EXP-1 is an excitatory GABA-gated cation channel.
Gamma-aminobutyric acid (GABA) mediates fast inhibitory neurotransmission by activating anion-selective ligand-gated ion channels. Although electrophysiological studies indicate that GABA may activate cation-selective ligand-gated ion channels in some cell types, such a channel has never been characterized at the molecular level. Here we show that GABA mediates enteric muscle contraction in the nematode Caenorhabditis elegans via the EXP-1 receptor, a cation-selective ligand-gated ion channel. The EXP-1 protein resembles ionotropic GABA receptor subunits in almost all domains. In the pore-forming domain of EXP-1, however, the residues that confer anion selectivity are exchanged for those that specify cation selectivity. When expressed in Xenopus laevis oocytes, EXP-1 forms a GABA receptor that is permeable to cations and not anions. We conclude that some of the excitatory functions assigned to GABA are mediated by cation channels rather than by anion channels.


Homodimerization of the death-associated protein kinase catalytic domain: development of a new small molecule fluorescent reporter.
Death-Associated Protein Kinase (DAPK) is a member of the Ca2+/calmodulin regulated serine/threonine protein kinases. Its biological function has been associated with induced cell death, and in vivo use of selective small molecule inhibitors of DAPK catalytic activity has demonstrated that it is a potential therapeutic target for treatment of brain injuries and neurodegenerative diseases. In the in vitro study presented here, we describe the homodimerization of DAPK catalytic domain and the crucial role played by its basic loop structure that is part of the molecular fingerprint of death protein kinases. Nanoelectrospray ionization mass spectrometry of DAPK catalytic domain and a basic loop mutant DAPK protein performed under a variety of conditions was used to detect the monomer-dimer interchange. A chemical biological approach was used to find a fluorescent probe that allowed us to follow the oligomerization state of the protein in solution. The use of this combined biophysical and chemical biology approach facilitated the elucidation of a monomer-dimer equilibrium in which the basic loop plays a key role, as well as an apparent allosteric conformational change reported by the fluorescent probe that is independent of the basic loop structure.


Congenital Syphilis Presenting with Prenatal Bowel Hyperechogenicity and Necrotizing.
Congenital syphilis is a severe disease that arises from the vertical transmission of Treponema pallidum. Clinical findings are related to the pregnancy stage, fetal gestational week, maternal treatment and fetal immunologic response. Prematurity, low birth weight, nonimmune hydrops fetalis, necrotizing enterecolitis, hepatomegaly, skin eruptions, thrombocytopenia, hemolytic anemia and fever can be detected in the symptomatic newborn. Postnatal respiratory insufficiency, hepatomegaly, anemia and thrombocytopenia were detected in a baby who was born at the 29th week of gestation, weighing 1.160 g and followed due to intestinal hyperechogenicity from the second trimester. Her and her mother's Venereal Disease Research Laboratory titers were positive, confirming test Treponema pallidum hemagglutination was reactive. After penicillin was administered for 10 days, anemia, and thrombocytopenia were regressed. In the 15th day of life, findings of perforated necrotising enterocolitis (NEC) suddenly appeared. The operation was performed due to NEC for three times but nonresponsive laboratory and clinical findings and died in the 54th day of life. We assumed that syphilis is the cause of both bowel hyperechogenicity and necrotising enterocolitis.


Human bocavirus capsid structure: insights into the structural repertoire of the parvoviridae.
Human bocavirus (HBoV) was recently discovered and classified in the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae) on the basis of genomic similarity to bovine parvovirus and canine minute virus. HBoV has been implicated in respiratory tract infections and gastroenteric disease in children worldwide, yet despite numerous epidemiological reports, there has been limited biochemical and molecular characterization of the virus. Reported here is the three-dimensional structure of recombinant HBoV capsids, assembled from viral protein 2 (VP2), at 7.9-A resolution as determined by cryo-electron microscopy and image reconstruction. A pseudo-atomic model of HBoV VP2 was derived from sequence alignment analysis and knowledge of the crystal structure of human parvovirus B19 (genus Erythrovirus). Comparison of the HBoV capsid structure to that of parvoviruses from five separate genera demonstrates strong conservation of a beta-barrel core domain and an alpha-helix, from which emanate several loops of various lengths and conformations, yielding a unique surface topology that differs from the three already described for this family. The highly conserved core is consistent with observations for other single-stranded DNA viruses, and variable surface loops have been shown to confer the host-specific tropism and the diverse antigenic properties of this family.


Insights into the Sustainable Return to Work of Aging Workers with a Work Disability: An Interpretative Description Study.
Purpose A sustainable return to work (S-RTW) following prolonged work disability poses particular challenges as workers age. This article provides a synthesis of the factors and issues involved in a S-RTW process for aging workers following such a disability. Methods Using interpretive description methods, a critical review was conducted of the literature specifying return-to-work factors and issues for aging workers with regard to four major causes of work disability (musculoskeletal disorders, common mental disorders, cancer or other chronic diseases). The initial review concerned the 2000-2016 literature, and was subsequently updated for November 2016-December 2018. To further explore and contextualise the results of this literature review, four focus groups were held with stakeholders, representing the workplace, insurance, and healthcare systems and workers. Qualitative thematic analysis was performed. Results Fifty-five articles were reviewed and 35 stakeholders participated in the focus groups. Returning to work and staying at work appear to be particularly challenging for aging workers, who face notable issues and stigma concerning their ability to meet work demands, as well as their mobilisation and engagement in these processes. Such findings echo in many ways the main assertions of the literature on aging at work, except those regarding the transformation of capacities with aging, which is not mentioned in relation to workers with a work disability. The influence of healthcare and compensation systems on the S-RTW of aging work-disabled workers has also received little attention to date. Conclusions The results underscore that aging workers with a disability are frequently vulnerable in terms of their health or their jobs. Intersectoral efforts are needed to remedy this situation to keep them at work.


Antiepileptics in the elderly. Pharmacoepidemiology and pharmacokinetics.
To evaluate antiepileptic (AE) use by nursing home residents. Medical records for 996 residents from six Minnesota nursing homes (5% of the nursing home residents in the Minneapolis-St Paul area) compared with medication records of 45,405 nursing home residents nationwide serviced by Pharmacy Corporation of America, Boulder, Colo. Reports comparing pharmacokinetics in younger adults and elderly volunteers or patients with epilepsy who were given AEs. Among Minnesota nursing home residents, 7.7% were taking AEs. Usage in a national survey was 10.1%. A review of published studies involving small numbers of elderly subjects or patients given phenytoin sodium, valproic acid, or carbamazepine demonstrates decreased protein binding and intrinsic clearance and increased half-life with advancing age. Concomitant drugs, especially those with central nervous system effects, can lower the concentration at which AEs cause dose-related side effects, thereby narrowing therapeutic ranges. Approximately 10% of nursing home residents receive AEs, usually with other maintenance medications. In 82% of residents receiving an AE, the indication was treatment of a seizure disorder. Other indications included aggressive behavior, essential tremors, and neurologic pain. Age-related alterations in AE pharmacokinetics result in protein-binding changes and decreases in drug elimination. Measurement of unbound drug concentrations may be helpful when altered binding is suspected or clinical response does not correlate with total AE concentration. Concomitant drugs pose the risk for significant drug interactions and adverse reactions. An understanding of the underlying pharmacokinetic processes, including the need of most elderly patients for lower doses and longer dosing intervals, permits more effective management of therapy and reduces the risk for adverse reactions.


[Antibiotics during pregnancy and breast feeding: consequences for the treatment of respiratory infections].
Respiratory infections are the second most frequent cause for antibiotic prescriptions during pregnancy, after genito-urinary infections. Overall, antibiotics are relatively innocuous. The following should be avoided: the tetracyclines, cotrimoxazole, chloramphenicol, metronidazole and the quinolones. Aminoglycosides should be administered controlling the plasma level. The beta-lactones (principally the penicillins) and the macrolides sold in France, are without any danger. Nevertheless, the rise in distribution volume and the overall physiological changes which accompany the developing pregnancy, particularly in the third trimester lead to a diminution in the serum concentration of these antibiotics and imply an adaptation, often a doubling, of the therapeutic dose administered. From the epidemiological data concerning the organisms involved in the respiratory infections, nearly the totality of extra-hospital infections may be cured by macrolides or penicillins (ampicillin). During more serious infections (nosocomial, or the immuno-depressed) the maternal prognosis should take precedence, adjusting the antibiotic to the organism, before the toxic risk to the child. All the antibiotics are excreted in the mother milk, but in very small quantities; they are generally destroyed in the digestive tract of the child so that the risk of any secondary effect during lactation is minimal.


[Self-treatment with baking soda can lead to severe metabolic alkalosis].
This case report describes a 66-year-old man, previously healthy besides mild hypertension. He ingested a self-made folk remedy consisting of baking soda and water against acid reflux in dosages that resulted in severe metabolic alkalosis (pH 7.8). Diagnosing and treating MA is easy and cheap, but if the condition is not treated, consequences can be severe. The challenge is to uncover patients' use of non prescription medications and folk remedies in the diagnostic process. Having this information it is possible to prevent MA in both high- and low-risk patients.


Maternal and fetal outcomes of COVID-19 infection in pregnant women with chronic rheumatic heart disease in a South Asian population: A case series.
Rheumatic heart disease (RHD) is associated with an increased risk of adverse maternal, fetal, and neonatal outcomes, particularly in developing countries. The current COVID-19 pandemic has also affected pregnant women, probably increasing the adverse effects. It is speculated that COVID-19 infection in pregnant women would further increase the risk of complications. However, factual data is still lacking, especially from resource-constrained countries. We conducted a case series of 20 pregnant women with RHD and COVID-19 infection and compared their outcomes with 40 with RHD but without COVDI-19. We observed a high risk of adverse cardiac and pregnancy effects across the whole cohort of 60 patients. However, the comparative study between the two groups failed to show any incremental risk of complications due to COVID-19 infection. Although the sample size was limited; the results are encouraging, particularly for developing countries.


Validation of Gazepoint low-cost eye-tracking and psychophysiology bundle.
Eye-tracking and recording of physiological signals are increasingly used in research within cognitive science and human-computer interaction. For example, gaze position and measures of autonomic arousal, including pupil dilation, skin conductance (SC), and heart rate (HR), provide an indicator of cognitive and physiological processes. The growing popularity of these techniques is partially driven by the emergence of low-cost recording equipment and the proliferation of open-source software for data collection and analysis of such signals. However, the use of new technology requires investigation of its reliability and validation with respect to real-world usage and against established technologies. Accordingly, in two experiments (total N = 69), we assessed the Gazepoint GP3-HD eye-tracker and Gazepoint Biometrics (GPB) system from Gazepoint. We show that the accuracy, precision, and robustness of the eye-tracker are comparable to competing systems. While fixation and saccade events can be reliably extracted, the study of saccade kinematics is affected by the low sampling rate. The GP3-HD is also able to capture psychological effects on pupil dilation in addition to the well-defined pupillary light reflex. Finally, moderate-to-strong correlations between physiological recordings and derived metrics of SC and HR between the GPB and the well-established BIOPAC MP160 support its validity. However, low amplitude of the SC signal obtained from the GPB may reduce sensitivity when separating phasic and tonic components. Similarly, data loss in pulse monitoring may pose difficulties for certain HR variability analyses.


[Larsen-syndrome: final diagnosis following multiple surgical interventions].
Larsen-syndrome is a rare genetic skeletal dysplasia belonging to the group of actin-binding filamin B associated diseases. The features include congenital dislocations of the large joints, scoliosis and cervical kyphosis, short, broad, spatulate distal phalanges, and distinctive craniofacies. Diagnosis is based on clinical and radiographic findings and confirmed by molecular genetic testing. The authors have performed filamin B molecular genetic analysis since 2005 and have found several cases with unusual phenotypes since. This case report presents the diagnostic difficulties of a 30-year-old woman, who was operated several times with congenital hip dislocations and foot deformities. The craniofacial features, short, broad, spatulate fingers, scoliosis and cervical kyphosis directed diagnosis towards Larsen-syndrome and molecular genetic analysis confirmed a previously-described heterozygous missense mutation (c.G679A). They conclude that genetic analysis performed in time would prevent additional superfluous long diagnostic procedures in patients with rare diseases and would ensure adequate supportive therapy and management of the symptoms.


Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation.
We demonstrate the long-term effectiveness of KRP-203 treatment in combination with a subtherapeutic dose of cyclosporine A (CsA) on rat renal allografts. We tested the effect of KRP-203 in combination with CsA using a rat skin allograft model. The Pharmacokinetic interaction between CsA and KRP-203 was evaluated. The selectivity of KRP-203 for sphingosine-1-phosphate (S1P)1 and S1P3 receptors were investigated in vitro. Heart rate alteration following bolus injection of phosphorylated KRP-203 (KRP-203-P) or FTY720 (FTY720-P) was also monitored in rats. Finally, the long-term effectiveness of KRP-203 in conjunction with a low dose of CsA was investigated in a rat renal transplantation model. Administration of KRP-203 with CsA prolonged skin allograft survival. KRP-203 and CsA had no effect on the pharmacokinetics of the other. While FTY720-P activated both S1P1 and S1P3 receptors, KRP-203-P selectively activated S1P1, but not the S1P3 receptor (EC50:>1000 nM). Compared to FTY720-P, a tenfold higher dose of KRP-203-P was necessary to induce transient bradycardia. With a low dose of CsA (1 mg/kg/day), KRP-203 (0.3 mg/kg/day) significantly prolonged renal allograft survival (P<0.05, survival time: 9.8 days (CsA) vs. >27.4 days (CsA+KRP)). Although a higher dose of CsA (3 mg/kg/day) alone kept recipients alive, this caused severe renal graft dysfunction. Use of KRP-203 (3 mg/kg/day) in conjunction with CsA markedly improved graft function (P<0.05, creatinine clearance: 0.41+/-0.25 ml/min [CsA] vs. 1.15+/-0.16 ml/min [CsA+KRP]). The selectivity of KRP-203 for S1P1 reduces the risk of bradycardia, and the combination therapy of KRP-203 with CsA represents a safe and effective strategy for use in renal transplantation.


Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.
Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention.


Pitfalls in the diagnosis of cerebellar infarction.
Cerebellar infarctions are an important cause of neurologic disease. Failure to recognize and rapidly diagnose cerebellar infarction may lead to serious morbidity and mortality due to hydrocephalus and brain stem infarction. To identify sources of preventable medical errors, the authors obtained pilot data on cerebellar ischemic strokes that were initially misdiagnosed in the emergency department. Fifteen cases of misdiagnosed cerebellar infarctions were collected, all seen, or reviewed by the authors during a five-year period. For each patient, they report the presenting symptoms, the findings on neurologic examination performed in the emergency department, specific areas of the examination not performed or documented, diagnostic testing, the follow-up course after misdiagnosis, and outcome. The different types of errors leading to misdiagnosis are categorized. Half of the patients were younger than 50 years and presented with headache and dizziness. All patients had either incomplete or poorly documented neurologic examinations. Almost all patients had a computed tomographic scan of the head interpreted as normal, and most of these patients underwent subsequent magnetic resonance imaging showing cerebellar infarction. The initial incorrect diagnoses included migraine, toxic encephalopathy, gastritis, meningitis, myocardial infarction, and polyneuropathy. The overall mortality in this patient cohort was 40%. Among the survivors, about 50% had disabling deficits. Pitfalls leading to misdiagnosis involved the clinical evaluation, diagnostic testing, and establishing a diagnosis and disposition. This study demonstrates how the diagnosis of cerebellar infarction can be missed or delayed in patients presenting to the emergency department.


Drug resistance profiles and trends in drug-resistant tuberculosis at a major hospital in Guizhou Province of China.
Tuberculosis (TB) is the leading cause of death from infectious diseases in the world, with an estimated 1.6 million deaths from TB in 2017. The objectives of this study were to determine drug resistance profiles of Mycobacterium tuberculosis clinical isolates and to analyze the trends in drug-resistant and multidrug-resistant tuberculosis (MDR-TB) from 2008 to 2015 at a major hospital in Guizhou, a high-TB burden and resource-limited province of China. A total of 462 clinical isolates were collected from patients with pulmonary TB during the period from January 2013 to December 2015 and used for determining drug resistance profiles against four first-line and six second-line anti-TB drugs, and the results were compared with those of two previous studies. Exactly 4.4% of new and 44.1% of previously treated TB cases were MDR/rifampicin-resistant TB (RR-TB), which were higher than the 2017 global average numbers of 3.5% and 18%, respectively. There were many drug-resistant patterns among MDR-TB isolates and most of them were resistant to three or four anti-TB drugs. The trends in drug-resistant and MDR-TB declined at the hospital from 2008 to 2015. Results of this study show that the prevalence of MDR/RR-TB at a major hospital in Guizhou is higher than the global average and confirm the existence of heterogeneity in drug resistance patterns of MDR-TB isolates. Additionally, three practical measures have played an important role in the overall decline of MDR-TB at the hospital from 2008 to 2015.


On the number of genes controlling the grass stage in longleaf pine.
The grass stage is an inherent and distinctive developmental trait of longleaf pine (Pinus palustris), in which height growth in the first few years after germination is suppressed. In operational forestry practice the grass stage extends for two to several years and often plays a role in planting failures and decisions to plant alternative species. Interspecies hybrids involving loblolly (P. taeda) and slash (P. elliottii var. elliottii) pines have been investigated as a means to produce planting stock with improved early height growth and to develop backcross populations for advanced generation breeding. We have reevaluated data from several interspecies populations, with the objective of estimating the number of genes contributing to the difference in first-year height growth between longleaf and loblolly pines. Estimates based on means and variances of parental and interspecies hybrid and backcross families suggest a minimum of 4 to 10 genes with standard errors less than half the estimates. These results suggest that the grass stage has evolved through the accumulation of alleles at several loci, each with small effects on various components of first-year height growth. Given the complexity of the grass-stage trait, tree breeders may need to combine genetic marker analysis with recurrent backcross breeding to efficiently develop longleaf pine planting stock for improved reforestation.


Childhood medical history and psychosis in adult life: Findings from the Bologna EU-GEI incidence and case-control study.
To estimate the association between the inpatient admissions and Emergency Department (ED) visits before age of 18 years and adulthood-onset first-episode psychosis (FEP). We conducted a FEP incidence and case-control study and calculated the odds ratios (ORs) for incident FEP associated with inpatient admissions and ED visits prior to age of 18 years, adjusting our results for cannabis use, parental socio-economic class and childhood trauma. In multivariate logistic regression analysis, odds of FEP increased significantly if the participant had a history of at least one inpatient admission (OR = 3.52; 95% confidence interval [95%CI] 1.07-11.54; P = .04) or at least one ED visit (OR = 8.93; 95%CI 2.41-33.14; P = .001) before age of 18. The associations remained significant adjusting for cannabis use, education, parental socio-economic class and childhood trauma. Consistently with the socio-neurodevelopmental model, we found a significant association between a positive history of hospital care in childhood and adulthood-onset psychosis.


Preparation of Chlorella vulgaris polysaccharides and their antioxidant activity in vitro and in vivo.
In the present study, six different polysaccharides (RFPs, MAPs, UWPs, AEPs, HWPs and CEPs) were extracted from Chlorella vulgaris using repeated freeze-thawing, microwave-assisted-, ultrasonic wave-, alkali-, hot water-, and cellulase-based methods; and antioxidant property assays were performed both in vitro and in vivo. Radical-scavenging capacity (using DPPH, superoxide and hydroxyl radicals) and metal chelating ability were assessed in vitro; Caenorhabditis elegans was used to assess antioxidant effects in vivo. Based on the in vitro screening tests, UWPs exhibited high antioxidant capacity. The UWP yield was 17.1% ± 2.2%; the DPPH-, superoxide-, and hydroxyl radical-scavenging rates were 65.1% ± 2.4%, 61.2% ± 2.7%, and 56.2% ± 2.2%, respectively, and the metal chelating ability was 63.6% ± 2.5% at a concentration of 0.4 mg/mL. UWPs also exhibited high antioxidant activity in vivo. UWPs significantly increased the lifespan of C. elegans under oxidative stress induced by hydrogen peroxide compared with the control group, enhanced stress-resistance-related enzymes, including catalase and superoxide dismutase by 7.29% ± 1.8% and 24.41% ± 4.8%, respectively. The results of the present study indicate that the extraction methods of C. vulgaris polysaccharides were a key factor influencing antioxidant activity.


Stimulation of collagen secretion by relaxin and effect of oestrogen on relaxin binding in uterine cervical cells of pigs.
The role of relaxin and oestrogen in the remodelling of connective tissue was investigated by testing collagenase-dispersed cells (3 x 10(5) cells per well) from the uterine cervix of gilts for relaxin binding and collagen secretion. Relaxin-binding sites on these cells were quantified by specific binding of a saturating dose of 125I-labelled monotyrosyl relaxin at optimal conditions. Oestrogen at doses from 0.4 to 50 ng ml-1 increased relaxin binding in a time- and dose-dependent manner. Scatchard plot analysis exhibited curvilinearity, which suggested two classes of relaxin-binding sites. The addition of relaxin (0, 100, 500 ng ml-1) alone (P < 0.05) or in combination with oestrogen (oestradiol benzoate: 0, 50, 250 ng ml-1) increased protein secretion into the culture medium. Hydroxyproline concentration (as an index of collagen) in the medium was increased (P < 0.05) only in the presence of both relaxin and oestrogen. Actinomycin D (500 ng ml-1) and cycloheximide (500 ng ml-1) inhibited hydroxyproline secretion induced by combined relaxin and oestrogen treatment. Dibutyryl cyclic adenosine 3',5'-monophosphate (dibutyryl cAMP: 0, 0.1, 1.0, 5.0 mmol l-1) was a potent stimulator of hydroxyproline secretion. These results indicate that relaxin, probably via a cAMP pathway, stimulates hydroxyproline secretion in the presence of oestrogen through a protein- and RNA-synthesis dependent process. Oestrogen plays a role in augmenting the sensitivity of uterine cervical cells to relaxin in the pig.


Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia.
CD8+ T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8+ T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8+ T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8+ T cells are suppressed. In decidual CD8+ T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8+ T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8+ T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8+ T cells (CD8+ EM cells) and naive CD8+ T cells (CD8+ N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8+ T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8+ T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRβ repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8+ EM cells was higher in the decidua than in the peripheral blood. CD8+ EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8+ EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8+ EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8+ EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8+ EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.


Bi-directional DNA Walking Machine and Its Application in an Enzyme-Free Electrochemiluminescence Biosensor for Sensitive Detection of MicroRNAs.
Herein, a dual microRNA (miRNA) powered bi-directional DNA walking machine with precise control was developed to fabricate an enzyme-free biosensor on the basis of distance-based electrochemiluminescence (ECL) energy transfer for multiple detection of miRNAs. By using miRNA-21 as the driving force, the DNA walker could move forth along the track and generated quenching of ECL response due to the proximity between Au nanoparticles (AuNPs) and Mn2+ doped CdS nanocrystals (CdS:Mn NCs) film as the ECL emitters, realizing ultrasensitive determination of miRNA-21. Impressively, once miRNA-155 was introduced as the driving force, the walker could move back along the track automatically, and surface plasmon resonance (SPR) occurred owing to the appropriate large separation between AuNPs and CdS:Mn NCs, achieving an ECL enhancement and realizing ultrasensitive detection of miRNA-155. The bi-directional movement of the DNA walker on the track led to continuous distance-based energy transfer from CdS:Mn NCs film by AuNPs, which resulted in significant ECL signal variation of CdS:Mn NCs for multiple detection of miRNA-21 and miRNA-155 down to 1.51 fM and 1.67 fM, respectively. Amazingly, the elaborated biosensor provided a new chance for constructing controllable molecular nanomachines in biosensing, disease diagnosis, and clinical analysis.


The effect of circulating miR-223 on surveillance of different cancers: a meta-analysis.
Abnormal expression of miR-223 in cancerous tissue has confirmed it as an important player in tumorigenesis of cancers, such as hepatocellular carcinoma, colorectal carcinoma, osteosarcoma, gastric cancer, and chronic lymphocytic leukemia. The present meta-analysis aimed to explore the association between circulating miR-223 and prognosis of cancers. The studies were accessed by an electronic search of multiple databases. RevMan5.3 and STATA14.0 were used to estimate the heterogeneity among studies, pooled effects, and publication bias. Ten studies with data of 1,002 patients with cancer were included in this meta-analysis. The risk of metastasis from stages 3 to 4 of TNM did not decrease when high versus low circulating expression of miR-223 were compared (pooled odds ratio =0.50, 95% CI: 0.24-1.03). In case of prognosis, the overall survival time was not significantly longer with high circulating miR-223 expression (pooled hazard ratio [HR] =0.64, 95% CI: 0.38-1.11) in all cancer types. However, the overall survival time of chronic lymphocytic leukemia (pooled HR =0.19, 95% CI: 0.07-0.54) increased in subgroup analysis. Moreover, the treatment-free survival of chronic lymphocytic leukemia was significantly increased with high circulating miR-223 expression (pooled HR =0.38, 95% CI: 0.23-0.64). Circulating miR-223 was not an effective biomarker in prognosis surveillance in all cancers but in chronic lymphocytic leukemia.


Penile cancer: epidemiology, pathogenesis and prevention.
Penile cancer is a disease with a high morbidity and mortality. Its prevalence is relatively rare, but the highest in some developing countries. Insight into its precursor lesions, pathogenesis and risk factors offers options to prevent this potentially mutilating disease. This review presents an overview of the different histologically and clinically identified precursor lesions of penile cancer and discusses the molecular pathogenesis, including the role of HPV in penile cancer development. A systematic review of the literature evaluating penile carcinogenesis, risk factors and molecular mechanisms involved. Careful monitoring of men with lichen sclerosis, genital Bowen's disease, erythroplasia of Queyrat and bowenoid papulosis seems useful, thereby offering early recognition of penile cancer and, subsequently, conservative therapeutic options. Special attention is given to flat penile lesions, which contain high numbers of HPV. Their role in HPV transmission to sexual partners is highlighted, but their potential to transform as a precursor lesion into penile cancer has been unsatisfactorily explored. Further research should not only focus on HPV mediated pathogenic pathways but also on the non-HPV related molecular and genetic factors that play a role in penile cancer development. Options for prevention of penile cancer include (neonatal) circumcision, limitation of penile HPV infections (either by prophylactic vaccination or condom use), prevention of phimosis, treatment of chronic inflammatory conditions, limiting PUVA treatment, smoking cessation and hygienic measures.


Cervical chyloma after neck dissection: a case report.
Cervical chylomas are rare pseudocystic collections that lack an epithelial lining and arise from the thoracic duct or its tributaries; although they typically develop after neck surgery or trauma, they can arise from unknown causes. Treatment options include not only conservative therapy, such as dietary modification, repeated aspirations, and sclerotherapy, but also include surgical excision. We describe a case of a chyloma in a 64-year-old Japanese woman with squamous cell carcinoma of the gingiva. The chyloma developed following left segmental mandibulectomy with radical neck dissection and reconstruction, using a titanium plate and a pectoralis major myocutaneous flap. One month after surgery, a left supraclavicular swelling was noted, so ultrasound-guided fine-needle aspiration and cytology were performed to exclude a recurrence of neck metastasis. The aspiration yielded a milky fluid without atypical or malignant cells on cytology, confirming the diagnosis of chyloma. Although we performed continuous compressive dressing and started the patient on a low-fat diet, the mass persisted. When the patient died of bone, lung, and liver metastases five months after the second surgery, the mass had not changed in size. Awareness of this complication is important to ensure timely diagnosis and appropriate treatment.


Ethnic and Gender Considerations in the Use of Facial Injectables: Asian Patients.
Asians have distinct facial characteristics due to underlying skeletal and morphological features that differ greatly with those of whites. This together with the higher sun protection factor and the differences in the quality of the skin and soft tissue create a profound effect on their aging process. Understanding of these differences and their effects in the aging process in Asians is crucial in determining effective utilization and placement of injectable products to ensure optimal aesthetic outcomes. For younger Asian women, the main treatment goal is to address the inherent structural deficits through reshaping and the provision of facial support. Facial injectables are used to provide anterior projection, to reduce facial width, and to lengthen facial height. In the older group, the aim is for rejuvenation and also to address the underlying structural issues that has compounded due to age-related volume loss. Asian women requesting cosmetic procedures do not want to be Westernized but rather seeking to enhance and optimize their Asian ethnic features.


Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use.
Colorectal cancer (CRC) is the second most common lethal cancer in the Western world. There is a 10 to 20 years lead time from normal mucosa to carcinoma which offers a window of opportunity to modify and prevent the outcome of CRC, with its incipient morbidity and mortality. The objective of this paper is to review the evidence for chemoprophylaxis in CRC, identify currently used agents and determine their role in the current management algorithm of CRC. Large cohort-control and randomised controlled trials in the most studied chemoprophylaxis agents are reviewed. Currently, the role for chemoprophylaxis in CRC remains a niche area, with celecoxib the only recommended agent for use in patients with familial polyposis syndromes. However, the role of chemoprophylaxis is likely to grow significantly in the next decade as understanding of the stepwise tumorigenesis cascade becomes better understood and current clinical trials are completed.


Post-TATA binding protein recruitment clearance of Gcn5-dependent histone acetylation within promoter nucleosomes.
Transcriptional activation of eukaryotic genes often requires the function of histone acetyltransferases (HATs), which is expected to result in the hyperacetylation of histones within promoter nucleosomes. In this study we show that, in Saccharomyces cerevisiae, the steady-state levels of Gcn5-dependent histone acetylation within a number of transcriptionally active promoters are inversely related to the rate of transcription. High acetylation levels were measured only when transcription was attenuated either by TATA element mutations or in a strain carrying a temperature-sensitive protein component of RNA polymerase II. In addition, we show that in one case the low levels of histone acetylation depend on the function of the Rpd3 histone deacetylase. These results point to the existence of an unexpected interplay of two opposing histone-modifying activities which operate on promoter nucleosomes following the initiation of RNA synthesis. Such interplay could ensure rapid turnover of chromatin acetylation states in continuously reprogrammed transcriptional systems.


Fractionation of soybean phospholipids by preparative high-performance liquid chromatography with sorbents of various particle size.
Normal-phase high-performance liquid chromatography was used on a preparative scale to seperate phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylcholine (PC) phospholipids from soybean. Separation was achieved using mixtures of three solvents, hexane, methanol and isopropanol. The optimized mobile phase compositions were experimentally determined while operating in a linear gradient mode using 15, 5-20, 25-40, and 40-63 microm preparative particles as well as 4 microm analytical particles. A gradient mobile phase was established on a commmercially available analytical Nova-Pak column such that hexane linearly decreased from 85 to 0 as isopropanol and methanol linearly increased in two gradient steps from 10 to 30 and 5 to 70 respectively. The total run time was 25 min at a flow-rate of 1.5 ml/min. A slight change in mobile phase composition was required to increase the resolution of phospholipids. The 15 microm particle size gave the best separation of the preparative particle sizes examined based on their resolutions between PE and PI and PI and PC. Finally, the retention factors of PE and PC were correlated in terms of mobile phase composition.


Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis.
Interleukin-31 (IL-31) is a member of the gp130/interleukin-6 cytokine family that is produced by cell types such as T helper 2 lymphocytes and cutaneous lymphocyte antigen positive skin homing T cells. When overexpressed in transgenic mice, IL-31 induces severe pruritus, alopecia and skin lesions. In humans, IL-31 serum levels correlate with the severity of atopic dermatitis in adults and children. To determine the role of IL-31 in canine pruritus and naturally occurring canine atopic dermatitis (AD). Purpose-bred beagle dogs were used for laboratory studies. Serum samples were obtained from laboratory animals, nondiseased client-owned dogs and client-owned dogs diagnosed with naturally occurring AD. Purpose-bred beagle dogs were administered canine interleukin-31 (cIL-31) via several routes (intravenous, subcutaneous or intradermal), and pruritic behaviour was observed/quantified via video monitoring. Quantitative immunoassay techniques were employed to measure serum levels of cIL-31 in dogs. Injection of cIL-31 into laboratory beagle dogs caused transient episodes of pruritic behaviour regardless of the route of administration. When evaluated over a 2 h period, dogs receiving cIL-31 exhibited a significant increase in pruritic behaviour compared with dogs that received placebo. In addition, cIL-31 levels were detectable in 57% of dogs with naturally occurring AD (≥ 13 pg/mL) but were below limits of quantification (<13 pg/mL) in normal, nondiseased laboratory or client-owned animals. Canine IL-31 induced pruritic behaviours in dogs. Canine IL-31 was detected in the majority of dogs with naturally occurring AD, suggesting that this cytokine may play an important role in pruritic allergic skin conditions, such as atopic dermatitis, in this species.


A study on the role of N-methyl-D-aspartate receptors in the rat visual cortex.
The amino acid L-glutamate is a major excitatory neurotransmitter in the central nervous system of vertebrates. NMDA (N-methyl-d-aspartate) is one of the L-glutamate receptor subtypes. During a critical period of early postnatal development, the visual cortex is susceptible to experience-dependent modification of neuronal responses. Recently, the activation of NMDA receptors has been supposed as a prerequisite for the induction of such modification. We therefore investigated developmental changes of NMDA receptors in the rat visual cortex and questioned whether they could be related to the visual development. We assessed the density of [3H]-NMDA receptor in the visual cortex of normally reared rate (Group I) and visually deprived rats (Group II) using quantitative autoradiography. The density of [3H]-NMDA receptor was significantly lower in Group II than in group I during the early postnatal period, and increased rapidly by postnatal 1 week and, decreased after postnatal 5 weeks. These results suggested that NMDA receptors may play a role in neuronal development in the visual cortex during the early postnatal period.


Remote autopsy services: A feasibility study on nine cases.
Introduction We have conducted a feasibility study on remote autopsy services in order to increase the flexibility of the service with benefits for teaching and interdepartmental collaboration. Methods Three senior staff pathologists, one senior autopsy technician and one junior resident participated in the study. Nine autopsies were performed by the autopsy technician or resident, supervised by the primary pathologist, through the secure, double encrypted video link using Jabber Video (Cisco) with a high-speed broadband connection. The primary pathologist and autopsy room each connected to the secure virtual meeting room using 14″ laptops with in-built cameras (Hewlett-Packard). A portable high-definition web camera (Cisco) was used in the autopsy room. Primary and secondary pathologists independently interpreted and later compared gross findings for the purpose of quality assurance. The video was streamed live only during consultations and interpretation. A satisfaction survey on technical and professional aspects of the study was conducted. Results Independent interpretations of gross findings between primary and secondary pathologists yielded full agreement. A definite cause of death in one complex autopsy was determined following discussions between pathologists and reviews of the clinical notes. Our satisfaction level with the technical and professional aspects of the study was 87% and 97%, respectively. Discussion Remote autopsy services are found to be feasible in the hands of experienced staff, with increased flexibility and interest of autopsy technicians in the service as a result.


Effects from a 90-day inhalation toxicity study with cerium oxide and barium sulfate nanoparticles in rats.
Nanomaterials like cerium oxide and barium sulfate are frequently processed in industrial and consumer products and exposure of humans and other organisms is likely. Generally less information is given on health effects and toxicity, especially regarding long-term exposure to low nanoparticle doses. Since inhalation is still the major route of uptake the present study focused on pulmonary effects of CeO2NM-212 (0.1, 0.3, 1.0, 3.0 mg/m3) and BaSO4NM-220 nanoparticles (50.0 mg/m3) in a 90-day exposure setup. To define particle-related effects and potential mechanisms of action, observations in histopathology, bronchoalveolar lavage and immunohistochemistry were linked to pulmonary deposition and clearance rates. This further allows evaluation of potential overload related effects. Lung burden values increased with increasing nanoparticle dose levels and ongoing exposure. At higher doses, cerium clearance was impaired, suggesting lung overload. Barium elimination was extremely rapid and without any signs of overload. Bronchoalveolar lavage fluid analysis and histopathology revealed lung tissue inflammation with increasing severity and post-exposure persistency for CeO2. Also, marker levels for genotoxicity and cell proliferation were significantly increased. BaSO4 showed less inflammation or persistency of effects and particularly affected the nasal cavity. CeO2 nanoparticles penetrate the alveolar space and affect the respiratory tract after inhalation mainly in terms of inflammation. Effects at low dose levels and post-exposure persistency suggest potential long-term effects and a notable relevance for human health. The generated data might be useful to improve nanoparticle risk assessment and threshold value generation. Mechanistic investigations at conditions of non-overload and absent inflammation should be further investigated in future studies.


Minimally invasive transforaminal lumbar interbody fusion: Results of 23 consecutive cases.
The use of minimally invasive surgical (MIS) techniques represents the most recent modification of methods used to achieve lumbar interbody fusion. The advantages of minimally invasive spinal instrumentation techniques are less soft tissue injury, reduced blood loss, less postoperative pain and shorter hospital stay while achieving clinical outcomes comparable with equivalent open procedure. The aim was to study the clinicoradiological outcome of minimally invasive transforaminal lumbar interbody fusion. This prospective study was conducted on 23 patients, 17 females and 6 males, who underwent MIS-transforaminal lumbar interbody fusion (TLIF) followed up for a mean 15 months. The subjects were evaluated for clinical and radiological outcome who were manifested by back pain alone (n = 4) or back pain with leg pain (n = 19) associated with a primary diagnosis of degenerative spondylolisthesis, massive disc herniation, lumbar stenosis, recurrent disc herniation or degenerative disc disease. Paraspinal approach was used in all patients. The clinical outcome was assessed using the revised Oswestry disability index and Macnab criteria. The mean age of subjects was 55.45 years. L4-L5 level was operated in 14 subjects, L5-S1 in 7 subjects; L3-L4 and double level was fixed in 1 patient each. L4-L5 degenerative listhesis was the most common indication (n = 12). Average operative time was 3 h. Fourteen patients had excellent results, a good result in 5 subjects, 2 subjects had fair results and 2 had poor results. Three patients had persistent back pain, 4 patients had residual numbness or radiculopathy. All patients had a radiological union except for 1 patient. The study demonstrates a good clinicoradiological outcome of minimally invasive TLIF. It is also superior in terms of postoperative back pain, blood loss, hospital stay, recovery time as well as medication use.


Chiral Yolk-Shell MOF as an Efficient Nanoreactor for Asymmetric Catalysis in Organic-Aqueous Two-Phase System.
It remains a great challenge to introduce large and efficient homogeneous asymmetric catalysts into MOFs and other microporous materials as well as retain their degrees of freedom. Herein, a new heterogeneous strategy of homogeneous chiral catalysts is proposed, that is, to construct a yolk-shell MOFs-confined, large-size, and highly efficient homogeneous chiral catalyst, which can be used as a nanoreactor for asymmetric catalytic reactions.


Machine Learning Approaches to Understand Cognitive Phenotypes in People With HIV.
Cognitive disorders are prevalent in people with HIV (PWH) despite antiretroviral therapy. Given the heterogeneity of cognitive disorders in PWH in the current era and evidence that these disorders have different etiologies and risk factors, scientific rationale is growing for using data-driven models to identify biologically defined subtypes (biotypes) of these disorders. Here, we discuss the state of science using machine learning to understand cognitive phenotypes in PWH and their associated comorbidities, biological mechanisms, and risk factors. We also discuss methods, example applications, challenges, and what will be required from the field to successfully incorporate machine learning in research on cognitive disorders in PWH. These topics were discussed at the National Institute of Mental Health meeting on "Biotypes of CNS Complications in People Living with HIV" held in October 2021. These ongoing research initiatives seek to explain the heterogeneity of cognitive phenotypes in PWH and their associated biological mechanisms to facilitate clinical management and tailored interventions.


Synergism Antiproliferative Effects of Apigenin and Naringenin in NSCLC Cells.
Non-small cell lung cancer (NSCLC) is one of the leading cancer killers. Apigenin (Api) and Naringenin (Nar) are natural bioactive substances obtained in various vegetables and fruits, possessing anti-tumor effects across multiple studies. This study investigated the latent synergistic antiproliferative functions of Api and Nar in A549 and H1299 NSCLC cells. Cell viability was determined after incubating with different concentrations of Api, Nar, or the combination of Api and Nar (CoAN) for 24 h. Analysis using the CompuSyn software revealed that the CI value of each combined dose was < 1, depicting that the two drugs had a synergistic inhibitory effect. The CoAN (A:N = 3:2) group with the lowest CI value was selected for subsequent experiments. The IC50 of CoAN (A:N = 3:2) was used to determine the cell cycle, the expression ratio of Bax to Bcl2, Caspase 3 activity, and mitochondrial function to assess oxidative stress and apoptosis. The results established that CoAN treatment caused significant cytotoxicity with cell cycle arrest at G2/M phases. Furthermore, CoAN significantly enhanced mitochondria dysfunction, elevated oxidative stress, and activated the apoptotic pathway versus Api or Nar alone groups. Thus, the CoAN chemotherapy approach is promising and deserves further research.


Primary Squamous Cell Carcinoma of the Stomach: A Case Report and Review of the Literature.
Primary gastric squamous cell carcinoma (PGSCC) is an exceedingly rare disease, accounting for 0.04% - 0.07% of all gastric cancers. First reported in 1895 by Rörig et al, less than 100 cases of PGSCC worldwide have been reported in the literature. These reports show PGSCC is more common in males (5:1 male to female ratio), and exhibits a peak incidence in the sixth decade of life. It may involve any portion of the stomach with predilection for the proximal stomach, especially along the lesser curvature. Although no clear pathogenesis of this tumor has been reported, several plausible theories have been proposed. These include squamous differentiation of preexisting gastric adenocarcinoma, cancerization of ectopic squamous epithelium, malignant transformation of squamous metaplasia of glandular epithelium, association with Helicobacter pylori or Epstein-Barr virus infection, and evolution in the setting of marked chronic gastritis with intestinal metaplasia. This report presents and discusses the case of a 64-year-old female who developed PGSCC arising in the gastric fundus.


Effects of cryopreservation on the depth-dependent elastic modulus in articular cartilage and implications for osteochondral grafting.
Cryopreservation of articular cartilage is often used in storage of experimental samples and osteochondral grafts, but the depth-dependence and concentration of glycosaminoglycan (GAG) are significantly altered when cryogenically stored without a cryoprotectant, which will reduce cartilage stiffness and affect osteochondral graft function and long-term viability. This study investigates our ability to detect changes due to cryopreservation in the depth-dependent elastic modulus of osteochondral samples. Using a direct-visualization method requiring minimal histological alterations, unconfined stepwise stress relaxation tests were performed on four fresh (never frozen) and three cryopreserved (-20 °C) canine humeral head osteochondral slices 125 ± 5 μm thick. Applied force was measured and tissue images were taken at the end of each relaxation phase using a 4× objective. Intratissue displacements were calculated by tracking chondrocytes through consecutive images for various intratissue depths. The depth-dependent elastic modulus was compared between fresh and cryopreserved tissue for same-depth ranges using analysis of variance (ANOVA) with Tukey post-test with a 95% confidence interval. Cryopreservation was found to significantly alter the force-displacement profile and reduce the depth-dependent modulus of articular cartilage. Excessive collagen fiber folding occurred at 40-60% relative depth, producing a "black line" in cryopreserved tissue. Force-displacement curves exhibited elongated toe-region in cryopreserved tissue while fresh tissue had nonmeasurable toe-region. Statistical analysis showed significant reduction in the elastic modulus and GAG concentration throughout the tissue between same-depth ranges. This method of cryopreservation significantly reduces the depth-dependent modulus of canine humeral osteochondral samples.


The effect of dietary anthocyanins on biochemical, physiological, and subjective exercise recovery: a systematic review and meta-analysis.
Anthocyanins (ACN), the sub-class of (poly)phenols responsible for the red-blue-purple pigmentation of fruit and vegetables, have gained considerable interest in sport and exercise research due to their potential to facilitate exercise recovery. A systematic literature search was performed using PubMed, The Cochrane Library, MEDLINE, SPORTDiscus and CINAHL. Thirty nine studies were included and the standardized mean difference (Hedges g) for creatine kinase (CK), anti-oxidative and inflammatory markers, strength, power and delayed onset muscle soreness (DOMS) indices were pooled in separate meta-analyses; meta-regression was also performed on reported ACN dose. Immediately post-exercise there was an increase in antioxidant capacity (g: 0.56) and reduced C reactive protein (g: -0.24) and tumor necrosis factor α (g: -40); p ≤ 0.02. Strength was improved with ACN at all time points (g: 0.45-0.67). DOMS (g: -0.23) was lower 24 hours post-exercise and power was improved 24 hours (g: 0.62) and 48 hours (g: 0.57) post exercise. The CK was lower 48 hours post-exercise (g: -0.31) and there was a trend for a positive association with ACN dose (p = 0.057). This systematic review provides new data showing ACN-rich foods promote functional and subjective recovery likely due to the antioxidant and anti-inflammatory properties of ACN.


Ultrasonography in the detection of intra-abdominal retained surgical sponges.
Six cases of confirmed retained surgical sponges are reviewed. In five patients a clean, clear-cut acoustic shadow could be identified in relation to a palpable mass. In four of these patients the sponges were identified preoperatively by their ultrasonographic appearance. Abdominal radiographs were usually obtained afterwards, to confirm the diagnostic impression or to rule out bowel gas or calcifications. Since this ultrasonographic finding has not been described previously, the authors call attention to it in order to prevent misdiagnosis.


Geometric Analysis of the Proximal Humerus in Elderly Japanese Patients: Implications for Implant Selection in Reverse Shoulder Arthroplasty.
The implants used in reverse shoulder arthroplasty were originally designed for white patients; thus, they might not be optimal for smaller Asian patients. The selection of reverse shoulder arthroplasty systems is limited in Japan. The purpose of this study was to measure the geometry of the proximal humerus in elderly Japanese patients to inform implant selection according to humerus size. This study included 155 shoulders from 148 patients 50 years or older who underwent computed tomography for shoulder disorders other than arthritis and trauma. There were 67 male and 81 female patients with mean ages of 68 and 66 years, respectively. The humeral head diameter, head height, neck-shaft angle, neck diameters, and osteotomy diameters for 155° inclination implants were measured using surface models created from computed tomography scans. The mean diameter of head curvature, humeral head height, and neck-shaft angle were 48.2 mm, 19.8 mm, and 136° for male patients and 42.4 mm, 17.1 mm, and 136° for female patients, respectively. The mean mediolateral and anteroposterior neck diameters were 46.9 mm and 43.7 mm for men and 41.6 mm and 38.4 mm for women, respectively. The mean mediolateral and anteroposterior osteotomy diameters were 42.2 mm and 41.2 mm for male patients and 38.6 mm and 36.7 mm for female patients, respectively. There were significant differences between the sexes in all measurements except neck-shaft angle. Humeral implants with 155° inclination will not fit the humerus of smaller Japanese women. Thus, implants with anatomical inclination and an onlay humeral tray may be a better choice for smaller patients. [Orthopedics. 2017; 40(3):e485-e490.].


Dynamic light scattering from an optically trapped microsphere.
Using a single microscope objective lens to optically trap, illuminate, and collect backscattered light of a dielectric microsphere, we measure the temporal-intensity-autocorrelation functions (ACFs), and intensity profiles to obtain the trap stiffness and friction coefficient of the bead. This is an interesting study of an harmonically bound Brownian particle, with nanometer resolution. We extend the work of Bar-Ziv et al. [Phys. Rev. Lett. 78, 154 (1997)] to more general situations allowing for the use of our simpler geometry in other applications. As examples, we present measurements of the parallel Stokes friction coefficient on the trapped bead as a function of its distance from a surface and the entropic force of a single lambda-DNA molecule.


What neurosurgeons should do to succeed in tomorrow's scientific and socioeconomic environment.
There will be major scientific advances and socioeconomic changes in the 21st century that will influence the development of medicine and neurosurgery. These changes will affect those in academic medical centers and the private practitioners of medicine and neurosurgery. Neurosurgeons' philosophy and practice methods must adapt to these trends. Because of the continuing growth in scientific knowledge and the rapid spread of communications of all types, physicians will best work in groups and teams. These group forces will require the physicians to surrender some independence to gain the power of the integrated knowledge and political and social force of a group. Graduate and postgraduate education programs will also change to adapt to these new realities. Those who understand these new shifts will be the most successful in establishing and conducting practices in academic centers and private practice.


Encapsulation, controlled release, and antitumor efficacy of cisplatin delivered in liposomes composed of sterol-modified phospholipids.
We employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shorter acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well-studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.


Advanced mast cell disease: an Italian Hematological Multicenter experience.
The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, alpha-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate. D816V c-kit mutation is frequent and associated with resistance against Imatinib. Because of the rarity of these forms, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies.


MR Imaging with Apparent Diffusion Coefficient Histogram Analysis: Evaluation of Locally Advanced Rectal Cancer after Chemotherapy and Radiation Therapy.
Purpose To determine response to neoadjuvant chemotherapy and radiation therapy in patients with locally advanced rectal cancer (LARC) by using magnetic resonance (MR) apparent diffusion coefficient (ADC) histogram analysis. Materials and Methods Ninety-two patients with LARC underwent MR imaging with rectal barium before and after chemotherapy and radiation therapy (CRT). Rectal expansion with barium expanded the lumen, provided similar imaging geometry before and after CRT, and eliminated fecal matter, air, and residual fluid. T2-weighted images, the percentage change in ADC, and ADC histogram skewness and kurtosis were assessed. The histopathologic tumor regression grade (TRG) ranged from 1a (66%-99% residual tumor cells) to 3 (no residual cells). The Wilcoxon signed-rank test, the Spearman correlation test, multivariable linear regression, and one-way analysis of variance were used to determine post- and pretreatment differences and correlations between tumor size and ADC. Results Of the 92 patients, 16 (17.4%) had TRG 3, 27 (29.3%) had TRG 2b, 24 (26.1%) had TRG 2a, 14 (15.2%) had TRG 1b, and 11 (12%) had TRG 1a. Post-CRT skewness (regression coefficient = 10.9, P = .06) and percentage ADC change (regression coefficient = -0.18, P = .03) were associated with the percentage of residual tumor. Post-CRT skewness and percentage ADC change, respectively, showed negative and positive correlation with histopathologic TRG (post-CRT skewness: P = .024; percentage ADC change: P = .001). Conclusion In patients with LARC, post-CRT skewness of the ADC histogram and percentage change in ADC were useful for predicting a favorable response to neoadjuvant CRT. © RSNA, 2018 Online supplemental material is available for this article.


Transport and storage of infusion supplies and blood products.
Home care nurses face many challenges in transporting and storing medications and blood products in their vehicles and in patients' homes. Unlike climate-controlled institutions, products subject to the cold of winter and the heat of summer can easily be damaged, which can be harmful to the patient. Additionally, several regulations and protocols demand that products be cared for in a certain manner, stored in the proper container, and labeled appropriately. The following information presents the current practices in storing and transporting these products safely. It can be used as a guide for policy and procedure development and a review for clinicians in assuring safe handling of these products from office to home to lab.


The effect of sex differences and nondefensiveness on the predictive validity of Barron's Es scale.
Extended research reported by Clayton and Graham (1979) on the relationship between Es scores and nondefensiveness with respect to prognosis for positive change in treatment (N = 103). Sex differences and the effect of restricting the F-K index as a measure of defensiveness to the normal range (+1 to +9) were investigated. Results indicated that for females only low Es scores and nondefensiveness (as measured by patients' willingness to admit to having problems and by an F-K index in the normal range) were to a limited degree significantly related to positive outcome. Implications of these findings in terms of the validity of Barron's Es scale for an inpatient psychiatric population were discussed.


Enhanced mesenchymal stromal cell recruitment via natural killer cells by incorporation of inflammatory signals in biomaterials.
An exacerbated inflammatory response questions biomaterial biocompatibility, but on the other hand, inflammation has a central role in the regulation of tissue regeneration. Therefore, it may be argued that an 'ideal' inflammatory response is crucial to achieve efficient tissue repair/regeneration. Natural killer (NK) cells, being one of the first populations arriving at an injury site, can have an important role in regulating bone repair/regeneration, particularly through interactions with mesenchymal stem/stromal cells (MSCs). Here, we studied how biomaterials designed to incorporate inflammatory signals affected NK cell behaviour and NK cell-MSC interactions. Adsorption of the pro-inflammatory molecule fibrinogen (Fg) to chitosan films led to a 1.5-fold increase in adhesion of peripheral blood human NK cells, without an increase in cytokine secretion. Most importantly, it was found that NK cells are capable of stimulating a threefold increase in human bone marrow MSC invasion, a key event taking place in tissue repair, but did not affect the expression of the differentiation marker alkaline phosphatase (ALP). Of significant importance, this NK cell-mediated MSC recruitment was modulated by Fg adsorption. Designing novel biomaterials leading to rational modulation of the inflammatory response is proposed as an alternative to current bone regeneration strategies.


Acquired vitamin K-dependent carboxylation deficiency in liver disease.
gamma-Carboxyglutamic acid residues on prothrombin are synthesized from glutamic acid on a prothrombin precursor in the liver through a vitamin K-dependent carboxylase. In the absence of vitamin K or in the presence of vitamin K antagonists, an inert form of prothrombin - abnormal prothrombin - circulates in the blood. We have developed specific immunoassays for native and abnormal human prothrombin. The prothrombin concentration in our normal subjects was 108 +/- 19 microgram per milliliter. The abnormal-prothrombin concentration varied over four orders of magnitude between the limits of detection in normal plasma and the level in patients with cirrhosis (0 to 5 microgram per milliliter), acute hepatitis (0 to 33 microgram per milliliter), or vitamin K deficiency (32 to 100 microgram per milliliter) and in those treated with sodium warfarin (12 to 65 microgram per milliliter). These studies indicate that abnormal prothrombin is not a component of normal plasma but appears in a variety of hepatic and nutritional disorders characterized by impaired hepatic vitamin-K-dependent carboxylation.


Compositional equivalence of barleys differing only in low- and normal-phytate levels.
Recent breeding advances have led to the development of several barley lines and cultivars with significant reductions (50% or greater) in phytate levels. Low-phytate (LP) grain is distinguished by containing not only a reduced level of phytate P but also an increased level of inorganic P, resulting in greater bioavailability of P and mineral cations in animal diets. It is important to determine whether other nutritional characteristics are altered by breeding for the low-phytate trait. This study was designed to investigate if breeding for reduced phytate content in barleys had any effect on the contents of other attributes measured by comparing mean and range values of the levels of protein, oil, ash, total carbohydrate, starch, and β-glucan, fatty acid composition, and levels of tocopherols and tocotrienols between five LP and five normal-phytate barleys grown in three Idaho locations. Results show that only the phytate level in the LP group was substantially lower than that of the normal-phytate group and that all other attributes measured or calculated were substantially equivalent between the two groups of barleys. Therefore, the phytate level had little effect on the levels of protein, oil, ash, total carbohydrate, starch, and β-glucan, fatty acid composition, and levels of tocopherols and tocotrienols in barley seeds.


[Polymorphonuclear leukocyte elastase (PMNE) levels in sepsis; the effect of PMNE on multiple organ failure (MOF)].
To study the role of lysosomal protease released from polymorphonuclear leukocytes during MOF, plasma PMNE levels were measured serially in 38 patients. The patients were divided into two groups, 14 patients of MOF from sepsis (group 1), and 24 injured patients without MOF (group 2). The normal value of PMNE was from 21 to 165 micrograms/l. The PMNE levels of the group 1 elevated (831 +/- 241 micrograms/l) at the time of diagnosis of sepsis and remained high during MOF. On the contrary, those of the group 2 were high on admission (574 +/- 131 micrograms/l), but returned to normal within seven days. There was no relationship between the levels of PMNE and the number of neutrophils. However, the PMNE/neutrophils ratio was significantly higher in group 1. Correlations were demonstrated between the amount of PMNE and the decrease in the levels of platelet counts, fibronectin and coagulation factor XIII. It is suggested that PMNE might play a major role in the pathobiochemical changes and tissue injury during MOF.


Genome-wide characterization of Mediator recruitment, function, and regulation.
Mediator is a conserved and essential coactivator complex broadly required for RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator binding in budding yeast have revealed new insights into the functions of this critical complex and raised new questions about its role in the regulation of gene expression.


Catalytic destruction of dichloromethane using perovskite-type oxide catalysts.
Dichloromethane (DCM, also known as methylene chloride [CH2Cl2]) is often present in industrial waste gas and is a valuable chemical product in the chemical industry. This study addresses the oxidation of airstreams that contain CH2Cl2 by catalytic oxidation in a tubular fixed-bed reactor over perovskite-type oxide catalysts. This work also considers how the concentration of influent CH2Cl2 (Co = 500-1000 ppm), the space velocity (GHSV = 5000-48,000 1/hr), the relative humidity (RH = 10-70%) and the concentration of oxygen (O2 = 5-21%) influence the operational stability and capacity for the removal of CH2Cl2. The surface area of lanthanum (La)-cobalt (Co) composite catalyst was the greatest of the five perovskite-type catalysts prepared in various composites of La, strontium, and Co metal oxides. Approximately 99.5% CH2Cl2 reduction was achieved by the catalytic oxidation over LaCoO3-based perovskite catalyst at 600 degrees C. Furthermore, the effect of the initial concentration and reaction temperature on the removal of CH2Cl2 in the gaseous phase was also monitored. This study also provides information that a higher humidity corresponds to a lower conversion. Carbon dioxide and hydrogen chloride were the two main products of the oxidation process at a relative humidity of 70%.


Adenovector-mediated expression of human thrombopoietin cDNA in immune-compromised mice: insights into the pathophysiology of osteomyelofibrosis.
Thrombopoietin (TPO) cDNA can be effectively delivered in vivo by adenovectors. Immune normal mice (BALB/c) and syngeneic mice with variable degrees of immune dysfunction nu, SCID, and NOD-SCID) were treated with an adenovirus vector expressing the human TPO cDNA (AdTPO). Platelet peaks were significantly higher in SCID and NOD-SCID mice compared with BALB/c and nu mice. Human plasma TPO concentration correlated with the platelet counts. SCID and NOD-SCID mice exhibited also granulocytosis and increased numbers of hemopoietic progenitors in bone marrow. Following platelet peak, BALB/c mice developed autoantibodies against murine TPO leading to thrombocytopenia and depletion of megakaryocytes and hemopoietic progenitors in bone marrow. AdTPO-treated SCID mice developed osteomyelofibrosis and extramedullary/extrasplenal hemopoiesis. In contrast, NOD-SCID mice with a similar magnitude of TPO overexpression did not show fibrotic changes in bone marrow. We conclude, first, that a chronic high level of TPO overexpression stimulates megakaryocytopoiesis and myelopoiesis leading to thrombocytosis and granulocytosis. Second, increased megakaryocytopoiesis is not sufficient for development of secondary osteomyelofibrosis. The functionally deficient monocytes and macrophages of NOD-SCID mice probably prevented fibrotic marrow changes. Third, immune deficiency enhances expression of adenovirally mediated transgenes, and fourth, xenogeneic transgene delivered by adenovector to a host with normal immune functions may induce loss of immune tolerance and autoimmune phenomenon.


[Hypothalamic-infundibular histiocytosis: magnetic resonance findings].
We report the magnetic resonance imaging (MRI) of a case of Langerhans cell histiocytosis in the pituitary. Isolated central nervous system involvement is uncommon. An eighteen-years old female patient who had an acute onset of central diabetes insipidus because of the Langerhans cell histiocytosis. The MRI evidenced a lesion in the hypothalamic-pituitary axis. The hyperintensity in the posterior pituitary lobe, which is seen in normal subjects on T1-weighted images, was absent. The pituitary stalk was thickened and enhanced homogeneously following contrast administration. During the follow-up, the infundibullar lesion extended to the hypothalamic region and other systemic manifestations appeared. Diagnosis of Langerhans cell histiocytosis was confirmed by lung biopsy. After radiotherapy and chemotherapy, MRI showed regression of the hypothalamic-pituitary lesion. The combination of these findings, although nonspecific of Langerhans cell histiocytosis, should nevertheless prompt further studies, including chest films, bone scanning and temporal bone computerized tomography in order to narrow the differential diagnosis.


Antigen-specific mouse lymphocyte stimulation by DNP-conjugated T-independent antigens studied by photobleaching recovery.
Fluorescence photobleaching recovery techniques have allowed us to measure the lateral mobility of T-independent antigens bound to antigen-specific mouse B cells. The in vitro immunogenicity or tolerogenicity of antigens we have examined, DNP-polymerized flagellin (DNP-POL), and DNP-linear dextran (DNP-DEX), depend upon the antigen dose and epitope density. These factors also determine the mobility of antigen bound to B cell surfaces. For DNP-POL bound to DNP-specific cells, the observed diffusion constants D decrease monotonically with increasing antigen dose and epitope density. Values of D range from 10.4 X 10(-11) cm2 sec-1 for DNP0.4-POL at 0.15 microgram/ml to 0.8 X 10(-11) cm2 sec-1 for DNP3.5-POL at 30 microgram/ml. For receptor bound DNP-DEX, D depends strongly on antigen epitope density but not observably on antigen concentration. For epitope densities of 1.2 or less, D is close to the value of 21 X10(-11) cm2 sec-1 observed for single sIg receptors. By an epitope density of 4.8, D has fallen to 2.1 X 10(-11) cm2 sec-1. Peak immunogenicities for DNP-POL and DNP-DEX are observed when antigen-receptor aggregates have mobilities 14-fold and 3-fold lower, respectively, than a single sIg molecule.


Extracellular Vesicles Facilitate the Transportation of Nanoparticles within and between Cells for Enhanced Tumor Therapy.
The interaction between nanoparticles and cells is closely associated with the therapeutic effects of nanomedicine. Nanoparticles could be transported among cells, but the process-related mechanism remains to be further explored. In this study, it was found that endocytosed cationic polymer nanoparticles (cNPs) could be excreted in an extracellular vesicle (EV)-coated form (cNP@EVs). It was deduced that cNPs may pass through early endosomes, multivesicular bodies (MVBs), and autophagic MVBs within cells. Moreover, a high level of autophagy facilitated the exocytosis process. Since EVs were the effective vehicles for conveying biological information and substances, cNP@EVs were proved to be efficient forms for the intercellular transportation of nanoparticles and have the potential as efficient biomimetic drug delivery systems. These properties endowed cNP@EVs with deep penetration and enhanced antitumor activity. Our findings provided a proof-of-concept for understanding the transfer process of nanoparticles among cells and may help us to further utilize EV-mediated transportation of nanoparticles, therefore, expanding its clinical application.


Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.
Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10-6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.


Extending the scope of eco-labelling in the food industry to drive change beyond sustainable agriculture practices.
New consumer awareness is shifting industry towards more sustainable practices, creating a virtuous cycle between producers and consumers enabled by eco-labelling. Eco-labelling informs consumers of specific characteristics of products and has been used to market greener products. Eco-labelling in the food industry has yet been mostly focused on promoting organic farming, limiting the scope to the agricultural stage of the supply chain, while carbon labelling informs on the carbon footprint throughout the life cycle of the product. These labelling strategies help value products in the eyes of the consumer. Because of this, decision makers are motivated to adopt more sustainable models. In the food industry, this has led to important environmental impact improvements at the agricultural stage, while most other stages in the Food Supply Chain (FSC) have continued to be designed inefficiently. The objective of this work is to define a framework showing how carbon labelling can be integrated into the design process of the FSC. For this purpose, the concept of Green Supply Chain Network Design (GSCND) focusing on the strategic decision making for location and allocation of resources and production capacity is developed considering operational, financial and environmental (CO2 emissions) issues along key stages in the product life cycle. A multi-objective optimization strategy implemented by use of a genetic algorithm is applied to a case study on orange juice production. The results show that the consideration of CO2 emission minimization as an objective function during the GSCND process together with techno-economic criteria produces improved FSC environmental performance compared to both organic and conventional orange juice production. Typical results thus highlight the importance that carbon emissions optimization and labelling may have to improve FSC beyond organic labelling. Finally, CO2 emission-oriented labelling could be an important tool to improve the effects eco-labelling has on food product environmental impact going forward.


Quantitative analysis of liquid crystal-based immunoassay using rectangular capillaries as sensing platform.
In past studies, liquid crystal (LC)-based immunoassays were accomplished by fabricating an LC cell with two pieces of glass slides after immunobinding, which makes the determination of the immunoassay not in real-time and requires trained personnel. Herein, we developed the LC-based immunoassay by using rectangular capillaries as the substrate for immunobinding. The inner surface of rectangular capillaries was decorated with a long alkyl saline, dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride (DMOAP), followed by immobilization of human serum albumin (HSA) as the probe. In this situation, the orientation of LC was homeotropic and dark LC image was observed under polarized light. When the solution containing anti-human serum albumin (anti-HSA) were dispensed into the capillary through capillary action, the specific immunobinding between HSA and anti-HSA formed an immunocomplex on the inner surface of capillary, which disrupted the original orientation of LC and led to a dark-to-bright transition of the LC images. The quantification of anti-HSA can be achieved by measuring the length of the bright LC image in the rectangular capillary. By using this immunoassay, the limit of detection (LOD) for anti-HSA is 1 μg/mL, and it did not respond to HSA and anti-human immunoglobulin G (anti-h-IgG). On the other hand, the diversity of the LC-based immunoassay can be extended for HSA detection when we immobilized anti-HSA in the capillary. Because the post-fabrication of LC cell was waived by using rectangular capillaries to develop the LC-based immunoassay, it is more convenient for users to handle and collect more reliable data. Moreover, the results of the immunoassay were visualized through naked-eye and could be recorded by a smartphone; it is more suitable for portable and point-of-care applications.


A comparative study of cardiac output measurement by dye dilution and pulsed Doppler ultrasound.
Dye dilution was compared with pulsed doppler for the measurement of cardiac output in eighteen children being ventilated after cardiac surgery. The mean difference between the two techniques was -0.04/min (dye minus doppler) with 95% confidence limits of 0.25 l/min and -0.33 l/min over a cardiac output range 0.27-6.12 l/min; this difference is not significant. Calculation of the product-moment correlation coefficient showed a close relationship between the dye dilution and doppler methods with r = 0.97. Pulsed doppler is a new noninvasive technique that can be used instead of dye dilution for the measurement of cardiac output in co-operative or anaesthetised children.


Two new erythroneurine leafhopper genera and first record of Thailus Mahmood from China (Hemiptera: Cicadellidae: Typhlocybinae), with description of four new species.
Two new genera of tribe Erythroneurini from China, Saccata gen. nov. and Variolosa gen. nov. are described and illustrated based on type species Saccata insolita sp. nov. and Variolosa meni sp. nov. respectively. Genus Thailus Mahmood with new species Thailus versicolor sp. nov. is reported from China for the first time and another new species, T rectilinea sp. nov. from Thailand is also described. A key to adult males of Thailus is provided.


Mechanisms underlying neuro-inflammation and neurodevelopmental toxicity in the mouse neocortex following prenatal exposure to ethanol.
Fetal alcohol spectrum disorders (FASD) constitute a wide range of disorders that arise from prenatal exposure to ethanol (EtOH). However, detailed reports regarding the adverse effects of prenatal EtOH exposure on neocortical morphology and its underlying pathogenic mechanisms are limited. In the present study, we aimed to characterize the anatomical abnormalities of neocortical development and their correlation with microglial properties and neuro-inflammation in a mouse model of FASD. We evaluated the development and maturation of the neocortex in ICR mice prenatally exposed to 25% (w/v) EtOH using histological and molecular analyses. Reduced proliferation and excessive cell death were observed in the dorsal telencephalon. Abnormal neuronal distribution, layer formation, and dopaminergic neuronal projections were observed in the neocortex. Disruption of microglial differentiation (M1/M2 microglial ratio) and abnormal expression of pro-inflammatory and neurotrophic factors were induced, and these abnormalities were ameliorated by co-treatment with an anti-inflammatory drug (pioglitazone). FASD model mice displayed histological abnormalities, microglial abnormalities, and neuro-inflammation in both the embryonic and newborn stages. Thus, anti-inflammatory therapeutics may provide a novel preventive approach for the treatment of FASD.


Automated transformation of probabilistic knowledge for a medical diagnostic system.
Iliad is a large medical diagnostic system that covers more than 2000 diagnoses and 9000 findings. Due to the size and the complexity of this system, a robust knowledge representation is essential to consistently and efficiently model the medical knowledge involved. In this paper, we describe the knowledge representation currently used in Iliad and a probabilistic representation based on the Bayesian network formalism which can be derived using the information that the Iliad knowledge base contains.


A comparative study of APLI and APCI in IMS at atmospheric pressure to reveal and explain peak broadening effects by the use of APLI.
The details of the ionization mechanism in atmospheric pressure are still not completely known. In order to obtain further insight into the occurring processes in atmospheric pressure laser ionization (APLI) a comparative study of atmospheric pressure chemical ionization (APCI) and APLI is presented in this paper. This study is carried out using similar experimental condition at atmospheric pressure employing a commercial ion mobility spectrometer (IMS). Two different peak broadening mechanisms can then be assigned, one related to a range of different species generated and detected, and furthermore for the first time a power broadening effect on the signals can be identified.


Tracking down the molecular architecture of the synaptonemal complex by expansion microscopy.
The synaptonemal complex (SC) is a meiosis-specific nuclear multiprotein complex that is essential for proper synapsis, recombination and segregation of homologous chromosomes. We combined structured illumination microscopy (SIM) with different expansion microscopy (ExM) protocols including U-ExM, proExM, and magnified analysis of the proteome (MAP) to investigate the molecular organization of the SC. Comparison with structural data obtained by single-molecule localization microscopy of unexpanded SCs allowed us to investigate ultrastructure preservation of expanded SCs. For image analysis, we developed an automatic image processing software that enabled unbiased comparison of structural properties pre- and post-expansion. Here, MAP-SIM provided the best results and enabled reliable three-color super-resolution microscopy of the SCs of a whole set of chromosomes in a spermatocyte with 20-30 nm spatial resolution. Our data demonstrate that post-expansion labeling by MAP-SIM improves immunolabeling efficiency and allowed us thus to unravel previously hidden details of the molecular organization of SCs.


Preparation of chains of magnetosomes, isolated from Magnetospirillum magneticum strain AMB-1 magnetotactic bacteria, yielding efficient treatment of tumors using magnetic hyperthermia.
Chains of magnetosomes isolated from Magnetospirillum magneticum strain AMB-1 magnetotactic bacteria by sonication at 30 W during 2 h are tested for magnetic hyperthermia treatment of tumors. These chains are composed of magnetosomes, which are bound to each other by a filament made of proteins. When they are incubated in the presence of cancer cells and exposed to an alternating magnetic field of frequency 198 kHz and average magnetic field strength of 20 or 30 mT, they produce efficient inhibition of cancer cell proliferation. This behavior is explained by a high cellular internalization, a good stability in solution and a homogenous distribution of the magnetosome chains, which enables efficient heating. When the chains are heated during 5 h at 90°C in the presence of 1% SDS, the filament binding the magnetosomes together is denatured and individual magnetosomes are obtained. By contrast to the chains of magnetosomes, the individual magnetosomes are prone to aggregation, are not stable in solution and do not produce efficient inhibition of cancer cell proliferation under application of an alternating magnetic field.


[Gastric juice secretion increases during extracorporeal circulation employed in cardiac surgery].
We evaluated gastric juice secretion during extracorporeal circulation (ECC) in cardiac surgery. The effect of pirenzepine, a muscarine receptor blocker, was also tested to clarify the mechanism involved. Gastric juice secretion increased significantly from pre ECC value of 3.8 +/- 1.3 ml.h-1 to 12.4 +/- 4.0 ml.h-1 during ECC. It decreased to 5.0 +/- 1.4 ml.h-1 (mean +/- SE) after ECC. Pirenzepine premedication reduced serum gastrin level. However, it did not suppress the increase of gastric juice secretion. There is no significant correlation between serum gastrin level and gastric juice secretion. ECC is a major stress and increases gastric juice secretion. This phenomenon is probably activated via sympathetic and hypophysis-adrenal gland system.


Food contact hypersensitivity syndrome: the mucosal contact urticaria paradigm.
Oral allergy syndrome (OAS) or pollen-fruit allergy syndrome represents a mucosal allergic contact urticaria in people sensitized to common pollens, due to IgE cross-reactivity between homologous pollen allergens and various plant foods. It is the most prevalent food allergy, affecting millions of people with respiratory allergies. Usually, symptoms are mild, self-limiting and localized to the oropharyngeal mucosa, although they may sometimes become generalized and life-threatening. Although patients usually recognize the offending foods, diagnosis may sometimes be complicated. Several clinical syndromes and association between pollens and plant-derived foods have been described. Crossreactivity on the basis of stringent immunological and allergological criteria can also occur in people without pollen sensitization or concomitant respiratory allergies, as in latex-fruit syndrome. The term 'food contact hypersensitivity syndrome' (FCHS) is proposed in this paper for the first time, to include all mucosal hypersensitivity reactions presenting with contact to food (both immunological and nonimmunological), whether due to crossreactivity with homologous plant-derived allergens or not. At this time, prophylaxis and treatment can only be attained by avoidance, even when symptoms are mild, with consequent impairment in quality of life. A better understanding of the pathophysiological mechanisms of FCHS and food allergy in general is essential for deeper insights and future emergence of effective therapies.


Formation of Oxazoles from Elusive Gold(I) α-Oxocarbenes: A Mechanistic Study.
The gold(I) catalyzed reaction between phenylacetylene, pyridine N-oxide and acetonitrile leading, via a putative gold-α-oxocarbene intermediate, towards an oxazole product has been investigated. A novel mass spectrometric method called "delayed reactant labeling" is used to track consecutive and parallel reactions. It clearly shows that the intramolecular formation of a pyridine adduct of gold-α-oxocarbene is in competition with the formation of the oxazole product. The reaction mechanism most probably corresponds to competition between acetonitrile and pyridine in an almost barrierless reaction with putative gold-α-oxocarbene within the solvent cage. The detected ionic species have been characterized by helium tagging infrared photodissociation spectroscopy.


Differential labelling of laminin alpha 2 in muscle and neural tissue of dy/dy mice: are there isoforms of the laminin alpha 2 chain?
Laminin alpha 2, a sub-unit of the basement membrane component laminin-2, is deficient in the dy/dy and allelic dy2 J/dy2 J mouse. It is also the defective protein in a proportion of children with congenital muscular dystrophy. Linkage and mutational analysis have established that this is a primary effect caused by defects in the LAMA2 gene. Laminin alpha 2 has previously been shown to be deficient in dy/dy skeletal muscle, peripheral nervous system and brain. We report here preliminary observations on differences in detection of laminin alpha 2 in muscle, peripheral nerves and brain of dy/dy mice using three, well characterized antibodies. In normal muscle laminin alpha 2 is localized to the basement membrane of the myofibres and the Schwann cells of peripheral nerves, whilst in adult brain it is only detected on blood vessels. Our results show that there is appreciable, but slightly reduced, expression of laminin alpha 2 in skeletal muscle of dy/dy mice but almost no detectable protein in the brain, peripheral nerve and spinal nerve roots. Our observations are at present unexplained but they raise the possibility for the first time that there may be different tissue specific isoforms of laminin alpha 2. Molecular characterization of possible differences responsible for our observations may aid the identification of the mutation in the dy/dy mouse and lead to a better understanding of the role and expression of laminin alpha 2 in pathological conditions.