Discrepancies between self- and adult-perceptions of social competence in children with neuropsychiatric disorders.
The present study examines discrepancies between self- and adult-perceptions of social competence in children with attention deficit-hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and possible co-morbid disruptive behaviour disorders (DBD). Self-reported questionnaires were collected from multiple informants at the baseline of a multi-systemic family intervention programme for children (aged 5-12) with ADHD, ASD and possible co-morbid DBD. In total, out of the 154 families eligible for the study, information was received concerning children from 124 families (children n = 121; mothers n = 117; fathers n = 86; teachers n = 97). In addition to this, a comparison community sample of 318 school-aged children (approximately 10 years old) was utilized to examine the perceptions of children's social competence across intervention and population groups in more detail. Children's self-perceptions in the prosocial dimension of social competence (i.e. cooperating skills, empathy) did not differ between the intervention and comparison groups. Interestingly, the children in the intervention sample expressed more impulsivity and disruptiveness - the antisocial dimension of social competence - when compared with the children in the comparison sample. Adult ratings demonstrated that mothers, fathers and teachers reported decreased prosocial behaviour and increased antisocial behaviour across overall dimensions and sub-dimensions when compared with adults' ratings of elementary school children. Informant discrepancies between self-ratings and adult ratings across intervention groups yielded significant effect sizes (eta-squared) across all domains of social competence ranging from .09 to .25. Children's positive self-ratings of social competence relative to adult ratings increased within intervention sample when compared with population sample. The intervention sample children appeared to acknowledge their social competence deficits, yet self-perceptions were inflated relative to adult ratings when focusing on peer relationship difficulties, particularly, aggression to peers.


Imaging P2X4 receptor subcellular distribution, trafficking, and regulation using P2X4-pHluorin.
P2X4 receptors are adenosine triphosphate (ATP)-gated cation channels present on the plasma membrane (PM) and also within intracellular compartments such as vesicles, vacuoles, lamellar bodies (LBs), and lysosomes. P2X4 receptors in microglia are up-regulated in epilepsy and in neuropathic pain; that is to say, their total and/or PM expression levels increase. However, the mechanisms underlying up-regulation of microglial P2X4 receptors remain unclear, in part because it has not been possible to image P2X4 receptor distribution within, or trafficking between, cellular compartments. Here, we report the generation of pH-sensitive fluorescently tagged P2X4 receptors that permit evaluations of cell surface and total receptor pools. Capitalizing on information gained from zebrafish P2X4.1 crystal structures, we designed a series of mouse P2X4 constructs in which a pH-sensitive green fluorescent protein, superecliptic pHluorin (pHluorin), was inserted into nonconserved regions located within flexible loops of the P2X4 receptor extracellular domain. One of these constructs, in which pHluorin was inserted after lysine 122 (P2X4-pHluorin123), functioned like wild-type P2X4 in terms of its peak ATP-evoked responses, macroscopic kinetics, calcium flux, current-voltage relationship, and sensitivity to ATP. P2X4-pHluorin123 also showed pH-dependent fluorescence changes, and was robustly expressed on the membrane and within intracellular compartments. P2X4-pHluorin123 identified cell surface and intracellular fractions of receptors in HEK-293 cells, hippocampal neurons, C8-B4 microglia, and alveolar type II (ATII) cells. Furthermore, it showed that the subcellular fractions of P2X4-pHluorin123 receptors were cell and compartment specific, for example, being larger in hippocampal neuron somata than in C8-B4 cell somata, and larger in C8-B4 microglial processes than in their somata. In ATII cells, P2X4-pHluorin123 showed that P2X4 receptors were secreted onto the PM when LBs undergo exocytosis. Finally, the use of P2X4-pHluorin123 showed that the modulator ivermectin did not increase the PM fraction of P2X4 receptors and acted allosterically to potentiate P2X4 receptor responses. Collectively, our data suggest that P2X4-pHluorin123 represents a useful optical probe to quantitatively explore P2X4 receptor distribution, trafficking, and up-regulation.


Schizophyllum commune A alpha mating-type proteins, Y and Z, form complexes in all combinations in vitro.
Tha A alpha locus of the basidiomycete fungus, Schizophyllum commune, regulates sexual development via proteins Y and Z. Each A alpha mating type encodes unique Y and Z isoforms. We used two isoforms of Y (Y4 and Y5) and two isoforms of Z (Z4 and Z5) in affinity assays of protein binding. These assays identified two types of protein interactions. Each full-length Y or Z protein binds to itself and other Y or Z proteins regardless of the A alpha mating type from which they are encoded (i.e., mating-type independent binding). A second type of binding, detected with partial-length polypeptides, occurs only between N-terminal regions of Y and Z proteins encoded from different A alpha mating types (e.g., Y4Z5 or Y5Z4); we refer to this binding as mating-type dependent binding. Deletion analysis shows that the Y4 specificity domain (an N-terminal region conferring recognition uniqueness to the Y4 isoform) is essential for mating-type dependent binding. Other regions of Y and Z are involved in mating-type independent binding. These results, obtained in vitro, raise the possibility that either of several protein complexes composed of Y and/or Z proteins may occur in vivo.


Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.
ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.


Evaluation of ketamine/xylazine anesthesia in the guinea pig: toxicological parameters.
The characteristics of ketamine/xylazine combinations were evaluated in guinea pigs. Particular attention was focused on the establishment of an LD50 and the development of a dose-response curve. Basic serum parameters (BUN, serum creatinine, and SGPT) were monitored for 5 days post-anesthesia. A large safety margin was indicated by an LD50 range of 361-373 mg/kg ketamine. The dose-response curve was linear between 40 and 120 mg/kg ketamine with constant 10 mg/kg xylazine. Although serum parameters were elevated 5 days postanesthesia they remained within normal limits for laboratory rodents.


Neuroendocrine carcinoma of the extrahepatic bile duct: case report and literature review.
Neuroendocrine carcinoma (NEC) of the extrahepatic bile duct is rare, and only 22 cases have been reported. Only two of these were large-cell NEC (LCNEC); the vast majority were small-cell NEC. Here, we report a third case of LCNEC of the extrahepatic bile duct. A 76-year-old male presented to a local hospital with painless jaundice. Imaging studies revealed a tumor at the hepatic hilum. The patient underwent right hepatic lobectomy, bile duct resection, and cholecystectomy. The resection specimen showed a 5.0-cm invasive neoplasm involving the hilar bile ducts and surrounding soft tissue. Histologically, the tumor consisted of nests of medium to large cells with little intervening stroma. The tumor invaded a large portal vein branch. All four excised lymph nodes were positive for metastasis, and metastatic deposits were also present in the gallbladder wall. The tumor was diffusely positive for synaptophysin and focally positive for chromogranin A. Approximately 70%-80% of the tumor cells were positive for Ki-67, indicating strong proliferative activity. A diagnosis of LCNEC was made. A few bile ducts within and adjacent to the invasive tumor showed dysplasia of the intestinal phenotype and were focally positive for synaptophysin and chromogranin A, suggesting that the dysplastic intestinal-type epithelium played a precursor role in this case. A postoperative computer tomography scan revealed rapid enlargement of the abdominal and retroperitoneal lymph nodes. The patient died 21 d after the operation. NEC of the bile duct is an aggressive neoplasm, and its biological characteristics remain to be better defined.


Pharmacological characterization of alpha adrenergic receptors in the young and old female rabbit urethra.
The pharmacological characteristics of alpha-1 and alpha-2 adrenergic receptors in young (6 month) and old (4.5-5 year) female rabbit urethra were studied using isolated muscle bath techniques. Norepinephrine, phenylephrine, clonidine, oxymetazoline and UK 14,304 produced concentration-dependent contractions in both age groups. The maximum contractile responses (Emax) to norepinephrine, phenylephrine, oxymetazoline and UK 14,304 were of similar magnitude and were significantly greater than the contractile responses to clonidine. The rank order of the ED50 values for these drugs was: oxymetazoline less than UK 14,304 much less than clonidine = norepinephrine = phenylephrine. Prazosin (10(-8) M) shifted the concentration-response curves to phenylephrine and UK 14,304 to the right, but did not shift the concentration-response curves to clonidine and oxymetazoline. Yohimbine (10(-7) M) shifted the concentration-response curves to clonidine, oxymetazoline and UK 14,304 to the right, but did not shift the concentration-response curve to phenylephrine. The ED50 values for phenylephrine and clonidine were smaller in the older than in the younger age group. There were no other age-dependent differences in the response to agonists. Pretreatment with chlorethylclonidine, which selectively alkylates the alpha-1B subtype, did not affect the Emax value of phenylephrine-induced contractions, but significantly shifted the curve to the right. The ratios of the Emax values in Ca++ free buffer to that in normal Ca++ buffer for phenylephrine, UK 14,304, clonidine, oxymetazoline and KCl were 0.30, 0.38, 0.08, 0.07 and 0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Utility of glucagon stimulation test in type 1 diabetes after pancreas transplantation.
Despite recent progress of immunosuppressive therapy with newly developed agents, long-term pancreatic graft survival after pancreas transplantation still remains low. Therefore, precise assessment of β-cell function after pancreas transplantation is necessary. Pancreatic β-cell secretory activity was measured by means of the peripheral plasma fasting serum C-peptide (CPR) response to 1 mg of glucagon intravenously in 23 patients after pancreas transplantation. The utility of ΔCPR after injection was compared with other indices that reflect insulin secretion. When we performed the test, 6 patients still needed insulin injection after the transplantation. Mean CPR before and after glucagon intravenously were 1.9 ± 0.98 ng/mL and 4.6 ± 2.29 ng/mL, respectively. Fasting serum CPR, secretory unit of islet in transplantation (SUIT) index, and ΔCPR after glucagon injection were significantly different between insulin users and nonusers. During follow-up (501 ± 228 days), 3 patients could stop using insulin, and their increase of CPR (1.8 ± 0.5 ng/mL) was significantly higher than that in continuous insulin users (0.3 ± 0.3 ng/mL). Fasting CPR, SUIT index, and ΔCPR after glucagon injection could reflect β-cell function for post-pancreas transplant patients, and glucagon stimulation test could give us additional information to predict insulin-free treatment.


Analysis of 3D elemental distribution in nanomaterials: Towards higher throughput and dose efficiency.
Many advanced nanomaterials rely on carefully designed morphology and elemental distribution to achieve their functionalities. Among the few experimental techniques that can directly visualise the 3D elemental distribution on the nanoscale are approaches based on electron tomography in combination with energy-dispersive X-ray spectroscopy (EDXS) and electron energy loss spectroscopy (EELS). Unfortunately, these highly informative methods are severely limited by the fundamentally low signal-to-noise ratio, which makes long experimental times and high electron irradiation doses necessary to obtain reliable 3D reconstructions. Addressing these limitations has been the major research question for the development of these techniques in recent years. This short review outlines the latest progress on the methods to reduce experimental time and electron irradiation dose requirements for 3D elemental distribution analysis and gives an outlook on the development of this field in the near future.


CD40 ligand blocks apoptosis induced by tumor necrosis factor alpha, glucocorticoids, and etoposide in osteoblasts and the osteocyte-like cell line murine long bone osteocyte-Y4.
During characterization of the osteocyte-like murine long bone osteocyte-Y4 (MLO-Y4) cell line, comparison was made with antigen-presenting cells of the immune system known as dendritic cells. It was observed that the MLO-Y4 osteocyte-like cells express CD40 antigen and MHC class I antigen, but they are negative for a series of other dendritic cells markers (DEC-205, CD11b, CD11c, CD86, and MHC class II) and immune cell markers [CD45, CD3, CD4, B220, Gr-1, and CD40 ligand (CD40L)]. RT-PCR results showed expression of CD40 mRNA and lack of CD40L mRNA expression. Like MLO-Y4 osteocyte cells, both primary osteoblasts and the osteoblast-like cell lines MC3T3, OCT-1, and 2T3 were shown to express CD40 antigen by fluorescence-activated cell sorting. Because CD40L has been shown to function as an antiapoptotic factor in dendritic cells, it was reasoned that this molecule may have a similar function in bone cells. In three different assays for apoptosis, including trypan blue exclusion, changes in nuclear morphology, and fluorescence-activated cell sorting staining for annexin V/propidium iodide, CD40L significantly inhibited apoptosis of MLO-Y4 cells induced by dexamethasone, TNF alpha, or etoposide. CD40L also inhibited dexamethasone and TNF alpha-induced apoptosis in the osteoblast cell lines, OCT1 and MC3T3-E1. These data support the hypothesis that CD40L preserves viability of osteoblasts and osteocytes against a wide variety of apoptotic factors independent of signaling or transcriptional mechanisms. Because osteocyte cell death appears to result in bone loss, these studies have important implications for the treatment of bone loss due to glucocorticoid excess and/or to osteoporosis in general.


Defect in B cell function in HTLV III/LAV positive hemophilia patients.
The capacity of the peripheral blood lymphocytes (PBL) to generate an antibody response in vitro T cell-dependent antigen ovalbumin was studied in 12 severe hemophilia patients who were otherwise in good health. PBL from four of 12 patients were not capable of generating such a response after stimulation in vitro, whereas all controls were normal. This negative plaque-forming cell (PFC) response coincided with the presence of antibodies directed toward human T-lymphotropic virus III/lymphadenopathy-associated virus (HTLV-III/LAV). Only one patient with antibodies against HTLV-III/LAV had a normal PFC response. The negative PFC response was not due to a deficient T helper cell activity, nor to an excessive T suppressor cell function. However, in the peripheral blood of these four patients, the presence of activated B cells that are refractory to antigen-specific T helper cell signals and secrete specific antibodies spontaneously could be demonstrated. Most of the patients showed a hyperimmunoglobulinemia. No correlation between the T4/T8 ratio and the level of the PFC response was demonstrable. From the data obtained in these investigations we raise the hypothesis that infection with HTLV-III/LAV in hemophilia patients will lead to in vivo (pre)activation of B cells that results in unresponsiveness or decreased response to antigen-specific signals.


Clinical potential of insulin therapy in critically ill patients.
Stress of critical illness is often accompanied by hyperglycaemia, whether or not the patient has a history of diabetes mellitus. This has been considered to be part of the adaptive metabolic response to stress. The level of hyperglycaemia in patients with acute myocardial infarction (MI) or stroke upon admission to the hospital has been related to the risk of adverse outcome. However, until recently, there was no evidence of a causal relationship and thus stress-induced hyperglycaemia was only treated with exogenous insulin when it exceeded 12 mmol/L (220 mg/dL). In patients with known diabetes, even higher levels were often tolerated. Recently, new data became available in support of another approach. In this review, we focus on the new evidence and the clinical aspects of managing hyperglycaemia with insulin in critically ill patients, drawing a parallel with diabetes management. Particularly, the 'Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study' and the 'insulin in intensive care study' have provided novel insights. The DIGAMI study showed that in patients with diabetes, controlling blood glucose levels below 12 mmol/L for 3 months after acute MI improves long-term outcome. In the recent study of predominantly surgical intensive care patients, the majority of whom did not previously have diabetes, it was shown that an even tighter control of blood glucose with exogenous insulin, aiming for normoglycaemia, dramatically improved outcome. Indeed, in this large prospective, randomised, controlled study, 1548 intensive care patients had been randomly allocated to either the conventional approach, with insulin infusion started only when blood glucose levels exceeded 12 mmol/L, or intensive insulin therapy, with insulin infused to maintain blood glucose at a level of 4.5-6.1 mmol/L (80-110 mg/dL). Intensive insulin therapy reduced intensive care mortality by more than 40% and also decreased a number of morbidity factors including acute renal failure, polyneuropathy, ventilator-dependency and septicaemia. Future studies will be needed to further unravel the mechanisms that explain the beneficial effects of this simple and cost-saving intervention. Although available evidence supports implementation of intensive insulin therapy in surgical intensive care, the benefit for other patient populations, such as patients on medical intensive care units or hospitalised patients who do not require intensive care but who do present with stress-induced hyperglycaemia, remains to be investigated.


Localized hyperkeratosis lenticularis perstans (Flegel's disease).
A case of hyperkeratosis lenticularis perstans involving only the back of a thirty-nine-year-old woman is reported. Histologic examination showed foci of compact and eosinophilic hyperkeratosis overlying a thinned stratum malpighii. In the underlying papillary dermis there was no evidence of inflammatory infiltrate. This case demonstrates that hyperkeratosis lenticularis perstans may appear as a localized disorder, and that the inflammation is not an essential pathogenic process in this disorder.


Adenovirus protein E4orf4 induces premature APCCdc20 activation in Saccharomyces cerevisiae by a protein phosphatase 2A-dependent mechanism.
Protein phosphatase 2A (PP2A) has been implicated in cell cycle progression and mitosis; however, the complexity of PP2A regulation via multiple B subunits makes its functional characterization a significant challenge. The human adenovirus protein E4orf4 has been found to induce both high Cdk1 activity and the accumulation of cells in G(2)/M in both mammalian and yeast cells, effects which are largely dependent on the B55/Cdc55 regulatory subunit of PP2A. Thus, E4orf4 represents a unique means by which the function of a specific form of PP2A can be delineated in vivo. In Saccharomyces cerevisiae, only two PP2A regulatory subunits exist, Cdc55 and Rts1. Here, we show that E4orf4-induced toxicity depends on a functional interaction with Cdc55. E4orf4 expression correlates with the inappropriate reduction of Pds1 and Scc1 in S-phase-arrested cells. The unscheduled loss of these proteins suggests the involvement of PP2A(Cdc55) in the regulation of the Cdc20 form of the anaphase-promoting complex (APC). Contrastingly, activity of the Hct1 form of the APC is not induced by E4orf4, as demonstrated by the observed stability of its substrates. We propose that E4orf4, being a Cdc55-specific inhibitor of PP2A, demonstrates the role of PP2A(Cdc55) in regulating APC(Cdc20) activity.


Winter storm intensity, hazards, and property losses in the New York tristate area.
Winter storms pose numerous hazards to the Northeast United States, including rain, snow, strong wind, and flooding. These hazards can cause millions of dollars in damages from one storm alone. This study investigates meteorological intensity and impacts of winter storms from 2001 to 2014 on coastal counties in Connecticut, New Jersey, and New York and underscores the consequences of winter storms. The study selected 70 winter storms on the basis of station observations of surface wind strength, heavy precipitation, high storm tide, and snow extremes. Storm rankings differed between measures, suggesting that intensity is not easily defined with a single metric. Several storms fell into two or more categories (multiple-category storms). Following storm selection, property damages were examined to determine which types lead to high losses. The analysis of hazards (or events) and associated damages using the Storm Events Database of the National Centers for Environmental Information indicates that multiple-category storms were responsible for a greater portion of the damage. Flooding was responsible for the highest losses, but no discernible connection exists between the number of storms that afflict a county and the damage it faces. These results imply that losses may rely more on the incidence of specific hazards, infrastructure types, and property values, which vary throughout the region.


Imaging-based clusters in current smokers of the COPD cohort associate with clinical characteristics: the SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).
Classification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD. Among the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering. Four clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters. Association of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.


[Intraspinal enterogenous cyst. Case report].
The authors report the case of a 7 years old boy with cervical pain and tetraparesis progressing by two months. He presented an intraspinal cystic lesion from C4 to C6. Exeresis of the lesion was undergone by anterior way through a corpectomy of C5-C6 followed by reconstruction with bone graft of the iliac crest and metallic plaque. Anatomic diagnosis of the lesion was enterogenous cyst. Aspects of clinical presentation, embryology and treatment of these cysts are discussed.


Genome-Wide Identification and Analysis of the Phosphoenolpyruvate Carboxylase Gene Family in Suaeda aralocaspica, an Annual Halophyte With Single-Cellular C4 Anatomy.
Phosphoenolpyruvate carboxylase (PEPC) plays pivotal roles in the carbon fixation of photosynthesis and a variety of metabolic and stress pathways. Suaeda aralocaspica belongs to a single-cellular C4 species and carries out a photosynthetic pathway in an unusually elongated chlorenchyma cell, which is expected to have PEPCs with different characteristics. To identify the different isoforms of PEPC genes in S. aralocaspica and comparatively analyze their expression and regulation patterns as well as the biochemical and enzymatic properties in this study, we characterized a bacterial-type PEPC (BTPC; SaPEPC-4) in addition to the two plant-type PEPCs (PTPCs; SaPEPC-1 and SaPEPC-2) using a genome-wide identification. SaPEPC-4 presented a lower expression level in all test combinations with an unknown function; two SaPTPCs showed distinct subcellular localizations and different spatiotemporal expression patterns but positively responded to abiotic stresses. Compared to SaPEPC-2, the expression of SaPEPC-1 specifically in chlorenchyma cell tissues was much more active with the progression of development and under various stresses, particularly sensitive to light, implying the involvement of SaPEPC-1 in a C4 photosynthetic pathway. In contrast, SaPEPC-2 was more like a non-photosynthetic PEPC. The expression trends of two SaPTPCs in response to light, development, and abiotic stresses were also matched with the changes in PEPC activity in vivo (native) or in vitro (recombinant), and the biochemical properties of the two recombinant SaPTPCs were similar in response to various effectors while the catalytic efficiency, substrate affinity, and enzyme activity of SaPEPC-2 were higher than that of SaPEPC-1 in vitro. All the different properties between these two SaPTPCs might be involved in transcriptional (e.g., specific cis-elements), posttranscriptional [e.g., 5'-untranslated region (5'-UTR) secondary structure], or translational (e.g., PEPC phosphorylation/dephosphorylation) regulatory events. The comparative studies on the different isoforms of the PEPC gene family in S. aralocaspica may help to decipher their exact role in C4 photosynthesis, plant growth/development, and stress resistance.


Dental wear and cultural behavior in Middle Paleolithic humans from the Near East.
Neanderthals and anatomically modern humans (AMHs) may have lived in close proximity in the Near East region during Middle Paleolithic times. Although functional morphological analyses suggest a marked behavioral contrast between these two human groups, new dental micro- and macro-wear studies, together with new archaeological data, have revealed some similarities in ecology and dietary habits. In this study, we analyze the tooth wear patterns of Neanderthals and AMH from Middle Paleolithic sites of Israel and Northern Iraq, using the Occlusal Fingerprint Analysis (OFA) method to virtually reconstruct the jaw movements responsible for the creation of the occlusal wear areas. We particularly focus on para-facets, a distinctive type of wear which has been previously described in the dentition of historic and modern hunter-gatherers. The analysis reveals a similarity in para-facet frequency between early Near Eastern Neanderthals and AMH, and a significant difference with other Pleistocene human groups. The absence of antagonist occlusal contacts in the lower teeth and the occlusal compass analysis suggest that para-facet formation is not related to normal mastication but to nonmasticatory activities. Thus, the identification of these nonmasticatory wear areas on the molars of early Near Eastern Neanderthals and AMH may indicate analogous tooth-tool uses for daily task activities. These may have emerged independently or could be interpreted as indirect evidence of cultural interactions between these two groups.


The incidence and risk factors of selected drug prescriptions and outpatient care after SARS-CoV-2 infection in low-risk subjects: a multicenter population-based cohort study.
Knowledge about the dynamics of transmission of SARS-CoV-2 and the clinical aspects of COVID-19 has steadily increased over time, although evidence of the determinants of disease severity and duration is still limited and mainly focused on older adult and fragile populations. The present study was conceived and carried out in the Emilia-Romagna (E-R) and Veneto Regions, Italy, within the context of the EU's Horizon 2020 research project called ORCHESTRA (Connecting European Cohorts to increase common and effective response to SARS-CoV-2 pandemic) (www.orchestra-cohort.eu). The study has a multicenter retrospective population-based cohort design and aimed to investigate the incidence and risk factors of access to specific healthcare services (outpatient visits and diagnostics, drug prescriptions) during the post-acute phase from day-31 to day-365 after SARS-CoV-2 infection, in a healthy population at low risk of severe acute COVID-19. The study made use of previously recorded large-scale healthcare data available in the administrative databases of the two Italian Regions. The statistical analysis made use of methods for competing risks. Risk factors were assessed separately in the two Regions and results were pooled using random effects meta-analysis. There were 35,128 subjects in E-R and 88,881 in Veneto who were included in the data analysis. The outcome (access to selected health services) occurred in a high percentage of subjects in the post-acute phase (25% in E-R and 21% in Veneto). Outpatient care was observed more frequently than drug prescriptions (18% vs. 12% in E-R and 15% vs. 10% in Veneto). Risk factors associated with the outcome were female sex, age greater than 40 years, baseline risk of hospitalization and death, moderate to severe acute COVID-19, and acute extrapulmonary complications. The outcome of interest may be considered as a proxy for long-term effects of COVID-19 needing clinical attention. Our data suggest that this outcome occurs in a substantial percentage of cases, even among a previously healthy population with low or mild severity of acute COVID-19. The study results provide useful insights into planning COVID-19-related services.


Pantheon 1.0, a manually verified dataset of globally famous biographies.
We present the Pantheon 1.0 dataset: a manually verified dataset of individuals that have transcended linguistic, temporal, and geographic boundaries. The Pantheon 1.0 dataset includes the 11,341 biographies present in more than 25 languages in Wikipedia and is enriched with: (i) manually verified demographic information (place and date of birth, gender) (ii) a taxonomy of occupations classifying each biography at three levels of aggregation and (iii) two measures of global popularity including the number of languages in which a biography is present in Wikipedia (L), and the Historical Popularity Index (HPI) a metric that combines information on L, time since birth, and page-views (2008-2013). We compare the Pantheon 1.0 dataset to data from the 2003 book, Human Accomplishments, and also to external measures of accomplishment in individual games and sports: Tennis, Swimming, Car Racing, and Chess. In all of these cases we find that measures of popularity (L and HPI) correlate highly with individual accomplishment, suggesting that measures of global popularity proxy the historical impact of individuals.


A standardisation approach to the control of socioeconomic confounding in small area studies of environment and health.
To assess how effectively a routine adjustment can be made for socio-economic confounding in small area studies of environment and health using indirect standardisation and small area deprivation indices, including analysis of the appropriate size of population unit on which to base the deprivation index and the importance of region and urban/rural status as axes of stratification. Standardised morbidity ratios were calculated for cancers in Great Britain for 1981 and standardised mortality ratios for all cause mortality in Great Britain between 1982 and 1985. Deprivation indices were calculated for enumeration districts and wards from 1981 small area census statistics. Cancers and deaths were allocated to enumeration districts via their postcode. Standardised morbidity and mortality ratios were calculated by quintile of enumeration district according to the deprivation index. Standardised mortality ratios were further analysed by deprivation of ward, region, and urban/rural status. Strong relationships were found between all cause mortality and the incidence of selected cancers and deprivation quintile-there was up to a twofold difference in lung cancer incidence between the highest and lowest quintile. The deprivation index can be used to measure gradients of deprivation according to the distance from industrial sites. The deprivation index for enumeration districts showed similar discrimination of mortality as the index forwards. There is some interaction between deprivation and region in their effect on the standardised mortality ratios, leading to a small bias in the estimation of expected numbers if this is not taken into account. The relationship between deprivation, urban/rural status, and mortality is complex and confounded by region, but mortality tends to be higher in urban than in rural areas within quintiles of deprivation. Whether calculated for enumeration districts or wards, the main problems in the interpretation of the deprivation index may be its limited correlation with the risk factors of interest and its concentration on present rather than past socioeconomic status. Indirect standardisation based on stratification for deprivation and other variable involves a trade off between bias and precision in determining the fineness and the number of axes of stratification. Some bias may occur due to interaction between region and deprivation and the effects of urban/rural status. Complementary approaches including modeling and proportional mortality or morbidity analyses may be needed and the possibility of residual socioeconomic confounding must always be considered. There is potential for important socioeconomic confounding in small area studies of environmental pollution and health where the health outcome under examination has a strong relationship to socioeconomic status and where the putative excess risk due to pollution may be small. One method of controlling for confounding is to use an ecological measurement of deprivation in small areas, and to adjust for deprivation by indirect standardisation. However, residual socioeconomic confounding can be expected, which may seriously complicate the interpretation of small area studies.


Olfactory Specific Satiety depends on degree of association between odour and food.
The pleasantness of a food odour decreases when that food is eaten to satiety or even smelled for a brief period (Olfactory Specific Satiety, OSS), which suggests that odours signal food variety and encourage approach behaviour toward novel foods. In the study here, we aimed to extend this theory to understand the consequence of manipulating the food consumed and its degree of association to the evaluated odour. We also wished to clarify if these effects related to individual sensitivity to the target odour. In the study here, participants (n = 94) rated the pleasantness of a food odour (isoamyl acetate) and then consumed confectionary that had either Low or High association to that odour or a No food control. This was followed by final pleasantness ratings for the odour and a threshold sensitivity test. Results revealed that in line with OSS, pleasantness decreased in the High association group only. This effect was not dependent on any differences in sensitivity to the target odour. These findings are consistent with OSS, and that this effect likely depends on activation of brain areas related to odour hedonics rather than the degree to which the odour is detected.


The broad spectrum of celiac disease and gluten sensitive enteropathy.
The celiac disease is an immune chronic condition with genetic transmission, caused by the intolerance to gluten. Gluten is a protein from cereals containing the following soluble proteins: gliadine, which is the most toxic, and the prolamins. The average prevalence is about 1% in USA and Europe, but high in Africa: 5.6% in West Sahara. In the pathogenesis several factors are involved: gluten as external trigger, genetic predisposition (HLA, MYO9B), viral infections, abnormal immune reaction to gluten. Severity is correlated with the number of intraepithelial lymphocytes, cryptic hyperplasia and villous atrophy, as well as with the length of intestinal involvement. The severity is assessed according to the Marsh-Oberhuber staging. Diagnostic criteria are: positive serological tests, intestinal biopsy, the reversal after gluten free diet (GFD). Beside refractory forms, new conditions have been described, like the non celiac gluten intolerance. In a time when more and more people adhere to GFD for nonscientific reasons, practitioners should be updated with the progress in celiac disease knowledge.


2,4-dichlorophenoxyacetic acid-induced leaf senescence in mung bean (Vigna radiata L. Wilczek) and senescence inhibition by co-treatment with silver nanoparticles.
Leaf senescence induced by 2,4-dichlorophenoxyacetic acid (2,4-D) and senescence inhibition caused by supplementation with silver (Ag(+)) ions in the form of silver nitrate (AgNO(3)) or silver nanoparticles (AgNPs) were investigated in 8-day-old mung bean (Vigna radiata L. Wilczek) seedlings. Inhibition of root and shoot elongation were observed in mung bean seedlings treated with 500μM 2,4-D. Concomitantly, the activity of 1-aminocyclopropane-1-carboxylic acid synthase was significantly induced in leaf tissue. Leaf senescence induced by 2,4-D was closely associated with lipid peroxidation as well as increased levels of cytotoxic hydrogen peroxide (H(2)O(2)) and superoxide radicals (O(2)(·-)). Despite decreased catalase activity, the activities of peroxidase, superoxide dismutase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase were increased during 2,4-D-induced leaf senescence. Further, the levels of reduced ascorbate, oxidized ascorbate, and reduced glutathione were markedly decreased, whereas the level of oxidized glutathione increased. 2,4-D-induced leaf senescence in mung bean was accompanied by an increase in positive terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, nuclear DNA fragmentation, and the activity of a 15-kDa Ca(2+)-dependent DNase. Supplementation with 100μM AgNO(3) or AgNPs inhibited 2,4-D-induced leaf senescence. The present results suggest that increased oxidative stress (O(2)(·-) and H(2)O(2)) led to senescence in mung bean leaves. Furthermore, significantly induced antioxidative enzymes are not sufficient to protect mung bean cells from 2,4-D-induced harmful ROS.


Isolation of new serotypes of bovine rotavirus. Brief report.
Two cytopathogenic bovine rotavirus strains were isolated. The infectivity of both isolates was relatively stable at pH 3.0 and resistant to ether. Their replication was not affected by 5-iodo-2'-deoxyuridine. The new isolates shared immunofluorescent antigen with the Lincoln strain of bovine rotavirus. By neutralization test, however, these strains were clearly distinguished from one another.


Global signal of top-down control of terrestrial plant communities by herbivores.
The theory of "top-down" ecological regulation predicts that herbivory suppresses plant abundance, biomass, and survival but increases diversity through the disproportionate consumption of dominant species, which inhibits competitive exclusion. To date, these outcomes have been clear in aquatic ecosystems but not on land. We explicate this discrepancy using a meta-analysis of experimental results from 123 native animal exclusions in natural terrestrial ecosystems (623 pairwise comparisons). Consistent with top-down predictions, we found that herbivores significantly reduced plant abundance, biomass, survival, and reproduction (all P < 0.01) and increased species evenness but not richness (P = 0.06 and P = 0.59, respectively). However, when examining patterns in the strength of top-down effects, with few exceptions, we were unable to detect significantly different effect sizes among biomes, based on local site characteristics (climate or productivity) or study characteristics (study duration or exclosure size). The positive effects on diversity were only significant in studies excluding large animals or located in temperate grasslands. The results demonstrate that top-down regulation by herbivores is a pervasive process shaping terrestrial plant communities at the global scale, but its strength is highly site specific and not predicted by basic site conditions. We suggest that including herbivore densities as a covariate in future exclosure studies will facilitate the discovery of unresolved macroecology trends in the strength of herbivore-plant interactions.


Intrasubunit and Intersubunit Steroid Binding Sites Independently and Additively Mediate α1β2γ2L GABAA Receptor Potentiation by the Endogenous Neurosteroid Allopregnanolone.
Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABAA receptor. The sites are located in the membrane-spanning domains of the receptor at the β-α subunit interface (site I) and within the α (site II) and β subunits (site III). Here, we have investigated the effects of mutations to these sites on potentiation of the rat α1β2γ2L GABAA receptor by the endogenous neurosteroid allopregnanolone (3α5αP). The mutations were introduced alone or in combination to probe the additivity of effects. We show that the effects of amino acid substitutions in sites I and II are energetically additive, indicating independence of the actions of the two steroid binding sites. In site III, none of the mutations tested reduced potentiation by 3α5αP, nor did a mutation in site III modify the effects of mutations in sites I or II. We infer that the binding sites for 3α5αP act independently. The independence of steroid action at each site is supported by photolabeling data showing that mutations in either site I or site II selectively change steroid orientation in the mutated site without affecting labeling at the unmutated site. The findings are discussed in the context of linking energetic additivity to empirical changes in receptor function and ligand binding. SIGNIFICANCE STATEMENT: Prior work has identified three distinct binding sites for potentiating steroids in the heteromeric γ-aminobutyric acid type A receptor. This study shows that the sites act independently and additively in the presence of the steroid allopregnanolone and provide estimates of energetic contributions made by steroid binding to each site.


Templated green synthesis of plasmonic silver nanoparticles in onion epidermal cells suitable for surface-enhanced Raman and hyper-Raman scattering.
We report fast and simple green synthesis of plasmonic silver nanoparticles in the epidermal cells of onions after incubation with AgNO3 solution. The biological environment supports the generation of silver nanostructures in two ways. The plant tissue delivers reducing chemicals for the initial formation of small silver clusters and their following conversion to plasmonic particles. Additionally, the natural morphological structures of the onion layers, in particular the extracellular matrix provides a biological template for the growth of plasmonic nanostructures. This is indicated by red glowing images of extracellular spaces in dark field microscopy of onion layers a few hours after AgNO3 exposure due to the formation of silver nanoparticles. Silver nanostructures generated in the extracellular space of onion layers and within the epidermal cell walls can serve as enhancing plasmonic structures for one- and two-photon-excited spectroscopy such as surface enhanced Raman scattering (SERS) and surface enhanced hyper-Raman scattering (SEHRS). Our studies demonstrate a templated green preparation of enhancing plasmonic nanoparticles and suggest a new route to deliver silver nanoparticles as basic building blocks of plasmonic nanosensors to plants by the uptake of solutions of metal salts.


The role of des-gamma-carboxyprothrombin expression in hepatocellular carcinoma.
Des-gamma-carboxyprothrombin (DCP), is a well-known tumor marker of hepatocellular carcinoma (HCC). On the other hand, some reports suggest that tissue expression of DCP is more useful as a prognostic factor than the serum DCP value. The aim of this study is to clarify the clinicopathological role of expression of DCP on HCC, especially when there is a low serum level of DCP. Fifty-one patients with HCC who underwent curative hepatectomy were included in this study. Immunohistochemical staining was performed using anti-DCP monoclonal antibody, which was classified into 2 groups (strong and weak) by a pathologist. The immunohistochemical expression of tumor microvessel density (MVD) was evaluated using CD34 monoclonal antibody, and counted with specific staining of the capillary-like vessels in the tumor. The clinicopathological variables were compared between the strong and weak-staining groups. A strong DCP expression was recognized in 31 patients. DCP expression was associated with tumor size (p < 0.05) and portal vein infiltration (p < 0.01). In addition, serum DCP levels and alpha-fetoprotein levels tended to be higher in the strong group. In 16 patients whose serum DCP level was < 200mAU/ml, the recurrence-free survival rate was significantly lower in the strong group. No correlation was observed between DCP expression and MVD. DCP expression in HCC is useful for the prediction of early recurrence in patients with a low serum DCP level.


Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo.
Use of estrogen or estrogen/progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.


Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.
Contactin-1 and contactin-2 are important for the maintenance of axonal integrity. To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration. Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing-remitting multiple sclerosis (n = 41), secondary progressive multiple sclerosis (n = 26) and primary progressive multiple sclerosis patients (n = 13) and controls (n = 18), and in a second cohort with clinically isolated syndrome patients (n = 88, median clinical follow-up period of 2.3 years) and controls (n = 20). Correlations/linear regressions were analysed with other baseline cerebrospinal fluid axonal damage markers and cross-sectional/longitudinal magnetic resonance imaging features. Contactin-1 and contactin-2 levels were up to 1.4-fold reduced in relapsing-remitting multiple sclerosis (contactin-1: p = 0.01, contactin-2: p = 0.02) and secondary progressive multiple sclerosis (contactin-1: p = 0.05, contactin-2: p = 0.02) compared to controls. In clinically isolated syndrome patients, contactin-1 tended to increase when compared to controls (p = 0.07). Both contactin-1 and contactin-2 correlated with neurofilament light, neurofilament heavy and magnetic resonance imaging metrics differently depending on the disease stage. In clinically isolated syndrome patients, baseline contactin-2 level (β = -0.42, p = 0.04) predicted the longitudinal decline in cortex volume. Cerebrospinal fluid contactin-1 and contactin-2 reveal axonal dysfunction in various stages of multiple sclerosis and their inclusion to the biomarker panel may provide better insight into the extent of axonal damage/dysfunction.


Nonuniform microtubular polarity established by CHO1/MKLP1 motor protein is necessary for process formation of podocytes.
Podocytes are unique cells that are decisively involved in glomerular filtration. They are equipped with a complex process system consisting of major processes and foot processes whose function is insufficiently understood (Mundel, P., and W. Kriz. 1995. Anat. Embryol. 192:385-397). The major processes of podocytes contain a microtubular cytoskeleton. Taking advantage of a recently established cell culture system for podocytes with preserved ability to form processes (Mundel, P., J. Reiser, A. Zúñiga Mejía Borja, H. Pavenstädt, G.R. Davidson, W. Kriz, and R. Zeller. 1997b. Exp. Cell Res. 36:248-258), we studied the functional significance of the microtubular system in major processes. The following data were obtained: (a) Microtubules (MTs) in podocytes show a nonuniform polarity as revealed by hook-decoration. (b) CHO1/ MKLP1, a kinesin-like motor protein, is associated with MTs in podocytes. (c) Treatment of differentiating podocytes with CHO1/MKLP1 antisense oligonucleotides abolished the formation of processes and the nonuniform polarity of MTs. (d) During the recovery from taxol treatment, taxol-stabilized (nocodazole- resistant) MT fragments were distributed in the cell periphery along newly assembled nocodazole-sensitive MTs. A similar distribution pattern of CHO1/MKLP1 was found under these circumstances, indicating its association with MTs. (e) In the recovery phase after complete depolymerization, MTs reassembled exclusively at centrosomes. Taken together, these findings lead to the conclusion that the nonuniform MT polarity in podocytes established by CHO1/MKLP1 is necessary for process formation.


The cargo in vacuolar storage protein transport vesicles is stratified.
Developing pea seeds contain two functionally distinct vacuoles--lytic vacuoles and protein storage vacuoles (PSV). The Golgi apparatus of these cells has to discriminate between proteins destined for these vacuolar compartments. Whereas it is known that sorting into the lytic vacuole is performed via the conserved clathrin-coated vesicle pathway, sorting of proteins into the protein storage vacuole remains enigmatic. In developing pea cotyledons, the major storage proteins are sorted via 'dense vesicles'. In this report we examined the sorting of a minor protein of the protein storage vacuole, the sucrose-binding-protein homolog (SBP), along the secretory pathway employing immunoelectron microscopy on cryosectioned pea cotyledons. SBP follows the same vesicular route into the PSV as the main storage proteins legumin and vicilin, via the dense-vesicles. Furthermore, legumin and SBP are sorted together into the same dense vesicle population at the stack. Although soluble cargo proteins of the dense vesicles, they show a stratified distribution in the lumen of the dense vesicles. Whereas the legumin label is equally distributed across the lumen, the SBP label is concentrated at the membrane of the vesicle. This observation is discussed with respect to a putative receptor-mediated sorting of the proteins into the dense vesicles.


Donkey Fascioliasis Within a One Health Control Action: Transmission Capacity, Field Epidemiology, and Reservoir Role in a Human Hyperendemic Area.
A One Health initiative has been implemented for fascioliasis control in a human hyperendemic area for the first time. The area selected for this multidisciplinary approach is the Northern Bolivian Altiplano, where the highest prevalences and intensities in humans have been reported. Within the strategic intervention axis of control activities concerning animal reservoirs, complete experimental studies, and field surveys have been performed to assess the fascioliasis transmission capacity and epidemiological role of the donkey for the first time. Laboratory studies with altiplanic donkey-infecting Fasciola hepatica and altiplanic Galba truncatula snail vector isolates demonstrate that the donkey assures the viability of the whole fasciolid life cycle. Several aspects indicate, however, that F. hepatica does not reach, in the donkey, the level of adaptation it shows in sheep and cattle in this high altitude hyperendemic area. This is illustrated by a few-day delay in egg embryonation, longer prepatent period despite similar miracidial infectivity and shorter patent period in the intramolluscan development, lower cercarial production per snail, different cercarial chronobiology, shorter snail survival after shedding end, shorter longevity of shedding snails, and lower metacercarial infectivity in Wistar rats. Thus, the role of the donkey in the disease transmission should be considered secondary. Field survey results proved that liver fluke prevalence and intensity in donkeys are similar to those of the main reservoirs sheep and cattle in this area. Fasciolid egg shedding by a donkey individual contributes to the environment contamination at a rate similar to sheep and cattle. In this endemic area, the pronounced lower number of donkeys when compared to sheep and cattle indicates that the epidemiological reservoir role of the donkey is also secondary. However, the donkey plays an important epidemiological role in the disease spread because of its use by Aymara inhabitants for good transport, movements, and travel from one locality/zone to another, a repercussion to be considered in the present geographical spread of fascioliasis in the Altiplano due to climate change. Donkey transport of parasite and vector, including movements inside the zone under control and potential introduction from outside that zone, poses a problem for the One Health initiative.


Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae.
We have mutated various features of the 5' noncoding region of the HIS4 mRNA in light of established Saccharomyces cerevisiae and mammalian consensus translational initiator regions. Our analysis indicates that insertion mutations that introduce G + C-rich sequences in the leader, particularly those that result in stable stem-loop structures in the 5' noncoding region of the HIS4 message, severely affect translation initiation. Mutations that alter the length of the HIS4 leader from 115 to 39 nucleotides had no effect on expression, and sequence context changes both 5' and 3' to the HIS4 AUG start codon resulted in no more than a twofold decrease of expression. Changing the normal context at HIS4 5'-AAUAAUGG-3' to the optimal sequence context proposed for mammalian initiator regions 5'-CACCAUGG-3' did not result in stimulation of HIS4 expression. These studies, in conjunction with comparative and genetic studies in S. cerevisiae, support a general mechanism of initiation of protein synthesis as proposed by the ribosomal scanning model.


Presence of lipids in mycobacteriophage i3.
The presence of lipids has been demonstrated in mycobacteriophage I3. The total lipid was composed of 69% phospholipids and 31% neutral lipids. More than two-thirds of phospholipids present in the phage were synthesized in the host prior to infection. The fatty acid composition of the phage differed markedly from that of its host, both in chain length and the degree of saturation. The phage lipid was mostly composed of saturated fatty acids of which more than 50% were short chain fatty acids. Changes in growth temperatures reflected variations in fatty acid composition, characteristic of the phage, and which were distinctly different from those of the host. Electron microscopic observations revealed that the phage has a membranous bilayer structure. The presence of lipids may facilitate the phage-host interaction especially in lipid-rich organisms like mycobacteria.


Amino acid use by the gastrointestinal tract of sheep given lucerne forage.
Essential amino acid (EAA) utilization by gastrointestinal tract (GIT) tissues has been investigated in sheep given 800 and 1,200 g/day lucerne pellets. Animals prepared with indwelling catheters into the aorta and the portal drained viscera plus cannulas into the small intestine were infused with mixed U-13C-labeled amino acid or (1-13C]leucine tracers into the jugular vein or directly into the small intestine. GIT sequestration of EAA from arterial and luminal AA pools was determined from tracer and tracee arterioportal concentration differences at both levels of intake. Proportional tracer 13C-labeled EAA extraction of the arterial supply, on first pass across the GIT during jugular infusion, ranged from 0.063 for histidine to 0.126 for leucine. Recovery of intestinally infused tracer 13C-EAA at the portal vein ranged from 0.61 for histidine to 0.83 for valine. These data were independent of intake. Calculated rates of tracee sequestration by GIT tissues represented 0.45-0.65 of whole body EAA flux, except for histidine, for which the values were much lower (0.25-0.32). With the exception of phenylalanine, more than 0.8 of the EAA used by the GIT was extracted from circulating blood, thus calling into question the theory that GIT tissues make preferential use of EAA during absorptive metabolism, restricting supply to peripheral tissues such as skeletal muscle (growth) or mammary glands (lactation). Instead the GIT seems to compete very successfully with these tissues for circulating blood EAA.


Multidrug resistance p-glycoprotein 2 is essential for the biliary excretion of indocyanine green.
Multidrug resistance P-glycoprotein 2 (Mdr2) is a phospholipid translocator in the canalicular membrane that is essential for the formation of biliary phospholipid vesicles and mixed lipid/bile salt micelles. Incorporation into biliary vesicles and micelles is thought to contribute to the hepatobiliary excretion of certain hydrophobic organic anions, such as indocyanine green (ICG). The present studies characterized the biliary excretion of two hydrophobic organic anions, ICG and estradiol-17beta(beta-D-glucuronide) (E(2)17G), in the single-pass isolated perfused liver and the biliary excretion of glutathione (GSH) in vivo in wild-type and Mdr2-/- female mice. The biliary excretion of ICG (0.4 micromol) was reduced by 90%, while the biliary excretion of total GSH was decreased by 65% in Mdr2-/- mice relative to wild-type mice. In contrast, the biliary excretion of E(2)17G (0.1 micromol) was increased by 30% in Mdr2-/- mice. These data indicate that the absence of Mdr2 differentially influences the biliary excretion of these organic anions and suggest that phospholipid vesicles and mixed micelles in bile are essential for the biliary excretion of ICG.


Long-term treatment of duodenal ulcer.
Eighty per cent or more of duodenal and gastric ulcers which have healed after a course of treatment with drugs relapse when therapy is discontinued. Only a gastric operation or continuous maintenance treatment with H2-receptor antagonists has so far been shown to produce sustained remission in the majority of patients. Maintenance treatment with drugs is safer than gastric surgery, since the adverse effects of medical therapy are uncommon, mild and reversible while the after-effects of surgery are common and may be severe and irreversible. Ranitidine is preferred to cimetidine because it has no unwanted effects. The maintenance treatment of ulcer patients with ranitidine must be continued for many years and may have to be life-long.


Human Induced Pluripotent Stem Cell-Derived Macrophages for Unraveling Human Macrophage Biology.
Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional, and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing, and cell therapeutics in cardiovascular diseases.


The study on the effect of mercury pollution on soil microorganisms around mercury mining area.
In order to further explore the effects of soil mercury pollution on soil microbial diversity and community structure, soil samples were randomly collected from 2 m, 20 m, 30 m, 500 m and 650 m periphery of Wanshan mining area, as 5 different treatments. Each treatment had 4 replicates. Soil microbial DNA was extracted from 20 soil samples, and then high-throughput sequencing technology was used to analyse the structure and distribution of bacterial and fungal communities. The results showed that the number of bacterial and fungal communities in T0-T30 treatments was significantly larger than that in T500-T650 treatments at order, family and genus level. Whatever, the number of uniquely distributed bacterial and fungal communities among 4 replicates soil samples was quite different at order, family and genus level. The results of the effect on the microbial community structure showed that there were both the same dominant bacterial and fungal communities, and the different dominant bacterial and fungal communities at any classification level, moreover, the number of same dominant bacterial and fungal communities was larger than that of different dominant bacterial and fungal communities. The results of relationship between soil environment factors and bacterial and fungal community structure showed that distance (Hg2+), EC and pH had a high correlation with community structure, especially the distance factor, that is, the content of mercury in soil had the highest effects on community structure. The internal heterogeneity of soil caused significant differences in bacterial and fungal community structure, and the emergence of dominant bacterial and fungal communities was a manifestation of better adaptability to long-term mercury stress and other stresses in soil, which will provide a scientific reference for further exploring the mechanism of mercury enrichment between microorganisms and plants.


Health disparities: examination of evidence relevant for occupational therapy.
Healthy People 2010 identified elimination of health disparities as a national priority. Few studies in the occupational therapy literature document health disparities. The purpose of this study was to examine the evidence on U.S. health disparities with specific relevance to occupational therapy and by racial/ethnic groups and income levels. National survey data were used to identify variables related to occupational performance or occupational therapy services that showed evidence of disparities. Data on U.S. citizens included health and behavioral characteristics, activity profiles, home and work environments, experiences in health systems, and outcomes of health care services. On many variables, the nature of differences for non-White groups and lower income-level groups provide evidence of health disparities. The findings support the National Healthcare Disparities Reports, which concluded that health disparities are still prevalent in the United States, and opportunities remain in health professions, like occupational therapy, to improve the health of all citizens.


Evaluation of Various Pretreatments to Fiber Post on the Push-out Bond Strength of Root Canal Dentin.
The aim of this in vitro study was to compare the effect of different pretreatments (fiber post) with the laser-activated irrigation (LAI) technique (for removal of the smear layer) on root canal dentin in terms of push-out bond strength (PBS) in a fiber post. Fifty freshly extracted mandibular single-rooted premolars were prepared, and LAI was applied to all roots (17% EDTA was 5 mL for 120 seconds with an erbium, chromium:yttrium-scandium-gallium-garnet laser [0.50 W, 20 Hz, 25 mJ]). In addition, 50 quartz fiber posts were randomly assigned to 5 groups (n = 10) according to the surface treatments as follows: group S (sandblasting), group N1 and group N2 (neodymium:yttrium-aluminum-garnet laser irradiation [2 W, 200 mJ, 10 Hz, with pulse durations of 180 or 320 microseconds), group HF (9.7% hydrofluoric acid etched), and group C (control with no treatment). Dual-cure resin cement was adhered onto the fiber posts after they were covered with a silane agent, and then the posts were placed into the canal space using a Lentulo spiral. The PBS test was performed after all specimens were transversally sectioned (root slices of 1-mm thickness). Data were analyzed with 1-way analysis of variance/Tukey post hoc test (α = 0.05). The highest PBS value was observed in group S (middle part), and the lowest value was observed in group C (apical part). There were no statistical differences among the groups regardless of the part. Furthermore, when the PBS values of the different parts of dentin were compared within treated groups, significant differences were observed in all groups except group N2 (P < .05). Within the limitations of this study, it can be concluded that the LAI technique when used with 17% EDTA had a significant effect on the amount of smear layer removed from the root canal dentin, which was also detected in the fracture pattern (adhesive failure [resin-post interface]). However, the various treatments of the fiber post did not improve the PBS of the root dentin.


Pharmacokinetics and pharmacodynamics of xylazine administered by the intravenous or intra-osseous route in adult horses.
In certain situations, an alternate route for parenteral drug administration in horses may be useful. The intra-osseous (IO) route may provide a safe alternative to the intravenous (i.v.) route for administration of sedatives to horses when the i.v. route is inaccessible or undesirable. Six adult horses were administered xylazine i.v. or IO in a block-randomized crossover design. For the i.v. trial, both jugular veins were catheterized, and one was used for xylazine administration, while the other was used for blood collection. For the IO trial, one jugular vein was catheterized for blood collection and an intra-osseous device was placed in the tuber coxae using a powered driver for xylazine administration. Heart rate, respiratory rate, and head position were measured, and concentration of sedation was assessed at various times up to 90 min. Xylazine concentrations were measured using high-performance liquid chromatography and noncompartmental analysis was performed. General linear mixed modeling and Wilcoxon signed-rank tests were used for statistical analysis, with P ≤ 0.05. There were no significant differences in heart rate, respiratory rate, head position, concentration of sedation, Cmax , Tmax , half-life, or AUC between the i.v. and the IO routes of drug administration. No complications were observed following placement of the intra-osseous device. Intra-osseous xylazine administration provides a useful option in emergent and other settings in which i.v. access is difficult or contraindicated.


Perioperative outcomes in radical cystectomy: how to reduce morbidity?
To define the incidence of perioperative morbidity following contemporary radical cystectomy and identify preoperative, intraoperative, and postoperative strategies to reduce complications. When complications are methodically and systematically recorded, 64% of patients will sustain a complication within 90 days of radical cystectomy. Various preoperative, postoperative, and intraoperative strategies have been identified to reduce morbidity. Prior to surgery, patients should have reversible medical conditions treated, mechanical bowel preparation can be omitted if using small bowel for reconstruction, venous thromboembolism and antimicrobial infection prophylaxis should be initiated, nutrition should be optimized, and patient education should be provided. During surgery, complications can be attenuated by utilizing meticulous surgical technique, minimizing blood loss, fluid management can be guided by transesophageal cardiovascular Doppler, and lower extremity repositioning should be performed as soon as feasible. After surgery, early mobilization, incentive spirometry, early nasogastric tube removal, alvimopan usage, and judicious jejunostomy tube feeding, or total parenteral nutrition usage may reduce morbidity. Morbidity is common following radical cystectomy, but careful attention to preoperative, intraoperative, and postoperative details can help reduce this risk.


Regulation of the mouse cellular retinoic acid-binding protein-I gene by thyroid hormone and retinoids in transgenic mouse embryos and P19 cells.
The regulation of mouse cellular retinoic acid-binding protein-I (CRABP-I) gene expression by the retinoids and thyroid hormones was examined, by using a beta-galactosidase (lacZ) reporter gene and a CRABP-I specific antibody, in transgenic mouse embryos and a mouse embryonal carcinoma cell line P19. The CRABP-lacZ reporter gene expression recapitulated the expression pattern of endogenous CRABP-I in the developing central nervous system. In mid-gestation mouse embryos the expression of both the transgene and the endogenous protein was elevated under the condition of hypovitaminosis A, suggesting that depletion of retinoic acid (RA) induced CRABP-I expression in embryos. Consistently, this reporter was suppressed by RA in P19 cells. In co-transfection experiments it was demonstrated that the expression of RAR beta, RAR gamma or RXR alpha suppressed this reporter expression. In experiments designed to alter the thyroid hormone status in animals it was demonstrated that both the reporter gene and the endogenous CRABP-I expression were reduced by triiodothyronine injection and were elevated in a hypothyroidic condition induced by feeding with iodine-deficient diet supplemented with 6-propyl-2-thiouracil. In co-transfection experiments it was also demonstrated that the expression of T3R beta suppressed the reporter expression in P19 cells. It was concluded that RA had a suppressive effect on CRABP-I gene expression in embryos and P19 cells and the effect could be mediated through RAR beta, RAR gamma or RXR alpha. A role of thyroid hormones in CRABP-I gene expression and vitamin A metabolism in animals is discussed.


Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation.
Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and required for tumor growth. However, the role of CMA in malignant transformation remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts augments the efficiency of MYC/c-Myc-driven cellular transformation. CMA blockage contributes to the increase of total and nuclear MYC, leading to enhancement of cell proliferation and colony formation. Impaired CMA functionality accentuates tumorigenesis-related metabolic changes observed upon MYC-transformation. Although not a direct CMA substrate, we have found that CMA regulates cellular MYC levels by controlling its proteasomal degradation. CMA promotes MYC ubiquitination and degradation by regulating the degradation of C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to increased levels of phosphorylated MYC (Ser62) and to stabilization of this oncogene. We demonstrate that this phosphorylation is essential for the CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is enough to normalize MYC levels in CMA-incompetent cells. Altogether these data demonstrate that CMA mitigates MYC oncogenic activity by promoting its proteasomal degradation and reveal a novel tumor suppressive role for CMA in nontumorigenic cells.


Deep learning for multi-year ENSO forecasts.
Variations in the El Niño/Southern Oscillation (ENSO) are associated with a wide array of regional climate extremes and ecosystem impacts1. Robust, long-lead forecasts would therefore be valuable for managing policy responses. But despite decades of effort, forecasting ENSO events at lead times of more than one year remains problematic2. Here we show that a statistical forecast model employing a deep-learning approach produces skilful ENSO forecasts for lead times of up to one and a half years. To circumvent the limited amount of observation data, we use transfer learning to train a convolutional neural network (CNN) first on historical simulations3 and subsequently on reanalysis from 1871 to 1973. During the validation period from 1984 to 2017, the all-season correlation skill of the Nino3.4 index of the CNN model is much higher than those of current state-of-the-art dynamical forecast systems. The CNN model is also better at predicting the detailed zonal distribution of sea surface temperatures, overcoming a weakness of dynamical forecast models. A heat map analysis indicates that the CNN model predicts ENSO events using physically reasonable precursors. The CNN model is thus a powerful tool for both the prediction of ENSO events and for the analysis of their associated complex mechanisms.


Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway.
To investigate the mechanism by which galangin, a polyphenolic compound derived from medicinal herbs, induces apoptosis of hepatocellular carcinoma (HCC) cells. The 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to measure cell viability. Apoptosis was evaluated by in situ uptake of propidium iodide and Hoechst 33258 and was then detected by fluorescence microscopy. Protein expressions were detected by Western blotting. To confirm the apoptotic pathway mediated by galangin, cells were transfected by bcl-2 gene to overexpress Bcl-2 or siRNA to down-regulate Bcl-2 expression. Galangin (46.25-370.0 micromol/L) exerted an anti-proliferative effect, induced apoptosis, and decreased mitochondrial membrane potential in a dose and time-dependent manner. Treatment with galangin induced apoptosis by translocating the pro-apoptotic protein Bax to the mitochondria, which released apoptosis-inducing factor and cytochrome c into the cytosol. Overexpression of Bcl-2 attenuated galangin-induced HepG2 cell apoptosis, while decreasing Bcl-2 expression enhanced galangin-induced cell apoptosis. Our data suggests that galangin mediates apoptosis through a mitochondrial pathway, and may be a potential chemotherapeutic drug for the treatment of HCC.


Stem cell therapy for ischemic heart disease.
Stem cell transplantation has emerged as a novel treatment option for ischemic heart disease. Different cell types have been utilized and the recent development of induced pluripotent stem cells has generated tremendous excitement in the regenerative field. Bone marrow-derived multipotent progenitor cell transplantation in preclinical large animal models of postinfarction left ventricular remodeling has demonstrated long-term functional and bioenergetic improvement. These beneficial effects are observed despite no significant engraftment of bone marrow cells in the myocardium and even lower differentiation of these cells into cardiomyocytes. It is thought to be related to the paracrine effect of these stem cells, which secrete factors that lead to long-term gene expression changes in the host myocardium, thereby promoting neovascularization, inhibiting apoptosis, and stimulating resident cardiac progenitor cells. Future studies are warranted to examine the changes in the recipient myocardium after stem cell transplantation and to investigate the signaling pathways involved in these effects.


Education-stratified base-rate information on discrepancy scores within and between the Wechsler Adult Intelligence Scale--Third Edition and the Wechsler Memory Scale--Third Edition.
The Wechsler Adult Intelligence Scale--Third Edition (WAIS-III; D. Wechsler, 1997a) and the Wechsler Memory Scale--Third Edition (WMS-III; D. Wechsler, 1997b) are 2 of the most frequently used measures in psychology and neuropsychology. To facilitate the diagnostic use of these measures in the clinical decision-making process, this article provides information on education-stratified, directional prevalence rates (i.e., base rates) of discrepancy scores between the major index scores for the WAIS-III, the WMS-III, and between the WAIS-III and WMS-III. To illustrate how such base-rate data can be clinically used, this article reviews the relative risk (i.e., odds ratio) of empirically defined "rare" cognitive deficits in 2 of the clinical samples presented in the WAIS-III--WMS-III Technical Manual (The Psychological Corporation, 1997).


Vulnerable child syndrome, parental perception of child vulnerability, and emergency department usage.
Vulnerable child syndrome (VCS) describes children perceived to be at risk for behavioral, developmental, or medical problems. Families with the dynamics of VCS overuse health care resources with frequent visits to doctors' offices. The objective of the study was to explore the relationship between VCS, parental perception of child vulnerability (PPCV), and frequency of emergency department (ED) visits. Parents of patients 1 to 15 years old presenting with nonurgent complaints to a pediatric ED were eligible. Participants completed questionnaires in which the Vulnerable Child Scale was used to generate a measure of PPCV. Primary outcomes included number of ED visits and PPCV assignment. Children were divided into 2 PPCV groups by Vulnerable Child Scale score: less than 40 (high PPCV) versus 40 or greater (low PPCV). The cutoff point was chosen as 1 SD (7.3) from the sample mean (46.8) on the vulnerable end of the scale (low scores). The mean ages of the 351 parents and children were 30 (SD, 7.7) years and 5 (SD, 3.9) years, respectively; 17% of children had high PPCV. Eleven variables differed statistically between subjects with high and low PPCV including number of ED visits and hospital admissions, excellent reported child health, pregnancy problems, delivery problems, child mental health problems, parent mental health problems, and child developmental problems. Our results reveal that children with higher PPCV had an increased number of ED visits, and risk factors for higher perceived vulnerability scores were identified. Future investigation on ways to intervene with families with the dynamics of VCS may be warranted.


Iodothyronine deiodinases and reduced sensitivity to thyroid hormones.
Iodothyronine deiodinases are selenoproteins that regulate thyroid hormone metabolism. Of the three types of deiodinases, type 2 is the major regulator of intracellular triiodothyronine concentration in both the hypothalamus and pituitary, and therefore the major regulator of thyrotropin secretion. A defect in iodothyronine deiodinase activity can lead to a reduced sensitivity to thyroid hormones action and the most recent literature includes these defects in the so-called "syndromes of reduced sensitivity to thyroid hormones". To date, the pathogenic variants of the selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene are the first and only inherited disorder of iodothyronine metabolism described. Moreover, there is a growing interest in understanding the possible role of polymorphisms of DIO1 and DIO2 genes in some pathological conditions and in determining the requirement of levothyroxine replacement and the role of combined levothyroxine-liothyronine therapy in carrying subjects affected by hypothyroidism and who need replacement therapy. Results on this topic are still conflicting and more studies are needed to assess the efficacy of combined levothyroxine-liothyronine replacement therapy in this subset of patients.


Are family medicine centres achieving their target in Turkey: Impact on health care utilization of mothers and infants.
The family medicine (FM) system was introduced as the main source of primary care in Turkey as a component of the Health Transformation Program reforms. During a gradual implementation process, provinces switched to the FM system at different points in time between 2005 and 2010. In this paper, we use a micro-level data set to test whether the health care utilization of mothers during pregnancy, childbirth and the postnatal period is affected by the program. Using a difference-in-differences method for estimation, we find that the program is only effective for pregnant women who lived in provinces with a limited availability of specialist doctors. As a result of the FM program, women are likely to have their first prenatal consultancy earlier and their probability of seeing a doctor during their prenatal visit and receiving an ultrasound and blood and urine sample checks increases if they live in a province with a low number of specialists per 10,000 people. We find that the impact of the FM program decreases as the rate of specialists in a province increases, which negates any positive effect of the program on health care use.


Primary structure of the long and short splice variants of mouse collagen XII and their tissue-specific expression during embryonic development.
Type XII collagen, a member of the FACIT group of extracellular matrix proteins, consists of molecules that are trimers of alpha 1(XII) chains. The three chains in each molecule form a cross-shaped structure with a central globule from which a triple-helical tail and three finger-like regions (containing von Willebrand factor A-like regions (containing von Willebrand factor A-like domains and fibronectin type III repeats) extend. cDNA cloning/sequencing of chicken alpha 1(XII) collagen and protein studies with mouse, bovine, and human material suggest that the alpha 1(XII) collagen gene gives rise to two molecular variants, differing in the length of the finger-like regions, by alternative splicing of the primary transcript. To provide a basis for studies of the function of the two variants in an organism that can be genetically manipulated, we have isolated and sequenced mouse cDNAs encoding both splice variants. The sequence provides the first complete nucleotide and amino acid sequence of mammalian type XII collagen. From these cDNAs we have generated digoxigenin-labeled RNA probes for in situ hybridization of developing mouse embryos to find out whether the splicing mechanism responsible for generation of the two forms is developmentally regulated. The results, combined with Northern blot and RT-PCR analysis of RNA from embryos at various developmental stages, demonstrate that the long form of collagen XII, XIIA, is the predominant form at early stages (ED7 and 11); at later stages of development (ED15 and 17) the short form, XIIB, becomes the major form. As the short form becomes the major product, the long splice variant continues to be expressed in several tissues, even after birth. An exception is dermis, which is positive for the long form up to embryonic day 15, but negative at day 18, when only the short form RNA can be detected.


Pioglitazone hydrochloride inhibits cholesterol absorption and lowers plasma cholesterol concentrations in cholesterol-fed rats.
Diabetes is associated with altered cholesterol metabolism that may contribute to cardiovascular complications. Treatment of rats with pioglitazone hydrochloride, a novel antidiabetic compound that improves the general response of target cells to insulin, significantly lowered cholesterol levels in rats fed a hypercholesterolemic diet and produced a significant reduction in cholesterol absorption. Drug treatment was ineffective in rats that were not given dietary cholesterol. To determine whether these effects of pioglitazone hydrochloride might be related to the known ability of this compound to improve the response to circulating insulin, similar studies were conducted in streptozocin-induced diabetic rats with and without insulin replacement. Diabetic rats absorbed a greater percentage of dietary cholesterol than control rats. Treatment of insulin-deficient diabetic rats with pioglitazone alone did not affect cholesterol absorption; however, the combination of insulin and pioglitazone was synergistic to lower absorption of cholesterol and circulating cholesterol and triglycerides. Treatment of either normal rats or diabetic rats receiving insulin with pioglitazone hydrochloride produced a twofold decrease in the ratio of total cholesterol to high-density lipoprotein cholesterol. These results suggest that treatments that improve insulin sensitivity may also have a positive impact on coronary artery disease associated with diabetes.


Mechanisms of accumulation of arachidonic acid in cultured myocardial cells during ATP depletion.
Previous studies have suggested that the accumulation of free arachidonic acid may be of major importance in the pathophysiology of myocardial ischemia. The purpose of the present study was to determine if the release of arachidonic acid from myocardial cells was more dependent on the extent of ATP depletion than on the inhibition of fatty acid oxidation. In addition, these studies were designed to determine if arachidonic acid release only occurred when ATP was depleted beyond a critical threshold level. To examine the relationship between arachidonic acid release and ATP depletion, cultured myocardial cells from neonatal rat hearts were labeled with [3H]arachidonate and [14C]palmitate. In response to ATP depletion with various metabolic inhibitors, [3H]arachidonic acid and [14C]palmitic acid were released from phospholipids. Phosphatidylcholine, phosphatidylethanolamine, and phosphatidic acid were the major esterified sources of the arachidonate. The release of both fatty acids was related to the extent of ATP depletion and not whether a glycolytic or respiratory inhibitor was utilized. Various combinations and doses of metabolic inhibitors were used, and experimental conditions that produced a greater than 75% decrease in ATP content were associated with the accumulation of arachidonic acid. These results suggest that an ATP-dependent step may be linked to the accumulation of arachidonic acid during myocardial ATP depletion. It is suggested that myocardial cells may release arachidonic acid directly in response to ATP depletion.


Detection of Loss of Heterozygosity (LOH) Using Circulating Cell-free DNA (cfDNA) by Fluorescence-based Multiplex PCR for Identification of Patients With Prostate Cancer.
Several lines of evidence suggest that loss of heterozygosity (LOH) in specific chromosomal regions is a common mechanism for the inactivation of tumor-suppressor genes that are implicated in the pathogenesis of prostate cancer (PCa). Short tandem repeat (STR) sequences are extremely reliable genetic markers for the detection of LOH associated with cancers. Hence, in the current study, we investigated the detection of LOH at 6 STR markers (D8S360, D9S1748, D9S171, D8S137, D6S1631, and THRB) using blood circulating cell-free DNA (cfDNA), which can be used to distinguish PCa from benign prostatic hyperplasia (BPH). A total of 136 individuals were included in the study, 76 male patients diagnosed with PCa (50 male patients with localized PCa and 26 male patients with metastatic PCa) as experimental subjects and 60 male patients with BPH as controls. Circulating cfDNA was extracted from plasma samples and amplified with fluorescence-labeled primers specific for known STR markers. We also evaluated the serum prostate-specific antigen in both groups. Our findings revealed that the frequency of LOH at D8S360, D9S1748, D9S171, D8S137, and D6S1631 was significantly higher in PCa subjects than in controls (P<0.05). Of the 6 STR markers, LOH at D8S360 could discriminate metastatic PCa from localized PCa. We found that 71.05% of patients with PCa and 1.66% of BPH subjects had LOH at least at 3 of the markers in cfDNA. Our findings provide additional evidence to support the hypothesis that analysis of LOH at D8S360, D9S1748, D9S171, D8S137, and D6S1631 STR markers using cfDNA can be applied as a noninvasive diagnostic approach for the detection of PCa.


[Impaired resonance in offenders with psychopathic traits].
Resonance is the phenomenon of unconsciously mirroring the motor actions of another person. Beside autism and schizophrenia psychopathic personality traits are associated with empathy dysfunction. We explore empathic resonance in terms of contagion by laughing and yawning in a group of offenders with psychopathic traits. Offenders with psychopathic traits (n = 12) and matched controls (n = 10) were video-taped while watching short video sequences of yawning, laughing or neutral faces. They were rated regarding contagion. Further, we assessed a self-report on psychopathy and on empathic tendencies. Compared to the control group, the offenders showed significantly less contagion and less self-reported empathic tendencies. Individuals who rated themselves as more empathic showed more contagion. The observed reduced resonance in terms of contagion may illuminate the cold-heartedness, with which some psychopathic offenders treat their victims: When embodied experiencing of other's physical and emotional situation is missing, a natural inhibition of violence may be overcome. The small sample size limits the generalisability of these findings.


Multiple scattered radiation emerging from Rayleigh and continental haze layers. 2: Ellipticity and direction of polarization.
The ellipticity and the direction of polarization are calculated for radiation that has undergone multiple scattering from plane parallel layers. Both the radiation emerging from the top of the layer and that transmitted through the bottom are considered. Two different phase functions are used for the scattering layer: Rayleigh and haze L. The direction of polarization of the reflected radiation shows little variation as the optical depth of the layer increases, while there is a much larger variation for the transmitted radiation. When the optical thickness is small, the direction of polarization for haze L varies rapidly with zenith angle near those angles at which the single scattered polarization is zero. The ellipticity of the radiation from haze L layers increases at first in direct proportion to the optical thickness of the layer. In general the ellipticity of the transmitted radiation is considerably greater than that of the reflected because of the greater average number of photon collisions in the frmer case. When the ellipticity is small, it is shown that the product of the polarization and the ellipticity is closely equal to -V/2I, where I and V are the first and fourth components of the Stokes vector.


Interleukin 2 and lymphokine-activated killer cells in the treatment of childhood primary hepatocellular carcinoma--a preliminary report.
Recombinant interleukin-2 (RIL-2) and lymphokine-activated killer (LAK) cells were administered to 2 boys with the end-stage of primary hepatocellular carcinoma (HCC); the efficacy and toxicity were evaluated. Immunologically, the natural killer and LAK activities were enhanced. Clinically, the side effects were similar to those reported for adults but milder. This kind of treatment may be considered for children with the early stages of hepatocellular carcinoma.


Troponin level at presentation as a prognostic factor among patients presenting with non-ST-segment elevation myocardial infarction.
Timely reperfusion within 120 min is strongly recommended in patients presenting with non-ST-segment myocardial infarction (NSTEMI) with very high-risk features. Evidence regarding the use of high-sensitivity cardiac troponin (hs-cTn) concentration upon admission for the risk-stratification of patients presenting with NSTEMI to expedite percutaneous coronary intervention (PCI) and thus potentially improve outcomes is limited. All patients admitted to a tertiary care center ICCU between July 2019 and July 2022 were included. Hs-cTnI levels on presentaion were recorded, dividing patients into quartiles based on baseline hs-cTnI. Association between initial hs-cTnI and all-cause mortality during up to 3 years of follow-up was studied. A total of 544 NSTEMI patients with a median age of 67 were included. Hs-cTnI levels in each quartile were: (a) ≤122, (b) 123-680, (c) 681-2877, and (d) ≥2878 ng/L. There was no difference between the initial hs-cTnI level groups regarding age and comorbidities. A higher mortality rate was observed in the highest hs-cTnI quartile as compared with the lowest hs-cTnI quartile (16.2% vs. 7.35%, p = .03) with hazard ratio (HR) for mortality of 2.6 (95% confidence interval [CI]: 1.23-5.4; p = .012) in the unadjusted model, and HR of 2.06 (95% CI: 1.01-4.79; p = .047) with adjustment for age, gender, serum creatinine, and significant comorbidities. Patients with NSTEMI and higher hs-cTnI levels upon admission faced elevated mortality risk. This underscores the need for further prospective investigations into early reperfusion strategies' impact on NSTEMI patients' mortality, based on admission troponin elevation.


Hormonal control of apical membrane Na transport in epithelia. Studies with fluctuation analysis.
To study the mechanisms by which antidiuretic hormone and prostaglandins regulate Na transport at the apical membranes of the cells of anuran tissues, studies were done with fluctuation analysis. Epithelia of frog skin (Rana pipiens) were treated with vasopressin alone, or treated with vasopressin after inhibition of Na transport by indomethacin. The tissues were bathed symmetrically with a Cl-HCO3 Ringer solution and short-circuited continuously. In this experimental circumstance, the amiloride-induced current noise power density spectra were of the Lorentzian type with little or no l/f noise, provided that "scraped" skins were used for study. Despite large changes of Na transport, especially in epithelia treated with indomethacin and vasopressin, the single-channel Na current remained essentially unchanged, whereas the density of amiloride-inhibitable, electrically conductive Na channels was increased by vasopressin and decreased by indomethacin.