Premorbid impairments in early-onset psychosis: differences between patients with schizophrenia and bipolar disorder.
Despite the large body of research on premorbid impairments in schizophrenia, studies comparing different early-onset psychoses are scarce. To examine premorbid impairments in first episodes of early-onset bipolar and schizophrenia disorders. We compared premorbid adjustment and other premorbid variables such as IQ and developmental abnormalities in a cohort of children and adolescents (N=69) with bipolar disorder (BP) or schizophrenia (SZ) experiencing their first psychotic episode and in a healthy control group (N=91). Schizophrenia patients showed more social impairment in childhood than bipolar patients (p<0.05) and healthy controls (p<0.001) and had higher rates of developmental abnormalities (p<0.05) than healthy controls. Between childhood and early adolescence, schizophrenia and bipolar patients showed a greater decline in academic adjustment than healthy controls, more specifically in adaptation to school (p<0.01). Early-onset schizophrenia patients show more early social impairment than early-onset bipolar patients. Intellectual premorbid abnormalities are less specific and probably more linked to early-onset psychosis.


Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities.
Methyl aminolaevulinate-photodynamic therapy (MAL-PDT) is an effective treatment in facial/scalp actinic keratosis (AK). The aims of this study were to compare efficacy, safety, cosmetic outcome and patient preference of MAL-PDT vs. cryotherapy in patients with AK at other locations. A multicentre, controlled, randomized, open, intraindividual, right-left comparison was performed. Patients with nonhyperkeratotic AK were treated once with MAL-PDT and cryotherapy on either side of the body. At week 12, lesions showing noncomplete response were retreated. The primary efficacy variable was the lesion response at week 24. Investigator's assessment of cosmetic outcome, patient's preference in terms of cosmetic outcome and a patient preference questionnaire were also analysed at week 24. In total, of 121 patients with 1343 lesions (98% located on the extremities and the remainder on the trunk and neck) were included. Both treatments provided a high mean percentage reduction in lesion count at week 24 with significantly higher efficacy for cryotherapy: 78% for MAL-PDT and 88% for cryotherapy (P=0.002, per protocol population). Investigator's assessment of cosmetic outcome was significantly better for MAL-PDT than cryotherapy (P<0.001), 79% of lesions having an excellent cosmetic outcome with MAL-PDT vs. 56% with cryotherapy at week 24. The cosmetic outcome achieved by MAL-PDT compared with cryotherapy was also preferred by patients (50% vs. 22%, respectively, P<0.001), and 59% of patients would prefer to have any new lesions treated with MAL-PDT compared with 25% with cryotherapy (P<0.001). Both treatment regimens were safe and well tolerated. MAL-PDT showed inferior efficacy for treatment of non-face/scalp AK compared with cryotherapy. However, both treatments showed high efficacy, and MAL-PDT conveyed the advantages of better cosmesis and higher patient preference.


A reference gene set for chemosensory receptor genes of Manduca sexta.
The order of Lepidoptera has historically been crucial for chemosensory research, with many important advances coming from the analysis of species like Bombyx mori or the tobacco hornworm, Manduca sexta. Specifically M. sexta has long been a major model species in the field, especially regarding the importance of olfaction in an ecological context, mainly the interaction with its host plants. In recent years transcriptomic data has led to the discovery of members of all major chemosensory receptor families in the species, but the data was fragmentary and incomplete. Here we present the analysis of the newly available high-quality genome data for the species, supplemented by additional transcriptome data to generate a high quality reference gene set for the three major chemosensory receptor gene families, the gustatory (GR), olfactory (OR) and antennal ionotropic receptors (IR). Coupled with gene expression analysis our approach allows association of specific receptor types and behaviors, like pheromone and host detection. The dataset will provide valuable support for future analysis of these essential chemosensory modalities in this species and in Lepidoptera in general.


Complications of Deep Brain Stimulation for Movement Disorders: Literature Review and Personal Experience.
The contemporary technique of deep brain stimulation (DBS) is very effective for management of movement disorders-including Parkinson's disease, generalized dystonia, and tremors-and has also been successfully applied for novel indications (e.g., intractable epilepsy and chronic pain). As a result, growing numbers of DBS procedures have been performed worldwide; correspondingly, the incidence of associated morbidity has also increased. All complications of DBS can be divided into those associated with (1) the surgical procedure, (2) the device itself, and (3) the applied electrical stimulation. On the basis of an analysis of the available literature and the personal experience of the author, it may be concluded that implantation of a DBS device is a relatively safe procedure accompanied by very low risks of major morbidity or a permanent neurological deficit. Nevertheless, awareness of the possible complications and application of appropriate preventive measures for their avoidance are very important for providing safe and effective treatment.


Mitochondrial quality control in neurodegenerative diseases.
Mutations causing genetic forms of Parkinson's disease or hereditary neuropathies have been recently shown to affect key molecular players involved in the recycling of defective mitochondria, most notably PARKIN, PINK1, Mitofusin 2 or dynein heavy chain. Interestingly, the same pathways are also indirectly targeted by multiple other mutations involved in familial forms of amyotrophic lateral sclerosis, Huntington's disease or Alzheimer's disease. These recent genetic results strongly reinforce the notion that defective mitochondrial physiology might cause neurodegeneration. Mitochondrial dysfunction has however been observed in virtually every neurodegenerative disease and appears not restricted to the most vulnerable neuronal populations affected by a given disease. Thus, the mechanisms linking defective mitochondrial quality control to death of selective neuronal populations remain to be identified. This review provides an update on the most recent literature on mitochondrial quality control and its impairment during neurodegenerative diseases.


Real-world GLP-1 RA therapy in type 2 diabetes: A long-term effectiveness observational study.
To evaluate in a real-world setting the effectiveness and tolerability of available GLP-1 RA drugs in patients with type 2 diabetes after a prolonged follow-up. Observational, retrospective, single-centre study in patients starting GLP-1 RA therapy. Change in HbA1c, fasting plasma glucose (FPG) and body mass index (BMI) along with gastrointestinal (GI) adverse events and withdrawal from GLP-1 RA therapy were evaluated. Lack of efficacy of GLP-1 RA therapy according to prespecified goals was also measured. A total of 735 patients were included, mean age 59.7 years, duration of diabetes 9.01 years, HbA1c 8.18% and BMI 38.56 kg/m2. Average follow-up was 18.97 months (range 4.2-39.09). All HbA1c (0.93%; P < 0.01), FPG (24 mg/dL; P < 0.01) and BMI (1.55 kg/m2; P < 0.05) were significantly reduced from baseline and maintained throughout follow-up, regardless of prescribed GLP-1 RA. GI adverse events were present in 13.81% of patients at first follow-up visit, 37.07% of patients discontinued GLP-1 RA treatment, and 38.63% did not meet efficacy goals. In a real-world setting, GLP-1 RA therapy is largely prescribed in severely obese patients with a long-standing and poorly controlled diabetes. All prescribed GLP-1 RAs significantly decreased HbA1c, FPG and BMI. GI adverse events affected a low proportion of patients. Inversely, a high proportion of patients did not meet efficacy goals and/or discontinued GLP-1 RA treatment. Baseline characteristics of patients and lack of adherence may represent important issues underlying differences in effectiveness in real-world studies versus randomized trials.


Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial.
The assessment of ovarian reserve by antral follicle count (AFC) following electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas. Forty-five patients between 18 and 35 years, with unilateral endometriomas were randomly analyzed. Laparoscopic cystectomy was performed by the stripping method. Ovarian hemostasis was obtained either by suturing (group A, n = 23) or by bipolar electrocoagulation (group B, n = 22). AFC was performed by ultrasound on the third day of the three postoperative menstrual cycles. The sum of AFC was compared between sutured (A1) and electrocoagulated (B1) ovaries, as well as between intact ovaries of both groups (A0: intact ovaries in sutured group, B0: intact ovaries in electrocoagulated group). The median of AFC was significantly lower in operated ovaries than in intact ovaries in both groups of patients, regardless of suturing [A1 median: 12 (range 9-19) vs. A0 median: 21.0 (range 15-27), p < 0.05] or electrocoagulation [B1: 5.0 (2-10) vs. B0: 18.5 (8-29), p < 0.05]. The median AFC was significantly higher in sutured ovaries than in electrocoagulated ovaries [A1: 12 (9-19) vs. B1: 5.0 (2-10), p < 0.05]. Our preliminary data show that operation on ovarian endometriomas could reduce ovarian reserve. The AFC value suggests that the ovarian reserve was less reduced in sutured ovaries than in those electrocoagulated. Suturing as a method of hemostasis could be a better choice after stripping ovarian endometriomas.


Hospital Employee Willingness to Work during Earthquakes Versus Pandemics.
Research indicates that licensed health care workers are less willing to work during a pandemic and that the willingness of nonlicensed staff to work has had limited assessment. We sought to assess and compare the willingness to work in all hospital workers during pandemics and earthquakes. An online survey was distributed to Missouri hospital employees. Participants were presented with 2 disaster scenarios (pandemic influenza and earthquake); willingness, ability, and barriers to work were measured. T tests compared willingness to work during a pandemic vs. an earthquake. Multivariate linear regression analyses were conducted to describe factors associated with a higher willingness to work. One thousand eight hundred twenty-two employees participated (15% response rate). More willingness to work was reported for an earthquake than a pandemic (93.3% vs. 84.8%; t = 17.1; p < 0.001). Significantly fewer respondents reported the ability to work during a pandemic (83.5%; t = 17.1; p < 0.001) or an earthquake (89.8%; t = 13.3; p < 0.001) compared to their willingness to work. From multivariate linear regression, factors associated with pandemic willingness to work were as follows: 1) no children ≤3 years of age; 2) older children; 3) working full-time; 4) less concern for family; 5) less fear of job loss; and 6) vaccine availability. Earthquake willingness factors included: 1) not having children with special needs and 2) not working a different role. Improving care for dependent family members, worker protection, cross training, and job importance education may increase willingness to work during disasters.


Effects of dolichol on membrane permeability.
Small vesicles containing the tetra-anionic fluorescent probe calcein were prepared by sonication of mixtures of plant phosphatidylethanolamine, plant phosphatidylcholine, and dolichol. Following chromatography, the isolated vesicles were found to retain entrapped calcein over the temperature range of 15 to 40 degrees C. Utilizing an assay measuring the fluorescence quenching of entrapped calcein by cobalt ions, the presence of dolichol in the membranes was found to promote the permeability of the phospholipid bilayers to the divalent cation. The permeability was shown to be dependent on temperature with an increase in rate of 17-fold between 15 and 35 degrees C although the plant phospholipids used in these experiments have no known phase transition within this temperature range. The incorporated dolichol was distributed uniformly throughout the vesicle population. Similar vesicles prepared from phosphatidylethanolamine and phosphatidylcholine without added dolichol, from phosphatidylcholine alone, or with phosphatidylcholine and dolichol were far less permeable to the divalent cation under the same assay conditions. These results demonstrate that dolichols have significant effects on the permeability properties of phospholipid bilayers that contain phosphatidylethanolamine.


Study of the expression levels of Hepatocyte nuclear factor 4 alpha and 3 beta in patients with different outcome of HBV infection.
Hepatocyte nuclear factors 4 alpha (HNF4α) and 3 beta (HNF3β) are members of a group of liver-enriched transcription factors (LETFs) that play important roles in regulating the replication of hepatitis B virus (HBV) and liver inflammation. However, the relationship of the level of HNF4α and HNF3β with the severity of HBV-infected liver diseases is unclear. In this study, liver tissue samples from different types of HBV patients were collected, and HNF4α and HNF3β expression were detected by immunohistochemistry. The expression of HNF4α was significant higher in patients with severe hepatitis B(SHB) than those with chronic hepatitis B(CHB) and liver cirrhosis(LC) (both P < 0.05), but similar between patients with CHB and LC (P > 0.05). And the expression of HNF3β was similar among patients with CHB, LC and SHB (P > 0.05 for all pairwise comparison). This suggests that the expression level of HNF4α was different in patients with different outcome of HBV infection, high expression level of HNF4α may correlate with occurrence of SHB.


Screen the Effective Components of Lycopodii herba on Rheumatoid Arthritis with the Aid of Spectrum-Effect Relationship and Uncover its Potential Mechanism.
Lycopodii herba (SJC), a traditional Chinese medicine, has the effect of dispelling wind and eliminating dampness (a therapeutic principle and method of traditional Chinese medicine for rheumatoid arthritis), relaxing tendon and activating collaterals. However, the major effective components and its therapeutic mechanism were unclear. In this study, different SJC samples with slightly different compositions were prepared by extracting with different concentrations of ethanol. Then, the therapeutic effects on rheumatoid arthritis (RA) of different SJC samples were evaluated. Finally, the spectrum-effect relationship between UPLC-Q-TOF/MS fingerprints and the effect of RA was explored to screen the effective components. Western blotting was used to study the potential mechanism. The volume of hind paw and the level of RF, TNF-α, and IL-1β were lower after administrating with different SJC samples, compared with the model group. Histopathological findings also confirmed that SJC could relieve the symptoms of RA. Combined with identification of the components in plasm from SJC, lycojaponicumin C, des-N-methyl-α-obscurine, 8β-acetoxy-12β-hydroxy-lycopodine or 8β-acetoxy-11α-hydroxy-lycopodine or 8β-hydroxy-11α-acetoxylycopodine were considered to be the major effective components. The mechanism may be related to AChE/NF-κB signaling pathway. This work provides a general method to screen the potential effective components of herb medicines and would be benefit to understand the mechanism of SJC for the treatment of RA.


Acute leukemia with unusual cytoplasmic inclusions: a cytochemical and ultrastructural study.
A 76-year-old woman with acute leukemia responded incompletely to prednisone and vincristine. Cytochemistry of the blast cells demonstrated only focal alpha-naphthyl acetate and alpha-naphthyl butyrate esterase activity and focal coarse granular beta-glucuronidase activity, a pattern usually associated with acute lymphocytic leukemia. Electron microscopy demonstrated primitive cells with features usually associated with promonocyte differentiation including prominent parallel arrays of microfilaments and nucleoli of the nucleolonema type. In Wright-stained films, blasts contained oval, pale-blue, yellow tinged cytoplasmic inclusions about 2 to 4 micrometers in diameter which did not stain with any of the cytochemical methods employed. With electron microscopy, these inclusions were nonmembrane bound structures, varying from amorphous electron dense stippling to irregularly arranged short segments of filaments to prominent parallel arrays of filaments. We propose that the inclusions may have arisen from the parallel arrays of microfilaments and are nonspecific.


Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics.
Hepatocellular carcinoma (HCC) is one of the most common cancers around the globe and third most fatal malignancy. Chronic liver disorders such as chronic hepatitis and liver cirrhosis often lead to the development of HCC. Accumulation of genetic and epigenetic alterations are involved in the development of HCC. Genetic research sparked by recent developments in next generation sequencing has identified the frequency of genetic alterations that occur in HCC and has led to the identification of genetic hotspots. Emerging evidence suggests that epigenetic aberrations are strongly associated with the initiation and development of HCC. Various important genes encoding tumor suppressors including P16, RASSF1A, DLC-1, RUNX3 and SOCS-1 are targets of epigenetic dysregulation during the development of HCC. The present review discusses the importance of epigenetic regulations including DNA methylation, histone modification and microRNA mediated regulation of gene expression during tumorigenesis and their use as disease biomarkers. Furthermore, these epigenetic alterations have been discussed in relationship with promising therapeutic perspectives for HCC and related cancers.


Successful treatment with bromocriptine of hypertension associated with polycystic ovarian disease.
The use of bromocriptine, 5 mg per day, markedly improved the severe hypertension (up to 180/120 mmHg) of a patient suffering from polycystic ovarian disease (PCOD). The response was rapid, with decreasing concentrations of serum testosterone and 11-deoxycorticosterone (DOC). Bromocriptine induced further renewal of the ovulatory cycle. Bromocriptine may thus be of considerable value in the treatment hypertensive patients with PCOD.


Application of genotype MTBDRplus in rapid detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin in a high volume laboratory in Southern China.
The alarmingly worsening epidemics of drug-resistant tuberculosis (TB) call urgent need for a simple method for the rapid detection of drug-resistant TB in clinical settings. In an attempt to establish a rapid procedure for laboratory diagnosis of TB and investigate the local TB epidemiology, molecular line probe assay of the Genotype MTBDRplus was used to identify Mycobacterium tuberculosis complex (MTBC) and detect mutations conferring resistance to two most active first-line drugs against TB: Rifampin and Isoniazid. 96 acid-fast bacillus (AFB) smear- positive sputums and 18 PCR-positive non-sputum specimens have been determined for the MTBC and resistance to Rifampin and Isoniazid. The MTBC detection rates in two sources of specimens were 93.8% (90/96) and 77.8% (14/18) respectively. The overall drug resistance (Rifampin or Isoniazid) occurred in 34.6% (36/104). Resistance to rifampin (RMP) was 28.8% (30/104) and 25% (26/104) was to Isoniazid (INH), in which high level drug resistance accounted for 88.5% (23/26) and low level drug resistance accounted for 7.7% (2/26). Multidrug resistance (MDR), defined as resistant to both RMP and INH, was found in 19.2% (20/104) of clinical samples, which was double that of official statistics. In addition, 63.3% (19/30) RMP-resistant mutations were identified in the region of RopB 530-533 and 57.9% (11/19) were the S531L mutation. 84.6% (22/26) of resistance to INH was mediated by Kat S315T1 mutations which conferred the high-level resistance to INH. The Genotype MTBDRplus line probe assay is a suitable and applicable method for establishing the rapidness in detection of drug-resistant TB in clinical laboratory. It will be a valuable addition to the conventional TB diagnostic approaches.


Influence of intense exercise on acid-base, blood gas and electrolyte status in bulls.
The aim of the present study was to obtain reference values in bulls after an intense exercise situation quantifying some biological variables in venous blood. The descriptive analysis was carried out using Statistica 8.0 program and the values obtained were pH (6.81), PCO2 (67.81 mmHg), PO2 (22.58 mmHg), HCO3(-) (10.82 mEq/l), BE (-23.48 mEq/l), TCO2 (12.83 mEq/l), sO2 (17.50%) for blood gas, and for mineral Na, iCa and K were 146.96; 1.14 and 7.49 mmol/l respectively. Finally, the mean value of Htc was 43.522%, Hb 14.80. Following exercise, and compared with values considered as physiological in cattle, some blood variables in our study were decreased (blood pH, HCO3(-), BE, PO2 and sO2), some remained in the normal limit (Na, K, iCa, Htc) and the rest are increased (PCO2, Hb, lactate) comparing with when compared to normal reference values for the bovine species.


Hearing preservation in perilymphatic fistula due to a congenital fistula in an adult.
Congenital fistula in the stapedial footplate usually can be diagnosed by the recurrence of meningitis caused by spontaneous cerebrospinal fluid (CSF) in infants or young children. We report the case of a 65-year-old woman, who was initially diagnosed as having an acquired perilymphatic fistula caused by aural barotrauma and demonstrated episodic vertigo and fluctuant sensorineural hearing loss in the right ear after air travel. Surgical exploration showed a congenital circular defect in the peripheral part of the stapedial footplate with leakage of CSF. The fistula was closed by inserting a tiny piece of fascia attached to both the tympanic and perilymphatic side of the stapedial footplate utilizing the back-pressure of perilymphatic fluid and fibrin glue; hearing was preserved.


Exploring the potential of problem-based learning in nurse education.
It could be argued that the role of the nurse is beginning to change from that of a medical assistant to one of a more research-aware, reflective professional. As a result, the education of nursing students has needed to adapt. This paper explores how problem-based learning (PBL) may be an appropriate means of achieving an educational preparation that can respond to changing needs. Particular attention is paid to the theoretical underpinnings of PBL, especially the concepts of adult education, cognitive processes and learning in context. Some of the relevant empirical studies are reviewed, and the authors attempt to identify the gaps in the literature, concluding by recommending a course of action to expand the existing levels of understanding and evidence that supports, or otherwise, the use of PBL.


Quantifying the dynamic evolution of organic, inorganic and biological synergistic fouling during nanofiltration using statistical approaches.
The dynamic process of membrane fouling was characterized during relatively long-term (30 d) continuous nanofiltration (NF) of a real wastewater secondary effluent, with the roles of organic, inorganic and biological foulants quantified via statistical analyses. The analyses were based on time-series data of physical properties (morphology, roughness, hydrophilicity and charge), chemical compositions (X-ray and infrared responses) and biomass (adenosine triphosphate, ATP) on the membrane surface during fouling evolution. The individual and interactive contributions of organic factor (typical functional groups), inorganic factor (Ca as a representative) and biological factor (ATP amount) to fouling were quantified via multiple linear regression coupled with variance partitioning analysis. About 78% of the variance of filtration resistance can be explained by these factors, among which 16% was contributed by individual effect of organics (via e.g. physical adsorption), 21% by organic-inorganic binary effect (in the form of e.g. Ca-complex), 13% by organic-biological binary effect (organics as the nutrient/product of microorganisms), and 24% by organic-inorganic-biological ternary interaction. Organic matter was universally involved in these effects. The interrelations among fouling factors, foulant layer properties and filtration time were comprehensively explored via redundancy analysis, which clearly delineated the fouling evolution into three major stages: Stage I (0-1 d) for initial fouling mainly due to rapid organic adsorption; Stage II (1-10 d) mainly for the gradual growth of Ca-organic combined fouling; and Stage III (10-30 d) for the eventual maturation of biofouling. These may provide foundations for a targeted fouling control based on foulant type or fouling stage.


The anti-SARS-CoV-2 activity of novel 9, 10-dihydrophenanthrene derivatives: an insight into molecular docking, ADMET analysis, and molecular dynamics simulation.
Originating in Wuhan, the COVID-19 pandemic wave has had a profound impact on the global healthcare system. In this study, we used a 2D QSAR technique, ADMET analysis, molecular docking, and dynamic simulations to sort and evaluate the performance of thirty-nine bioactive analogues of 9,10-dihydrophenanthrene. The primary goal of the study is to use computational approaches to create a greater variety of structural references for the creation of more potent SARS-CoV-2 3Clpro inhibitors. This strategy is to speed up the process of finding active chemicals. Molecular descriptors were calculated using 'PaDEL' and 'ChemDes' software, and then redundant and non-significant descriptors were eliminated by a module in 'QSARINS ver. 2.2.2'. Subsequently, two statistically robust QSAR models were developed by applying multiple linear regression (MLR) methods. The correlation coefficients obtained by the two models are 0.89 and 0.82, respectively. These models were then subjected to internal and external validation tests, Y-randomization, and applicability domain analysis. The best model developed is applied to designate new molecules with good inhibitory activity values against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). We also examined various pharmacokinetic properties using ADMET analysis. Then, through molecular docking simulations, we used the crystal structure of the main protease of SARS-CoV-2 (3CLpro/Mpro) in a complex with the covalent inhibitor "Narlaprevir" (PDB ID: 7JYC). We also supported our molecular docking predictions with an extended molecular dynamics simulation of a docked ligand-protein complex. We hope that the results obtained in this study can be used as good anti-SARS-CoV-2 inhibitors.


Cadmium exposure induces vascular injury due to endothelial oxidative stress: the role of local angiotensin II and COX-2.
Cadmium is an environmental pollutant that is closely linked with cardiovascular diseases, such as atherosclerosis and hypertension. Moreover, cadmium can induce an increase in oxidative stress. One of the main sites affected by oxidative stress is the aorta, which consequently develops atherosclerosis. However, there are few reports demonstrating aortic effects induced by small concentrations of cadmium that are similar to those found in the blood resulting from occupational exposure. Furthermore, several studies have reported on chronic cadmium exposure, and the results of these studies may have been influenced by the secondary effects induced by this metal, such as hypertension. Therefore, we investigated the effects of acute cadmium exposure on the vascular reactivity to phenylephrine of aortic rings isolated from male Wistar rats. Cadmium increased phenylephrine reactivity without changing the vasorelaxation induced by acetylcholine and sodium nitroprusside. Endothelial damage or incubation with L-NAME shifted the phenylephrine concentration-response curves leftward in arteries incubated with or without cadmium, but the curves were shifted to a lesser degree after cadmium incubation. Enalapril, losartan, the nonselective COX inhibitor indomethacin, the TXA(2) synthase inhibitor furegrelate, the selective COX-2 inhibitor NS 398, the TP receptor antagonist SQ 29.548, the EP1 receptor antagonist SC 19.220, superoxide dismutase, and the NADPH oxidase inhibitor apocynin partially reverted the cadmium-induced effects on the reactivity to phenylephrine. Cadmium exposure increased vasoconstrictor activity by reducing NO bioavailability owing to the increased production of ROS by NADPH oxidase. The results of the tested cadmium concentration, which is below the reference values, suggest that acute cadmium exposure may induce vascular injury through endothelial oxidative stress. These data contribute to the evidence indicating that cadmium is a high risk to public health.


Quantitative determination of nucleosides and their phosphate esters--1. The acidic nucleosides, 3-deazauridine and 6-azauridine.
A relatively rapid, high-resolution chromatographic procedure, using mini-columns of DEAE cellulose equilibrated with 10 mM sodium phosphate, pH 6.0, is described in sufficient detail to permit ready replication. This initial paper demonstrates the quantitative separation, using suction, of the acidic nucleosides, 3-deazauridine and 6-azauridine, from their phosphorylated derivatives. The chemically stable, tritium-labeled nucleosides are eluted from the mini-columns (capacity approximately equal to 1.8 ml) with 10 mM sodium phosphate, pH 6.0; subsequently, the nucleotides are eluted completely with 0.5 M HCl/0.5 M NaCl. Quantitation is based on liquid scintillation counting of aliquots of the eluates.


Thyroid hormone receptor α1: a novel regulator of thyroid cancer cell differentiation.
Thyroid hormone receptor α1 (TRα1) mediates the genomic actions of thyroid hormone (T3). The biology of TRα1 in growth and development has been well studied, but the functional role of TRα1 in cancers remains to be elucidated. Analysis of the human thyroid cancer database of The Cancer Genome Atlas (TCGA) showed that THRA gene expression is lost in highly dedifferentiated anaplastic thyroid cancer (ATC). We, therefore, explored the effects of TRα1 on the progression of ATC. We stably expressed TRα1 in two human ATC cell lines, THJ-11T (11T-TRα1 #2, #7, and #8) and THJ-16T (16T-TRα1 #3, #4, and #8) cells. We found that the expressed TRα1 inhibited ATC cell proliferation and induced apoptosis. TCGA data showed that THRA gene expression was best correlated with the paired box gene 8 (PAX8). Consistently, we found that the PAX8 expression was barely detectable in parental 11T and 16T cells. However, PAX8 gene expression was elevated in 11T- and 16T-TRα1-expressing cells at the mRNA and protein levels. Using various molecular analyses, we found that TRα1 directly regulated the expression of the PAX8 gene. Single-cell transcriptomic analyses (scRNA-seq) demonstrated that TRα1 functions as a transcription factor through multiple signaling pathways to suppress tumor growth. Importantly, scRNA-seq analysis showed that TRα1-induced PAX8, via its transcription program, shifts the cell landscape of ATC toward a differentiated state. The present studies suggest that TRα1 is a newly identified regulator of thyroid differentiation and could be considered as a potential therapeutic target to improve the outcome of ATC patients.


Coxsackievirus B3 infection and PBDE exposure causes organ-specific effects on CYP-gene expression in the mouse.
Common viral infections have been shown to change the tissue distribution of xenobiotics, including polybrominated diphenyl ethers (PBDEs). In previous studies, it has been shown that CYP2B gene expression is induced after PBDE exposure whereas coxsackievirus B3 (CBV3) infection suppresses the expression of CYP-gene expression in the liver. In the present study, CVB3 adapted to Balb/c mice was used to study the combined effects of infection and exposure to pure BDE-99 or the commercial mixture Bromkal on CYP1A1 and CYP2B expression in the lungs and pancreas on day 3 of the infection. The quantitative gene expression of virus, CYP1A1 and CYP2B was measured by real-time polymerase chain reaction (RT-PCR). PBDE exposure in the non-infected mice tended to increase CYP2B expression in the lungs but not in the pancreas. Infection in both non-exposed and PBDE-exposed mice increased CYP2B expression in the lungs but was non-detectable in the pancreas. In the non-infected mice PBDE exposure left the CYP1A1 expression unaltered in both the lungs and pancreas. Infection in both non-exposed and PBDE-exposed mice tended to decrease the gene expression of CYP1A1 in the lungs but to induce it in the pancreas. A correlation between the amount of virus and the gene expression of CYP2B was found in the lungs. However, no effects of PBDE on virus replication were observed in any organ. In conclusion, viral infection affects CYP-gene expression differently in the pancreas and lungs whereas PBDE-induced effects were not obvious. The organ-specific change in gene expression could explain a changed tissue distribution of xenobiotics during infection.


The effect of breakfast type on total daily energy intake and body mass index: results from the Third National Health and Nutrition Examination Survey (NHANES III).
The objective of this study was to investigate the relationship between breakfast type, energy intake and body mass index (BMI). We hypothesized not only that breakfast consumption itself is associated with BMI, but that the type of food eaten at breakfast also affects BMI. Data from the Third National Health and Nutrition Examination Survey (NHANES III), a large, population-based study conducted in the United States from 1988 to 1994, were analyzed for breakfast type, total daily energy intake, and BMI. The analyzed breakfast categories were "Skippers," "Meat/eggs," "Ready-to-eat cereal (RTEC)," "Cooked cereal," "Breads," "Quick Breads," "Fruits/vegetables," "Dairy," "Fats/sweets," and "Beverages." Analysis of covariance was used to estimate adjusted mean body mass index (BMI) and energy intake (kcal) as dependent variables. Covariates included age, gender, race, smoking, alcohol intake, physical activity and poverty index ratio. Subjects who ate RTEC, Cooked cereal, or Quick Breads for breakfast had significantly lower BMI compared to Skippers and Meat and Egg eaters (p < or = 0.01). Breakfast skippers and fruit/vegetable eaters had the lowest daily energy intake. The Meat and Eggs eaters had the highest daily energy intake and one of the highest BMIs. This analysis provides evidence that skipping breakfast is not an effective way to manage weight. Eating cereal (ready-to-eat or cooked cereal) or quick breads for breakfast is associated with significantly lower body mass index compared to skipping breakfast or eating meats and/or eggs for breakfast.


Unruptured aneurysmal clipping complicated by delayed and refractory vasospasm: case report.
Delayed symptomatic vasospasm is a rare complication following clipping of an unruptured intracranial saccular aneurysm. There have been ten reported cases of delayed symptomatic vasospasm and only two of these occurred after 2 weeks from initial intervention. Our case is the first to document the refractory nature of such vasospasm despite aggressive first line therapy. Here, we present a 67-year-old female who had surgical clipping of a 10x7mm right middle cerebral artery (MCA) bifurcation aneurysm. Her surgery and initial postoperative course were uncomplicated, but she presented with acute left hemiparesis, dysarthria, headache and vomiting on post-op day 29 secondary to vasospasm of M2. She was initially stabilized with intra-arterial verapamil then managed with volume expansion, permissive hypertension, and nimodipine. She developed recurrent vasospasm of M2 the following day and was again treated with intra-arterial verapamil. Magnetic resonance imaging (MRI) brain showed an infarction involving the right basal ganglia, frontal lobe, and parietal lobe and her hospital course was complicated by super-refractory status epilepticus. At her follow up appointment she displayed continued left lower extremity weakness, left visual field defect, and left-sided neglect. Overall, cerebral vasospasms associated with unruptured aneurysms remain rare complications and are not often monitored for after initial recovery. Reviewing the documented cases highlights the unpredictability of when these events occur with our current knowledge. Current hypotheses for the mechanisms responsible for delayed and refractory vasospasms include: blood-derived breakdown products, mechanically induced vasospastic responses, and delayed reactions from the trigemino-cerebrovascular system (TCVS). The uncertainly of these events warrants further research and supports a strong argument for monitoring patients with initial surgical clipping up to a month out from their initial procedure.


[Survival time and life quality after operative treatment of colonic cancer (author's transl)].
In regard to other intestinal malignomas colon cancer shows the chance of a long survival time. In cases of stage Dukes A and B the patient has a 5 year survival time of 100 to 82% depending on his age. In carcinoma of the rectum preoperative biopsy is necessary. In cases with grade III we prefer the exstirpation. The Erlangen magnetic closure of the colostomy gives continence in 70%.


Supercritically exfoliated ultrathin vanadium pentoxide nanosheets with high rate capability for lithium batteries.
Ultrathin V2O5 nanosheets were successfully prepared through supercritical solvothermal reaction followed by annealing treatment. The formation of ultrathin nanosheets is owing to Ostwald ripening and the effect of supercritical fluids. As cathode material for lithium batteries, the ultrathin V2O5 nanosheets exhibit a capacity of 108 mA h g(-1) at a high rate of up to 10 C at 2.4-4 V and excellent cyclability with little capacity loss after 200 cycles. The enhanced rate performance is attributed to the shortened diffusion distance and the increased electrode-electrolyte contact area of the ultrathin nanosheet structure. It is also demonstrated that the supercritical solvothermal method is effective and facile to scalably synthesize ultrathin nanomaterials for lithium batteries.


Twenty-five years of experience with stapedectomy.
The purpose of this report is to review the outcomes of patients undergoing stapes surgery by the senior author during the past 25 years, and to compare these results with those obtained in other series. A retrospective analysis of 902 patients who underwent stapes surgery by the senior author from 1970 to 1994 was performed. Twenty-two patients underwent stapedotomy; the remainder underwent stapedectomy. Pure-tone averages for air and bone conduction, air-bone gap closure, technique, complications, and patient satisfaction were compared with results obtained in other stapedectomy and stapedotomy series.


Prenatal cocaine exposure: increased striatal dopamine transporter binding in offspring at 3 and 6 months of age.
Prior studies indicate that prenatal cocaine exposure can alter dopamine transporter binding in mature mice. To determine the persistence of these effects, pregnant mice were treated with cocaine, 10 mg/kg/d, during days 13 to 20 of gestation and dopamine transporter binding was evaluated in offspring at 3 and 6 months of age. In contrast to prior studies, binding in striatum was significantly increased at both time points in cocaine-exposed mice compared to controls.


Synthesis of chemically crosslinked pullulan/gelatin-based extracellular matrix-mimetic gels.
In order to develop pullulan/gelatin-based gels as potential extracellular matrix-mimetic scaffolds, a "one-step" synthesis method using 1,1'‑carbonyldiimidazole (CDI) as activator in DMSO under mild conditions was reported for the first time. Particularly, in contrast to conventional critical requirement of absolute dryness for CDI, it was interesting to find that the formation of gels could be accomplished in the presence of aqueous solvent within a much shorter time, while obtaining improved mechanical properties as demonstrated by compressive tests. UV-Visible spectroscopy, NMR spectrum, TEM and SEM analysis have been employed to evaluate the underlying reaction mechanisms. This method implied that absolute dryness might not be necessary for using CDI as activator in certain cases. This method also represents a new rapid and efficient approach for synthesizing a great variety of chemically crosslinked polysaccharide/protein-based gels as promising material platform potential for tissue engineering and drug delivery applications.


Asymmetric Synthesis of a Fused Tricyclic Hydronaphthofuran Scaffold by Desymmetric [2+2+2] Cycloaddition.
A rhodium(I)-BINAP-catalyzed highly enantioselective [2+2+2] cycloaddition of enynes with alkynes has been developed. Diverse fused tricyclic hydronaphthofuran scaffolds with three consecutive stereogenic centers were constructed in one step from easily available materials with excellent chemo-, regio-, diastereo-, and enantioselectivity. Notable features of these reactions include 100 % atom economy, very broad scope, and mild reaction conditions.


Irsogladine maleate alters expression of a tight junction protein in portal hypertensive gastropathy.
Portal hypertensive gastropathy (PHG) is characterized by noninflammatory edema and vasodilatation of the lamina propria of the mucosal epithelium. In addition, the alterations of intercellular junction proteins and dilatation of the endothelial gaps have been reported. In this study, we examined whether irsogladine maleate (IM), a gastric mucosal protective agent, has the potential to improve PHG by restoration of tight junctions (TJs). Twenty-four patients with PHG were registered and randomly assigned into two groups: 12 patients in the IM-administration group and 12 patients in the non-administration group. In the administration group, IM (4 mg/day) was administered orally for 12 weeks. Gastric mucosa with a red color in patients with PHG were obtained endoscopically on the registration day and 12 weeks later. The endoscopic findings were evaluated, an immunohistochemical analysis of claudin-3 (a TJ protein) expression in gastric mucosal tissues by a laser microscope was performed, and claudin-3 expression was quantified by western blot analysis. Irsogladine maleate improved the degree of PHG in 2/12 patients endoscopically, in contrast to none of the 12 patients in the non-administration group. Immunohistochemical analysis showed that expression of claudin-3 increased in 8/12 patients in the IM-administration group and 2/12 patients in the non-administration group (P = 0.036). Western blot analysis revealed that the increase in claudin-3 after 12 weeks was significantly higher in the IM-administration group than in the non-administration group (P = 0.010). The present pilot study suggested that IM might improve the gastric mucosa in PHG through restoration of TJ-protein claudin-3.


Evaluation of the first open-access hepatitis B and safe injection online training course for health professionals in China.
Despite the high prevalence of chronic hepatitis B virus (HBV) infection in China, HBV infection prevention and long-term care knowledge of health professionals is inadequate. To address this knowledge gap, we developed an open-access evidence-based online training course, "KnowHBV", to train health professionals on prevention of HBV transmission and safe injections. We conducted an evaluation of the course with health professionals in China to examine its effectiveness in improving knowledge and learner's satisfaction of the course. Between July and December 2011, 1015 health professionals from selected hospitals and disease control institutions of Shandong province registered for the course and 932 (92 %) completed the three-module course. Participants' demographic information, pre- and post-course knowledge test results and learner's feedback were collected through the course website. Pre-course knowledge assessment confirmed gaps in HBV transmission routes, prevention and long-term care knowledge. Only 50.4 % of participants correctly identified all of the transmission routes of HBV, and only 40.7 % recognized all of the recommended tests to monitor chronically infected persons. The number of participants that answered all six multi-part multiple-choice knowledge questions correctly increased from 183 (19.7 %) before taking the course to 395 (42.4 %) on their first attempt upon completion of the course. Over 90 % of the 898 participants who completed the learner-feedback questionnaire rated the course as 'good' or 'very good'; over 94 % found the course instructional design helpful; 57.5 %, 65.7 % and 68.5 % reported that half or more than half of the course content in modules 1, 2 and 3 respectively provided new information; and 93.2 % of the participants indicated they preferred the online learning over traditional face-to-face classroom learning. The "KnowHBV" online training course appears to be an effective online training tool to improve HBV prevention and care knowledge of the health professionals in China.


Longevity of synaptic depression in the hippocampal dentate gyrus.
This study used urethane-anesthetized rats to investigate the longevity of heterosynaptically evoked depression of the monosynaptic response generated by synapses between entorhinal cortical (EC) afferents and the cells of the dentate gyrus (DG). Brief, high-frequency activation of the converging ipsilateral EC-DG input depressed the synaptic response of the contralateral EC-DG synapses without prior experimentally induced potentiation. This depression lasted for hours. Such observations are consistent with a role for heterosynaptically induced long-term depression in the encoding functions of synapses.


Identification of EhTIF-IA: The putative E. histolytica orthologue of the human ribosomal RNA transcription initiation factor-IA.
Initiation of rDNA transcription requires the assembly of a specific multi-protein complex at the rDNA promoter containing the RNA Pol I with auxiliary factors. One of these factors is known as Rrn3P in yeast and Transcription Initiation Factor IA (TIF-IA) in mammals. Rrn3p/TIF-IA serves as a bridge between RNA Pol I and the pre-initiation complex at the promoter. It is phosphorylated at multiple sites and is involved in regulation of rDNA transcription in a growth-dependent manner. In the early branching parasitic protist Entamoeba histolytica, the rRNA genes are present exclusively on circular extra chromosomal plasmids. The protein factors involved in regulation of rDNA transcription in E. histolytica are not known. We have identified the E. histolytica equivalent of TIF-1A (EhTIF-IA) by homology search within the database and was further cloned and expressed. Immuno-localization studies showed that EhTIF-IA co-localized partially with fibrillarin in the peripherally localized nucleolus. EhTIF-IA was shown to interact with the RNA Pol I-specific subunit RPA12 both in vivo and in vitro. Mass spectroscopy data identified RNA Pol I-specific subunits and other nucleolar proteins to be the interacting partners of EhTIF-IA. Our study demonstrates for the first time a conserved putative RNA Pol I transcription factor TIF-IA in E. histolytica.


Morphological and quantitative analysis of spermatogonia in mouse testes using whole mounted seminiferous tubules. II. The irradiated testes.
In adult male mice exposed to 300 R X-irradiation, the spermatogonial population was selectively killed except for the radioresistant type As stem cells. Type A spermatogonia were minimal two days after irradiation, when only 20% of the control population was present in stage 5-6; these were predominately single and paired undifferentiated cells. When multiple injections of 3HTdR were given between 2 and 3.5 days post-irradiation, 90-95% of these survivors in stages 4-6 became labeled. Enhanced proliferation of these stem cells, and at times when they were normally quiescent, led to restoration of all classes of spermatogonia by 11 days after irradiation. Several autoradiographic studies were undertaken to better characterize the radioresistant cells. In mice given single or multiple injections of 3HTdR prior to irradiation, there was appreciable retention of label by those type As spermatogonia that had originally incorporated 3HTdR in stages 2-4. This labeling pattern was identical to that of the long-cycling As stem cells in nonirradiated testes. Since the long-cycling As stem cells are thought to be characterized by a prolonged G1 or "A-phase" which is known to be a highly radioresistant portion of the cell cycle, it was clear why these cells could preferentially survive irradiation doses that killed other spermatogonial types. It was proposed that following germ cell depletion, as after irradiation injury, the long-cycling As survivors could be prematurely triggered from A-phase into DNA synthesis, thereby, initiating restoration of the germ cell population.


Diet-Induced Modification of the Sperm Epigenome Programs Metabolism and Behavior.
Globally, obesity has reached epidemic proportions. The rapidly increasing numbers of overweight people can be traced back to overconsumption of energy-dense, poor-quality foods as well as physical inactivity. This development has far-reaching and costly implications. Not only is obesity associated with serious physiological and psychological complications, but mounting evidence also indicates a ripple effect through generations via epigenetic changes. Parental obesity could induce intergenerational and transgenerational changes in metabolic and brain function of the offspring. Most research has focused on maternal epigenetic and gestational effects; however, paternal contributions are likely to be substantial. We focus on the latest advances in understanding the mechanisms of epigenetic inheritance of obesity-evoked metabolic and neurobiological changes through the paternal germline that predict wide-ranging consequences for the following generation(s).


Effect of two tidal volumes on oxygenation and respiratory system mechanics during the early stage of adult respiratory distress syndrome.
To study the effect of two tidal volumes on gas exchange, lung mechanics, and hemodynamics in 12 patients with acute respiratory distress syndrome (ARDS) within the first 72 hours of mechanical ventilation. Tidal volume (VT) was increased by 40% from the initial value at fixed positive end-expiratory pressure (PEEP) and matched minute ventilation by adjusting the respiratory rate (RR) of the ventilator. Initial VT and RR were 592 +/- 42 mL and 19 +/- 1 min-1, respectively. High VT amounted to 825 +/- 54 mL with a RR of 12 +/- 1 min-1. We found that at high VT (1) the index of oxygenation increased from 0.22 +/- 0.03 to 0.32 +/- 0.04 (P < .001) with a parallel decrease in the right to left venous admixture from 0.26 +/- 0.02 to 0.23 +/- 0.02 (P < .001), and in the ratio of physiological dead space to tidal volume (VDS/VT) from 0.53 +/- 0.05 to 0.46 +/- 0.04 (P < .01), without impairment to hemodynamics and (2) respiratory system compliance improved significantly from 34.8 +/- 2.8 mL/cm H2O to 37.2 +/- 2.9 mL/cm H2O (P < .05). In 4 patients, we performed pressure-volume curves on PEEP with the ventilator finding an upward concavity reflecting progressive alveolar recruitment with increasing inflation volume in 3. High-tidal ventilation in the early stage of ARDS improved gas exchange, suggesting recruitment during the inspiratory phase. However, the benefit of better oxygenation should be weighed against the potential risk of barotrauma induced at high VT.


Flicker cone electroretinogram in dichromats and trichromats.
To measure cone signal strengths in the flicker electroretinogram (ERG) of dichromats and trichromats, we developed a set of flickering stimuli (30 Hz), which excite the middle-wavelength-sensitive (M-) and long-wavelength-sensitive (L-) cones independently. ERG responses to eight different ratios of L- to M-cone contrasts were recorded from each subject. The short-wavelength-sensitive (S-) cone contrast was 0% in all measurements. The recordings were Fourier analyzed to determine the amplitude of the fundamental component. ERG threshold values for each subject resulted in ellipses when plotted in an L-/M-cone contrast space. As expected, the orientations of the threshold ellipses of the protanopes (N = 2) were parallel to the L-cone axis, whereas those of the deuteranopes (N = 2) were parallel to the M-cone axis. For the trichromats (N = 5), there was considerable interindividual variation in ellipse orientation.


Assessment of Sleep Disturbances on Mental Health in Patients with Restless Legs Syndrome.
In our study, we aimed to evaluate the sleep disturbances of patients diagnosed with restless legs syndrome (RLS) regarding their mental health according to the severity of the disease. The study included 166 patients diagnosed with RLS and 161 healthy controls in the same age interval as patients. Sleep disturbances of patients were defined with the "personal information form" (PIF) prepared by the researchers, while the mental health status of patients was defined with the "Brief Symptom Inventory" (BSI). All RLS patients had an increase in BSI subscale points, with a positive correlation to disease severity, and subscale points were significantly higher than the control group (p < 0.05). Those with the "frequent waking" problem had higher BSI subscale points compared to those without the problem (p<0.01 or 0.001). Those with "waking with respiratory distress," "daytime sleepiness," "very early waking," and "sleep disorder" problems had statistically significantly high BSI subscale points for all subscales, apart from hostility, compared to those without these problems (p<0.01 or 0.001). It is considered that assessment of sleep disturbances causing disrupted quality of life and mood disorders is beneficial for the treatment of patients with RLS. Our study data appears to be related to the result that sleep disturbances and mental health disruptions might be associated with the disease severity among RLS patients.


Variation in T-lymphocyte activation and susceptibility to SIVPBj-14-induced acute death in macaques.
In contrast to pig-tailed and cynomolgus macaques, which die in 6-10 days following infection with the SIV-PBj-14 isolate, only about 50% of rhesus succumbed to rapid disease. Using a CD45RA MAb that delineates memory (CD45RAlo), naive (CD45RAmed) and "activated" (CD45RAhi) T-cell subsets, it was seen that PBMC from pig-tailed and cynomolgus monkeys, unlike rhesus, have reduced CD4/CD8 ratios and a skewing of T cells towards CD45RAhi expression. Such preactivation of CD4+ cells could lead to enhanced viral replication and early death.


Preparation and characterization of aqueous colloids of Pt-Ru nanoparticles.
A synthetic method for platinum-ruthenium (PtRu) nanoparticles in aqueous media is proposed. This method employs citric acid as a capping agent and NaBH(4) as a reducing agent with the aid of pH control. The number-averaged size of the PtRu nanoparticles was ca. 2 nm. The crystal phase and chemical composition of the nanoparticles was investigated by X-ray diffraction measurement and scanning transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy analysis, which indicated that the nanoparticles mainly consisted of an alloy of Pt and Ru. Electrochemical measurement showed that the PtRu nanoparticles had catalytic activity for methanol oxidation.


Active surfaces engineered by immobilizing protein-polymer nanoreactors for selectively detecting sugar alcohols.
We introduce active surfaces generated by immobilizing protein-polymer nanoreactors on a solid support for sensitive sugar alcohols detection. First, such selective nanoreactors were engineered in solution by simultaneous encapsulation of specific enzymes in copolymer polymersomes, and insertion of membrane proteins for selective conduct of sugar alcohols. Despite the artificial surroundings, and the thickness of the copolymer membrane, functionality of reconstituted Escherichia coli glycerol facilitator (GlpF) was preserved, and allowed selective diffusion of sugar alcohols to the inner cavity of the polymersome, where encapsulated ribitol dehydrogenase (RDH) enzymes served as biosensing entities. Ribitol, selected as a model sugar alcohol, was detected quantitatively by the RDH-nanoreactors with GlpF-mediated permeability in a concentration range of 1.5-9 mM. To obtain "active surfaces" for detecting sugar alcohols, the nanoreactors optimized in solution were then immobilized on a solid support: aldehyde groups exposed at the compartment external surface reacted via an aldehyde-amino reaction with glass surfaces chemically modified with amino groups. The nanoreactors preserved their architecture and activity after immobilization on the glass surface, and represent active biosensing surfaces for selective detection of sugar alcohols, with high sensitivity.


Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine.
The aim of this study was to investigate the preparation of co-amorphous mixture-layered pellets using solventless pelletization and amorphization using a high shear granulator (as suggested in the first part of this study) by high shear mixing of drug crystals and a crystalline co-former with inactive spheres. Mixtures of crystalline indomethacin and arginine at various molar ratios were mixed with microcrystalline cellulose spheres at a weight ratio of 1:10 using the granulator and the resulting particles were characterized using solid-state and particle analytical techniques as well as dissolution testing and physical stability. At jacket temperatures of 20 °C or more of the granulator, co-processing of indomethacin and arginine enhanced amorphization of indomethacin and provided a co-amorphous mixture due to homogenous mixing of indomethacin and arginine amorphous phases. The co-amorphous mixture was deposited on the surface of the spheres, yielding co-amorphous mixture-layered pellets. The co-amorphous mixtures at molar ratios of indomethacin to arginine of 2:1 and 1:1, deposited on the pellets, did not recrystallize for at least 4 weeks. The pellets exhibited higher dissolution characteristics as additional hypromellose could prevent precipitation. These findings demonstrate the potential of this technique as a solventless approach to prepare co-amorphous mixture-layered pellets through a one-step process.


Medical education across three colleges of medicine: perspectives of medical students.
This study aimed to explore and evaluate various components of the medical education process (lectures, labs, small-group discussions, clinical rotations, and undergraduate research) in three colleges of medicine in Jordan. This cross-sectional questionnaire-based study included 849 undergraduate students from three main medical colleges in Jordan. Statically valid responses were considered for 684 students. The participants were from Jordan University of Science and Technology, Yarmouk University, and the University of Jordan. The distribution of students according to their admission status was 276 (40%) regular, 266 (38.9%) parallel, and 142 (20.8%) international programs. Personal interest and self-initiation were the major motives for studying medicine in 66.1%. Regarding the frequency of attending classes, University of Jordan students reported the highest rate of regular classes' attendance (93%). The study also reported that lecture notes and textbooks were the main sources of learning for medical students. The study also reported superior academic performance of students in the regular program compared to students in the parallel and international programs. Participants of the study criticized the medical curricula in the three colleges mentioned above because of the lack of active research programs. Most of the students (40%-56%) also complained that the lectures within the modules were not well-integrated, and they felt that the academic environment was moderate (48-59%). In addition, most students in the clinical phase complained of overcrowding in hospital wards during clinical rotation. Based on students' feedback, multiple aspects of the medical education process require substantial reform to meet the expectations of medical students in Jordan.


Microglial responses after focal radiation-induced injury are affected by alpha-difluoromethylornithine.
The objective of this study was to quantify microglial and astrocytic cell responses after focal 125I irradiation of normal brain and to determine the effects of an intravenous infusion of alpha-difluoromethylornithine (DFMO) on those responses. Adult beagle dogs were irradiated using high activity 125I sources. Saline or DFMO (75 mg/kg/day) was infused for 18 days, and 1 to 10 weeks later brain tissues were collected. Immunohistochemical stains were used to label phagocytes and amoeboid microglia (lectin RCA-1), astrocytes (GFAP), and cells synthesizing deoxyribonucleic acid (DNA) (BrdU). Cell densities (cells/mm2) and BrdU labeling indices were quantified. In dogs infused with saline, increases in phagocytes and amoeboid microglia were observed at 1-2 weeks and 4 weeks, respectively. The labeling indices for phagocytes and amoeboid microglia peaked at 4 weeks with maximum values of 4.8 and 13.4%, respectively. Astrocyte cell numbers increased from 2-6 weeks following irradiation; increased labeling indices were observed after 2 weeks. An infusion of DFMO significantly suppressed BrdU labeling and delayed the increase in cell numbers for phagocytes and amoeboid microglia. In both treatment groups, the proportion of total BrdU labeling accounted for by phagocytes was maximum 1 week after irradiation and then decreased. The proportion of total BrdU labeling accounted for by amoeboid microglia and astrocytes was zero for 2 weeks and then increased. Microglial reactions after focal irradiation involve the phagocytic and amoeboid cell forms and are characterized by increased BrdU uptake and increased cell number. DFMO significantly alters these responses. Changes in astrocyte cell number and BrdU labeling may be related to changes in microglia. Studies of cell responses and their modification may lead to a better understanding of the pathogenesis of radiation injury, and to new strategies to optimize the use of therapeutic irradiation.


Studies on the mode of bacterial contamination of an operating theatre corridor floor.
Bacterial contamination of the floor of a corridor leading into an operating theatre suite was studied in relation to the site chosen for changing footwear. Recovery of bacteria showed a peak at the site of exchange of footwear, and decreased with increasing distance from the site. When the site of exchange was moved further away from the clean area, the peak of contamination moved to the new site and bacterial contamination decreased in the clean area. These results indicate that exchange of footwear should occur as far from the operating theatre as possible.


[Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria?].
The development of multi-drug resistance to antibiotics during the last years and the few number of new active molecules launched on the market have limited the treatment of some infectious diseases. Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria? Considering the bibliographic data, we can note different facts: (1) some alternatives already exist, but correspond more to targeted useful and usable therapeutics as phage therapy, honey therapy, or maggot therapy; (2) some "old" antibiotics can find new bacterial targets and reinforce the anti-infectious therapy towards some multi-drug resistant bacteria; (3) new formulations can allow targeted drug delivery via nanoparticles and the association of molecules can reinforce the antibiotic antimicrobial effect; (4) new treatment could be potentially usable as: antimicrobial peptides, probiotics, herbal medicines, statins, phosphonosulfonates, fecal transplants...; (5) at least, we must not forget that "it's better to prevent than cure". So, besides the principles of hygiene that must be respected, it is necessary to promote (if possible) the development of new vaccines against bacteria responsible for nosocomial infections. Facing with this potential, we can say that new orientations are open with very different levels of success and that it is urgent to find new targets ignored or forgotten until now.


Effect of ruthenium red on the Ca2+ and Sr2+ efflux from rat liver mitochondria: influence of nupercaine.
The rate of ruthenium-red-induced Ca2+ efflux depends on the time that the calcium interacts with the mitochondria prior to the addition of the inhibitor. This time-dependency is abolished in the presence of nupercaine; it does not occur in the case of Sr2+ efflux from mitochondria in which the endogenous Ca2+ has been substituted by strontium (strontium-treated mitochondria, STM). Ruthenium red inhibits the respiratory-inhibitor- or uncoupler-induced Sr2+ efflux from STM, but not the Ca2+ efflux from standard mitochondria. The influence of the calcium-induced mitochondrial damage upon the effect of ruthenium red is discussed.


Associations between the maternal healthy lifestyle score and its individual components during early pregnancy with placental outcomes.
The influence of maternal lifestyle behaviours on placental growth have been investigated individually, but with conflicting results, and their combined effect is under-researched. Therefore, we examined associations between a composite maternal healthy lifestyle score (HLS), and its individual components, during early pregnancy with placental outcomes. Participants included Lifeways Cross-Generational Cohort mother-child pairs (n = 202). A composite HLS based on a less inflammatory diet (bottom 40% of the energy-adjusted Dietary Inflammatory Index (E-DII™)), moderate-to-vigorous physical activity (MVPA), healthy pre-pregnancy BMI (18.5-24.9 kg/m2), never smoking, and non-/moderate alcohol intake was calculated. Quantile regression analysed HLS (and individual components) associations with measures of placental development (untrimmed placental weight (PW)) and function (birth weight:placental weight (BW:PW) ratio) at the 10th, 25th, 50th, 75th and 90th centiles. A more pro-inflammatory diet was positively, and smoking and heavy alcohol consumption were negatively, associated with PW at median centiles (B: 41.97 g, CI: 3.71, 80.22, p < 0.05; B: -58.51 g, CI: -116.24, -0.77, p < 0.05; B: -120.20 g, CI: -177.97, -62.43, p < 0.05 respectively). Low MVPA was inversely associated with BW:PW ratio at the 10th and 90th centiles (B: -0.36, CI: -0.132, -0.29, p < 0.01 and B: -0.45, CI: -0.728, -0.182, p < 0.01, respectively). Heavy alcohol intake was positively associated with BW:PW ratio at the 10th centile (B: 0.54, CI: 0.24, 0.85, p < 0.01). Results of sex-stratified analysis provide evidence of sexual dimorphism. Associations of certain lifestyle factors, but not the composite HLS, during early pregnancy with measures of placental development (PW) and function (BW:PW ratio) varied by quantiles and by sex.


Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease.
Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization. ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0. 51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0. 74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes). Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.


The absence of beta 2-microglobulin in Daudi cells: active gene but inactive messenger RNA.
The Daudi cell line is characterized by an absence of HLA antigen on its surface. This has been attributed to a lack of beta 2-microglobulin (beta 2m) while the heavy chain of HLA is present intracellularly. Karyotype analysis of Daudi cells has shown a deletion involving one of the beta 2-microglobulin alleles. It was generally believed that the absence of beta 2-microglobulin in that cell line resulted from an absence of expression of the remaining gene. We report here the unexpected finding of a normal amount of beta 2-microglobulin messenger RNA in Daudi cells. This was demonstrated by "Northern blot" hybridization with cDNA plasmid clones as a probe. This mRNA, however, when purified by hybridization-selection with beta 2-microglobulin plasmid DNA, is unable to function as messenger in protein synthesis and is therefore an inactive mRNA. The finding of a translationally inactive beta 2-microglobulin mRNA provides a new explanation for the absence of beta 2-microglobulin and therefore of HLA antigens in Daudi cells.


Laparoscopic fundoplication.
The effectiveness of laparoscopic Nissen fundoplication (LNF) was assessed in patients with chronic gastroesophageal reflux disease (GERD) using pH study and different quality-of-life indexes. We correlated both types of data and hypothesised that improvement in quality of life following LNF does not necessarily correlate with improvement in pH values. Seventy patients presenting with typical symptoms of GERD (14 with Barrett's esophagus) underwent LNF between May 1997 and December 2000. All patients were evaluated both prior to and 3 months after surgery using 24-h pH study, endoscopy, and a validated quality-of-life questionnaire. Following LNF, reflux was reduced to normal in all but six patients. Howevers despite persistent reflux, the Gastrointestinal Quality of Life Index (GQLI), of these six patients improved postoperatively from 79.5 +/- 12.2 to 111.7 +/- 8.3. These results correlate with those of patients who had normal postoperative pH studies-namely, 88.5 +/- 19.3 to 112 +/- 16.7. There was no difference in quality-of-life improvement between patients with Barrett's esophagus and those without it. There is only a weak correlation between quality-of-life assessment and pH study. Because the patient's quality of life is likely to improve following LNF, an objective means parameter of assessing the effectiveness of antireflux surgery, such as pH study or endoscopy, is recommended.


Mefloquine sulfadoxine pyrimethamine (MSP) combination delays in vitro emergence of mefloquine resistance in multiple drug resistant Plasmodium falciparum.
Sulfadoxine-pyrimethamine-resistant and chloroquine resistant, but mefloquine sensitive (MIC 5 x 10(-9] isolates of Plasmodium falciparum were used to study the emergence of mefloquine resistance. The continuously cultured isolates which were exposed intermittantly to varying concentrations of mefloquine alone became insensitive to the drug at 1 x 10(-7) M after 12 months, whereas the culture line exposed to the combination of mefloquine, sulfadoxine and pyrimethamine became only slightly insensitive to mefloquine (MIC 2 x 10(-8]. Thus, the efficacy of mefloquine may be prolonged through use in combination with sulfadoxine-pyrimethamine.


Higher B-cell activating factor levels at birth are positively associated with maternal dairy farm exposure and negatively related to allergy development.
A high proportion of circulating immature/naive CD5(+) B cells during early infancy is a risk factor for allergy development. B-cell activating factor (BAFF) is an important cytokine for B-cell maturation. We sought to investigate whether BAFF levels are related to environmental exposures during pregnancy and early childhood and whether BAFF levels are associated with postnatal B-cell maturation and allergic disease. In the FARMFLORA study, including both farming and nonfarming families, we measured BAFF levels in plasma from mothers and their children at birth and at 1, 4, 18, and 36 months of age. Infants' blood samples were also analyzed for B-cell numbers and proportions of CD5(+) and CD27(+) B cells. Allergic disease was clinically evaluated at 18 and 36 months of age. Circulating BAFF levels were maximal at birth, and farmers' children had higher BAFF levels than nonfarmers' children. Higher BAFF levels at birth were positively associated with proportions of CD27(+) memory B cells among farmers' children and inversely related to proportions of CD5(+) immature/naive B cells among nonfarmers' children. Children with allergic disease at 18 months of age had lower cord blood BAFF levels than nonallergic children. At birth, girls had higher BAFF levels and lower proportions of CD5(+) B cells than boys. Farm exposure during pregnancy appears to induce BAFF production in the newborn child, and high neonatal BAFF levels were associated with more accelerated postnatal B-cell maturation, which lend further strength to the role of B cells in the hygiene hypothesis.


An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models.
The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A 2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis. Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A 2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days. There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-alpha, MIP-1 alpha, MCP-1, IFN-gamma, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01). Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.


Deformable Electronics: Conducting Polymer Dough for Deformable Electronics (Adv. Mater. 22/2016).
A simple strategy for changing a brittle conducting polymer ( PSS) into a solution-processed highly deformable viscoelastic polymer is presented by H.-K. Baik, U. Jeong, and co-workers on page 4455. The storage modulus versus loss modulus of the polymer is adjusted to control the viscoelastic properties to fit the properties required in deformable electronics. Rapid self-healing of conductivity, custom-designed LEDs with complex micropatterns, and foldable stretchable LEDs are demonstrated.


Out with AI, in with the psychiatrist: a preference for human-derived clinical decision support in depression care.
Advancements in artificial intelligence (AI) are enabling the development of clinical support tools (CSTs) in psychiatry to facilitate the review of patient data and inform clinical care. To promote their successful integration and prevent over-reliance, it is important to understand how psychiatrists will respond to information provided by AI-based CSTs, particularly if it is incorrect. We conducted an experiment to examine psychiatrists' perceptions of AI-based CSTs for treating major depressive disorder (MDD) and to determine whether perceptions interacted with the quality of CST information. Eighty-three psychiatrists read clinical notes about a hypothetical patient with MDD and reviewed two CSTs embedded within a single dashboard: the note's summary and a treatment recommendation. Psychiatrists were randomised to believe the source of CSTs was either AI or another psychiatrist, and across four notes, CSTs provided either correct or incorrect information. Psychiatrists rated the CSTs on various attributes. Ratings for note summaries were less favourable when psychiatrists believed the notes were generated with AI as compared to another psychiatrist, regardless of whether the notes provided correct or incorrect information. A smaller preference for psychiatrist-generated information emerged in ratings of attributes that reflected the summary's accuracy or its inclusion of important information from the full clinical note. Ratings for treatment recommendations were also less favourable when their perceived source was AI, but only when recommendations were correct. There was little evidence that clinical expertise or familiarity with AI impacted results. These findings suggest that psychiatrists prefer human-derived CSTs. This preference was less pronounced for ratings that may have prompted a deeper review of CST information (i.e. a comparison with the full clinical note to evaluate the summary's accuracy or completeness, assessing an incorrect treatment recommendation), suggesting a role of heuristics. Future work should explore other contributing factors and downstream implications for integrating AI into psychiatric care.


Legal issues impacting women's access to care in the United States-the malpractice insurance crisis.
Professional liability insurance costs have increased rapidly in the last 10 years in the United States, while availability of companies offering professional liability insurance has decreased. The result is that ob-gyn physicians are changing their practice patterns. Many are no longer performing difficult or complex surgical procedures while others have stopped caring for obstetrical patients. Some physicians are retiring early or moving to other localities where there are less liability concerns. These changes all impact on the availability of health care for women. In addition, these problems have become a concern of medical students, and this is reducing the numbers considering a career in ob-gyn. Even where ob-gyns are available, hospitals and insurance carriers are limiting their ability to practice the wide range of procedures for which they were trained. Although legislative efforts to correct the problems are proposed, very few have been enacted. The end result is that women's health care has been threatened and will continue to face shortages and restrictions.


Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1.
Polyhexamethylene biguanide (PHMB) is a polybiguanide (PBG) oligomer with antimicrobial activity that is used extensively and safely as a disinfectant. The reported mechanism of PHMB antimicrobial activity, which involves interactions with cell membrane components, suggested that PHMB or other PBG-based compounds might also have antiviral or virucidal activity against the human immunodeficiency virus type 1 (HIV-1). PHMB had modest in vitro activity against both cell-free and cell-associated HIV-1, as well as the ability to interfere with viral binding and entry. However, PHMB was comparable in cytotoxicity to the spermicidal agent nonoxynol-9 (N-9), a compound that has been characterized in previous studies as generally cytotoxic and detrimental to cervicovaginal epithelial integrity. To identify structural variants of PHMB with greater anti-HIV-1 activity and/or less cytotoxicity, modified versions of PHMB incorporating length changes in the hydrocarbon linker units were synthesized and evaluated for in vitro cytotoxicity and inhibition of HIV-1 infectivity. These experiments demonstrated that the PHMB variant polyethylene hexamethylene biguanide (PEHMB) was just as active against HIV-1 as PHMB, yet was much less cytotoxic than either N-9 or PHMB, resulting in an in vitro therapeutic index (TI) approximately 114-fold greater than the TI of N-9. PEHMB, which has been identified in these studies as a promising microbicidal candidate in this family of compounds, will be the focus of further in vitro and in vivo evaluations of anti-HIV-1 activity, toxicity, and mechanisms of action.


Bilateral spontaneous pneumothorax, pneumomediastinum, and subcutaneous emphysema: rare and fatal complications of asthma.
Simultaneous bilateral spontaneous pneumothorax (SBSP) and pneumomediastinum are complications rarely observed synchronously during an acute asthma attack. It is a clinical condition that manifests itself with serious respiratory distress and must be rapidly diagnosed and treated. Although bilateral spontaneous pneumothorax has already been reported in asthma patients in the literature, its concurrence with subcutaneous emphysema and pneumomediastinum is extremely rare except for iatrogenic conditions. By sharing this case about a 39-year-old patient who presented to the emergency room with severe respiratory distress and developed cardiopulmonary arrest during his physical examination, our aim is to emphasize that a rapid diagnosis and treatment by the emergency physicians is the only way for survival in these patients.


16 years of topographic surveys of rip-channelled high-energy meso-macrotidal sandy beach.
Sandy beaches are highly dynamic environments buffering shores from storm waves and providing outstanding recreational services. Long-term beach monitoring programs are critical to test and improve shoreline, beach morphodynamics and storm impact models. However, these programs are relatively rare and mostly restricted to microtidal alongshore-uniform beaches. The present 16-year dataset contains 326 digital elevation models and their over 1.635 × 106 individual sand level measurements at the high-energy meso-macrotidal rip-channelled Truc Vert beach, southwest France. Monthly to bimonthly topographic surveys, which coverage progressively extended from 300 m to over 2000 m to describe the alongshore-variable changes, are completed by daily topographic surveys acquired during a 5-week field campaign. The dataset captures daily beach response at the scale of a storm to three large cycles of interannual variability, through the impact of the most energetic winter since at least 75 years and prominent seasonal erosion/recovery cycles. The data set is supplemented with high-frequency time series of offshore wave and astronomical tide data to facilitate its future use in beach research.


Solid ovarian teratoma with neuroglial metastases to periaortic lymph nodes and omentum.
We have described a 16-year-old girl who had a unilateral adnexectomy for a solid ovarian teratoma, grade 0. Periaortic nodes and omentum contained grade 0 neuroglial metastases.


The mesenchymal substrate influences the epithelial phenotype in a three-dimensional cell culture.
Cell-matrix interactions are thought to influence epithelial structure, growth, and differentiation. Three-dimensional cell cultures were used to study the effects of the composition of the dermal equivalent on the morphology of epithelium grown from HaCaT skin keratinocytes. Three commercial preparations, a basement membrane preparation from a tumor (matrix 1), two preparations consisting of collagen type I and III (matrix 3 and 4) and a noncommercial preparation containing collagen type I (matrix 2) were investigated. The effects of fibroblasts of different origin (vaginal mucosa, oral buccal mucosa, and skin) were investigated in connection with matrix 4. The histomorphology and expression of the proteins PCNA, Ki-67, p53, p21, pankeratin, involucrin, cytokeratin 10 (Ck10), Ck17, Ck19 and collagen type IV were evaluated. Three-dimensional cultures of HaCaT cells gave rise to an epithelium with an immature and hyperproliferative character, showing active proliferation with intense PCNA staining. Both matrix 1 and matrix 2 resulted in an epithelium with budding into the matrix and some degree of layering. These epithelia showed only scattered Ck17 and Ck19 expression but a low terminal differentiation potential as indicated by scattered Ck10 and involucrin staining. The epithelia of cocultures with matrices 3 and 4 were positive for Ck17 and Ck19. However, the epithelium on matrix 3 showed strong expression of the terminal differentiation marker Ck10 and involucrin. This methodological study provides evidence of the importance of standardization of the composition of the matrix to avoid confounding effects on epithelial morphology and protein expression in studies using a three-dimensional epithelial culture model.


In vivo persistence of genetically modified T cells generated ex vivo using the fibronectin CH296 stimulation method.
Recombinant human fibronectin fragment (FN-CH296, RetroNectin) has been widely used for retroviral gene therapy to enhance gene transfer efficiency. Based on the observation that immobilized FN-CH296 together with anti-CD3 monoclonal antibodies (anti-CD3) enhanced cell proliferation while conserving the naive phenotype of T cells, we used FN-CH296 costimulation to generate engineered T cells. For comparison, human peripheral blood mononuclear cells were stimulated under three kinds of conditions including anti-CD3 only, anti-CD3 and anti-CD28 monoclonal antibodies conjugated with beads (anti-CD3/anti-CD28) and immobilized FN-CH296 together with anti-CD3 (anti-CD3/FN-CH296); all three treatments were followed by retroviral gene transfer. Of all the stimulation methods, the one involving anti-CD3/FN-CH296 produced the most cell expansion with conservation of the naive phenotype. Engineered T cells were transplanted into NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice, and all the mice were killed 14 days later. Transplanted T cells were detected in all the mice; however, mice injected with anti-CD3/FN-CH296-stimulated T cells showed higher transgene expression in organs than mice injected with anti-CD3-stimulated cells. These results demonstrate that the anti-CD3/FN-CH296 stimulation can be an efficient way to generate large numbers of genetically modified T cells that can provide higher and longer lasting levels of transgene expression in vivo and that are suitable for adoptive T-cell transfer therapy.


The mental health implications of detaining asylum seekers.
The possible mental health impact on asylum seekers of Australia's policy of mandatory detention is an issue of special relevance to health professionals and the public. Independent commissions of inquiry in Australia have found varying degrees of mental distress to be common in detained asylum seekers. Research studies in Australia and elsewhere suggest that detained asylum seekers may have suffered greater levels of past trauma than other refugees, and this may contribute to their mental health problems, with their detention providing a retraumatising environment. Studies are urgently required to examine the mental health consequences of detention, and to determine the effect of detention on acculturation and adaptation for asylum seekers subsequently released into the community.


Analysis of human pure pancreatic juice in chronic pancreatitis and cancer of the pancreas.
Pure pancreatic juice was collected from 8 control subjects, 12 patients with chronic pancreatitis and 4 patients with cancer of the pancreas by endoscopic retrograde cannulation of the papilla. Samples were collected at 1 minute intervals for 20 minutes after rapid intravenous injection of secretin (Eisai, 1 U/kg) and for 10 minutes after rapid intravenous injection of CCK-PZ (Boots, 1 U/kg). Determinations of volume, bicarbonate concentration and three hydrolases (amylase, chymotrypsinogen and lipase) were made. Our tentative conclusions are (1) pancreatic enzymes are likely to be affected one after another, not in parallel fashing, in chronic pancreatitis and in cancer of the pancreas, (2) bicarbonate concentration and chymotrypsinogen or lipase are most susceptible in chronic pancreatitis and lipase secretion seems to be more susceptible than other parameters in cancer of the pancreas. Amylase is the least affected enzyme in both pancreatic diseases, and (3) determinations of chymotrypsinogen and/or lipase should be preferably performed among hydrolytic enzymes in the evaluation of exocrine pancreatic function in chronic pancreatitis and cancer of the pancreas.


A Novel Approach in the Surgical Management of Nasal Tip Hemangiomas: A 26-Year Experience.
Infantile hemangiomas are common benign tumors of infancy with a predilection for the face. Nasal-tip hemangiomas, termed the "Cyrano deformity," can have especially devastating psychological effects. The ideal surgical approach and timing for these patients is unclear, as numerous designs have been reported in the literature. The authors present a novel approach to nasal tip reconstruction involving an algorithmic approach to incision selection and leaving a thin rim of hemangioma tissue under the dermis after debulking to minimize skin envelope atrophy. Nineteen cases were treated with the senior author's preferred method, with a mean age of 3.3 years and follow-up of 2.5 years. At follow-up, 10 patients were deemed by the senior author to have a very good aesthetic result, and the remaining nine patients were deemed to have an excellent one. The results of this study suggest that surgical intervention as early as 3 to 4 years of age is safe and provides good aesthetic outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.


The differentiation of normal and transformed human fibroblasts in vitro is influenced by electromagnetic fields.
We studied the effect of symmetric, biphasic sinusoidal electromagnetic fields (EMF) (20 Hz, 6 mT) on the differentiation of normal human skin fibroblasts (HH-8), normal human lung fibroblasts (WI38), and SV40-transformed human lung fibroblasts (WI38SV40) in in vitro cultures. Cells were exposed up to 21 days for 2 x 6 h per day to EMF. Normal mitotic human skin and lung fibroblasts could be induced to differentiate into postmitotic cells upon exposure to EMF. Concomitantly, the synthesis of total collagen as well as total cellular protein increased significantly by a factor of 5-13 in EMF-induced postmitotic cells. As analyzed by two-dimensional gel electrophoresis of [35S]methionine-labeled polypeptides, EMF-induced postmitotic cells express the same differentiation-dependent and cell type-specific marker proteins as their spontaneously arising counterparts. In SV40-transformed human lung fibroblasts (cell line WI38SV40) the exposure to EMF induced the differentiation of mitotic WI38SV40 cells into postmitotic and degenerating cells in subpopulations of WI38SV40 cell cultures. Other subpopulations of WI38SV40 cells did not show any effect of EMF on cell proliferation and differentiation. These results indicate that long-term EMF exposure of fibroblasts in vitro induces the differentiation of mitotic to postmitotic cells that are characterized by differentiation-specific proteins and differentiation-dependent enhanced metabolic activities.


Enzyme Cascade Reactions on DNA Origami Scaffold.
The protocols for constructing, characterizing, and analyzing enzyme cascade reaction systems on the DNA scaffold are described. Two-step and three-step enzyme cascade reactions were adapted from the xylose metabolic pathway as the example of natural metabolic pathway and were assembled on the DNA scaffold by using the DNA binding adaptors.


Sensing site-specific structural characteristics and chirality using vibrational circular dichroism of isotope labeled peptides.
Isotope labeling has a long history in chemistry as a tool for probing structure, offering enhanced sensitivity, or enabling site selection with a wide range of spectroscopic tools. Chirality sensitive methods such as electronic circular dichroism are global structural tools and have intrinsically low resolution. Consequently, they are generally insensitive to modifications to enhance site selectivity. The use of isotope labeling to modify vibrational spectra with unique resolvable frequency shifts can provide useful site-specific sensitivity, and these methods have been recently more widely expanded in biopolymer studies. While the spectral shifts resulting from changes in isotopic mass can provide resolution of modes from specific parts of the molecule and can allow detection of local change in structure with perturbation, these shifts alone do not directly indicate structure or chirality. With vibrational circular dichroism (VCD), the shifted bands and their resultant sign patterns can be used to indicate local conformations in labeled biopolymers, particularly if multiple labels are used and if their coupling is theoretically modeled. This mini-review discusses selected examples of the use of labeling specific amides in peptides to develop local structural insight with VCD spectra.


Negative affectivity and enhanced symptom reports: differentiating between symptoms in men and women.
This study aimed to characterize individual bodily symptoms as regards their differential relationship with negative affectivity (NA). In a first step, 73 symptoms were rated by independent groups of raters (psychologists, medical doctors, healthy students) on the following characteristics: the extent to which a symptom (1) refers to a specific location in the body (vagueness), (2) may refer to both a physical condition and a negative emotional state (overlap), and (3) is likely to be a physiological manifestation of anxiety (anxiety). Each symptom was also rated on (4) the probability that it is caused by a clearly defined somatic pathology (somatic pathology), (5) how life-threatening or (6) compromising for the quality of life a symptom is, and (7) how worried one would be if the symptom were to be experienced in daily life (worrying). Two factors, severity and somatic versus psychic, explained 75% of the variance in the ratings on the symptom characteristics. Next, based on the data of 1017 university students (858 women), correlations of each individual symptom with NA were calculated for each gender. The pattern of correlation was highly variable and differed in important ways for men and women. Whereas the correlation of an individual symptom with NA could be predicted by both symptom factors in women (R(2)=52%), only the somatic versus psychic factor was a significant predictor in men (R(2)=11%). These results suggest that (1) NA should not be considered a general complaining factor, and (2) important gender differences exist regarding the type of symptoms that relate most strongly to NA.


Extraction and Purification, Structural Characterization and Biological Activity of a Polysaccharide, PRP-1, from Plumeria rubra.
Polysaccharides derived from the flowers of Plumeria rubra (PRP) have shown a variety of beneficial effects on improving human health. However, the structural features and bioactivities of PRP remain unclear. A novel neutral polysaccharide (named PRP-1) with a molecular weight of 23 kDa was extracted and purified from the flowers of P. rubra. PRP-1 was consisted of arabinose, galactose, glucose, xylose and mannose, with a molar ratio of 1.49: 27.89: 50.24: 13.02: 7.36. The structural characterization based on the methylation and 1D/2D nuclear magnetic resonance analyses indicated that PRP-1 was composed of →4)-Glcp-(1→, →4,6)-Glcp-(1→, →4)-Galp-(1→, →2)-Galp-(1→, t-Gal(p), →4)-Manp-(1→, →4,6)-Manp-(1→, t-Man(p), →2)-Xylp-(1→, and t-Xyl(p). Scanning electron microscopy revealed that PRP-1 possess a compact three-dimensional curling network structure in the terms of morphology. PRP-1 exhibited anti-inflammatory activity, which have moderate inhibitory effects on TNF-α and IL-6 production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In addition, PRP-1 showed ABTS, OH radicals scavenging and the Fe2+ chelating effects in a concentration dependent manner. In α-glucosidase inhibition assay, PRP-1 did not exhibit inhibitory activity. Overall, these results provide a scientific basis for the utilization of the flowers of P. rubra as a potential functional food ingredient.