Headache as a crucial symptom in the etiology of convexal subarachnoid hemorrhage.
Convexal subarachnoid hemorrhage has been associated with different diseases, reversible cerebral vasoconstriction syndrome and cerebral amyloid angiopathy being the 2 main causes. To investigate whether headache at onset is determinant in identifying the underlying etiology for convexal subarachnoid hemorrhage. After searching in the database of our hospital, 24 patients were found with convexal subarachnoid hemorrhage in the last 10 years. The mean age of the sample was 69.5 years. We recorded data referring to demographics, symptoms and neuroimaging. Cerebral amyloid angiopathy patients accounted for 46% of the sample, 13% were diagnosed with reversible cerebral vasoconstriction syndrome, 16% with several other etiologies, and in 25%, the cause remained unknown. Mild headache was present only in 1 (9%) of the 11 cerebral amyloid angiopathy patients, while severe headache was the dominant feature in 86% of cases of the remaining etiologies. Headache is a key symptom allowing a presumptive etiological diagnosis of convexal subarachnoid hemorrhage. While the absence of headache suggests cerebral amyloid angiopathy as the more probable cause, severe headache obliges us to rule out other etiologies, such as reversible cerebral vasoconstriction syndrome.


Long noncoding RNA ELDR promotes cell cycle progression in normal oral keratinocytes through induction of a CTCF-FOXM1-AURKA signaling axis.
Long noncoding RNAs (lncRNAs) have gained widespread attention as a new layer of regulation in biological processes during development and disease. The lncRNA ELDR (EGFR long noncoding downstream RNA) was recently shown to be highly expressed in oral cancers as compared to adjacent nontumor tissue, and we previously reported that ELDR may be an oncogene as inhibition of ELDR reduces tumor growth in oral cancer models. Furthermore, overexpression of ELDR induces proliferation and colony formation in normal oral keratinocytes (NOKs). In this study, we examined in further detail how ELDR drives the neoplastic transformation of normal keratinocytes. We performed RNA-seq analysis on NOKs stably expressing ELDR (NOK-ELDR), which revealed that ELDR enhances the expression of cell cycle-related genes. Expression of Aurora kinase A and its downstream targets Polo-like kinase 1, cell division cycle 25C, cyclin-dependent kinase 1, and cyclin B1 (CCNB1) are significantly increased in NOK-ELDR cells, suggesting induction of G2/M progression. We further identified CCCTC-binding factor (CTCF) as a binding partner of ELDR in NOK-ELDR cells. We show that ELDR stabilizes CTCF and increases its expression. Finally, we demonstrate the ELDR-CTCF axis upregulates transcription factor Forkhead box M1, which induces Aurora kinase A expression and downstream G2/M transition. These findings provide mechanistic insights into the role of the lncRNA ELDR as a potential driver of oral cancer during neoplastic transformation of normal keratinocytes.


Reconstruction and analysis of circRNA‑miRNA‑mRNA network in the pathology of cervical cancer.
The present study was performed with the aim of understanding the mechanisms of pathogenesis and providing novel biomarkers for cervical cancer by constructing a regulatory circular (circ)RNA‑micro (mi)RNA‑mRNA network. Using an adjusted P-value of <0.05 and an absolute log value of fold-change >1, 16 and 156 miRNAs from GSE30656 and The Cancer Genome Atlas (TCGA), 5,321 mRNAs from GSE63514, 4,076 mRNAs from cervical squamous cell carcinoma and endocervical adenocarcinoma (from TCGA) and 75 circRNAs from GSE102686 were obtained. Using RNAhybrid, Venn and UpSetR plot, 12 circRNA‑miRNA pairs and 266 miRNA‑mRNA pairs were obtained. Once these pairs were combined, a circRNA‑miRNA‑mRNA network with 11 circRNA nodes, 4 miRNA nodes, 153 mRNA nodes and 203 edges was constructed. By constructing the protein‑protein interaction network using Molecular Complex Detection scores >5 and >5 nodes, 7 hubgenes (RRM2, CEP55, CHEK1, KIF23, RACGAP1, ATAD2 and KIF11) were identified. By mapping the 7 hubgenes into the preliminary circRNA‑miRNA‑mRNA network, a circRNA‑miRNA‑hubgenes network consisting of 5 circRNAs (hsa_circRNA_000596, hsa_circRNA_104315, hsa_circRNA_400068, hsa_circRNA_101958 and hsa_circRNA_103519), 2 mRNAs (hsa‑miR‑15b and hsa‑miR‑106b) and 7 mRNAs (RRM2, CEP55, CHEK1, KIF23, RACGAP1, ATAD2 and KIF11) was constructed. There were 22 circRNA‑miRNA‑mRNA regulatory axes identified in the subnetwork. By analyzing the overall survival for the 7 hubgenes using the Gene Expression Profiling Interactive Analysis tool, higher expression of RRM2 was demonstrated to be associated with a significantly poorer overall survival. PharmGkb analysis identified single nucleotide polymorphisms (SNPs) of rs5030743 and rs1130609 of RRM2, which can be treated with cladribine and cytarabine. RRM2 was also indicated to be involved in the gemcitabine pathway. The 5 circRNAs (hsa_circRNA_000596, hsa_circRNA_104315, hsa_circRNA_400068, hsa_circRNA_101958 and hsa_circRNA_103519) may function as competing endogenous RNAs and serve critical roles in cervical cancer. In addition, cytarabine may produce similar effects to gemcitabine and may be an optional chemotherapeutic drug for treating cervical cancer by targeting rs5030743 and rs1130609 or other similar SNPs. However, the specific mechanism of action should be confirmed by further study.


Advances in the use of bisphosphonates in the prostate cancer setting.
Prostate cancer incidence is rising, and represents a major public health issue. Bone is by far the most common site for metastases in this disease, accounting for considerable morbidity. Until recently, there have been few viable options for the treatment of patients with hormone-refractory metastatic disease. This review examines the pathophysiology underlying the development of bone metastases. It also summarises some of the clinical approaches for the management of this common condition, focusing on recent evidence supporting the use of zoledronic acid, a member of one of the most promising groups of pharmacological agents, the third-generation bisphosphonates.


Cannabis: A joint problem for patients and the dental profession.
Cannabis is one of the most commonly abused drugs in the UK. The debate about its legality has grown in recent times but the health implication of cannabis use is an issue of today. It is a drug commonly described as being 'soft' but its use has profound effects on many of the body's systems, including the oral cavity. This is of particular importance to the dental clinician. This paper aims to discuss the oral implications of cannabis use and provide advice on ways in which dental professionals can approach this sensitive topic and provide support.


Symptomatic vitamin E deficiency diagnosed after histological recognition of myometrial lipofuscinosis.
We report a 44-year-old woman in whom intestinal bypass for obesity at age 23 resulted in chronic malabsorption. After hysterectomy for menorrhagia due to atypical endometrial hyperplasia, the finding of myometrial lipofuscinosis led to a demonstration of vitamin E deficiency. Vitamin E supplementation led to an unexpected improvement in the unsteadiness of gait and slurring of speech of which she had also complained. We suggest that supplementation with vitamin E should be routine in all patients with persistent severe steatorrhoea.


Effects of caloric restriction on lipid metabolism in man: changes of tissue lipoprotein lipase activities and of serum lipoproteins.
Heparin-releasable lipoprotein lipase (LPL) activity was measured in biopsy samples of adipose tissue and skeletal muscle of 8 normal healthy females, first during an isocaloric diet and then after 2 and 7 days on a 400-kcal diet. In adipose tissue the LPL activity expressed per tissue weight fell to 38% and to 22% of the initial level after 2 and 7 days' caloric restriction, respectively. In skeletal muscle the LPL activity rose slightly after two days (+24%) but decreased to 49% of the initial value after seven days on diet. The estimated total body LPL activity decreased to 50% and to 20% of the baseline value after 2 and 7 days, respectively, but the relative contribution of skeletal muscle to the total LPL increased from 10 to 30%. The triglyceride and VLDL triglyceride concentrations were not significantly changed during the low calorie diet but the LDL triglyceride increased and the HDL cholesterol decreased significantly (P less than 0.01). It is concluded that substantial restriction of calorie intake results in a decrease of over-all triglyceride removal capacity but in an increase of the fraction removed by skeletal muscle. The decrease of HDL cholesterol is probably a consequence of the low turnover of exogenous and endogenous triglyceride-rich lipoproteins.


Predicting histopathology markers of endometrial carcinoma with a quantitative image analysis approach based on spherical harmonics in multiparametric MRI.
Identifying optimal machine learning pipelines for computer-aided diagnosis is key for the development of robust, reproducible, and clinically relevant imaging biomarkers for endometrial carcinoma. The purpose of this study was to introduce the mathematical development of image descriptors computed from spherical harmonics (SPHARM) decompositions as well as the associated machine learning pipeline, and to evaluate their performance in predicting deep myometrial invasion (MI) and histopathological high-grade in preoperative multiparametric magnetic resonance imaging (MRI). This retrospective study included 128 women with histopathology-confirmed endometrial carcinomas who underwent 1.5-T MRI before hysterectomy between January 2011 and July 2015. SPHARM descriptors of each tumor were computed on multiparametric MRI images (T2-weighted, diffusion-weighted, dynamic contrast-enhanced-MRI and apparent diffusion coefficient maps). Tensor-based logistic regression was used to classify two-dimensional SPHARM rotationally-invariant descriptors. Head-to-head comparisons with radiomics analyses were performed with DeLong tests with Bonferroni-Holm correction to compare diagnostic performances. With all MRI contrasts, SPHARM analysis resulted in area under the curve, sensitivity, specificity, and balanced accuracy values of 0.94 (95% confidence interval [CI]: 0.85, 1.00), 100% (95% CI: 100, 100), 74% (95% CI: 51, 92), 87% (95% CI: 78, 98), respectively, for predicting deep MI. For predicting high-grade tumor histology, the corresponding values for the same diagnostic metrics were 0.81 (95% CI: 0.64, 0.90), 93% (95% CI: 67, 100), 63% (95% CI: 45, 79) and 78% (95% CI: 64, 86). The corresponding values achieved via radiomics were 0.92 (95% CI: 0.82, 0.95), 82% (95% CI: 65, 93), 80% (95% CI: 51, 94), 81% (95% CI: 70, 91) for deep MI and 0.72 (95% CI: 0.58, 0.83), 93% (95% CI: 65, 100), 55% (95% CI: 41, 69), 74% (95% CI: 52, 88) for high-grade histology. The diagnostic performance of the SPHARM analysis was not significantly different (P = 0.62) from that of radiomics for predicting deep MI but was significantly higher (P = 0.044) for predicting high-grade histology. The proposed SPHARM analysis yields similar or higher diagnostic performance than radiomics in identifying deep MI and high-grade status in histology-proven endometrial carcinoma.


Haemodialysis patients with diabetes eat less than those without: A plea for a permissive diet.
The main cause of malnutrition in haemodialysis patients is a spontaneous decline in energy and protein intakes. This study aims to report the dietary energy intake (DEI), dietary protein intake (DPI), and dietary micronutrient intake in a French HD population, to report factors associated with a low DPI and DEI, and to analyze if nutritional intake was correlated with nutritional status. We conducted an observational cross-sectional study in a haemodialysis population of 87 adult patients in July 2014. Daily nutritional oral intake, handgrip strength, body composition measured by bioimpedancemetry, and biological and dialysis parameters were obtained from medical records. Statistical analyses of parameters associated with DEI and DPI were performed. The median age (interquartile range) of the population was 77.3 [71.1; 84.8] years, 57.5% were men, and 52.9% had diabetes mellitus. Median weight-adjusted DEI was 18.4 [15.7;22.3] kcal/kg per day (1308 [1078; 1569] kcal/day), and median weight-adjusted DPI was 0.80 [0.66; 0.96] g/kg per day (57.5 [47.1; 66.8] g/day). In multivariate analysis, weight-adjusted DEI was statistically lower in patients with diabetes (coefficient [95%CI] -3.81[-5.21;-2.41] kcal/kg per day; P = 0.01) but was not associated with the others parameters. When DEI was not adjusted for weight, diabetes was no longer associated with DEI, but female gender (-178[-259;-961] kcal/day; P = 0.03) and a higher Charlson comorbidity index (-30[-44;-15]; P = 0.04) were associated with a lower calorie intake. Results for DPI were similar except that the Charlson comorbidity index did not reach significance. Diabetes is an important factor associated with low dietary intake in haemodialysis patients. Restrictive regimens should be prescribed cautiously in haemodialysis patients, especially in those with diabetes.


Vancomycin-chitosan composite deposited on post porous hydroxyapatite coated Ti6Al4V implant for drug controlled release.
Through the hydrogen bonds and the deprotonation, the vancomycin-chitosan composite has been originally deposited on Ti4Al4V by electrochemical technology. However, the rapid destruction of the hydrogen bonding between them by polar water molecules during immersion tests revealed 80% drug burst in a few hours. In this study, the post porous hydroxyapatite (HA) coated Ti4Al4V is prepared for the subsequent electrolytic deposition of vancomycin-chitosan composite to control the drug release. As expected, the initial burst is reduced to 55%, followed by a steady release about 20% from day 1 to day 5 and a slower release of the retained 25% after day 6, resulting in bacterial inhibition zone diameter of 30 mm which can last for more than a month in antibacterial tests, compared with the coated specimen without HA gradually loosing inhibition zone after 21 days. Besides, the cell culture indicates that the vancomycin-chitosan/HA composite coated has enhanced the proliferation, the differentiation and the mineralization of the osteoblast-like cell. In general, it is helpful for the osteointegration on permanent implants. Consistently, it effectively provides the prophylaxis and therapy of osteomyelitis according to the results of the rabbit infection animal model.


Conservative inlay fixed partial denture: a clinical and laboratory technique.
Fiber-reinforced composite (FRC) fixed partial dentures (FPDs) offer a clinical alternative for the restoration of single missing teeth and short-span posterior and anterior FPDs. This treatment modality is conservative and cost-efficient. The continuous improvement of adhesives and resin-based composite systems makes this type of restoration successful with good esthetic and functional results. This article reports the case of a patient who received an FRC FPD as a treatment modality and illustrates the clinical procedure as well as a new laboratory technique utilizing a clear matrix for the fabrication of the prosthesis.


Searching for novel hydrogen sulfide donors: The vascular effects of two thiourea derivatives.
The gasotransmitter hydrogen sulfide (H2S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H2S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H2S-donors, exhibiting long-lasting H2S release; however, novel H2S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H2S-donors. The thioureas showed long-lasting H2S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of KATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by KATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H2S-donor functional group, which releases H2S with slow and long lasting kinetic, and promotes typical H2S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H2S.


Effects of preincubation of eggs and activation medium on the percentage of eyed embryos in ide (Leuciscus idus), an externally fertilizing fish.
Standardization of fertilization protocols is crucial for improving reproductive techniques for externally fertilizing fish in captive breeding. Therefore, the objectives of this study were to determine the effects of preincubation of eggs and activation medium on the percentage of eyed embryos for ide (Leuciscus idus). Pooled eggs from five females were preincubated in three different activating media for 0, 30, 60, 90, and 120 seconds and then fertilized by pooled sperm from five males. At the eyed-egg stage, the percentage of viable embryos was later calculated. Results showed that preincubation time was significant for the freshwater activation medium (P < 0.001), such that the percentage of eyed embryos declined across the preincubation time gradient. Additionally, there was an effect on the percentage of eyed embryos when eggs were incubated with Woynarovich solution (P < 0.001), such that a decline was detected at 90 seconds, whereas no effect was detected for the saline water medium. Activating medium had a significant effect on the percentage of eyed embryos for each preincubation time (P < 0.05). More precisely, freshwater produced the lowest percentage of eyed embryos at all preincubation times (ranged from 1.9% at 120 seconds to 43.6% at 0 seconds), whereas saline water and Woynarovich solution produced the highest percentage of eyed embryos at 0 seconds and 30 seconds before incubation. Woynarovich solution produced the highest percentage of eyed embryos at 60 seconds (65.26%), whereas saline water produced the highest percentage at 90 seconds (68.37%). No difference was detected between saline water and Woynarovich solution at 120 seconds. Examination of sperm traits showed no impact of activating medium on computer assisted sperm analysis parameters. Together, these results suggest that saline water or Woynarovich solution improve fertilization rate in ide during IVF; thus, these media are useful for standardizing fertilization protocols and controlled reproduction for this species.


Raw and processed microscope images of fixed cells at baseline and following various experimental perturbations.
The data included in this article comprise raw and processed images of fixed cells at baseline and subjected to various experimental perturbations. This dataset includes images of HUVEC cells fixed and subsequently incubated at either 37 °C or room temperature, primary rat vascular smooth muscle cells exposed to 25 mM glucose, and SH-SY5Y neurons exposed to hydrogen peroxide. Raw images appear exactly as they were captured on the microscope, while processed images show the binarization provided by software used for measurements of mitochondrial morphology. For in-depth discussion of the experiments and computational methods pertaining to this data, please refer to the corresponding research article titled "Fully automated software for quantitative measurements of mitochondrial morphology" (McClatchey et al., in press) [1].


Risk prediction tools for cancer in primary care.
Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed.


Escherichia coli umuDC mutants: DNA sequence alterations and UmuD cleavage.
The products of the chromosomally encoded umuDC genes are directly required for mutagenesis in Escherichia coli. Strains with either umuD or umuC mutations are rendered phenotypically non-mutable. To ascertain the molecular basis of this non-mutability, we determined the DNA sequence alterations of seven chromosomal umuDC mutants. Six mutants (umuD1, umuD44, umuD77, umuC36, umuC25, and umuC104) were found to be single base-pair substitutions that resulted in missense mutations. The Tn5 transposon insertion mutation (umuC122) resulted in a missense mutation followed immediately by a termination codon, producing a truncated UmuC protein lacking 102 carboxyl-terminal amino acids. All of the mutations were found to reside in regions of the UmuD and UmuC proteins that share high homology with analogous proteins. Chemiluminescent immunoassays revealed that the umuD1, umuD44, and umuD77 mutations all resulted in a non-cleavable UmuD protein. Because UmuD cleavage is a prerequisite for mutagenesis, the lack of UmuD processing appears to be the molecular basis for the non-mutable phenotype in these strains. These studies re-emphasize the critical nature of the RecA-mediated cleavage of UmuD for inducible mutagenesis and provide insights into the functional domains of the UmuC protein.


Opposite effects of mild and severe stress on in vitro activation of rat peripheral blood lymphocytes.
The effects of short-term handling and different durations of immobilization on serum levels of catecholamines, ACTH, prolactin, and corticosterone and in vitro functions of lymphocytes were examined in rats. The results show that changes in the immune response of peripheral blood lymphocytes (PBL) depend on the intensity of the stressor: Short (1 min) handling of cannulated rats induced an enhanced stimulation of PBL to respond to T and B cell mitogens, whereas immobilization of the same animals led to suppression, dependent on the time this stressor was applied. The decrease in the mitogen reactivity of PBL after 120 min of immobilization was reversible within 24 h, and could be largely prevented by adrenalectomy, confirming that factors released by this gland are mainly responsible for immunosuppression. In contrast to PBL, spleen cells showed an enhanced mitogen response to immobilization and adrenalectomy, indicating that the immune response is differently regulated in the various compartments of the immune system. Possible correlations of the various effects with changes in stress hormone levels are discussed.


Catecholamine distribution patterns in rat thalamus.
Detailed distribution patterns for norepinephrine and dopamine in rat thalamus were determined by liquid chromatographic assays. The norepinephrine distribution is in good accord with that suggested previously by neuroanatomical tracing techniques. Detailed anterior-posterior concentration profiles for norepinephrine are summarized. An unexpected finding was a strong animal variability in thalamic dopamine content. Thalami were distinguished as having either low, intermediate or extremely high dopamine concentrations.


Isolation of lysosomes from the tail of metamorphosing bullfrog tadpole.
A mitochondrial-lysosomal fraction obtained by differential centrifugation of the tail homogenate of metamorphosing Rana catesbeiana tadpoles was fractionated on iso-osmotic self generating gradients composed of modified colloidal silica (Percoll). More than half the activities of most lysosomal hydrolases were recovered to a heavy fraction, which contained little activities of cytochrome oxidase and of catalase. The activities of lysosomal enzymes in the heavy fraction showed latency, and the median density of those was 1.09. These results indicate that intact lysosomes, which are considerably purified, could be obtained by this method.


Disk solid-phase extraction of multi-class pharmaceutical residues in tap water and hospital wastewater, prior to ultra-performance liquid chromatographic-tandem mass spectrometry (UPLC-MS/MS) analyses.
In this work, a new clean-up and pre-concentration method based on disk solid-phase extraction (SPE) was developed to determine multi-class pharmaceutical residues covering a wide range of polarities (log K ow values from -0.5 to 5.1) in water systems, prior to ultra-performance liquid chromatographic-tandem mass spectrometry (UPLC-MS/MS) analyses. Electrospray ionisation in positive and negative modes was used for the simultaneous determination of both acidic and basic pharmaceuticals. The performances of disk SPE and cartridge SPE were compared. The targeted pharmaceutical compounds list included bronchodilators, antidiabetic drugs, antihypertensive drugs, a lipid-lowering agent, analgesics, and anti-inflammatory drugs. Based on our results, the disk SPE demonstrated a higher sensitivity and recovery value and less analysis time as compared to the cartridge SPE method. The limits of detection (LOD) for the new method ranged from 0.02-3.2 ng L-1, 0.02-3.1 ng L-1 and 0.02-4.7 ng L-1 for tap, effluent and influent wastewater, respectively. The method's absolute recovery values ranged from 70% to 122% for tap water, 62% to 121% for effluent wastewater and 62% to 121% for influent wastewater, except for metformin in which the absolute recovery value was approximately 48% for all samples. Intra-day precision for tap water, effluent and influent wastewater ranged from 3-12%, 4-9% and 2-8%, respectively. The method developed was applied for the determination of targeted pharmaceuticals in tap, effluent, and influent wastewater from one hospital treatment plant in Malaysia. The results revealed that the highest concentrations of certain pharmaceuticals were up to 49 424 ng L-1 (acetaminophen) and 1763 ng L-1 (caffeine) in the influent and effluent wastewater, respectively. The results also showed a variation in the treatment efficiencies for the hospital treatment plant from one compound to another. Nevertheless, the removal efficiencies ranged from 0-99%.


Accuracy of MRI for nodal restaging in rectal cancer: a retrospective study of 166 cases.
Assessing metastatic mesorectal nodal involvement is a challenge in rectal cancer, especially in the post chemoradiation setting. We aim to assess the accuracy of MRI for nodal restaging and the validity of SAR criteria (≥ 5 mm size being metastatic). This was an IRB-approved retrospective study of 166 patients with locally advanced rectal cancers, operated after neoadjuvant treatment. Two dedicated oncoradiologists reviewed the 166 post-chemoradiation presurgical MRIs in consensus. Nodal size and morphology (shape, margins, and signal intensity) were noted. The most accurate cut-off for size for predicting positive pN status was determined using the Youden index. MRI understaged 30/166 (18%) and overstaged 40/166 (24%) patients using the SAR criteria. The most accurate cut-off for node size was 5.5 mm, with a sensitivity of 75%, specificity of 60.2%, PPV of 40.7%, NPV of 86.9% (95% CI:78-92.5%), accuracy of 64.2%, and area under the curve (AUC) 0.657 (95% CI-0.524-0.79). Morphological characteristics were not significant to determine involvement, with positive nodes including 42% of round and 31% of oval nodes, 40% of heterogeneous and 45% of homogeneous nodes, and 31% irregularly marginated and 46% nodes with regular margins being positive on pathology. MRI was accurate in predicting pathology for mucinous nodes in 9/29 (31%) cases. Seven cases which were yN2 on MRI and yN0 on pathology demonstrated mucinous changes on MRI and had acellular mucin on histopathology. MRI has good negative predictive value, poor positive predictive value and moderate accuracy in nodal restaging. The cut-off of 5.5 mm demonstrated in our study is close to the SAR cut-off of 5 mm in the post-treatment setting. MRI accuracy is lower in patients with mucinous nodes.


Neurovirulence effects of dengue-2 viruses on the rhesus (Macaca mulatta) brain and spinal cord.
Vaccines prepared from attenuated virus can cause symptomatic viral infection of the central nervous system. In the present study, dengue-2 parental and its live attenuated viruses were tested by intrathalamic and intraspinal injections in rhesus monkeys. The dengue-2 viruses were found to be only very weakly neurovirulent when injected directly into the brain or spinal cord of rhesus monkeys.


Design of stretchable and self-powered sensing device for portable and remote trace biomarkers detection.
Timely and remote biomarker detection is highly desired in personalized medicine and health protection but presents great challenges in the devices reported so far. Here, we present a cost-effective, flexible and self-powered sensing device for H2S biomarker analysis in various application scenarios based on the structure of galvanic cells. The sensing mechanism is attributed to the change in electrode potential resulting from the chemical adsorption of gas molecules on the electrode surfaces. Intrinsically stretchable organohydrogels are used as solid-state electrolytes to enable stable and long-term operation of devices under stretching deformation or in various environments. The resulting open-circuit sensing device exhibits high sensitivity, low detection limit, and excellent selectivity for H2S. Its application in the non-invasive halitosis diagnosis and identification of meat spoilage is demonstrated, emerging great commercial value in portable medical electronics and food security. A wireless sensory system has also been developed for remote H2S monitoring with the participation of Bluetooth and cloud technologies. This work breaks through the shortcomings in the traditional chemiresistive sensors, offering a direction and theoretical foundation for designing wearable sensors catering to other stimulus detection requirements.


Surgical approach to anterior septal accessory pathways in 20 patients with the Wolff-Parkinson-White syndrome.
Right anterior septal accessory pathways in the Wolff-Parkinson-White syndrome are generally defined by electrophysiological criteria, the most important being that earliest retrograde atrial activation during AV reciprocating tachycardia occurs at the anterior medial segment of the tricuspid annulus (His bundle catheter). The purpose of our study is to describe intraoperative mapping in 20 patients with anterior septal accessory pathways, and to assess if intraoperative mapping contributes to the operative approach. At surgery, all patients had identical early ventricular activation during pre-excitation at the infundibulum. However, two groups could be identified on the basis of retrograde atrial epicardial activation during AV reciprocating tachycardia or right ventricular pacing. Group 1 comprised 16 patients with earliest activation at the interatrial septum adjacent to the His bundle. Epicardial dissection failed to affect accessory pathway conduction. The accessory pathway was only ablated when a discrete endocardial approach to the atrial septum was used. Group 2 comprised 4 patients with early atrial activation "paraseptally" in the right coronary fossa. These accessory pathways were ablated by an epicardial approach without using cardiopulmonary bypass. We conclude that right anterior septal accessory pathways as defined by electrophysiological criteria can be divided into two groups on the basis of the atrial activation sequence: (1) right septal accessory pathways in the septal para-Hissian region and (2) right anterior 'paraseptal' accessory pathways. This classification is of practical importance because the latter can be ablated using an epicardial approach without the need for cardiopulmonary bypass or atriotomy.


Intranasal delivery of nanoparticles encapsulating BPI3V proteins induces an early humoral immune response in mice.
Vaccine adjuvants are typically designed to stimulate both systemic and mucosal immune responses. Polymeric nanoparticles have been used as adjuvants in the development of vaccines against a number of viral pathogens and tested in laboratory animals. The objective of the study was to assess if synthetic bovine parainfluenza virus type-3 (BPI3V) peptide motifs and solubilised BPI3V proteins encapsulated in poly (dl-lactic-co-glycolide) (PLGA) nanoparticles (NPs) induce specific humoral immune responses in a mouse model following intranasal administration. BPI3V-specific and peptide specific IgG ELISAs were used to measure serum IgG levels to BPI3V. Intranasal delivery of PLGA nanoparticles encapsulating BPI3V proteins elicited an early, gradually increasing BPI3V-specific IgG response that persisted over the subsequent 6 weeks, suggesting slow, persistent release of antigen. PLGA-BPI3V particles administered intranasally induced a stronger IgG antibody response at an earlier time point compared with solubilised BPI3V antigen alone. Such an approach could be deployed in the development of new generation vaccines.


Client engagement and change during drug abuse treatment.
Previous work has shown length of time in drug abuse treatment is associated with better outcomes, but the role of therapeutic engagement and process needs further examination. In this study, the total number of counseling sessions attended by 557 clients in their first 90 days of community-based outpatient treatment was examined in relation to indicators of treatment delivery and progress. Significant client improvements were found on behavioral criteria and psychosocial functioning during the first 3 months of treatment, and session attendance was positively related to favorable behavioral changes as well as to positive perceptions by clients and counselors of their therapeutic interactions. Client background, treatment motivation, and therapeutic focus of counseling in Month 1 were significant predictors of session attendance in the first 3 months following admission to methadone treatment.


High temperature can improve the performance of invasive plants by facilitating root growth.
The ever-increasing temperatures of the Anthropocene may facilitate plant invasions. To date, studies of temperature effects on alien plants have mainly focused on aboveground plant traits but ignored belowground traits, which may confound predictions of plant invasion risks. The temperature effects on the root growth dynamics of two alien shrubs, invasive Mimosa sepiaria and naturalized Corchorus capsulari, were studied using a 3D, transparent growth system under five temperature treatments (day/night: 18°C/13°C to 34°C/29°C) that cover the present and future warming temperature scenarios in China. We measured root depth and width growth in response to temperature treatments over 84 days. We also investigated intra- and interspecific competition of paired plants of the two species grown together at the five temperatures. Shoot growth of M. sepiaria and C. capsularis was optimal at the mid-range temperature. Root growth, however, was faster at the highest temperature (34°C/29°C) for M. sepiaria, but decreased for C. capsularis as temperatures increased. Root depth growth was more sensitive than root width for both species during neighbor competition. Compared to C. capsularis, M. sepiaria had relatively greater advantage during intra- and interspecific competition with increasing temperature, possibly because of its better root growth at high temperatures. These results suggest that temperature increases can improve the performance of some alien plants by facilitating width and depth growth of their roots. This enhancement requires serious attention when managing and predicting invasion risk.


The landscape of childhood vaccine exemptions in the United States.
Once-eliminated vaccine-preventable childhood diseases, such as measles, are resurging across the United States. Understanding the spatio-temporal trends in vaccine exemptions is crucial to targeting public health intervention to increase vaccine uptake and anticipating vulnerable populations as cases surge. However, prior available data on childhood disease vaccination is either at too rough a spatial scale for this spatially-heterogeneous issue, or is only available for small geographic regions, making general conclusions infeasible. Here, we have collated school vaccine exemption data across the United States and provide it at the county-level for all years included. We demonstrate the fine-scale spatial heterogeneity in vaccine exemption levels, and show that many counties may fall below the herd immunity threshold. We also show that vaccine exemptions increase over time in most states, and non-medical exemptions are highly prevalent where allowed. Our dataset also highlights the need for greater data sharing and standardized reporting across the United States.


The role of the C-terminal region of rat brain natriuretic peptide in receptor selectivity.
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have different C-terminal tail structures compared with the rather conservative ring structures which consist of 17 amino acid residues. To examine the different effects of the tail structures of ANP and BNP on their interaction with receptors, we synthesized several peptide analogs and measured their biological actions in three different assay systems. Deletion of the C-terminal tail from rat BNP did not effect the vasorelaxation activity against rat aorta, but it promoted cGMP production in cultured rat aortic smooth muscle cells (RASMC). Deletion of the C-terminal tail from rat ANP diminished both vasorelaxant and cGMP producing activities. In a binding competition assay with RASMC and [125I]rat ANP-(1-28), the competition activities of both ANP and BNP were greatly reduced by C-terminal deletion. In addition, we obtained agonists with novel receptor selectivity.


Differences in problem alcohol drinking by military service type among male professional military personnel in South Korea using Military Health Survey data.
Alcohol drinking prevalence in Korea is higher than in other countries and is associated with various social and health problems. Korean culture tends to be tolerant of alcohol drinking and to regard it as an important medium for maintaining good interpersonal relationships in one's social life. Although alcohol drinking is a means of relieving stress, especially among soldiers, who engage in more binge drinking than civilians, there is lack of research focused on problem drinking among soldiers. Therefore, the purpose of this study was to explore the extent of problem drinking across all military services and to identify factors associated with problem drinking by military service type. Secondary data analysis. Dataset of the Military Health Survey in 2015. Altogether, 2252 male professional military personnel were included in this study. Problem drinking in this study was defined as at-risk drinking and alcohol abuse or dependence with an Alcohol Use Disorders Identification-Korean (AUDIT-K) score of 10 points or higher. The average AUDIT-K score was 7.38±4.10 points. The prevalence of problem drinking was 16.4% for the Army, 34.5% for the Navy and 32.1% for the Air Force. Factors associated with problem drinking for each military service type were sleep satisfaction (OR 2.33, 95% CI 1.284 to 4.236) and family support (OR 0.66, 95% CI 0.487 to 0.904) in the Army, smoking status (OR 1.85, 95% CI 1.130 to 3.039) and sleep satisfaction (OR 2.29, 95% CI 1.142 to 4.574) in the Navy and marital status (OR 0.60, 95% CI 0.382 to 0.951), smoking (past smokers and non-smokers OR 2.81, 95% CI 1.593 to 4.973, current smokers and non-smokers OR 1.68, 95% CI 1.114 to 2.544), subjective oral health (OR 1.83, 95% CI 1.011 to 3.297) and family support (OR 0.63, 95% CI 0.45 to 0.88) in the Air Force. When implementing health projects to address drinking problems, it is necessary to ensure that service-type-specific factors are considered for integrated management.


Amplification in the leader sequence of late polyoma virus mRNAs.
Ribonuclease T1 fingerprints of the three "late" polyoma virus mRNAs show that oligonucleotides of the leader sequence are present in multiple copies in each mRNA. These oligonucleotides, however, appear unimolar in fingerprints of complete, continuous transcripts of the late strand of the viral DNA. Oligonucleotides which are represented only once in the DNA are thus reiterated in the mature mRNAs. Consequently, when mRNA was hybridized to the leader region of immobilized viral DNA, those copies present in excess of their genomic representation failed to hybridize and were released by RNAase treatment. Analysis of the RNAase-resistant hybrids revealed a series of leader species with complex sequence arrangements. We suggest that these complicated reiterated sequences are generated during the processing of a precursor RNA which extends several times around the genome. This RNA would be shortened by a series of splicing reactions which conserve sequences from the leader region and attach them to a suitable coding sequence.


Ankle bracing, fatigue, and time to stabilization in collegiate volleyball athletes.
Fatigue has been shown to disrupt dynamic stability in healthy volunteers. It is not known if wearing prophylactic ankle supports can improve dynamic stability in fatigued athletes. To determine the type of ankle brace that may be more effective at providing dynamic stability after a jump-landing task during normal and fatigued conditions. Two separate repeated-measures analyses of variance with 2 within-subjects factors (condition and time) were performed for each dependent variable. Research laboratory. Ten healthy female collegiate volleyball athletes participated (age = 19.5 +/- 1.27 years, height = 179.07 +/- 7.6 cm, mass = 69.86 +/- 5.42 kg). Athletes participated in 3 separate testing sessions, applying a different bracing condition at each session: no brace (NB), Swede-O Universal lace-up ankle brace (AB), and Active Ankle brace (AA). Three trials of a jump-landing task were performed under each condition before and after induced functional fatigue. The jump-landing task consisted of a single-leg landing onto a force plate from a height equivalent to 50% of each participant's maximal jump height and from a starting position 70 cm from the center of the force plate. Time to stabilization in the anterior-posterior (APTTS) and medial-lateral (MLTTS) directions. For APTTS, a condition-by-time interaction existed (F(2,18) = 5.55, P = .013). For the AA condition, Tukey post hoc testing revealed faster pretest (2.734 +/- 0.331 seconds) APTTS than posttest (3.817 +/- 0.263 seconds). Post hoc testing also revealed that the AB condition provided faster APTTS (2.492 +/- 0.271 seconds) than AA (3.817 +/- 0.263 seconds) and NB (3.341 +/- 0.339 seconds) conditions during posttesting. No statistically significant findings were associated with MLTTS. Fatigue increased APTTS for the AA condition. Because the AB condition was more effective than the other 2 conditions during the posttesting, the AB appears to be the best option for providing dynamic stability in the anterior-posterior direction during a landing task.


Myocardial redox state during coronary artery bypass grafting assessed with microdialysis.
Microdialysis allows the biochemical analysis of interstitial fluids of nearly every organ as a bedside procedure. This technique could be useful to reveal data about the myocardial metabolism during cardiopulmonary bypass in human coronary artery bypass graft (CABG) surgery. In 17 patients undergoing CABG a myocardial microdialysis catheter (CMA 70, CMA/Microdialysis AB, Sweden) was inserted in the apical region of the beating heart. Microdialysis measurements were performed at timed intervals before, during, and after cardiopulmonary bypass (CPB). The concentrations of lactate and pyruvate were analyzed semi-continuously. During CPB the myocardial lactate-pyruvate-ratio (LPR) rose from an initial 11 (8-15) to 33 (29-41) ( P<0.01). After CPB the LPR decreased to 4 (3-7) at the end of observation ( P<0.05). The pyruvate concentration showed an immediate increase from 34 (30-42) microM at the end of CPB to 181 (147-234) microM after removal of the cross-clamp with subsequent increase during reperfusion ( P<0.01). Plasma lactate and pyruvate showed no essential changes during the study. Using the microdialysis technique it was possible to analyze myocardial metabolic changes during CABG. The course of myocardial LPR as a sensitive indicator of the myocardial redox state showed profound changes during and after CPB. We propose the microdialysis technique as an additional monitoring tool in CABG.


A stereoscopic diagonal inverter (SDI) for wide-angle vitreous surgery.
All known methods of wide-angle observation of the fundus deliver an inverted image. To overcome these difficulties a stereoscopic diagonal inverter (SDI) was developed, which serves as an accessory to the operating microscope. This device permits the microscopic image to be vertically inverted and laterally reversed, while retaining full stereopsis, and thus makes wide-angle observation devices such as the Rodenstock Panfundoscope contact lens (150 degrees) and a modified version of the binocular indirect ophthalmoscope (70 degrees-90 degrees) usable in vitreous microsurgery.


The evidential value of distorted and rectified digital images in footwear imprint examination.
The procedure for forensic photography requires that the film plane be parallel to the taken image. Another procedure must be used when the print is located on reflecting surfaces such as vehicles, or faint marks on porous surfaces. Examination was made of the evidential value of footprint images received from the scene or taken deliberately at an angle out of proper perspective (i.e., the lens axis is not perpendicular to the target plane). An artificial target was prepared and photographed from several lens axis angles ranging from 10 degrees to 85 degrees to the perpendicular, and then rectified using the Adobe Photoshop Version 7.0. It was found that at angles less than 40 degrees , the shape and location of all the individual characteristics were similar enough in comparison to the original image. In images taken at higher angles, the original image could not be adequately restored. The full potential of this image, therefore, could not be achieved after rectification. The results of this study show that the images of a footprint taken at an angle less than 40 degrees , preserve the evidential value of the unique characteristics.


Effect of race/ethnicity and persistent recognition of depression on mortality in elderly men with type 2 diabetes and depression.
To determine whether mortality risk from depression among elderly men with type 2 diabetes differs by ethnicity and persistent recognition of depression. Data on a cohort of 14,500 male veterans with type 2 diabetes were analyzed. Diagnoses of depression and diabetes were based on ICD-9 codes. Persistent recognition was defined as an ICD-9 code for depression documented in at least the second or third visit after the initial diagnosis of depression. Hazards of death were compared using Cox proportional hazards regression models adjusting for relevant covariates. Over 10 years, 2,305 deaths were documented. Mortality risk was higher for depressed than nondepressed veterans with diabetes (hazard ratio [HR] 1.6 [95% CI 1.3-1.8]). Among those with depression, mortality risk was lower with persistent recognition (0-2 visits vs. >or=3 visits after initial diagnosis, HR 0.58 [0.40-0.89]) but higher for whites than blacks (1.60 [1.11-2.31]). Increased mortality from depression differs by ethnicity and persistent recognition.


Individual myasthenia gravis autoantibody clones can efficiently mediate multiple mechanisms of pathology.
Serum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct molecular mechanisms: complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether multi-pathogenicity is mediated by individual or multiple autoantibody clones. Using an unbiased B cell culture screening approach, we generated a library of 11 human-derived AChR-specific recombinant monoclonal autoantibodies (mAb) and assessed their binding properties and pathogenic profiles using specialized cell-based assays. Five mAbs activated complement, three blocked α-bungarotoxin binding to the receptor, and seven induced antigenic modulation. Furthermore, two clonally related mAbs derived from one patient were each highly efficient at more than one of these mechanisms, demonstrating that pathogenic mechanisms are not mutually exclusive at the monoclonal level. Using novel Jurkat cell lines that individually express each monomeric AChR subunit (α2βδε), these two mAbs with multi-pathogenic capacity were determined to exclusively bind the α-subunit of AChR, demonstrating an association between mAb specificity and pathogenic capacity. These findings provide new insight into the immunopathology of MG, demonstrating that single autoreactive clones can efficiently mediate multiple modes of pathology. Current therapeutic approaches targeting only one autoantibody-mediated pathogenic mechanism may be evaded by autoantibodies with multifaceted capacity.


Pelvic floor muscle training protocol for stress urinary incontinence in women: A systematic review.
Strengthening exercises for pelvic floor muscles (SEPFM) are considered the first approach in the treatment of stress urinary incontinence (SUI). Nevertheless, there is no evidence about training parameters. To identify the protocol and/or most effective training parameters in the treatment of female SUI. A literature research was conducted in the PubMed, Cochrane Library, PEDro, Web of Science and Lilacs databases, with publishing dates ranging from January 1992 to March 2014. The articles included consisted of English-speaking experimental studies in which SEPFM were compared with placebo treatment (usual or untreated). The sample had a diagnosis of SUI and their age ranged between 18 and 65 years. The assessment of methodological quality was performed based on the PEDro scale. Seven high methodological quality articles were included in this review. The sample consisted of 331 women, mean age 44.4±5.51 years, average duration of urinary loss of 64±5.66 months and severity of SUI ranging from mild to severe. SEPFM programs included different training parameters concerning the PFM. Some studies have applied abdominal training and adjuvant techniques. Urine leakage cure rates varied from 28.6 to 80%, while the strength increase of PFM varied from 15.6 to 161.7%. The most effective training protocol consists of SEPFM by digital palpation combined with biofeedback monitoring and vaginal cones, including 12 week training parameters, and ten repetitions per series in different positions compared with SEPFM alone or a lack of treatment.


Seizure semiology reflects spread from frontal to temporal lobe: evolution of hyperkinetic to automotor seizures as documented by invasive EEG video recordings.
This patient report demonstrates the importance of seizure evolution in the localising value of seizure semiology. Spread of epileptic activity from frontal to temporal lobe, as demonstrated by invasive recordings, was reflected by change from hyperkinetic movements to arrest of activity with mild oral and manual automatisms. [Published with video sequences].


Fertility preservation options in transgender people: A review.
Gender affirming procedures adversely affect the reproductive potential of transgender people. Thus, fertility preservation options should be discussed with all transpeople before medical and surgical transition. In transwomen, semen cryopreservation is typically straightforward and widely available at fertility centers. The optimal number of vials frozen depends on their reproductive goals and treatment options, therefore a consultation with a fertility specialist is optimal. Experimental techniques including spermatogonium stem cells (SSC) and testicular tissue preservation are technologies currently under development in prepubertal individuals but are not yet clinically available. In transmen, embryo and/or oocyte cryopreservation is currently the best option for fertility preservation. Embryo cryopreservation requires fertilization of the transman's oocytes with a donor or partner's sperm prior to cryopreservation, but this limits his future options for fertilizing the eggs with another partner or donor. Oocyte cryopreservation offers transmen the opportunity to preserve their fertility without committing to a male partner or sperm donor at the time of cryopreservation. Both techniques however require at least a two-week treatment course, egg retrieval under sedation and considerable cost. Ovarian tissue cryopreservation is a promising experimental method that may be performed at the same time as gender affirming surgery but is offered in only a limited amount of centers worldwide. In select places, this method may be considered for prepubertal children, adolescents, and adults when ovarian stimulation is not possible. Novel methods such as in-vitro activation of primordial follicles, in vitro maturation of immature oocytes and artificial gametes are under development and may hold promise for the future.


Correction to: Abstracts : 31st European Congress of Pathology.
In E-Poster Sessions of the published abstract, the authors' affiliations as well as the abstract text were incorrectly presented. The correct abstract and the author's affiliations are shown in full in this article.


Agreement between self-reported and register-based cardiovascular events among Danish breast cancer survivors.
We examined the degree of over- and under-reporting of cardiovascular diseases (CVDs) among female breast cancer survivors comparing self-reports to diagnostic codes from the Danish National Patient Register (NPR). The study comprised 357 Danish breast cancer patients from the WECARE study who completed a telephone interview concerning CVDs. Disease diagnoses for these women were obtained from the NPR. Agreement was calculated as the number of diagnoses that were both self-reported and in the NPR divided by (1) number of self-reported diagnoses (over-reporting) or (2) number of diagnoses in the NPR (under-reporting). In total, 68 women reported 96 specific cardiovascular outcomes of which 56 (58%) were found in the NPR. Ninety cardiovascular diagnoses were found in the NPR of which 56 (62%) were specifically reported at the interview. There was 80% agreement as to the occurrence of a cardiovascular diagnosis overall. Of 289 women reporting no CVD, 273 (94%) had no diagnoses in the NPR. Breast cancer survivors seem to report absence of CVD accurately, but they both over-report and under-report specific cardiovascular diagnoses. Using a broader definition of CVDs improves the agreement between self-reported and NPR data. Determining how cancer treatments affect the risk of cardiovascular morbidities is essential, and the development of high-quality methods for collecting such data is critical. While self-reported data are adequate for assessing the presence of any CVD condition, medical record review will yield higher quality data on specific CVD conditions.


Cytotoxic taraxerane triterpenoids from Saussurea graminea.
Four new taraxerane triterpenoids, 1β,3β-dihydroxy-11α,12α-oxidotaraxerane (1), 28-hydroxy-11α,12α-oxidotaraxerane-3-one (2), 3β-hydroxy-11α,12α-oxidotaraxerane-28-al (3), and 3-O-acetyl-11α,12α-oxidotaraxerane-28-al (4), together with three known compounds 3β-hydroxy-11α,12α-oxidotaraxerane (5), 3β,28-dihydroxy-11α,12α-oxidotaraxerane (6), and 11α,12α-oxidotaraxerane-3-one (7), were isolated from the 70% EtOH extract of Saussurea graminea. Their structures were elucidated on the basis of extensive 1D and 2D NMR (COSY, HMQC, HMBC and NOESY) analyses. The isolated compounds were evaluated in vitro for cytotoxic properties against eight tumor cell lines (A-549, BGC-823, HCT15, HeLa, HepG2, MCF-7, SGC-7901 and SK-MEL-2).


Performance of the Pooled Cohort Equations in non-alcoholic fatty liver disease: The Multi-Ethnic Study of Atherosclerosis.
Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk of cardiovascular disease. Whether risk scores developed in the general population accurately assess cardiovascular risk in the NAFLD population is unknown. This study aimed to evaluate the performance of the Pooled Cohort Equations (PCE) in NAFLD. Individuals in the Multi-Ethnic Study of Atherosclerosis with baseline non-contrast cardiac computed tomography scans with sufficient data to determine the presence of hepatic steatosis were identified and assessed for the development of incident 10-year atherosclerotic cardiovascular disease. The discrimination and calibration of the PCE were evaluated, and the observed and expected events by risk category (<5%, 5-<7.5%, 7.5-<20%, ≥20%) were determined. Risk reclassification with the addition of NAFLD to the PCE was assessed. Of 4014 participants included, 698 (17.4%) with NAFLD were identified, including 247 (35.3%) with moderate-to-severe steatosis. Discrimination of the PCE was suboptimal in NAFLD (c-statistic 0.69), particularly moderate-to-severe steatosis (0.65), and calibration was overall poor. While risk was overestimated in non-NAFLD, it was underestimated in NAFLD in lower/intermediate risk categories, predominantly in women (5-<7.5% observed/expected ratio = 1.67). The addition of NAFLD to the PCE improved risk classification in women. The PCE overall performed suboptimally in cardiovascular risk assessment in NAFLD, particularly in women and individuals with moderate-to-severe steatosis in clinically relevant risk categories. Primary prevention may need to be considered at a lower risk threshold in these groups, and further work is needed to improve risk stratification in this growing high-risk population.


Orthotopic and heterotopic tracheal transplantation model in studying obliterative bronchiolitis.
Several animal models have been established to investigate the mechanisms of obliterative bronchiolitis after lung transplantation. In this study, we compared three prevalent murine models of obliterative bronchiolitis in terms of several basic pathologic changes in a relatively short span of time after transplantation. Each of the recipient mice simultaneously received orthotopic, intra-omental and subcutaneous tracheal transplantation in both syngeneic and allogeneic settings. No immunosuppressive treatment was administered. Tracheal grafts were harvested on Day 14, 21 and 28 after transplantation for histological and immunohistochemical analyses. Syngeneic tracheal grafts from different transplant sites retained normal histologic structures, while their corresponding allografts demonstrated more occlusion of the airway lumen as well as more infiltration of CD4(+)/CD8(+) mononuclear cells and myofibroblasts, but less regenerative epithelium and neovascularized vessels at indicated times (P<0.05). Compared with two heterotopic allografts, orthotopic allografts had less occlusion of the tracheal lumen as well as less infiltration of CD4(+)/CD8(+) mononuclear cells and myofibroblasts, but more regenerative epithelium and neovascularized vessels (P<0.05). Orthotopic tracheal transplantation in mice can be considered as a model to study early stages of obliterative bronchiolitis, and heterotopic tracheal transplantation can be a model for late stages of obliterative bronchiolitis.


Effects of Cr(VI) long-term and low-dose action on mammalian antioxidant enzymes (an in vitro study).
In order to investigate the low-dose long-term Cr(VI) action on antioxidant enzymes in cultured mammalian cells we estimated the activity of glutathione dependent antioxidant enzymes, catalase and superoxide dismutase (SOD) under various chromium concentrations in human epithelial-like L-41 cells. The long-term action of 20 microM causes the toxicity that results in losing of the cell viability by activating the apoptotic process, as identified by morphological analysis, the activation of caspase-3, and DNA fragmentation. The toxic chromium concentration totally destroys glutathione antioxidant system, and diminishes the activity of catalase and cytosolic Cu, ZnSOD. The non-toxic concentration (2 microM) causes the activation of the antioxidant defense systems, and they neutralize the oxidative impact.


Lessons Learned in Change Management in Deploying Novel Informatics Solutions: Experience Implementing a Point-of-Care Patient Photography System with Radiography.
We describe implementation of a point-of-care system for simultaneous acquisition of patient photographs along with portable radiographs at a large academic hospital. During the implementation process, we observed several technical challenges in the areas of (1) hardware-automatic triggering for photograph acquisition, camera hardware enclosure, networking, and system server hardware and (2) software-post-processing of photographs. Additionally, we also faced cultural challenges involving workflow issues, communication with technologists and users, and system maintenance. We describe our solutions to address these challenges. We anticipate that these experiences will provide useful insights into deploying and iterating new technologies in imaging informatics.


Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer's disease.
The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer's disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer's disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.


Bioconversion of olive-mill dry residue by Fusarium lateritium and subsequent impact on its phytotoxicity.
The present study investigated the ability of the non-pathogenic fungus Fusarium lateritium to either degrade or modify aromatic substances in olive-mill dry residue (DOR) and to reduce its phytotoxicity. The 80% reduction of ethylacetate extractable phenols in DOR colonized by the fungus for 20 weeks appeared to be due to polymerization reactions of phenol molecules as suggested by mass-balance ultrafiltration and size-exclusion chromatography experiments. Several lignin-modifying oxidases, including laccase, Mn-peroxidase and Mn-inhibited peroxidase were detected in F. lateritium solid-state cultures. Tests performed with tomato seedlings in soils containing 6% (w/w) sterilized non-inoculated DOR showed that the waste was highly phytotoxic. By contract, F. lateritium growth on DOR for 20 weeks led to a complete removal of the waste toxicity and to a higher shoot dry weight of tomato plants than that obtained in the absence of DOR.


Racial discrimination and health: health professionals' actions in providing care women in the induced abortion process.
This paper aims to evaluate the racial inequalities in the care provided by health professionals concerning induced abortion. This systematic review study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) model, based on the following bases: Brazilian Virtual Health Library (BVS), Scientific Electronic Library Online (SciELO), National Library of Medicine, and National Institutes of Health (PubMed), Science Direct, Capes periodicals portal, with the descriptors: "racism OR social discrimination AND abortion, induced AND health personnel OR comprehensive health care OR delivery of health care OR human rights", selected via the DeCS and Medical Subject Heading (MeSH). Eighteen papers published between 2005 and 2020 in national and international literature were analyzed following the inclusion and exclusion criteria. Most studies found a significant relationship between racial discrimination and institutional violence, including access and quality of care for patients undergoing an induced abortion. Racial discrimination is a significant risk factor for adverse care outcomes.


Body mass index and contralateral ratio predict outcome following unilateral adrenalectomy in primary aldosteronism.
The effect of unilateral adrenalectomy on blood pressure (BP) outcome in primary aldosteronism (PA) is diverse. Therefore, we sought to investigate the preoperative factors contributing to postoperative BP outcome. Data for 96 PA patients who underwent unilateral adrenalectomy at our institution from January 2000 to February 2015 were retrospectively collected. Based on postoperative BP after a 12-month follow-up period, the patients were categorized into two groups: cured (C) (<140/90 mm Hg with no antihypertensive drug) and not cured (NC) (if not normotensive). Patient demographics, blood and urine data, data of loading tests and adrenal vein sampling were evaluated. In all, 46 patients were categorized as C and 50 patients as NC. There were significantly more males in the NC group. Age, body mass index (BMI), number of antihypertensive drugs prescribed, serum uric acid concentration and contralateral ratio (CR) after adrenocorticotropic hormone stimulation were significantly higher in the NC group. In the multivariate model, BMI and CR significantly correlated with resolution outcome. The optimal cutoff values were 23.3 kg m-2 for BMI and 0.5 for CR, and when both parameters were used as predictors, the most optimal cutoff values for BMI and CR were 25.2 kg m-2 and 0.1, respectively. BMI and CR significantly correlated with BP outcome after adrenalectomy. To our knowledge, this is the first report to show that in addition to BMI, CR is a factor in postoperative BP outcome and to determine the optimal cutoff values of BMI and CR and calculate their sensitivities and specificities.


Association mapping for pre-harvest sprouting resistance in white winter wheat.
Association mapping identified quantitative trait loci (QTLs) and the markers linked to pre-harvest sprouting (PHS) resistance in an elite association mapping panel of white winter wheat comprising 198 genotypes. A total of 1,166 marker loci including DArT and SSR markers representing all 21 chromosomes of wheat were used in the analysis. General and mixed linear models were used to analyze PHS data collected over 4 years. Association analysis identified eight QTLs linked with 13 markers mapped on seven chromosomes. A QTL was detected on each arm of chromosome 2B and one each on chromosome arms 1BS, 2DS, 4AL, 6DL, 7BS and 7DS. All except the QTL on 7BS are located in a location similar to previous reports and, if verified, the QTL on 7BS is likely to be novel. Principal components and the kinship matrix were used to account for the presence of population structure but had only a minor effect on the results. Although, none of the QTLs was highly significant across all environments, a QTL on the long arm of chromosome 4A was detected in three different environments and also using the best linear unbiased predictions over years. Although previous reports have identified this as a major QTL, its effects were minor in our biparental mapping populations. The results of this study highlight the benefits of association mapping and the value of using elite material in association mapping for plant breeding programs.


Digitized image processing and pattern recognition in dental radiographs with emphasis on the interdental bone.
Diagnosis of bone lesions on dental radiographs can be difficult due to the irregular trabecular pattern and subjectivity on the part of the observer. The purpose of this study is to improve the recognition of bone lesions by means of objective computer-aided pattern recognition techniques. This article describes a method for the separation of teeth and bone regions in the image to facilitate further analysis, especially of the interdental bone.


Hysteroscopic treatment of intrauterine lesions in premenopausal and postmenopausal women.
To compare the safety and efficacy of hysteroscopic surgery in the management of intrauterine lesions in premenopausal and postmenopausal women and, in particular, to investigate whether glycine absorption is different between these populations. Comparative study (Canadian Task Force classification II-2). Tertiary care university hospital. Thirty postmenopausal and 78 premenopausal women with intrauterine polyps or myomas. Hysteroscopic myomectomy or polypectomy. One hundred eight procedures were completed successfully by hysteroscopy; in two cases myomectomy was completed in a second operation for a deeply embedded myoma. No major complications occurred in either group. Median operating time, mean glycine absorption, and median postoperative hospital stay were not significantly different between groups. During mean follow-up of 15 months (range 1-39 mo), four women underwent hysterectomy (1 for endometrial cancer, 1 for complex hyperplasia with atypia, 2 for pelvic pain and menorrhagia). Hysteroscopic surgery is an effective and safe therapeutic option for intrauterine lesions regardless of a woman's menopausal status.


[Legal implication of DNA profiling].
In recent years, DNA profiling has been used regularly by the justice system, and has seen a number of improvements, with the need for fewer cells, more efficient DNA extraction and purification, and more rapid genotyping. These methods can now identify an individual more rapidly, from a corpse, blood stain, sperm or epithelial cells, by comparison with familial profiles. In France, DNA profiling can only be ordered by a judge.


Investigating proteasome inhibitors as potential adjunct therapies for experimental cerebral malaria.
Aside from antimalarials, there is currently no treatment for cerebral malaria, a fulminant neurological complication of P. falciparum infection that is a leading cause of death in African children. In the mouse model of cerebral malaria, cross-presentation of parasite antigens by brain endothelial cells is thought to be a crucial late step in pathogenesis. We have investigated three proteasome inhibitors as potential adjunct therapies: bortezomib, carfilzomib and ONX-0914. Only carfilzomib, an irreversible inhibitor of both constitutive proteasomes and immunoproteasomes, was able to inhibit cross-presentation of malaria antigen by murine brain endothelial cells in vitro. To mimic the clinical setting, carfilzomib was co-administered with artesunate only when infected mice exhibited neurological defects. However, there was no improvement in survival compared to artesunate monotherapy. The treatment failure was explained by the inability of daily or twice daily bolus doses of carfilzomib to inhibit cross-presentation by brain endothelial cells in vivo. We also report here that bortezomib, which has been associated with neurological adverse events, accelerated death in ECM-infected mice. Future investigations of proteasome inhibitors for modulating cross-presentation during malaria infection should focus on sustained and targeted delivery to brain endothelial cells.


Exploring knowledge of parents and caregivers on cancer symptoms in children: an observational study regarding the need for educational tools and health promotion in low- and middle-income countries.
Although most cases of childhood cancer are unlikely to be prevented, by today's standards, most children with cancer can now be cured. However, disparities about survival exist among countries; in Mexico, the overall survival is 49.6%, with 70% of childhood cancers diagnosed at advanced stages. Therefore, parents and caregivers must have optimal knowledge of the early signs and symptoms of childhood malignancies as they are largely non-specific. This study was designed to explore the current knowledge of childhood cancer among parents and caregivers in Mexico and identify the need for education and health promotion in low- and middle-income countries. An online survey of 112 parents and caregivers was performed to assess their knowledge of childhood cancer, focusing on the signs and symptoms and early diagnostic strategies. Sixty-nine (61.6%) mothers, 23 (20.5%) fathers, 17 (15.2%) familiar caregivers, and 3 (2.7%) non-familiar caregivers responded. Forty-six (41.1%) respondents said that they knew a child diagnosed with cancer, 92.9% mentioned leukemia as the most common type of cancer among children, the most highly ranked option when asked which sign/symptom they considered as a warning for suspicion was growth/lump in any part of the body, 97.3% considered that an early diagnosis is related to a higher cure rate, and 92.9% expressed the desire to receive reliable information about childhood cancer. Although parents and caregivers have some knowledge of childhood cancer, there are concepts that should be reinforced to improve their understanding of this group of diseases, as they are the frontline for children to seek medical attention. In the future, the use of tools that help educate more caregivers will strengthen knowledge and contribution regarding this issue and promote the generation of public policies that support the early diagnosis of childhood cancer.


[Use of lectins in pathomorphology: the results and prospects].
Uses of lectin for diagnostic differentiation between neoplastic and nonneoplastic diseases and for other purposes in histopathologic investigations (in particular, to gain a better understanding of the pathogenesis of various diseases) are reviewed. Unresolved issues are discussed and prospects for further studies are outlined.


Simple assay for evaluation of Epstein-Barr virus specific cytotoxic T lymphocytes.
Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL) are considered to be one of major defenses against the activation of EBV infection. We have developed a simple assay for evaluation of EBV-CTL by means of culturing peripheral blood mononuclear cells at the concentration of 2 x 10(6) cells/ml infected by B95-8 EBV, in the presence or absence of cyclosporin A (CSA). No lymphoblastoid cell line was established from ten EBV-seropositive healthy individuals in the absence of CSA. In contrast, cell lines were established from ten EBV-seronegative healthy individuals in the absence of CSA, indicating lack of EBV-CTL in these individuals. Methods described herein are simple and correlate well with EBV-CTL activity when compared to conventional methods, such as outgrowth regression or chromium-51 release assays.


Flexible Energy Storage Devices to Power the Future.
The field of flexible electronics is a crucial driver of technological advancement, with a strong connection to human life and a unique role in various areas such as wearable devices and healthcare. Consequently, there is an urgent demand for flexible energy storage devices (FESDs) to cater to the energy storage needs of various forms of flexible products. FESDs can be classified into three categories based on spatial dimension, all of which share the features of excellent electrochemical performance, reliable safety, and superb flexibility. In this review, the application scenarios of FESDs are introduced and the main representative devices applied in disparate fields are summarized first. More specifically, it focuses on three types of FESDs in matched application scenarios from both structural and material aspects. Finally, the challenges that hinder the practical application of FESDs and the views on current barriers are presented.


Buffers for the reconstitution of aspartate aminotransferase.
The cofactor activation of the apoenzyme of pig heart cytosolic aspartate aminotransferase was studied in various buffers. Cationic buffers are shown to allow maximal reconstitution in the pH range of 5.0 to 9.0. Anionic buffers made up of mono- and dicarboxylates are found to affect reconstitution in a pH-dependent manner. At low pH, the carboxylates strongly inhibit reconstitution, but at high pH, they show less effect. In contrast, the more potent inhibitor Pi shows the opposite pH profile. Dicarboxylates are considerably more inhibitory than monocarboxylates. Substantial protection against inhibition by a number of carboxylates may be achieved by the addition of sodium chloride.


Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.
Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.


Testing for food-specific antibodies in saliva and blood of food allergic and healthy dogs.
An elimination diet (ED) followed by re-challenge has been the reference standard to diagnose adverse food reactions (AFR) in dogs, but can be challenging to conduct. This study investigated the accuracy of a saliva-based test for food-specific IgA and IgM and an ELISA serum test for food-specific IgE. Three groups of dogs were tested. Group 1 (n=11) included dogs with previously diagnosed and controlled AFR; group 2 (n=15) comprised dogs with allergic dermatitis at the beginning of their ED; and group 3 (n=16) was composed of clinically healthy research dogs. Saliva samples were collected from all groups and blood samples from group 1 and group 3. The results of clinical re-challenges with individual food components were compared with the test results. Specificity, sensitivity, positive and negative predictive values and likelihood ratios were determined. Forty-one dogs completed the study; one dog was lost to follow up. There was a total of 163 re-challenges. Sensitivity, positive predictive value and likelihood ratio, specificity, negative predictive value and likelihood ratios were unsatisfactory for both tests in most instances, except for IgM testing in group 2, which had moderate specificity. There was no clear difference in the number of positive reactions between the allergic dogs and healthy dogs from a research population. Based on these results, the saliva test for food specific IgA and IgM and the ELISA serum test for food specific IgE were not reliable to diagnose adverse food reactions in dogs. Until more data are available, elimination diets remain the reference standard in the diagnosis of this disease.


Distribution and redistribution of pancreatic islet cell surface antigen reactive with islet cell surface antibody in the rat.
Antigens on the rat pancreatic islet cell surface were redistributed into patch and cap formation when the cells were incubated in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, in tissue culture medium 199 for 24 h, before addition of rat pancreatic islet cell surface antibody. In contrast, if the cells were cultured in tissue culture medium 199 supplemented with glucose (5.5 or 16.7mmol/l) and 10% heat-inactivated fetal calf serum without 3-isobutyl-1-methylxanthine, cap formation was not detectable. These results suggest that mobile antigen on the surface of pancreatic B cells can be induced to aggregate into patch and cap formations during conditions of increased cellular metabolism.


Geometric changes of parotid glands caused by hydration during chemoradiotherapy.
Plan adaptation during the course of (chemo)radiotherapy of H&N cancer requires repeat CT scanning to capture anatomy changes such as parotid gland shrinkage. Hydration, applied to prevent nephrotoxicity from cisplatin, could temporarily alter the hydrogen balance and hence the captured anatomy. The aim of this study was to determine geometric changes of parotid glands as function of hydration during chemoradiotherapy compared to a control group treated with radiotherapy only. This study included an experimental group (n = 19) receiving chemoradiotherapy, and a control group (n = 19) receiving radiotherapy only. Chemoradiotherapy patients received cisplatin with 9 l of saline solution during hydration in the first, fourth and seventh week. The delineations of the parotid glands on the planning CT scan were automatically propagated to Cone Beam CT scans using deformable image registration. Relative volume and position of the parotid glands were determined at the second chemotherapy cycle (week four) and at fraction 35. When saline solution was administrated, the volume temporarily increased on the first day (7.2 %, p < 0.001), second day (10.8 %, p < 0.001) and third day (7.0 %, p = 0.016). The gland positions shifted lateral, the distance between glands increased on the first day with 1.5 mm (p < 0.001), on the second day 2.2 mm (p < 0.001). At fraction 35, with both groups the mean shrinkage was 24 % ± 11 % (1SD) and the mean medial distance between the parotid glands decreased by 0.47 cm ± 0.27 cm. Hydration significantly modulates parotid gland geometry. Unless, in the context of adaptive RT, a repeat CT scan is timed during a chemotherapy cycle, these effects are of minor clinical relevance.


Prednisone withdrawal followed by recombinant alpha interferon in the treatment of chronic type B hepatitis. A randomized, controlled trial.
To determine the efficacy of a short course of prednisone followed by recombinant interferon treatment in patients with chronic type B hepatitis. Randomized, controlled trial with a 5-month treatment phase and a 9-month observation period after treatment. Two referral-based university-affiliated medical centers. Thirty-nine clinically stable patients with chronic type B hepatitis, all of whom were positive for hepatitis B antigen, hepatitis B virus-associated-DNA (HBV-DNA), and DNA polymerase for at least 6 months before entry. Patients included 20 heterosexuals and 19 male homosexuals. Eighteen patients were treated with a 6-week tapered regimen of prednisone, followed by 90 days treatment with recombinant interferon alpha-2b; 21 patients were untreated controls. Paired liver biopsy specimens of 27 patients (pretreatment and 9 months after treatment) were blindly evaluated. Nine treated patients had a sustained loss of HBV-DNA. In addition, eight treated patients lost hepatitis B e antigen and four became negative for hepatitis B surface antigen (HBsAg). When compared with controls the differences were statistically significant for clearance of HBV-DNA and HBsAg (P = 0.035 and 0.037, respectively). Treated patients who had a sustained loss of HBV-DNA had higher initial alanine aminotransferase lower initial DNA and DNA polymerase levels, and were more frequently heterosexual. Patients who responded to treatment with the disappearance of hepatitis B e antigen and HBV-DNA had normal liver function tests and markedly improved liver histology during follow-up. The immunologic priming provided by a short course of prednisone used with alpha interferon may be an effective treatment for selected patients with chronic type B hepatitis.


A systematic review comparing clinical features in early age at onset and late age at onset late-life depression.
Although evidence suggests that there are neurobiological differences between unipolar depression in younger versus older adults, conflicting evidence exists about whether these manifest as clinically identifiable differences. We conducted a systematic review of aetiological, phenomenological and outcome studies to examine the evidence for a distinction between early onset (EOD) and late onset (LOD) depression. A literature search was completed using the computer databases MEDLINE, EMBASE, PSYCHINFO and PUBMED for papers published between January 1982 and December 2012 which compared groups with EOD and LOD. Studies were included if they were of older people and compared symptoms, aetiological factors or outcomes. We conducted a quality assessment of included articles. We identified 23 articles which met entry criteria. The only clinical feature which was different between the groups was a higher frequency of a family history of mood disorders in EOD. The number of studies identified was low and their quality was generally poor. Although neurobiological studies have reported differences between EOD and LOD, generally these do not appear to translate into identifiable distinguishing clinical features.


A simplified function-first method for the discovery and optimization of bispecific immune engaging antibodies.
Bi-specific T-cell engager antibodies (BiTEs) are synthetic fusion molecules that combine multiple antibody-binding domains to induce active contact between T-cells and antigen expressing cells in the body. Blinatumomab, a CD19-CD3 BiTE is now a widely used therapy for relapsed B-cell malignancies, and similar BiTE therapeutics have shown promise for treating various other forms of cancer. The current process for new BiTE development is time consuming and costly, requiring characterization of the individual antigen binding domains, followed by bi-specific design, protein production, purification, and eventually functional screening. Here, we sought to establish a more cost-efficient approach for generating novel BiTE sequences and assessing bioactivity through a function first approach without purification. We generate a plasmid with a bi-modular structure to allow high-throughput exchange of either binding arm, enabling rapid screening of novel tumour-targeting single chain variable (scFv) domains in combination with the well-characterized OKT3 scFv CD3-targeting domain. We also demonstrate two systems for high throughput functional screening of BiTE proteins based on Jurkat T cells (referred to as BiTE-J). Using BiTE-J we evaluate four EGFRvIII-scFv sequenced in BiTE format, identifying two constructs with superior activity for redirecting T-cells against the EGFRvIII-tumour specific antigen. We also confirm activity in primary T cells, where novel EGFRvIII-BiTEs induced T cell activation and antigen selective tumor killing. We finally demonstrate similar exchange the CD3-interacting element of our bi-modular plasmid. By testing several novel CD3-targeting scFv elements for activity in EGFRvIII-targeted BiTEs, we were able to identify highly active BiTE molecules with desirable functional activity for downstream development. In summary, BiTE-J presents a low cost, high-throughput method for the rapid assessment of novel BiTE molecules without the need for purification and quantification.


Strategies to reverse melanoma-induced T-cell dysfunction.
Patients with advanced melanoma can develop spontaneous cellular and humoral responses to tumor antigens. Understanding the failure of spontaneous or vaccine-induced tumor antigen-specific T-cell responses to promote the immunologic clearance of melanomas is critical. Multiple mechanisms of melanoma-induced immune escape, which are likely to cause the failure of the spontaneous or vaccine-induced immune responses to promote tumor regression in humans, have been elucidated. In addition, a number of negative factors in the tumor microenvironment dampen antitumor immune responses, including cytokines (like transforming growth factor-β or interleukin-10), suppressive cells (regulatory T cells and myelosuppressive dendritic cells), defective antigen presentation by tumor cells (human leukocyte antigen or T antigen expression loss, antigen processing machinery defects), amino acid catabolizing enzymes (indoleamine-2-3 dioxygenase, arginase), and immune inhibitory pathways (like cytotoxic T-lymphocyte antigen 4/cluster of differentiation 28, programmed death 1/programmed death 1 ligand 1). This information has been used to develop a number of therapies to specifically target these negative regulators of antimelanoma immune responses to enhance tumor antigen-specific immune responses and to increase the likelihood of clinical benefits in patients with advanced melanoma.


Putative golden proportions as predictors of facial esthetics in adolescents.
In orthodontics, facial esthetics is assumed to be related to golden proportions apparent in the ideal human face. The aim of the study was to analyze the putative relationship between facial esthetics and golden proportions in white adolescents. Seventy-six adult laypeople evaluated sets of photographs of 64 adolescents on a visual analog scale (VAS) from 0 to 100. The facial esthetic value of each subject was calculated as a mean VAS score. Three observers recorded the position of 13 facial landmarks included in 19 putative golden proportions, based on the golden proportions as defined by Ricketts. The proportions and each proportion's deviation from the golden target (1.618) were calculated. This deviation was then related to the VAS scores. Only 4 of the 19 proportions had a significant negative correlation with the VAS scores, indicating that beautiful faces showed less deviation from the golden standard than less beautiful faces. Together, these variables explained only 16% of the variance. Few golden proportions have a significant relationship with facial esthetics in adolescents. The explained variance of these variables is too small to be of clinical importance.


Control of cell selectivity of antimicrobial peptides.
Antimicrobial peptides (AMPs) are promising novel antibiotics, because they exhibit broad antimicrobial spectra and do not easily induce resistance. For clinical applications, it is important to develop potent AMPs with less toxicity against host cells. This review article summarizes the molecular basis for the cell selectivity (bacteria versus host cells) of AMPs and various attempts to control it, including the optimization of physicochemical parameters of peptides, the introduction of D-, fluorinated, and unusual amino acids into peptides, the constraining of peptide conformations, and the modification of peptides by polymers. Pros and cons of these approaches are discussed.


Combining simplicity with cost-effectiveness: Investigation of potential counterfeit of proton pump inhibitors through simulated formulations using thin-layer chromatography.
A simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for the analysis of proton pump inhibitors (PPIs) and their co-formulated drugs, available as binary combination. Planar chromatographic separation was achieved using a single mobile phase comprising of toluene: iso-propranol: acetone: ammonia 5.0:2.3:2.5:0.2 (v/v/v/v) for the analysis of 14 analytes on aluminium-backed layer of silica gel 60 FG254. Densitometric determination of the separated spots was done at 290nm. The method was validated according to ICH guidelines for linearity, precision and accuracy, sensitivity, specificity and robustness. The method showed good linear response for the selected drugs as indicated by the high values of correlation coefficients (≥0.9993). The limit of detection and limit of quantiation were in the range of 6.9-159.2ng/band and 20.8-478.1ng/band respectively for all the analytes. The optimized conditions afforded adequate resolution of each PPI from their co-formulated drugs and provided unambiguous identification of the co-formulated drugs from their homologous retardation factors (hRf). The only limitation of the method was the inability to separate two PPIs, rabeprazole and lansoprazole from each other. Nevertheless, it is proposed that peak spectra recording and comparison with standard drug spot can be a viable option for assignment of TLC spots. The method performance was assessed by analyzing different laboratory simulated mixtures and some marketed formulations of the selected drugs. The developed method was successfully used to investigate potential counterfeit of PPIs through a series of simulated formulations with good accuracy and precision.


Definitive expression of c-mos in late meiotic prophase leads to phosphorylation of a 34 kda protein in cultured rat spermatocytes.
To investigate the role of c-mos in rat spermatogenesis, expression of c-mos, MAP kinase kinase (MAPKK), MAP kinase (MAPK), cdc2 and protein kinase A (PKA) by spermatogenic cell culture of 14 day-old rats was examined. MAPKK and PKA expressions were constitutive, whereas the expression of MAPK and cdc2 in spermatogonia initially decreased, but later increased on meiotic maturation of spermatocytes. c-mos expression was definitive of late meiotic prophase. c-mos immunoprecipitates prepared from the c-mos-enriched fraction (pI9.0-9.6) could form complex(es) in the cultured spermatogenic cell lysates. In vitro phosphorylation of the c-mos immune complexes revealed a 34 kDa protein that was phosphorylated at serine and threonine residues as a target of the c-mos signal. Its pI value was 4.4-4.5, and cdc2 was not detected, making it different from cdc2 (p34). These results suggest that the phosphorylation of the 34 kDa protein by the c-mos signal may play a crucial role in the meiotic division of rat spermatocytes.


Randomized clinical trial comparing infrahepatic inferior vena cava clamping with low central venous pressure in complex liver resections involving the Pringle manoeuvre.
Control of bleeding remains key to successful hepatic resection. The present randomized clinical trial compared infrahepatic inferior vena cava (IVC) clamping with low central venous pressure (CVP) during complex hepatectomy using portal triad clamping (PTC). Consecutive patients undergoing complex hepatectomy were allocated randomly to PTC combined with infrahepatic IVC clamping or to PTC with low CVP. Primary outcome was blood loss during parenchymal transection. Secondary outcomes were intraoperative surgical and haemodynamic parameters, postoperative recovery of liver and renal function, postoperative morbidity and mortality, and duration of hospital stay. Between January 2008 and September 2010, 192 patients were randomized. Compared with low CVP, infrahepatic IVC clamping significantly decreased blood loss during parenchymal transection (mean(s.e.m.) 243(158) versus 372(197) ml; P < 0·001), was associated with faster recovery of liver function, and caused less impairment in renal function and fewer haemodynamic changes. The degree of cirrhosis correlated positively with CVP (R(2) = 0·963, P = 0·019) and with infrahepatic IVC pressure (R(2) = 0·950, P = 0·025). For patients with moderate or severe cirrhosis, infrahepatic IVC clamping was more efficacious in controlling blood loss during parenchymal transection (mean(s.e.m.) 2·9(1·8) versus 6·1(2·4) ml/cm(2); P < 0·001). PTC combined with infrahepatic IVC clamping is more efficacious in controlling bleeding during complex hepatectomy than PTC with low CVP, especially in patients with moderate to severe cirrhosis. NCT01355887 (http://www.clinicaltrials.gov).