that the system does not approach its thermodynamic limit. The setup can be viewed as an advanced particle collider that allows one to watch the collision process itself.


A mirror therapy system using virtual reality and an actuated exoskeleton for the recovery of hand motor impairments: a study of acceptability, usability, and embodiment.
Hand motor impairments are one of the main causes of disabilities worldwide. Rehabilitation procedures like mirror therapy are given crucial importance. In the traditional setup, the patient moves the healthy hand in front of a mirror; the view of the mirrored motion tricks the brain into thinking that the impaired hand is moving as well, stimulating the recovery of the lost hand functionalities. We propose an innovative mirror therapy system that leverages and couples cutting-edge technologies. Virtual reality recreates an immersive and effective mirroring effect; a soft hand exoskeleton accompanies the virtual visual perception by physically inducing the mirrored motion to the real hand. Three working modes of our system have been tested with 21 healthy users. The system is ranked as acceptable by the system usability scale; it does not provoke adverse events or sickness in the users, according to the simulator sickness questionnaire; the three execution modes are also compared w.r.t. the sense of embodiment, evaluated through another customized questionnaire. The achieved results show the potential of our system as a clinical tool and reveal its social and economic impact.


Vertebral architecture in the earliest stem tetrapods.
The construction of the vertebral column has been used as a key anatomical character in defining and diagnosing early tetrapod groups. Rhachitomous vertebrae--in which there is a dorsally placed neural arch and spine, an anteroventrally placed intercentrum and paired, posterodorsally placed pleurocentra--have long been considered the ancestral morphology for tetrapods. Nonetheless, very little is known about vertebral anatomy in the earliest stem tetrapods, because most specimens remain trapped in surrounding matrix, obscuring important anatomical features. Here we describe the three-dimensional vertebral architecture of the Late Devonian stem tetrapod Ichthyostega using propagation phase-contrast X-ray synchrotron microtomography. Our scans reveal a diverse array of new morphological, and associated developmental and functional, characteristics, including a possible posterior-to-anterior vertebral ossification sequence and the first evolutionary appearance of ossified sternal elements. One of the most intriguing features relates to the positional relationships between the vertebral elements, with the pleurocentra being unexpectedly sutured or fused to the intercentra that directly succeed them, indicating a 'reverse' rhachitomous design. Comparison of Ichthyostega with two other stem tetrapods, Acanthostega and Pederpes, shows that reverse rhachitomous vertebrae may be the ancestral condition for limbed vertebrates. This study fundamentally revises our current understanding of vertebral column evolution in the earliest tetrapods and raises questions about the presumed vertebral architecture of tetrapodomorph fish and later, more crownward, tetrapods.


Traditional healthy Mediterranean diet: estrogenic activity of plants used as food and flavoring agents.
The Italian-style Mediterranean diet has been defined as healthy by epidemiologists and nutritionists. Besides being low fat, the Mediterranean diet is rich in biologically active minor compounds. Among these, phytoestrogens seem to have an impact on the prevention of chronic degenerative disease. It is important to understand how this occurs. The in vitro estrogenic activity of crude extracts from typical Mediterranean foods was tested using a yeast estrogen screen (YES), containing human estrogen receptor. Species belonging to Leguminosae, Apiaceae, Graminaceae, Iridaceae, Chenopodiaceae, Cruciferae and Solanaceae showed the greatest number of positive responses. These species include some foods which are traditionally widely consumed, such as beans and other legumes, tomatoes, cabbage, carrots and some cereals. The highest activity was found in the more polar extracts (aqueous, methanol and chloroform: methanol) indicating that polar compounds are mainly responsible for the estrogenic activity. This is also supported by the traditional cooking practices. According to data from in vitro tests, the estrogenic activity is present in numerous plants which are commonly used as food in the Mediterranean diet. Vegetable foods rich in phytoestrogens, as in the Mediterranean tradition, may contribute to the maintenance of health status.


Lipid A and resistance of Salmonella typhimurium to antimicrobial granule proteins of human neutrophil granulocytes.
Granule extracts from human polymorphonuclear leukocytes were prepared and fractionated by chromatography on Sephadex G75-SF. One fraction exhibited potent antimicrobial activity against an Rd1 lipopolysaccharide (LPS) mutant of Salmonella typhimurium. Susceptibility of the mutant to antimicrobial activity appeared to be due to binding of granule proteins to lipid A because isolated native LPS succeeded in blocking the antimicrobial activity of granule extracts whereas base-hydrolyzed LPS failed to do so. Centrifugation of control and base-hydrolyzed LPS-protein mixtures in cesium chloride gradients suggested that only control LPS formed complexes with antimicrobial proteins. Further evidence that bactericidal proteins from polymorphonuclear leukocyte granules interact with lipid A was that sublethal concentrations of polymyxin B (an antibiotic known to bind to lipid A) rendered target bacteria phenotypically resistant to granule proteins. Moreover, a mutant of S. typhimurium which synthesized a lipid A with decreased electronegativity due to increased 4-amino-4-deoxy-L-arabinosylation at the 4'-phosphate exhibited increased resistance to both polymyxin B and granule proteins. These results suggest that polymyxin B and antimicrobial proteins derived from polymorphonuclear leukocyte granules interact with lipid A in an analogous manner.


Vitamin B12 Intake and Related Biomarkers: Associations in a Dutch Elderly Population.
Vitamin B12 status is measured by four plasma/ serum biomarkers: total vitamin B12 (total B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and homocysteine (tHcy). Associations of B12 intake with holoTC and tHcy and associations between all four biomarkers have not been extensively studied. A better insight in these associations may contribute to an improved differentiation between vitamin B12 deficiency and a normal vitamin B12 status. This study investigates associations between vitamin B12 intake and biomarkers and associations between biomarkers. In this cross-sectional observational study, levels of total B12, HoloTC, MMA and tHcy were determined in participants of the B-PROOF study: 2919 elderly people (≥65 years, with a mean age of 74.1 years, a mean BMI of 27.1 and 50% women) with elevated tHcy levels (≥12 µmol/L). B12 intake was assessed in a subsample. We assessed the association between intake and status with multivariate regression analysis. We explored the dose-response association between B12 intake and biomarkers and the association of total B12 and holoTC with tHcy and MMA with restricted cubic spline plots. A doubling of B12 intake was associated with 9% higher total B12, 15% higher HoloTC, 9% lower MMA and 2% lower tHcy. Saturation of biomarkers occurs with dietary intakes of >5 μg B12. Spline regression showed that levels of MMA and tHcy started to rise when vitamin B12 levels fall below 330 pmol/L and with HoloTC levels below 100 pmol/L, with a sharp increase with levels of B12 and HoloTC below 220 and 50 pmol/L respectively. In this study we observed a significant association between vitamin B12 intake and vitamin B12 biomarkers and between the biomarkers. The observed inflections for total B12 and holoTC with MMA and tHcy could indicate cut-off levels for further testing for B12 deficiency and determining subclinical B12 deficiency.


Emotional intelligence in medical students: does it correlate with selection measures?
Much attention and emphasis are placed on the selection of medical students. Although selection measures have been validated in the literature, it is not yet known whether high scores at selection are indicative of high levels of interpersonal aptitude. Emotional intelligence (EI) is reported to be a predictor of the interpersonal and communications skills medical schools are looking for in applicants. This study describes EI scores in medical students and explores correlations between EI and selection scores at the University of Western Australia. Senior medical students from a 6-year undergraduate curriculum completed the online MSCEIT (Mayer-Salovey-Caruso Emotional Intelligence Test) survey. Scores for EI were described and correlations between EI and Undergraduate Medicine and Health Sciences Admission Test (UMAT), Interview and Tertiary Entrance Rank (TER) scores were analysed. Mean scores of the 177 respondents (58%) reflected the normal distribution of scores (mean 98, standard deviation [SD] 15.0) in the general population. Males had higher EI scores than females and Asian students demonstrated higher EI Total and branch scores than White students. The highest and lowest EI scores were obtained for the branches Understanding Emotions (mean 110, SD 19.0) and Perceiving Emotions (mean 94, SD 15.6), respectively. No significant correlations were found between EI Total or EI branch scores and any of the selection scores (UMAT, TER and Interview). This study offers information that can be used to compare the EI scores of medical students with those of other health professionals. No relationship was identified between cognition (measured by the UMAT) and skill (measured by the MSCEIT) in the interpersonal domain and EI. Further studies are required to explore whether UMAT Section 2 is measuring EI, if there are associations between EI and academic performance and if EI can be used to predict the performance of junior doctors.


Clinical Implications of Sodium Zirconium Cyclosilicate Therapy in Patients with Systolic Heart Failure and Hyperkalemia.
Sodium zirconium cyclosilicate (SZC), a newly introduced specific potassium binder, is introduced to treat hyperkalemia. However, the implications of SZC in up-titrating renin-angiotensin-aldosterone system inhibitors in patients with systolic heart failure remain unknown. Patients with heart failure with left ventricular ejection fraction <50% and hyperkalemia who had completed 3-month SZC therapy were retrospectively included. Serum potassium levels, the dose of renin-angiotensin-aldosterone system inhibitors, and echocardiographic parameters during the 3-month SZC therapy as compared with the pretreatment 3-month period were investigated. A total of 24 patients (median 77 years old, 71% men, median left ventricular ejection fraction 41%) received a 3-month SZC therapy without any associated adverse events including hypokalemia. Compared with the pretreatment period, serum potassium levels decreased, doses of renin-angiotensin-aldosterone system inhibitors increased, and the left ventricular ejection fraction and plasma B-type natriuretic peptide levels improved following the 3-month SZC therapy (p < 0.05 for all). SZC may be a promising therapeutic option to improve hyperkalemia, indirectly allowing up-titration of renin-angiotensin-aldosterone system inhibitors and facilitating reverse remodeling in patients with heart failure with a left ventricular ejection fraction <50% and hyperkalemia.


Biocompatibility of Root Canal Sealers: A Systematic Review of In Vitro and In Vivo Studies.
(1) Aim: To perform a systematic review of the literature on the biocompatibility of root canal sealers that encompasses the various types of sealers that are commercially available as well as both in vitro and in vivo evidence. (2) Methods: This systematic review has been registered in PROSPERO (ID 140445) and was carried out according to PRISMA guidelines using the following databases: PubMed, Cochrane Library, ClinicalTrials.gov, Science Direct, and Web of Science Core Collection. Studies published between 2000 and 11 June 2019 that evaluated cytotoxicity (cell viability/proliferation) and biocompatibility (tissue response) of root canal sealers were included. (3) Results: From a total of 1249 studies, 73 in vitro and 21 in vivo studies were included. In general, studies suggest that root canal sealers elicit mild to severe toxic effects and that several factors may influence biocompatibility, e.g., material setting condition and time, material concentration, and type of exposure. Bioactive endodontic sealers seem to exhibit a lower toxic potential in vitro. (4) Conclusions: The available evidence shows that root canal sealers exhibit variable toxic potential at the cellular and tissue level. However, the methodological heterogeneity among studies included in this systematic review and the somewhat conflicting results do not allow a conclusion on which type of sealer presents higher biocompatibility. Further research is crucial to achieve a better understanding of the biological effects of root canal sealers.


CHEMICAL ANTAGONISM OF IONS : III. EFFECT OF SALT MIXTURES ON GELATIN ACTIVITY.
1.25 per cent gelatin solutions containing enough NaOH to bring them to pH 7.367 (or KOH to pH 7.203) were made up with various concentrations of NaCl, KCl and MgCl(2), alone and in mixtures, up to molar ionic strength. The effects of these salts on the pH were observed. MgCl(2) and NaCl alone lower the pH of the Na gelatinate or the K gelatinate, in all amounts of these salts. KCl first lowers the pH (up to 0.01 M K(+)), then raises the pH. Mixtures of NaCl and KCl (up to 0.09 M of the salt whose concentration is varied) raise the pH; then (up to 0.125 M Na(+) or K(+)) lower the pH; and finally (above 0.125 M) behave like KCl alone. Mixtures of MgCl(2) and NaCl raise the pH up to 0.10 M Na(+), and lower it up to 0.15 M Na(+)regardless of the amount of MgCl(2). Higher concentrations of NaCl have little effect, but the pH in this range of NaCl concentration is lowered with increase of MgCl(2). Mixtures of MgCl(2) and KCl behave as above described (for MgCl(2) and NaCl) and the addition of NaCl plus KCl to gelatin containing MgCl(2) produces essentially the same effect as the addition of either alone, except that the first two breaks in this curve come at 0.07 M and 0.08 M [Na(+) + K(+)] and there is a third break at 0.12 M. In this pH range the free groups of the dicarboxylic acids and of lysine are essentially all ionized and the prearginine and histidine groups are essentially all non-ionized. The arginine group is about 84 per cent ionized. Hence we are studying a solution with two ionic species in equilibrium, one with the arginine group ionized, and one with it non-ionized. It is shown that the effect of each salt alone depends upon the effect of the cation on the activity of these two species due to combination. The anomalous effects of cation mixtures may be qualitatively accounted for if one or both of these species fail to combine with the cations in a mixture in proportion to the relative combination in solutions of each cation alone. Special precautions were taken to ensure accuracy in the pH measurements. The mother solutions gave identical readings to 0.001 pH and the readings with salts were discarded when not reproducible to 0.003 pH. All doubtful data were discarded.


Understanding the links between cardiovascular disease and Parkinson's disease.
Studies investigating the associations between genetic or environmental factors and Parkinson's disease (PD) have uncovered a number of factors shared with cardiovascular disease, either as risk factors or manifestations of cardiovascular disease itself. Older age, male sex, and possibly type 2 diabetes are examples. On the other hand, coffee consumption and physical activity are each associated with a lower risk of both PD and cardiovascular disease. This observation raises questions about the underlying pathophysiological links between cardiovascular disease and PD. There is evidence for common mechanisms in the areas of glucose metabolism, cellular stress, lipid metabolism, and inflammation. On the other hand, smoking and total/low-density lipoprotein cholesterol appear to have opposite associations with cardiovascular disease and PD. Thus, it is uncertain whether the treatment of cardiovascular risk factors will impact on the onset or progression of PD. The available data suggest that a nuanced approach is necessary to manage risk factors such as cholesterol levels once the associations are better understood. Ultimately, the choice of therapy may be tailored to a patient's comorbidity profile. This review presents the epidemiological evidence for both concordant and discordant associations between cardiovascular disease and PD, discusses the cellular and metabolic processes that may underlie these links, and explores the implications this has for patient care and future research. © 2019 International Parkinson and Movement Disorder Society.


Observations on the perioperative management of aneurysmal subarachnoid hemorrhage.
Thirty-two patients with aneurysmal subarachnoid hemorrhage (SAH) were managed according to a protocol based on pain control and hemodynamic manipulation, monitored by an arterial line and Swan-Ganz catheter. Hemodynamic parameters were adjusted to four clinical situations. 1) For the unoperated patient with no neurological deficit, the regimen aims to maintain pulmonary wedge pressure (PWP) at 10 to 12 mm Hg, and the cardiac index (CI) and blood pressure (BP) at normal levels. 2) For the unoperated patient presenting with or developing neurological deficit, the PWP is increased until the deficit is reversed or the CI falls; the CI is high, and the BP normal. 3) For the postoperative patient with no neurological deficit, the PWP is maintained at 12 to 14 mm Hg, the CI is a high normal, and the BP is normal. 4) For the postoperative patient developing neurological deficit but showing no surgical complication on the computerized tomography scan, the PWP is increased until the deficit is reversed or the CI falls; the CI is high and the BP is increased with vasopressors if necessary. Fourteen patients developed neurological deficits either preoperatively, postoperatively, or both. Neurological deficits were repeatedly reversed by increasing the PWP, as measured hourly. In several patients an optimal wedge pressure was determined, below which deficits would reappear. In one patient whose neurological deficit was reversed on several occasions by increasing the PWP, the optimal PWP rose after each episode until it reached 22 mm Hg. Detailed event-related analysis of these patients' course illustrates these phenomena well. The optimal PWP varied from patient to patient, but ranged most frequently from 14 to 16 mm Hg. Meticulous monitoring of the patients' neurological status coupled with prompt correction of low PWP (assuming an adequate CI) has proven to be an effective way to prevent and reverse neurological deficits following aneurysmal SAH.


Epidermal growth factor-like activity in mares' milk.
Epidermal growth factor (EGF)-like activity was measured in mares' colostrum and milk by radioreceptor assay. Milk samples were collected from 22 mares 1 or more times during early lactation. Samples of colostrum were taken after parturition and before the foal first suckled (presuckle), within 6 hours after the foal first suckled (postsuckle), and on days 1, 2, 4, and 8 of lactation. In the 5 mares from which milk samples were obtained at each sampling time, presuckle colostral mean EGF-like activity (17.8 ng/ml) was greatest (P less than 0.05). The mean values for EGF-like activity at all other sampling times were not significantly different from each other (postsuckle colostrum, 9.7 ng/ml; day 1, 9.6 ng/ml; day 2, 8.5 ng/ml; day 4, 8.0 ng/ml; day 8, 7.8 ng/ml).


Effect of oxatomide on calcium ions in smooth muscle.
In an attempt to elucidate the mechanism of inhibitory action of oxatomide on smooth muscle against various spasmogens, we studied the effect of this drug on cumulative dose response curves (CDRC) to CaCl2 in guinea pig ileum. We found that oxatomide induces a shift to right and a non-surmountable depression of the maximal response of these CDRC which suggests non-competitive antagonism. Furthermore, oxatomide inhibits 45Ca2+ uptake by guinea pig ileum after acetylcholine stimulation which constitutes strong evidence that inhibition of calcium ion utilization by smooth muscle cells plays a major role in the mode of action of oxatomide.


Bowel stricture due to ischemic colitis: report of three cases requiring surgery.
The diagnosis of ischemic colitis is challenging and still based upon a high index of suspicion. We report here, three patients affected by ischemic colitis causing stenosis and intestinal obstruction that required surgical treatment. Results of surgery in the three cases were not fair reflecting the high mortality and morbidity rate of ischemic colitis. However, the three cases showed peculiar features allowing us to make a few speculative considerations. Better results in the treatment of ischemic colitis might be achieved by means of a prompt recognition of the initial picture and through a better control of the many associated diseases, that represent the main risk factor for the development of ischemic colitis itself and for the bad prognosis of surgical treatment.


Perceiving vowels in the presence of another sound: constraints on formant perception.
Speech is normally heard against a background of other sounds, yet our ability to isolate perceptually the speech of a particular talker is poorly understood. The experiments reported here illustrate two different ways in which a listener may decide whether a tone at a harmonic of a vowel's fundamental forms part of the vowel. First, a tone that starts or stops at a different time from a vowel is less likely to be heard as part of that vowel than if it is simultaneous with it; moreover, this effect occurs regardless of whether the tone has been added to a normal vowel, or to a vowel that has already been reduced in energy at the tone's frequency. Second, energy added simultaneously with a vowel, at a harmonic frequency near to the vowel's first formant, may or may not be fully incorporated into the vowel percept, depending on its relation to the first formant: When the additional tone is just below the vowel's first formant frequency, it is less likely to be incorporated than energy that is added at a frequency just above the first formant. Both experiments show that formants may only be estimated after properties of the sound wave have been grouped into different apparent sound sources. The first result illustrates a general auditory mechanism for performing perceptual grouping, while the second result illustrates a mechanism that may use a more specific constraint on vocal-tract transfer functions.


Lymphoid and myeloid differentiation of fetal liver CD34+lineage- cells in human thymic organ culture.
In this article, we report that the human fetal thymus contains CD34bright cells (< 0.01% of total thymocytes) with a phenotype that resembles that of multipotent hematopoietic progenitors in the fetal bone marrow. CD34bright thymocytes were CD33-/dull and were negative for CD38, CD2, and CD5 as well as for the lineage markers CD3, CD4, and CD8 (T cells), CD19 and CD20 (B cells), CD56 (NK cells), glycophorin (erythrocytes), and CD14 (monocytes). In addition, total CD34+ lineage negative (lin-) thymocytes contained a low number of primitive myeloid progenitor cells, thus suggesting that the different hematopoietic lineages present in the thymus may be derived from primitive hematopoietic progenitor cells seeding the thymus. To investigate whether the thymus is permissive for the development of non-T cells, human fetal organ culture (FTOC) assays were performed by microinjecting sorted CD34+lin- fetal liver cells into fragments of HLA-mismatched fetal thymus. Sequential phenotypic analysis of the FTOC-derived progeny of CD34+lin- cells indicated that the differentiation into T cells was preceded by a wave of myeloid differentiation into CD14+CD11b+CD4dull cells. Donor-derived B cells (CD19+CD20+) were also generated, which produced immunoglobulins (IgG and IgM) when cultured under appropriate conditions, as well as functional CD56+CD3- NK cells, which efficiently killed K562 target cells in cytotoxicity assays. These results demonstrate that the microinjection of fetal liver hematopoietic progenitors into fetal thymic organ fragments results in multilineage differentiation in vitro.


Isolation and characterization of a highly malignant variant of the SW480 human colon cancer cell line.
We found that the human colon cancer cell line SW480 consists of two distinct subpopulations which we have designated E-type (epithelial) and R-type (round). Pure cultures of each type were obtained by subcloning, and both have maintained their characteristic phenotypes for at least 1 year (40 passages). E-type cells are the major (> 98%) type in the parental SW480 cell line. They form flat epithelial-like colonies. In contrast, R-type cells, which constitute a minor fraction (< 2%) of the parental cell line, have a rounded shape and grow in clusters of piled-up cells. Compared to E-type cells or the parental SW480 cells, isolated R-type cells display decreased doubling time, loss of contact inhibition, less adhesiveness to culture plates, higher anchorage-independent growth in soft agar, and a much more aneuploid karyotype. When injected s.c. into nude mice, R-type cells produce much larger tumors within the same period of time than E-type cells, and the tumors are less differentiated than those produced by the E-type cells. Cell fusion experiments between R-type and E-type cells revealed that the R-type phenotype is dominant, and the results suggest that this is due to one or a few genetic changes. Taken together, these findings suggest that the R-type cells represent a more malignant variant of the E-type cells. They may be useful, therefore, for studying mechanisms involved in tumor progression.


Freezing and melting of lipid bilayers and the mode of action of nonactin, valinomycin, and gramicidin.
An abrupt loss of effectiveness of the presumed carriers, nonactin and valinomycin, in mediating ion conductance occurred at the same temperature as the membrane fluidity, judged visually, was lost. By contrast, the effects of the presumed channel-former, gramicidin, were the same on solid and liquid membranes. Taken together, these findings imply that freezing the membrane primarily reduces the mobility of these antibiotics with little effect on their solubility.


Keratinocyte cancer incidence in Australia: a review of population-based incidence trends and estimates of lifetime risk.
To review the most recent population-based estimates of keratinocyte cancer incidence in Australia, to describe the trends over time and to calculate lifetime risk of developing these skin cancers. We conducted a literature search of PubMed/MEDLINE from 2001 to August 2021 to identify relevant literature. We defined eligible articles as those reporting population-based studies of adults and excluded studies that reported only on high-risk or paediatric populations, or on incidence of precursor or related lesions. We summarised identified studies qualitatively. We calculated lifetime risk of developing keratinocyte cancer using the methods of Cancer Research UK, adjusting for multiple primaries and the competing risk of death. We identified six eligible studies. In the absence of compulsory notifications of keratinocyte cancer to state and territory cancer registries in Australia, all estimates of national incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have limitations. The most recent population-based estimates of people annually affected for the period 2011-2014 (BCC: 770/100 000 person years; SCC: 271/100 000 person years) represent the lower end of the possible range of incidence rates nationally. Because many people are affected by multiple lesions, the lesion-based incidence estimates are more than double the person-based rates (BCC: 1565/100 000 person years; SCC: 580/100 000 person years). Analyses of temporal trends in treatment rates (excisions, cryotherapy/curettage) show increases over time, most marked for people aged 55 years or older. We estimate that 69% of Australians will have at least one excision for histologically confirmed keratinocyte cancer in their lifetime (60% to age 79 years). The available evidence on national incidence rates is out of date and of moderate quality, but indicates very high rates of keratinocyte cancer in Australia. We recommend that population-based cancer registries work towards statutory notification and routine reporting of keratinocyte cancer in Australia.


YAP and AP-1 Cooperate to Initiate Pancreatic Cancer Development from Ductal Cells in Mice.
The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of Lats1 and Lats2, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of Lats1/2 in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in Lats1/2 knockout organoids and attenuated YAP-dependent transformation of the pancreas in vivo. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. SIGNIFICANCE: A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.


Comparison of 3 surgical approaches to laparoscopic adrenalectomy: a nonrandomized, background matched analysis.
To clarify the characteristics of surgical approaches to laparoscopic adrenalectomy we performed background matched analysis of clinical outcomes of the 3 approaches. From February 1992 to July 2000 we performed 118 laparoscopic adrenalectomies in 115 patients with adrenal tumors. For these operations we used the anterior transperitoneal approach in 46 patients, the lateral transperitoneal approach in 32 and the lateral retroperitoneal approach in 40. To exclude the learning curve effect we eliminated our initial 20 patients treated with the anterior transperitoneal approach. To allow background matching of the 3 groups we also excluded 14 patients with tumors more than 5 cm., 6 who underwent conversion to open surgery and 1 patient who required 5 days of bed rest for retroperitoneal hematoma caused by bleeding from a trocar port. The final analysis included 16, 25 and 36 cases managed via the anterior transperitoneal, lateral transperitoneal and lateral retroperitoneal approach, respectively. Average operative time was significantly shorter for the lateral transperitoneal approach. Postoperative recovery was not significantly different in the lateral transperitoneal and lateral retroperitoneal groups. Postoperative complications included mild paralytic ileus in 2 patients and shoulder tip pain, probably peritoneal irritation due to carbon dioxide insufflation and bowel preparation, in 4 in the transperitoneal groups. Our results imply that the easiest procedure is the lateral transperitoneal approach but the lateral retroperitoneal approach is slightly less invasive. Although it is important to remember that this study was not a prospective randomized trial and, thus, had from certain biases, we believe that if a tumor is more than 5 cm. and/or the surgeon is not yet skilled in laparoscopic adrenalectomy, the lateral transperitoneal approach is the most suitable method. If the surgeon has performed at least 20 operations, the adrenal tumor is unilateral and the lesion is less than 5 cm., the lateral retroperitoneal approach seems to be more suitable because of its minimally invasive nature. The lateral retroperitoneal approach is also preferred in patients with a history of upper abdominal surgery. With improvements in technique and new instruments the time required for the lateral retroperitoneal approach has been significantly decreased.


Inflammatory cytokines and non-alcoholic fatty liver disease (NAFLD) in obese children and adolescents.
Non-alcoholic fatty liver disease is characterized by the intrahepatic deposition of fat. It is the most prevalent liver disease in the world, affecting obese children and adolescents. Its pathophysiology is not fully understood, although it is often related to insulin resistance. This in turn would be due to an inflammatory condition common to obesity. Thus, the objective of this study was to describe the behavior of proinflammatory cytokines in obese children and adolescents, with and without non-alcoholic fatty liver disease. A fasting venous blood sample was obtained of consecutive 90 obese individuals aged 8-18 years, of both sexes, for laboratory determinations of glycaemia, basal insulin and homeostasis model assessment insulin-resistance index, and the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukins 2 and 6 (IL-2 and IL-6), interferon-gamma and high sensitive C-reactive protein. The clinical evaluation included weight, height and waist circumference. We used the body mass index/age indicator for the severity of overweight assessment. The degrees of steatosis were determined by ultrasonography. Quantitative and qualitative variables were respectively expressed by measures of central tendency/dispersion and simple/relative frequency, using Statistical Program for Social Sciences, version 20.0. A p-value < 0.05 was considered as significant. A total of 90 individuals were studied, with a mean age of 11.98 (2.72) years, of which 48 (53%) were male. The body mass index (BMI) for age (BMI/i) and sex (z-score) classified 38 (42.2%) participants as obese and 52 (57.7%) as severe obese; Hepatic steatosis was identified in 56 (62.2%) participants and approximately 90% of them presented grade I steatosis. The inflammatory markers TNF-α, and C-reactive protein were increased in the studied sample and correlated in a positive and statistically significant way with the index of body mass/age and sex. Hepatic steatosis was prevalent in the group of children and adolescents studied, but was not related to obesity degrees.


Treatment Intensification Patterns and Utilization in Patients with Metastatic Castration-Sensitive Prostate Cancer.
Patients with mCSPC experience a longer overall survival with treatment intensification by addition of novel hormonal therapy (NHT) or docetaxel to androgen deprivation vs androgen deprivation alone. Real-world data report, however, that nearly half of mCSPC patients do not receive treatment intensification. In this study, treatment patterns and utilization of treatment intensification in mCSPC patients were described using the IQVIA Anonymized Patient Longitudinal Data, a dataset of fully adjudicated pharmacy and medical claims. Reports on first line (1L) treatment patterns were obtained for years 2015 to 2021. Medicaid, Medicare, Medicare part D, cash transactions, and commercial data were included for years 2012 to 2021. Nationwide, of 66,844 men with newly diagnosed mCSPC since 2015, on average 25% were prescribed NHT, and another 12% were prescribed chemotherapy. No differences were noted in treatment patterns based on U.S. regions and/or rural vs. urban communities. The disparity was observed in prescribing patterns between oncology and urology providers. Oncology providers prescribed 1L NHT on average 32% of the time, while urology providers did so 12% of the time. Furthermore, oncology providers prescribed chemotherapy on average 20% of the time, resulting in 52% of men with mCSPC receiving treatment intensification as 1L therapy. Patients' age group, community or health insurance did not account for the disparity between the 2 specialties. Both medical oncology and urology providers need to improve their treatment intensification efforts for men with mCSPC to increase their patients' overall survival.


Egg binding in caged and aviary birds.
Egg binding most often affects budgerigars, cockatiels, finches and canaries. Causes include oversized or malpositioned eggs, lack of exercise, nesting too early or late, excessive egg laying, uterine damage or infection, obesity, malnutrition, sudden drops in ambient temperature and genetic factors. Clinical signs are perching unsteadily with ruffled feathers and half-closed eyelids, frequent tail-wagging or straining, swelling over the tail base, and sitting on the cage bottom. Diagnosis is by physical examination and radiography. Treatment may involve increasing the ambient temperature to 85-90 F, lubricating the vent, IM injections of Ca solution and/or oxytocin, egg aspiration and laparotomy.


Regulating the electron density of dual transition metal sulfide heterostructures for highly efficient hydrogen evolution in alkaline electrolytes.
Exploring highly effective electrocatalysts with heterostructures is significant for sustainable hydrogen production by the hydrogen evolution reaction (HER). However, there are still challenges in improving the HER activities of the heterostructures to achieve efficient hydrogen production. Here, nitrogen-decorated dual transition metal sulphide heterostructures (N-NiS/MoS2) were constructed with an enhanced HER performance in alkaline electrolytes. These novel N-NiS/MoS2 heterostructures exhibited a low overpotential of 71 mV (10 mA cm-2), small Tafel slope of 79 mV dec-1 and favorable stability. In particular, the experimental and theoretical calculation results consistently demonstrated that the introduction of nitrogen can effectively tune the electronic structure of the heterostructures. Furthermore, the synergistic effect between dual-active components N-NiS and N-MoS2 in the N-NiS/MoS2 heterostructures effectively promoted water dissociation and hydrogen formation, leading to remarkable increase in the HER performance in an alkaline medium. This work provides a valuable avenue for the rational modulation of the electronic structure of heterostructures by hetero-atoms for highly efficient HER catalysts.


Targeting the incretin system in type 2 diabetes mellitus.
The incretins have emerged as key targets in the modern treatment of type 2 diabetes mellitus. Understanding the physiology of the incretins is essential to the physician's ability to appropriately use emerging pharmacotherapies that target this system. This review describes incretin physiology and discusses recent trials of drugs that modulate this system in the treatment of type 2 diabetes. A MEDLINE search using the terms "GLP-1" (ie, glucagon-like peptide 1), "incretins," "exenatide," and "DPP-IV inhibitors" (ie, dipeptidyl peptidase IV inhibitors) was performed, and pertinent articles from the past 10 years were reviewed. Articles describing incretin physiology and clinical trials with exenatide and dipeptidyl peptidase IV inhibitors were identified and discussed. As the articles show, new medications manipulating the incretin system are an important part of treating type 2 diabetes. The cost of these drugs and their potential side effects in comparison with existing agents must be considered when they are being selected as part of a treatment regimen. However, the evidence to date offers much promise and enthusiasm.