Esophageal safety in CLOSE-guided 50 W high-power-short-duration pulmonary vein isolation: The PREHEAT-PVI-registry.
Pulmonary vein isolation (PVI) using high-power-short-duration (HPSD) radiofrequency ablation (RF) is emerging as the standard of care for treatment of atrial fibrillation (AF). While procedural short-term to midterm efficacy and efficiency are very promising, this registry aims to investigate esopahgeal safety using an optimized ablation approach. In a single-center experience, 388 consecutive standardized first-time AF ablation were performed using a CLOSE-guided-fixed-50 W-circumferential PVI and substrate modification without intraprocedural esophageal temperature measurement. Three hundred patients underwent postprocedural esophageal endoscopy to diagnose and grade endoscopically detected esophageal lesions (EDEL) and were included in the analysis. EDEL were detected in 35 of 300 patients (11.6%), 25 of 35 were low-grade Kansas-city-classification (KCC) 1 lesions with fast healing tendencies. Six patients suffered KCC 2a lesions, 4 patients had KCC 2b lesions (1.3% of all patients). No esophageal perforation or fistula formation was observed. Patient baseline characteristics, especially patients age, gender, and body mass index did not influence EDEL incidence. Additional posterior box isolation did not increase the incidence of EDEL. In patients diagnosed with EDEL, mean catheter contact force during posterior wall ablation was higher (11.9 ± 1.8 vs. 14.7 ± 3 g, p < .001), mean RF duration was shorter (11.9 ± 1 vs. 10.7 ± 1.2 s, p < .001), while achieved ablation index was not different between groups (434 ± 4.9 vs. 433 ± 9.5, n.s.). Incidence of EDEL after CLOSE-guided-50 W-HPSD PVI is lower compared to historical cohorts using standard-power RF settings. Catheter contact force during posterior HPSD ablation should not exceed 15 g.


Fetal acoustic stimulation test for early intrapartum fetal monitoring.
The fetal acoustic stimulation test (FAST) is a simple cost effective screening test for antenatal fetal monitoring. The aim of the study was to evaluate the FAST as a screening test for early intrapartum fetal well being. An initial non stress test (NST) followed by a FAST using corometric model 146 was carried out in 486 participants in early labour with uncomplicated singleton pregnancies and > 32 weeks gestation. A repeat NST was recorded in the participants who had an initial non reactive NST. The results of the NST and FAST were compared with fetal outcome. Maternal perception of fetal movements after FAST, results of NST before and after FAST, and the babies' 5 minute APGAR scores were measured. Of the 486 participants 413 (85%) noticed fetal movements after FAST. Initial NST was non reactive in 203 (42%) but 149 (31%) became reactive after FAST. Compared to the NST, FAST had a better sensitivity (97% vs 62%, p < 0.001), specificity (100% vs 87%, p = 0.017), positive predictive value (100% vs 98%, p = 0.024), negative predictive value (79% vs 17%, p < 0.001) and accuracy (99%vs 64%, p < 0.001) in predicting 5 minute APGAR < 7 in the baby. FAST is a reliable screening test for assessing fetal well being in early labour. It complements the NST and is better than the NST alone.


Impact of angle on photothermal radiometry and modulated luminescence (PTR/LUM) value.
To evaluate the impact of scanning angles to detect/quantify non-cavitated caries by photothermal-radiometry and modulated-luminescence (PTR/LUM, Canary System) and to evaluate the association of PTR/LUM value with lesion depth (LD), including sound tissue thickness under the lesion (ST). Thirty human extracted premolars were selected based on micro-computed tomography [μ-CT: sound (n=12), lesions into outer-half of enamel (n=6), lesions into inner-half of enamel (n=6), lesions into outer one-third of dentine (n=6)]. Each tooth sample was scanned 90° directly contacted to the center of non-cavitated lesion or sound smooth surface, and tilted 10° and 20° in four directions: buccal/lingual/occlusal/cervical. The procedure was repeated 48 h later. Lesion depth and ST [ST=5000 µm (maximum PTR/LUM scanning depth)-LD] were measured at the same scanning direction on μ-CT images. Sensitivity, specificity, area under the Receiver Operating Characteristic curve (AUC), and intraclass correlation coefficients (ICC) for different scanning angles were calculated. Sensitivity was further evaluated based on lesion extensions. Relationships between PTR/LUM value and lesion depth, and between PTR/LUM value and LD/ST-Ratio were evaluated. PTR/LUM value showed significant differences among scanning angles. Overall sensitivity (78%-89%), specificity (66%-87%), AUC (0.86-0.92) and ICC (0.89-0.99), sensitivity based on lesion extensions presented no significant differences among angles. PTR/LUM value showed moderate correlations (0.56-0.74) with deepest lesion depth and LD/ST-Ratios. The scanning angle within 20° increments might impact PTR/LUM value statistically; however, it did not affect PTR/LUM detection performance. PTR/LUM values were positively correlated with non-cavitated lesion depth, and not affected by sound tissue thickness under the lesion. Clinically, it is challenging to measure/scan at the same location and same angle longitudinally, however, it is important to standardize these parameters. Scanning within 20° deviation from perpendicular did not affect detection performance of PTR/LUM, and PTR/LUM value showed positive moderate correlation with caries depth.


Traditional herbal medicine in Transkei.
The indigenous people of Transkei depend on natural plant resources from the forests for the medicinal, cultural, religious and other needs. This area, predominantly occupied by the Xhosa people, has remained ethnobotanically unexplored until recently. The present survey among the traditional doctors, herbalists, herb sellers, tribal priests and local people recorded medicinal uses of 26 plants. The firsthand information points out the significance of local plants to tribal groups and people of Transkei.


Hybrid nanocrystal-amorphous solid dispersions (HyNASDs) as alternative to ASDs for enhanced release of BCS Class II drugs.
A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal-amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer-surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol's stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.


Feasibility of ozone absorption by H2O2 solution in rotating packed beds.
This work examined the feasibility of ozone (O(3)) absorption by H(2)O(2) solution in a rotating packed bed (RPB). The O(3) removal efficiency was determined at various operating variables including RPB speed, gas flow rate, and liquid flow rate in three RPBs. For each RPB, the results demonstrated that the RPB speed positively affected the O(3) removal efficiency. Also, the O(3) removal efficiency increased with the liquid flow rate but decreased with the gas flow rate. Moreover, the obtained results indicated that the O(3) removal efficiency increased as the inner radius of the bed was increased and the outer radius of the bed was decreased. Furthermore, the developed method for O(3) absorption using H(2)O(2) solution could provide the removal efficiency of more than 95%. Consequently, the novel method would have a great potential in the removal of O(3) from the exhausted gases.


Pesticide residue levels in vegetables and surface waters at the Central Rift Valley (CRV) of Ethiopia.
Seven pesticides, profenofos, metalaxyl, λ-cyhalothrin, 4,4'-DDT, 4,4'-DDE, and α- and β-endosulfan, were determined in vegetables (tomato, onion) from 20 locations and surface waters from 12 locations in the Central Rift Valley (CRV) of Ethiopia. Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) and solid phase extraction (SPE) methods were used for the vegetables and water, respectively. In 2.5% of the tomato samples, profenofos was detected above European maximum residue limits (MRLs), in 12.5% of the samples metalaxyl, and in 2.5% α- and β-endosulfan. In 5% of the onion samples, profenofos was detected above European MRLs, in 7.5% of the onion samples metalaxyl, and in 5% λ-cyhalothrin. In surface water, profenofos was detected at the highest concentration of 2300 μg/L in the Bulbula River, 890 μg/L near the agricultural land north of Lake Ziway (ANLZ-1), 1700 μg/L in the floriculture effluent (FE-1), and 900 μg/L in tap water at the Batu Drinking Water (BDW) supply. These results show that the levels of pesticides are in several cases substantially elevated, and emphasize the need of regular pesticide monitoring programs for surface waters and vegetables in the Ethiopian CRV.


[Relevance of COMT inhibitors in the treatment of motor fluctuations].
Catechol O‑methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20 years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of a working group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.


Successful use of long acting octreotide in two cases with Beckwith-Wiedemann syndrome and severe hypoglycemia.
Hyperinsulinism associated with Beckwith-Wiedemann syndrome (BWS) can occur in about 50% of cases, causing hypoglycemia of variable severity. Parenteral use of octreotide may be indicated if unresponsive to diazoxide. There is limited data on use of octreotide in BWS. Chart review describing 2 cases with BWS and hypoglycemia treated with long acting Octreotide as a monthly injection. We describe two unrelated females born large for gestational age found to have clinical features consistent with BWS, who developed severe hypoglycemia. Genetic diagnosis of BWS was confirmed. The first patient was born at 37 weeks and developed hypoglycemia shortly after birth. She was initially started on diazoxide but developed pulmonary congestion and was therefore switched to depot octreotide (LAR). She maintained euglycemia with LAR. In the second patient (born at 26-4/7 weeks), onset of hypoglycemia was delayed till 11 weeks of age due to hydrocortisone (indicated hemodynamically) and continuous feeding, and was partially responsive to diazoxide. She was switched to octreotide 4 times daily, treated till at age 18 months. Despite frequent feeds, she required treatment again between ages 4-6.5 years, initially with diazoxide but due to severe hypertrichosis she was switched to LAR with an excellent response. Both patients treated with LAR for over two years achieved euglycemia above 70 mg/dl and had normal height gain, without side effects. Successful treatment of hypoglycemia can be achieved and maintained with LAR in infants and children with BWS who are either resistant or cannot tolerate diazoxide.


Facile preparation of cellulose nanofibrils (CNFs) with a high yield and excellent dispersibility via succinic acid hydrolysis and NaClO2 oxidation.
An efficient and low-cost approach to preparing CNFs with succinic acid hydrolysis and NaClO2 oxidation is explored. High-temperature-short-time hydrolysis can depolymerize the cellulose, whereas the dispersibility of the CNFs is hugely enhanced by NaClO2 oxidation under alkaline condition. The degradation of cellulose in succinic acid hydrolysis follows first-order reaction kinetics and is severely influenced by the hydrolysis temperature, moreover, the molecular chains of the cellulose are seriously cracked under the optimized condition. The NaClO2 oxidation greatly improves the zeta potential (-36.2 mV) and the dispersibility of the CNFs. The obtained CNFs have an ultimate yield of 94.6%, and the diameter distribution is mainly within 20-40 nm. In addition, some amount of carboxyl groups in the cellulose will be instead of the hydroxyl groups, and the crystallinity of the CNFs is significantly increased.


Prognostic significance of preoperative serum CYFRA 21-1 in patients with upper urinary tract urothelial carcinoma.
The prognosis for upper urinary tract urothelial carcinoma is generally poorer than that for bladder cancer, and prognostic predictors with a high specificity for upper urinary tract urothelial carcinoma (UUT-UC) are needed to optimize treatment. In fact, the only preoperative predictor currently available is C-reactive protein. In the present study, we investigated the usefulness of pretreatment serum CYFRA 21-1 as a new prognostic predictor in UUT-UC. A total of 45 UUT-UC patients for whom serum CYFRA 21-1 was measured before treatment were included in this retrospective analysis. Patients were separated into high and low serum CYFRA 21-1 groups based on a cut-off value of 2.7 ng/mL determined from a receiver operating characteristic curve. Kaplan-Meier survival curves were calculated and the overall survival rate was statistically analyzed for the high and low pretreatment serum CYFRA 21-1 groups using the log-rank test. Multivariable analysis was carried out using the Cox proportional hazards analysis. By the median follow-up period of 14.4 months, 20 patients (44.4%) had died. Of the 45 patients, 23 (51.1%) were in the high pretreatment serum CYFRA 21-1 group, and the overall survival rate of this group was significantly lower (P < 0.001). Multivariable analysis identified only distant metastasis (P < 0.001) and pretreatment serum CYFRA 21-1 (P = 0.039) as independent prognostic predictors. Distant metastasis did not significantly differ between the two groups or correlate with pretreatment serum CYFRA 21-1. These findings suggest that pretreatment serum CYFRA 21-1 values could serve as a prognostic predictor of UUT-UC.


Randomized controlled pilot study assessing fructose tolerance during fructose reintroduction in non-constipated irritable bowel syndrome patients successfully treated with a low FODMAP diet.
Limited data exist to guide FODMAP (fermentable oligo-, di-, monosaccharides, and polyols) reintroduction to assess tolerance following a low FODMAP diet (LFD). Fructose reintroduction is often stepwise up to 7.5 g fructose (e.g., three tsp of honey). We aimed to determine the fructose tolerance threshold in non-constipated, LFD-responsive patients with irritable bowel syndrome (IBS) and assess whether stool microbiome predicted LFD response or fructose tolerance. Thirty-nine non-constipated IBS patients (51% women, mean age 33.7 years) completed a 4-week LFD. LFD responders were defined as those who reported adequate relief of IBS symptoms following the LFD. Responders were randomized to one of the three solution groups (100% fructose, 56% fructose/44% glucose, or 100% glucose) and received four doses (2.5, 5, 10, 15 g) for 3 days each. Patients reached their tolerance dose if their mean daily IBS symptom severity (visual analog scale [VAS], 0-100 mm) was >20 mm higher than post-LFD VAS. Stool samples before and after LFD were analyzed using shotgun metagenomics. Seventy-nine percent of patients were LFD responders. Most responders tolerated the 15 g sugar dose. There was no significant difference in mean dose tolerated between solution groups (p = 0.56). Compared to baseline, microbiome composition (beta diversity) significantly shifted and six bacterial genes in fructose and mannose metabolism pathways decreased after LFD, irrespective of LFD response or the solution group. Non-constipated, LFD-responsive IBS patients should be reintroduced to fructose in higher doses than 15 g to assess tolerance. LFD is associated with significant changes in microbial composition and bacterial genes involved in FODMAP metabolism.


A MODEL FOR THE EVOLUTION OF ASYMMETRICAL MALE HYBRID STERILITY AND ITS IMPLICATIONS FOR SPECIATION.
Chromosomal analysis of several cases of asymmetrical male hybrid sterility in Drosophila has implicated the X- or the Y-chromosome and one or more autosomes. Here, I develop a model for the evolution of this phenomenon. An autosomal locus is assumed to affect viability and to interact with a Y-linked or an X-linked locus to determine male fertility. In a new environment, selection for viability favors a new allele at the autosomal locus, but incompatibility of this new allele with the sex-chromosome-linked gene generates male sterility. The incompatibility can be resolved if a new allele at the sex-linked locus invades the population. This results in nonreciprocal male hybrid sterility, the direction of the nonreciprocity being determined by the dominance or recessiveness of the new autosomal gene in its effect on fertility. It is shown that stable polymorphism for the autosomal locus is possible and that, if the equilibrium frequency of the new allele is above a critical value, the population will be constantly at the verge of speciation, "waiting" for the sex-linked mutation to occur. The appearance of this mutation causes a runaway process leading to rapid fixation of the new autosomal and sex-linked alleles. If the equilibrium frequency of the new autosomal allele is less than the critical value, deterministic speciation is impossible, but random drift may increase the frequency above the critical value and predispose the population to the invasion of the new sex-linked allele. Thus, both deterministic and stochastic modes of speciation are possible. Because deterministic speciation requires large selection coefficients, which impose a severe genetic load on the population, and because stochastic speciation requires repeated population bottlenecks, it is concluded that relative to the number of successful speciation events there will be many more events of deme extinction.


The effect of hippocampal function, volume and connectivity on posterior cingulate cortex functioning during episodic memory fMRI in mild cognitive impairment.
Diminished function of the posterior cingulate cortex (PCC) is a typical finding in early Alzheimer's disease (AD). It is hypothesized that in early stage AD, PCC functioning relates to or reflects hippocampal dysfunction or atrophy. The aim of this study was to examine the relationship between hippocampus function, volume and structural connectivity, and PCC activation during an episodic memory task-related fMRI study in mild cognitive impairment (MCI). MCI patients (n = 27) underwent episodic memory task-related fMRI, 3D-T1w MRI, 2D T2-FLAIR MRI and diffusion tensor imaging. Stepwise linear regression analysis was performed to examine the relationship between PCC activation and hippocampal activation, hippocampal volume and diffusion measures within the cingulum along the hippocampus. We found a significant relationship between PCC and hippocampus activation during successful episodic memory encoding and correct recognition in MCI patients. We found no relationship between the PCC and structural hippocampal predictors. Our results indicate a relationship between PCC and hippocampus activation during episodic memory engagement in MCI. This may suggest that during episodic memory, functional network deterioration is the most important predictor of PCC functioning in MCI. • PCC functioning during episodic memory relates to hippocampal functioning in MCI. • PCC functioning during episodic memory does not relate to hippocampal structure in MCI. • Functional network changes are an important predictor of PCC functioning in MCI.


Simultaneously realizing intelligent color change and high haze of κ-carrageenan film by incorporating black corn seed powder for visually monitoring pork freshness.
Although intelligent films containing various anthocyanins have exhibited a good pH-response, high light-transmittance makes it difficult to accurately observe color changes in monitoring food freshness. In this study, black corn seed powder (BCSP) containing anthocyanins, starch, lipid and fibers, was used to provide κ-carrageenan film (κCF) with simultaneous intelligent color change and high haze. As the mass ratio of BCSP to κ-carrageenan increased from 1:4 to 1:1, the haze of composite films increased from 49.44 % to 79.25 %, the transmittance decreased from 43.62 % to 18.90 %, respectively. The composite films turned from red to green along with the increase of pH from 2 to 10. When the TVB-N of pork increased from 2.7 ± 0.15 mg/100 g to 14.03 ± 0.14 mg/100 g, the 50BC50κC changed from pink to greyish-green and the haze increased up to 91.83 %, which will make it more visible and effective to indicate food freshness and popular for use.


Application of the threshold of toxicological concern approach for the safety evaluation of calendula flower (Calendula officinalis) petals and extracts used in cosmetic and personal care products.
Calendula flower (Calendula officinalis) (CF) has been used in herbal medicine because of its anti-inflammatory activity. CF and C. officinalis extracts (CFE) are used as skin conditioning agents in cosmetics. Although data on dermal irritation and sensitization of CF and CFE's are available, the risk of subchronic systemic toxicity following dermal application has not been evaluated. The threshold of toxicological concern (TTC) is a pragmatic, risk assessment based approach that has gained regulatory acceptance for food and has been recently adapted to address cosmetic ingredient safety. The purpose of this paper is to determine if the safe use of CF and CFE can be established based upon the TTC class for each of its known constituents. For each constituent, the concentration in the plant, the molecular weight, and the estimated skin penetration potential were used to calculate a maximal daily systemic exposure which was then compared to its corresponding TTC class value. Since the composition of plant extracts are variable, back calculation was used to determine the maximum acceptable concentration of a given constituent in an extract of CF. This paper demonstrates the utility and practical application of the TTC concept when used as a tool in the safety evaluation of botanical extracts.


Missed Opportunities for Timely Recognition of Chronic Limb Threatening Ischaemia in Patients Undergoing a Major Amputation: A Population Based Cohort Study Using the UK's Clinical Practice Research Datalink.
Opportunities for timely recognition of chronic limb-threatening ischaemia (CLTI) within primary care, such as performing cardiovascular assessment during clinical consultation, are possibly being missed. This study aimed to investigate for potential "missed opportunities" within primary care. This was a population based cohort study, using the UK's Clinical Practice Research Datalink (CPRD). Patients undergoing a major amputation for CLTI between 1 January 2000 and 31 December 2016 were included. Primary care consultation and patient clinical data within the one year period prior to amputation were extracted from the CPRD. Dates of last primary care consultation and cardiovascular assessment prior to amputation were evaluated. Timings of latest cardiovascular assessments were stratified into "recent" (7-90 days before amputation) and "late" (> 91 days). In total, 3 260 patients were included. In the year prior to amputation, patients attended a median of 19 (range 9-32) primary care consultations; however, prescription of secondary preventive medications was poor (antiplatelet 49.7%; lipid lowering agent 40.7%). Overall, 2 175 patients (66.7%) attended a primary care consultation 7-30 days before their amputation. However, only 416 (12.8%) underwent a cardiovascular assessment within this period, with 2 073 (63.6%) undergoing no assessment within 90 days of their amputation. Of these 2 073 patients, 1 230 (59.3%) had a primary care consultation 7-30 days before their procedure. Patients undergoing "late" assessment were younger (p = .003), with higher systolic (p = .008) and diastolic (p = .001) blood pressures than those undergoing "recent" assessment. Differences were also observed between assessment timings by deprivation (p = .003) and ethnicity (p = .006). Missed opportunities for timely recognition potentially exist and may be related to age, deprivation, and ethnicity. Further work is required to investigate these factors, as well as individual amputations to identify the causes precipitating amputation. Greater emphasis on the medical management of peripheral arterial disease and identifying cardiovascular risk factors in patients who may not fit the "at risk" stereotype, are also required.


Assaying Intracellular Arginylation Activity Using a Fluorescent Reporter.
In this chapter, we present a simplified version of the method described in Chapter 9 of this book, adapted for fast and convenient evaluation of intracellular arginylation activity in live cells. As in the previous chapter, this method utilizes a GFP-tagged N-terminal β-actin peptide transfected into cells as a reporter construct. Arginylation activity can then be evaluated by harvesting the reporter-expressing cells and analyzing them directly by Western blot using an arginylated β-actin antibody and a GFP antibody as an internal reference. While absolute arginylation activity cannot be measured in this assay, different types of reporter-expressing cells can be directly compared, and the effect of genetic background or treatment can be evaluated. For its simplicity and broad biological application, we felt this method merited presentation here as a separate protocol.


A novel automated immunoassay for serum NY-ESO-1 and XAGE1 antibodies in combinatory prediction of response to anti-programmed cell death-1 therapy in non-small-cell lung cancer.
Anti-programmed cell death-1 (PD-1) antibodies (Abs) are key drugs in non-small-cell lung cancer (NSCLC) treatment; however, clinical benefits with anti-PD-1 monotherapy are limited. We reported that serum Abs against cancer-testis antigens NY-ESO-1 and XAGE1 predicted clinical benefits. We aimed to develop a fully automated immunoassay system measuring NY-ESO-1/XAGE1 Abs. Sera from 30 NSCLC patients before anti-PD-1 monotherapy were reacted with recombinant NY-ESO-1 protein- or synthetic XAGE1 peptide-coated magnetic beads. ALP-conjugated Ab and chemiluminescent substrate were added and luminescence measured. These procedures were automated using high sensitivity chemiluminescent enzyme immunoassay (HISCL™). NY-ESO-1/XAGE1 Ab stability was tested under various conditions. Response prediction accuracy was evaluated using area under receiver operating curve (AUROC). HISCL detected specific serum NY-ESO-1/XAGE1 Abs, which levels in ELISA and HISCL were highly correlated. The Ab levels in HISCL were stable at four temperatures, five freeze/thaw cycles, and long-term storage; the levels were not interfered by common blood components. The Ab levels in 15 NSCLC responders to anti-PD-1 monotherapy were significantly higher than those in non-responders and healthy donors. The AUROC was the highest (0.91; 95% CI, 0.78-1.0) in combinatory prediction with NY-ESO-1/XAGE1 Abs. Our immunoassay system is useful to predict clinical benefits with NSCLC immune-checkpoint therapy.


Preparation of polyamine antibody and its use in enzyme immunoassay of spermine and spermidine with beta-D-galactosidase as a label.
An enzyme immunoassay for polyamines is described which uses beta-galactosidase labeled spermine and antiserum raised in rabbits against spermine-bovine serum albumin synthesized by coupling spermine to mercaptosuccinylated bovine serum albumin with a bifunctional cross-linker, N-(gamma-maleimidobutyryloxy)-succinimide. The lower limit of detection by this assay, which involves a double antibody technique for the separation of antibody-bound and free antigen, was 1 ng of spermine per tube. The anti-spermine serum showed 88% cross-reaction with spermidine but only 0.13% with putrescine, 0.08% with 1,3-diaminopropane, and 0.04% with cadaverine. The method has been used to measure serum polyamine levels in healthy subjects and cancer patients, in whom mean concentrations of 58.1 ng/ml and 94.8 ng/ml (as spermine), were respectively noted. This enzyme immunoassay is specific, accurate and easy to perform, and appears suitable for routine clinical use.


Energy and phosphorus utilization of pulses fed to broiler chickens.
Energy and P utilization in faba beans and peas were evaluated in 3 broiler chicken experiments. In Exp. 1, 240 birds were allotted to 5 diets in a randomized complete block design with BW as a blocking factor on d 18 post hatching to determine the regression-derived energy utilization of faba beans (FB) and field peas (FP). In each of the respective Exp. 2 and 3, regression-derived P utilization in FB and FP were determined with 162 birds assigned to each of 3 diets in a randomized complete block design with BW as a blocking factor on d 19 post hatching. There were 8 replicate cages with 6 birds per cage in Exp. 1, and 6 replicate cages with 9 birds per cage in Exp. 2 and 3. The test ingredients were added to a corn-soybean meal-based diet at 15% or 30% in Exp. 1, whereas FB was included at 21%, 42%, or 63% and FP at 16%, 32%, or 48% in Exp. 2 and 3, respectively. In Exp. 1, the apparent ileal digestibility (AID) of gross energy (GE) and the ileal digestible energy (IDE) in the diets decreased linearly (P < 0.01). There was a quadratic response or a linear decrease (P < 0.05) with increasing concentrations of FB or FP, respectively, on the apparent total tract utilization (ATTU) of GE, metabolizable energy (ME), and nitrogen-corrected ME (MEn). The respective IDE, ME, and MEn determined were 2,541, 2,628, and 2,394 kcal/kg DM in FB and 2,254, 2,540, and 2,331 kcal/kg DM in FP. In Exp. 2 and 3, the ileal digestible and retainable P intake were linearly increased (P < 0.01). The estimated true ileal digestibility and true total tract utilization of P in FB were 66.5% and 66.7%, respectively. The respective corresponding values for FP were 73.4% and 73.8%. In conclusion, the information on utilization of energy and P in FB and FP provided could enhance proper diet formulation when using these ingredients.


Left bronchial compression after an arterial switch operation with the LeCompte maneuver for transposition of the great arteries: A case report and literature review.
Left bronchial compression is a rarely reported, postoperative complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries. Postoperative neopulmonary root dilatation and the anterior-posterior, anatomical relationship of the great vessels may cause this condition. Hypoxic pulmonary vasoconstriction may mask the condition even if the left bronchus has been severely obstructed. The apparent inconsistency between the abnormally decreased pulmonary blood flow and the absence of any irregularities in the vascular structure that might account for it suggested hypoxic pulmonary vasoconstriction to be the cause. We present herein a case of left bronchial compression presenting malacia after an arterial switch operation with the LeCompte maneuver and also present a review of seven, other, reported cases. Left bronchial compression is a rare complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries and is possibly caused by root dilatation and the anatomical relationship of the great vessels. Hypoxic pulmonary vasoconstriction may mask the condition.


Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth.
Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN-PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b+/CD163+ TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro-tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN-PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN-PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential.


[The use of the concentrate of nucleus containing cells of umbilical cord blood for treatment of asthenic disorders (schizoasthenia) in patients with schizophrenia with negative symptoms].
To assess the safety and efficacy of umbilical cord blood (UCB) cells in the treatment of schizoasthenia and comorbid negative disorders. The study was conducted in men (n=15) with remission of schizophrenia with a predominance of asthenic disorders (ICD-10 items F20.6 and F21.5). Patients received intravenous infusions of UCB cells at the average dose of 250 mln viable cells per infusion (4 injections at 2 week intervals). The efficacy and safety were assessed using the Positive and Negative Symptoms of Schizophrenia (PANSS), the General Clinical Impression Scale (CGI), Asthenia Scale MFI-20 3, the MATRIX Consensus Cognitive Battery (MCCB), the Clinical evaluation of adverse events (side effects). The infusions of UCB cells have a positive effect on asthenic disorders, increase the level of general activity and minimize cognitive impairments. The authors assume that UCB cells potentiate the activity of typical and atypical antipsychotics.


Enabling modular dosage form concepts for individualized multidrug therapy: Expanding the design window for poorly water-soluble drugs.
Multidrug dosage forms (aka combination dosage forms, polypills, etc.) create value for patients through reduced pill burdens and simplified administration to improve adherence to therapy. Enhanced flexibility of multidrug dosage forms would provide further opportunities to better match emerging needs for individualized therapy. Through modular dosage form concepts, one approach to satisfy these needs is to adapt multidrug dosage forms to a wider variety of drugs, each with a variety of doses and release profiles. This study investigates and technically explores design requirements for extending the capability of modular multidrug dosage form concepts towards individualization. This builds on our recent demonstration of independent tailoring of dose and drug release, which is here extended towards poorly water-soluble drugs. The challenging design requirement of carrying higher drug loads in smaller volumes to accommodate multiple drugs at their clinical dose is here met regarding dose and release performance. With a modular concept, we demonstrate high precision (<5% RSD) in dose and release performance of individual modules containing felodipine or naproxen in Kollidon VA64 at both a wide drug loading range (5% w/w and 50% w/w drug) and a small module size (3.6 mg). In a forward-looking design-based discussion, further requirements are addressed, emphasizing that reproducible individual module performance is predictive of dosage form performance, provided the modules are designed to act independently. Therefore, efforts to incorporate progressively higher drug loads within progressively smaller module volumes will be crucial to extend the design window further towards full flexibility of future dosage forms for individualized multidrug therapy.


Albinism for the busy clinician.
Albinism is a group of disorders characterized principally by its ophthalmic features with or without systemic manifestations. Persons with albinism manifest a wide variety of phenotypes and limited number of genotypes. Modern molecular genetics has encouraged a new classification and understanding of the subtypes of these disorders. In addition to the ocular and systemic manifestations, ophthalmologists must be familiar with the specific visual needs and psychological challenges of these individuals as well as those of their families.


No effect of thyroid hormones on 5-year mortality in patients with subjective cognitive decline, mild cognitive disorder, and Alzheimer's disease.
The present study aimed to investigate differences in circulating thyroid hormone levels, gender, education, depressive symptoms, and cognitive performance among patients with cognitive impairment, and also to examine their associations, as well as that of cognitive decline, with 5-year mortality. Between 1998 and 2017, a hospital-based, single-centre (Neurology Department of the General Hospital in Vienna, Austria), retrospective follow-up study enrolled 2102 patients with mild to severe cognitive impairment (grouped into subjective cognitive decline, mild cognitive impairment, and Alzheimer's disease). Cox proportional hazards models were used to calculate hazard ratios (HRs), with 95% confidence intervals (CIs), as well as to calculate stepwise adjustments for demographic variables (age, gender, and education), depressive symptoms (Geriatric Depression Scale, GDS-15), and neuropsychological abilities (four domains of a neuropsychological test battery of Vienna, NTVB). In univariate analyses, total triiodothyronine (TT3) levels differed significantly between Alzheimer's disease and mild cognitive impairment patients (pdiff = .001). No other differences in cognitive impairment subgroups with any of the measured thyroid hormones were observed. Furthermore, in multivariate models, circulating TT3 was not associated with mortality (multivariable-adjusted HR per unit increase in TT3 = 0.56; 95% CI = 0.29-1.07). In multivariate models, we observed significantly lower 5-year mortality among women (HR = 0.56; 95% CI = 0.43-0.73) and those who scored higher on any of the four domains of the NBTV (e.g., attention and perceptual speed, HR = 0.63; 95% CI = 0.54-0.72); we also observed significantly higher 5-year mortality among patients with depressive symptoms (HR per one point score increase in GDS-15 = 1.06; 95% CI = 1.02-1.10), regardless of cognitive impairment subgroup. Among patients with various degrees of cognitive impairment, we found no associations of thyroid hormone levels with 5-year mortality. Gender, neuropsychological abilities, and depressive symptoms were each significant predictors of 5-year mortality. These results suggest that a neurocognitive test performance could serve as an important predictor of 5-year mortality among patients with cognitive impairment, although further studies with a more complete adjustment for comorbidities are needed to confirm these findings.


Tumor-Triggered Disassembly of a Multiple-Agent-Therapy Probe for Efficient Cellular Internalization.
Integration of multiple agent therapy (MAT) into one probe is promising for improving therapeutic efficiency for cancer treatment. However, MAT probe, if entering the cell as a whole, may not be optimal for each therapeutic agent (with different physicochemical properties), to achieve their best performance, hindering strategy optimization. A peptide-conjugated-AIEgen (FC-PyTPA) is presented: upon loading with siRNA, it self-assembles into FCsiRNA -PyTPA. When approaching the region near tumor cells, FCsiRNA -PyTPA responds to extracellular MMP-2 and is cleaved into FCsiRNA and PyTPA. The former enters cells mainly by macropinocytosis and the latter is internalized into cells mainly through caveolae-mediated endocytosis. This two-part strategy greatly improves the internalization efficiency of each individual therapeutic agent. Inside the cell, self-assembly of nanofiber precursor F, gene interference of CsiRNA , and ROS production of PyTPA are activated to inhibit tumor growth.


The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet.
Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-gamma expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-alpha. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, alpha-smooth muscle actin, and transforming growth factor-beta1 in comparison to rats without PGZ. These results suggest that PPAR-gamma agonist is a potential therapeutic modality to treat NASH.


Decline of serum CYFRA21-1 during chemoradiotherapy of NSCLC: a probable predictive factor for tumor response.
We investigated the predictive value of decline in the serum levels of tumor markers on tumor response during the chemoradiotherapy (CRT) in patients with non-small cell lung cancer (NSCLC). The serum levels of cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), neurone-specific enolase and carcinoembryonic antigen were measured by enzyme-linked immunosorbent assays, while the tumor responses were assessed according to the World Health Organization response criteria. The relationship between the changes of serum level of tumor markers and the radiologic response were analyzed. The effective rates (CR + PR) in CYFRA21-1 (pretreatment serum level) high and low groups were 45.8% (33/72) and 66.7% (24/36), respectively (p=0.032). Independent sample t test showed that the relationship between the response of CYFRA21-1 and the radiologic objective response are significantly different (p=0.008). The best cutoff value of the decline ratio of CYFRA21-1 was established as 18.48% by ROC curve. CYFRA 21-1 responses appeared to be reliable surrogate markers to predict chemoradiotherapy efficacy in patients with NSCLC, an average drop of 18.48% in serum CYFRA21-1 appears to provide the predictive information for the sensitivity of CRT.


Reduced retention of cadmium in the liver of metallothionein-null mice.
The distribution of cadmium (Cd) in the organs of mice was studied using metallothionein (MT)-null transgenic mice. When mice were administered with Cd chloride at a single subcutaneous dose of 1.0 mg Cd/kg body weight, Cd accumulated mainly in the liver and kidney by 6 h after injection without any significant difference between the MT-null mice and control (C57BL/6J) mice. MT was not detected in these organs of MT-null mice both before and after Cd administration whereas MT was induced mainly in these organs of the control mice. There was a marked elimination of Cd from the liver of MT-null mice by 21 days after administration, compared with a relatively slow Cd elimination in the C57BL/6J mice. Under the condition that no significant liver or kidney damage was observed, MT was considered to play a significant role in the retention of Cd in the liver but not in the uptake of this metal.


Pheochromocytoma with an unusual presentation.
Pheochromocytoma, is a rare neuroendocrine tumor, which usually presents as hypertension. We report a young male patient, who presented with intracerebral hemorrhage and intractable hypertension. On further evaluation, for uncontrolled secondary hypertension, he was diagnosed to have right adrenal pheochromocytoma. After hemodynamic stabilization, laparoscopic adrenelectomy was performed. Pheochromocytoma crisis presenting as intracerebral hemorrhage and cardiomyopathy is an uncommon phenomena. Even though it is a crisis, it is not a surgical emergency. Proper preoperative hemodynamic stabilization is essential before surgery is performed. An experienced anesthetist, to manage intraoperative fallacies, is warranted. Postoperatively, they must be on lifelong follow-up to watch for recurrence.


Pictures of a crisis. Destination marketing organizations' Instagram communication before and during a global health crisis.
The COVID-19 pandemic enhanced social media communications at a time individuals were unable to leave their homes due to the lockdown measures. A lack of research has been identified on how destination marketing organizations use social media during global health crises. Addressing this gap, the present research uses a mixed-method approach to examine the use of Instagram by Milan and Paris' Destination Marketing Organizations before and during COVID-19 and user engagement with it. Via a quantitative content analysis, Study 1 reveals communication differences between destinations and a change in promotion focus during the pandemic. Both DMOs focus on posts portraying "Culture, History and Art", which signifies stability and eternity as opposed to uncertain times. Using a thematic analysis, Study 2 reveals that both organizations promoted pro-social behavior also by employing influencers. Overall, research results document tourism organizations' pro-social use of social media during a global health crisis.


Genotoxic evaluation of two mercury compounds in the Drosophila wing spot test.
Few studies on the genotoxicity of mercury compounds have been carried out in Drosophila melanogaster, most of them focused in the effects on germinal cells, whereas studies in somatic cells are scarce. In the present study we have analyzed for the first time the genotoxic activity of mercury (II) chloride (MC) and methyl mercury (II) chloride (MMC) in the in vivo wing somatic mutation and recombination test in Drosophila, also known as the wing spot assay. This test is based on the principle that loss of heterozygosis and the corresponding expression of the suitable recessive markers, multiple wing hairs (mwh) and flare-3 (flr(3)), can lead to the formation of mutant clones in larval cells, which are then expressed as spots on the wings of adult flies. The mercury compounds were supplied to third instar larvae (72+/-2h old) at concentrations ranging from 1 to 50 microM for mercury chloride (MC) and from 0.5 to 5 microM for methyl mercury chloride (MMC). Both mercury compounds showed high toxicity; however, MMC was more toxic than MC. The results showed that none of the three categories of mutant spots recorded (small, large, and twin) increased significantly by the treatments, independently of the dose supplied, indicating that the mercury compounds tested exhibit a lack of genotoxic activity in the wing spot assay of D. melanogaster. These results contribute to increase the genotoxicity database on the in vivo evaluation of mercury compounds in Drosophila.


Road traffic accidents in Greece: recent trends (1981-1991).
This study describes trends of road traffic accidents (RTAs) in Greece over the past 11-year period. All casualties that occurred in Greece during the period 1981-1991 are analyzed. Trends in severity (as judged by the proportion of fatal or serious casualties) are studied. The rate 'casualty per registered vehicle' is also used and is mainly based on the number of road users killed or seriously injured. The total number of deaths presents a considerable increase by about 32%, but an important reduction of serious injuries was observed during the same period. The number of fatal injuries increased significantly only in drivers whereas no such increase is observed in passengers and pedestrians. In all three categories of road users, serious injuries decreased significantly with a similar linear regression slope. RTAs in Greece are also becoming less severe in all categories of road users. Accidents per registered vehicle decrease significantly in all road user groups and age groups. The slope of this decrease is rather exponential, suggestion that any further increase of the number of registered vehicles will be followed by a similar increase of the number of casualties so that the rate will tend to remain stable. This represents a very challenging situation of how to keep the number of casualties as low - or, at least, as stable - as possible despite high vehicle densities. There is uncertainty about the factors that led to the observed decreases, as it was difficult to single out effects of specific measures, because of data limitations. An improved data collection system is necessary in order to enable a more thorough analysis of casualty trends not fully addressed in this study.


Genetic variants of TCF7L2 gene and its coherence with metabolic parameters in Lithuanian (Kaunas district) women population with previously diagnosed gestational diabetes mellitus compared to general population.
To determine the association of genetic variants rs7901695, rs7903146, rs7895340, rs11196205, rs12255372 of transcription factor 7 like 2 (TCF7L2) gene and its coherence with metabolic parameters in Lithuanian (Kaunas district) women population with previously diagnosed gestational diabetes mellitus (GDM) and to compare the prevalence of TCF7L2 single nucleotide polymorphism (SNP) results to general population. Women with previously diagnosed GDM participated in the study. Anthropometric measurements were taken. Carbohydrate and fat metabolism were evaluated. TCF7L2 SNP common variants (rs7901695, rs7903146, rs7895340, rs11196205, rs12255372) were set. The prevalence of TCF7L2 the same SNP alleles were also evaluated for women of the general population. The results were compared to the main study group (women with previously diagnosed GDM). The results were calculated in a ratio of 1:2. General population group comprised 300 women who were selected from the random sample of the Kaunas city population. Statistical analysis was made with the statistical package IBM SPSS Statistics version 21. Quantitative parametric variables presented as mean and standard deviation, qualitative variables - as absolute numbers and percentage. ANOVA test was used, for the comparison between three or more groups. Quantitative variables were compared using Student's t-test. Categorical variables were compared using chi-square test. Correlation analysis of parametrical data was performed by Pearson's correlation. Odds ratios (OR) with 95% CIs were presented. The results were considered statistically significant at p < 0.05. 158 women with previously (15-47 years ago) diagnosed GDM participated in the study. The mean age of participants was 53.0 ± 8.2 years and 60.2 ± 7.5 years (p < 0.001), BMI - 31.4 ± 7.9 kg/m2 and 29.9 ± 5.8 kg/m2 (p < 0.001) in GDM group and general population respectively. GDM group women had significantly larger waist, hip circumference and waist to hip ratio compared to general population women: 98.9 ± 18.1 cm vs. 89.2 ± 13.3 (p < 0.001), 112.5 ± 14.8 cm vs. 105.6 ± 10.9 cm (p < 0.001), 0.87 ± 0.08 vs. 0.84 ± 0.07 (p < 0.001). There was no significant difference in blood pressure results between groups (p > 0.05). Carbohydrate dysmetabolism was set for 57.6% women with previously diagnosed GDM: 11 (7.0%) were diagnosed with impaired fasting glycemia (IFG), 14 (8.9%) with impaired glucose tolerance (IGT), type 2 Diabetes Mellitus (DM) was diagnosed for 58 (36.7%), DM type 1 for 7 (4.4%), MODY2 (maturity onset diabetes of the young) - 1 (0.6%) patients. TCF7L2 SNPs in women with previously diagnosed GDM and various carbohydrate metabolism groups did not differed (p > 0.05). Body weight, body mass index (BMI), waist and hip circumference in GDM group participants with different TCF7L2 SNP alleles did not differ (p > 0.05). There was no statistically significant difference in fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) results, cholesterol levels and different TCF7L2 SNP alleles in GDM group (p > 0.05). We found higher prevalence of TCF7L2 SNP rs7901695 CC/CT, rs7903146 CT/TT and rs12255372 GT/TT alleles in women previously diagnosed GDM compared to general population women's group. The OR of being in GDM group with TCF7L2 SNP: rs7901695 CC/CT alleles, was 1.703 (95% CI 1.153-2.515); rs7903146 CT/TT - 1.708 (95% CI 1.149-2.538); rs12255372 GT/TT - 1.575 (95% CI 1.058-2.343). No statistically significant difference in glucose, cholesterol levels and different TCF7L2 SNP alleles in GDM group was found. TCF7L2 SNPs did not differed in women with previously diagnosed GDM and various carbohydrate metabolism groups, though a significantly higher incidence of TCF7L2 rs7901695 SNP CC/CT, rs7903146 SNP CT/TT, rs12255372 GT/TT alleles in study subjects compared to the general population women were observed.


Association of depression & health related quality of life with body composition in children and youth with obesity.
There is an increasing recognition of the relationship between mental illness and obesity in the pediatric population. Our objective was to explore the individual, biological and family determinants of depressive symptoms and HRQOL in youth with obesity in a clinical setting. We studied 244 youth aged 8-17 years at the time of entry to a weight management program. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale for Children questionnaire, with a score of ≥15 or antidepressant use indicating depression. HRQOL was examined using the PedsQL4.0. We considered the influence of age, sex, health history, anthropometry, body fat, family health and socioeconomic status (SES) on depression and HRQOL. Depression was common in this population (36.4%). In multivariate analysis, the extent of obesity (body fat) predicted both depression (OR 1.1 (1.0-1.2); p=0.05) and low HRQOL scores (β -0.63 (p<0.001)). Family SES was an important predictor of depression but not of HRQOL. In contrast to population-based studies, sex, age, pubertal status and family history of depression did not predict depressive symptoms. As this study included children and adolescents seeking obesity treatment, results may not be generalizable to the general population of obese youth. Depression and low HRQOL are common in youth entering weight management programs. Extent of obesity predicted depressive symptoms and low HRQOL. Predictors of depression in this population differ from non-obese populations studied. It is important to consider these characteristics to assist clinicians in identifying these children.


Case reports: red scrotal syndrome: a localized phenotypical expression of erythromelalgia.
We report a case of red scrotal syndrome responding to oral gabapentin, a neuropathic mediator that is commonly used in the treatment of primary erythromelalgia. The positive response to oral gabapentin and the resemblance of these 2 conditions supports that red scrotal syndrome is a phenotypical expression of localized primary erythromelalgia.


Molecular network of ChIP-Seq-based NF-κB p65 target genes involves diverse immune functions relevant to the immunopathogenesis of multiple sclerosis.
The transcription factor nuclear factor-kappa B (NF-κB) acts as a central regulator of immune response, stress response, cell proliferation, and apoptosis. Aberrant regulation of NF-κB function triggers development of cancers, metabolic diseases, and autoimmune diseases. We attempted to characterize a global picture of the NF-κB target gene network relevant to the immunopathogenesis of multiple sclerosis (MS). We identified the comprehensive set of 918 NF-κB p65 binding sites on protein-coding genes from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset of TNFα-stimulated human B lymphoblastoid cells. The molecular network was studied by a battery of pathway analysis tools of bioinformatics. The GenomeJack genome viewer showed that NF-κB p65 binding sites were accumulated in promoter (35.5%) and intronic (54.9%) regions with an existence of the NF-κB consensus sequence motif. A set of 52 genes (5.7%) corresponded to known NF-κB targets by database search. KEGG, PANTHER, and Ingenuity Pathways Analysis (IPA) revealed that the NF-κB p65 target gene network is linked to regulation of immune functions and oncogenesis, including B cell receptor signaling, T cell activation pathway, Toll-like receptor signaling, and apoptosis signaling, and molecular mechanisms of cancers. KeyMolnet indicated an involvement of the complex crosstalk among core transcription factors in the NF-κB p65 target gene network. Furthermore, the set of NF-κB p65 target genes included 10 genes among 98 MS risk alleles and 49 molecules among 709 MS brain lesion-specific proteins. These results suggest that aberrant regulation of NF-κB-mediated gene expression, by inducing dysfunction of diverse immune functions, is closely associated with development and progression of MS.


A new high protein-to-energy enteral formula with a whey protein hydrolysate to achieve protein targets in critically ill patients: a prospective observational tolerability study.
Current guidelines and expert recommendations stress the need to implement enteral feeds with a higher protein-to-energy ratio to meet protein requirements as recommended while avoiding gastrointestinal side effects and energy overfeeding in ICU patients. Prospective tolerability study in 18 critically ill patients with a high protein formula (high protein-to-energy (HP:E) formula = Fresubin® Intensive; HPG) compared to a contemporary matched conventional therapy group (CTG). The primary outcome was GI intolerance defined as ≥300 ml daily gastric residual volume (GRV), vomiting, or diarrhea on days 1 and 2. Secondary outcomes were the percentage of patients reaching their protein target on day 4 and overall protein intake. Groups were comparable regarding demographic characteristics, disease severity, organ failures, mechanical ventilation, and NUTRIC score at baseline. Eighteen patients completed the 4-day feeding period. The number of events of GRV of ≥300 ml/day was equal in both groups (33.3%). The incidence of diarrhea and vomiting was low in the HPG (two patients concerned). EN did not need to be discontinued due to intolerance in any group. Seventy-two percent of patients reached protein targets ≥1.3 g/kgBW/d within 4 days after initiation of enteral feeding, which was superior to the CTG (33%). Post-hoc testing showed group differences of protein intake between HPG and CTG were significant at t = 72 h and t = 96 h. Energy targets were met in both groups. The HP:E formula containing 33% whey protein hydrolysate is well tolerated in this tolerability study. Due to the HP:E ratio protein targets can be reached faster. Larger randomized trials are needed to confirm preliminary results. ClinicalTrials.gov Identifier: NCT02678325. Registered 2 May 2016.


NMR Analysis of Apo Glutamine-Binding Protein Exposes Challenges in the Study of Interdomain Dynamics.
Glutamine-binding protein (GlnBP) displays an apo, "open" and a holo, "closed" crystal form, mutually related by a rigid-body reorientation of its domains. A fundamental question about such large-scale conformational transitions, whether the closed state exists in the absence of ligand, is controversial in the case of GlnBP. NMR observations have indicated no evidence of the closed form, whereas experimentally validated computations have suggested a remarkable ca. 40 % population. Herein, a paramagnetic NMR strategy designed to detect the putative apo-closed species shows that a major population of the latter is highly improbable. Further, NMR residual dipolar couplings collected under three anisotropic conditions do not reveal differential domain alignment and establish that the average solution conformation is satisfied by the apo-open crystal structure. Our results indicate that the computational prediction of large-scale interdomain motions is not trivial and may lead to erroneous conclusions without proper experimental validation.


Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer.
Cyclin E is a G1 cyclin that is essential for the transition from G1 to S phase in the cell cycle. Alterations to cyclin E expression or regulation could be important in tumorigenesis. Previous immunohistochemical and immunoblotting studies have investigated the expression of cyclin E in breast carcinomas. In this study, cyclin E has been investigated in a range of non-malignant and malignant breast using immunohistochemistry. Normal and benign tissue from pre- and post-menopausal women (39 cases), non-involved tissue from cancer-containing breasts (47 cases), ductal carcinoma in situ (22 cases) and invasive breast carcinomas (109 cases) have been examined. There was no reactivity in any of the non-malignant breast. Only one ductal carcinoma in situ contained more than 5% reactive cells. A total of 28% of invasive carcinomas had > 5% of reactive cells (range 0-88% positive cells, mean 12.59%, median 1.0%). A significant association was found with poorer differentiation (P < 0.001), high MIB1 index (P < 0.001), lack of oestrogen receptor (0.05 > P > 0.025) and the presence of p53 protein (0.05 > P > 0.025). Virtually all cases with cyclin E and p53 were poorly differentiated. The presence of cyclin E is therefore only found in breast malignancies and is associated with more aggressive features, including high proliferation.


Lactoferrin-derived antimicrobial peptide induces a micellar cubic phase in a model membrane system.
The observation of a micellar cubic phase is reported for a mixture of an antimicrobial peptide from the Lactoferrin family, LFampin 265-284, and a model membrane system of dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (3:1), as derived from small-angle x-ray diffraction (SAXD) measurements. The system shows remarkable thermotropic polymorphism: the peptide disrupts the lipid bilayer, forming a cubic phase of the space group Pm3n (t < 28°C), and as the temperature increases it shows a complex phase behavior (not fully clarified by SAXD). The onset, volume fraction of each phase, and phase parameters are seen to vary with peptide/lipid ratio and temperature. The obtained SAXD data represent the first experimental evidence, to our knowledge, of a micellar cubic phase in the context of antimicrobial peptide/membrane interaction. We propose that the micellization of the membrane according to the carpet model, for long proposed as a possible mechanism of action, can go through the formation of a cubic micellar phase.


Inhibition of staphylococcal enterotoxin-driven lymphocyte proliferation by anti-MHC class II monoclonal antibody.
Staphylococcal enterotoxins (SE) bind to major histocompatibility complex (MHC) class II molecules and the V beta region of T cell receptors (TCR) and subsequently induces T cell proliferation. This mitogenicity is the basis of pathological effects seen in food poisoning and toxic shock syndrome. Toxin-specific monoclonal antibodies have previously been shown to be effective in blocking toxin stimulated T cell responses. In this study, a monoclonal antibody, 52BL1, was found to be a potent inhibitor of SEA-, SEB-, SEC1-, SED-, and SEE-induced lymphocyte proliferation assays, which indicates that a single anti-HLA (human leukocyte antigen) class II antibody is effective in blocking the biological effects of these toxins. These results demonstrate the possibility of using anti-HLA class II antibodies in a clinical setting as an antagonist to staphylococcal enterotoxinmediated pathogenesis.


Planning and instituting new tests in the clinical laboratory.
The laboratory director will eventually face the problem of introducing a new test method. A whole spectrum of decisions must be made depending on the degree of novelty and complexity of the new test. The statistical comparison studies discussed in this article are generally applicable for all tests reported in a quantitative manner.


Over-expression of aspartate aminotransferase genes in rice resulted in altered nitrogen metabolism and increased amino acid content in seeds.
Aspartate aminotransferase (AAT) is a key enzyme in the synthesis of amino acids. It plays an important role in regulating carbon and nitrogen metabolism in almost all organisms. In this study, we over-expressed in rice separately all three AAT genes from rice (OsAAT1~3) and one AAT gene from Escherichia coli (EcAAT). Over-expression was driven by the CaMV 35S promoter and constructs were introduced into rice by Agrobacterium tumefaciens-mediated transformation. Compared with control plants, the transformants showed significantly increased leaf AAT activity and greater seed amino acid and protein contents. No other phenotypic changes were observed. The total leaf AAT activities in plants over-expressing OsAAT1, OsAAT2, and EcAAT were 26.6, 23.6, and 19.6 A min(-1) mg(-1) FW (A: units of activity, defined as increase of absorbency per min per mg; FW: fresh weight), which were significantly higher than that in the wild-type control (17.7 A min(-1) mg(-1) FW). The amino acid content in seeds of transgenic plants over-expressing OsAAT1, OsAAT2, and EcAAT was 119.36, 115.36, and 113.72 mg g(-1), respectively, which were 16.1, 12.0, and 5.4% higher, respectively, than that in the control plants. The transgenic plants over-expressing OsAAT1, OsAAT2, and EcAAT had significantly higher protein contents (increased 22.2, 21.1, and 11.1%, respectively) than wild-type plants. No significant changes were found in leaf AAT activity, seed amino acid content or protein content in OsAAT3 over-expressed plants. The expression patterns of the three OsAAT genes and their different functions are also discussed.


Is the interaction between felbamate and valproate against seizures induced by 4-aminopyridine and pentylenetetrazole in mice beneficial?
We compared the effects of adding a non-protective dose of valproate (VPA) to increasing single doses of felbamate (FBM) with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by 14 mg kg(-1) of 4-aminopyridine (4-AP) and by 110 mg kg(-1) of pentylenetetrazole (PTZ), and neurotoxicity by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate in the whole brain. VPA increased the potency ratio of FBM against 4-AP (1.94, P<0.05) but not against PTZ. VPA increased the neurotoxicity of FBM (3.30, P<0.05) and the protective index of FBM was, therefore, reduced from 12.0 to 7.0 for the 4-AP model and from 11.8 to 5.2 for the PTZ model; VPA reduced brain FBM, and increased brain GABA in relation to FBM monotherapy. On the other hand, FBM increased the potency ratio of VPA against 4-AP (1.60, P<0.05) but not against the PTZ, and had no effect on the rotarod model. Therefore, the protective index increased from 1.1 to 1.6 for the 4-AP model and decreased from 1.9 to 1.7 for the PTZ model. FBM did not change brain VPA, and changes in brain GABA and glutamate were not clearly related to anticonvulsant effects. In conclusion, although the addition of a low dose of FBM to VPA was beneficial in the 4-AP model, the addition of a low dose of VPA to FBM was not; both combinations were disadvantageous in the PTZ model. This interaction appears to be pharmacodynamic because a pharmacokinetic mechanism was discarded.


Presumed Sertraline-Associated Maculopathy: A Case Series.
To report findings of maculopathy after treatment with sertraline in three patients. This case series includes three patients who presented with reduced visual acuity after treatment with sertraline for various psychiatric indications. All patients had been treated with sertraline for varying periods of time between 4 weeks and 5 years. Data were collected from three patients (age range, 27-68 years). All three patients were white females, with both eyes being affected in all cases. The range of presenting visual acuities was between 20/30 and 20/100 after presentation with central visual disturbance. All patients underwent comprehensive ocular examination and imaging with the main ocular findings being outer retinal layer and retinal pigment epithelial disruption. The follow-up period was between 1 and 9 months with final visual acuities between 20/25 and 20/100. Patients showed objective clinical evidence of phenotypically similar maculopathy supported by appropriate imaging CONCLUSION: In this cohort, we report the possible association of sertraline use and associated maculopathy in three patients. This is potentially significant, given the large numbers of patients treated with sertraline currently; however, further evidence is required to both quantify how common this association is and establish a possible causative mechanism.


Isolation and characterization of lipid globules from the zoospores of Blastocladiella emersonii.
Lipid globules were isolated and characterized both chemically and morphologically. They were composed mainly of triglyceride and free sterol, which accounted for over 90% of the total globule content. Smaller amounts of diglyceride, carotenoid, free fatty acid, phospholipid and protein were found. No sterol esters or monoglycerides were detected. Morphologically, the isolated lipid globules resembled the lipid globules in situ. They were spherical, 0.4-1.5 mum in diameter and lacked a trilaminar membrane.


Coronavirus Disease 2019 (COVID-19) and Neurosurgery: Literature and Neurosurgical Societies Recommendations Update.
Since January 2020, when the pathogen causing the coronavirus disease was identified in humans, the literature on coronavirus disease 2019 (COVID-19) has grown exponentially to more than 4000 publications. There is the need to provide an update for each single medical discipline, including neurosurgery, to be used by single professionals or to be distributed through the neurosurgical community and to be used by governments in designing new scenario of care. A review of the MEDLINE database was performed on April 13, 2020. Search terms included "COVID-19," "neurosurgery," and "surgery." A review of documents published on the webpage of the WFNS (World Federation of Neurosurgical Societies) and of the 5 continental associations of neurosurgical societies, AANS (American Association of Neurological Surgeons), AASNS (Asian Australasian Society of Neurological Surgeons), CAANS (Continental Association of African Neurosurgical Societies), EANS (European Association of Neurosurgical Societies), and FLANC (Latin American Federation of Neurosurgical Societies), representing the 119 national neurosurgical societies around the world, was performed. The literature search yielded 38 results that were manually reviewed. Fourteen manuscripts were considered eligible. They described suggestions and considerations to optimize care of neurosurgical patients, editorials on operational models, perspectives from neurosurgical departments, letters to the editor describing experiences on how to help medical staff to be prepared in advance for pandemic situations, and descriptions of regional or departmental models and/or organizational schemes. The webpages of the searched societies reported a total of 57 documents. The neurosurgical scientific community has promptly reacted to the COVID-19 outbreak by producing a growing number of documents that could serve as guidance for neurosurgeons all over the world. Neurosurgical societies will represent the key institutions for guiding the neurosurgical community to overcome the COVID-19 crisis.


Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET).
Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.


Local adaptation drives the diversification of effectors in the fungal wheat pathogen Parastagonospora nodorum in the United States.
Filamentous fungi rapidly evolve in response to environmental selection pressures in part due to their genomic plasticity. Parastagonospora nodorum, a fungal pathogen of wheat and causal agent of septoria nodorum blotch, responds to selection pressure exerted by its host, influencing the gain, loss, or functional diversification of virulence determinants, known as effector genes. Whole genome resequencing of 197 P. nodorum isolates collected from spring, durum, and winter wheat production regions of the United States enabled the examination of effector diversity and genomic regions under selection specific to geographically discrete populations. 1,026,859 SNPs/InDels were used to identify novel loci, as well as SnToxA and SnTox3 as factors in disease. Genes displaying presence/absence variation, predicted effector genes, and genes localized on an accessory chromosome had significantly higher pN/pS ratios, indicating a higher rate of sequence evolution. Population structure analyses indicated two P. nodorum populations corresponding to the Upper Midwest (Population 1) and Southern/Eastern United States (Population 2). Prevalence of SnToxA varied greatly between the two populations which correlated with presence of the host sensitivity gene Tsn1 in the most prevalent cultivars in the corresponding regions. Additionally, 12 and 5 candidate effector genes were observed to be under diversifying selection among isolates from Population 1 and 2, respectively, but under purifying selection or neutrally evolving in the opposite population. Selective sweep analysis revealed 10 and 19 regions that had recently undergone positive selection in Population 1 and 2, respectively, involving 92 genes in total. When comparing genes with and without presence/absence variation, those genes exhibiting this variation were significantly closer to transposable elements. Taken together, these results indicate that P. nodorum is rapidly adapting to distinct selection pressures unique to spring and winter wheat production regions by rapid adaptive evolution and various routes of genomic diversification, potentially facilitated through transposable element activity.


Analysis of direction of association between radiation risk perception and relocation using a random-intercept and cross lagged panel model: The Fukushima Health Management Survey.
In the aftermath of a nuclear disaster, a person's radiation risk perception can harm their sociopsychological health. Although there are reports of an association between radiation risk perception and relocation, the direction of this association has not been clarified yet. In this study, we used a random-intercept and cross lagged panel model (RI-CLPM) to investigate the association and its direction between radiation risk perception and the prefectural-level relocation (i.e., inside/outside of Fukushima Prefecture). We did this by using five waves of longitudinal surveys between 2011 fiscal year and 2015 fiscal year among the people affected by the Fukushima disaster in 2011. We included 90,567 participants aged ≥15 years during the time of the disaster who responded to the questionnaire at least once. RI-CLPM was applied to examine the reciprocal relationship between radiation risk perception and locations. We used two radiation risk perception indicators (i.e., genetic effect and delayed effect) and two handling methods on missing data (i.e., listwise deletion and full information maximum likelihood estimation) as sensitive analyses. The effects of radiation risk perception on relocation were found to be negligibly small. Living inside Fukushima Prefecture reduced radiation risk perception irrespective of the difference of indicators or methods, highlighting that radiation risk perception did not dominantly govern whether people were living inside Fukushima Prefecture, but that the locations also affected radiation risk perception. This was the first study to reveal the direction of the association between radiation risk perception and relocation in the aftermath of nuclear disasters.


Influence of body temperature during cardiopulmonary bypass on the haemodynamics early after aorto-coronary bypass surgery.
The haemodynamic adaptation early after aorto-coronary bypass surgery, with special reference to the influence of body temperature on postoperative vasoconstriction, was studied in 20 patients. Cardioplegia arrest was used in all cases. Eleven patients were cooled to 30 degrees C during cardiopulmonary bypass, and nine were normothermic (37.5 degrees C) while the heart was cooled selectively. The normothermic patients had significantly higher oesophageal and skin temperatures in the immediate postoperative period, indicating better heat preservation. However, the systemic vascular resistance was similar in the two groups; i.e. it was moderately elevated initially and subsequently decreased. There was no significant difference regarding postoperative myocardial function. The normothermic patients woke up earlier after the operation than the hypothermic patients, and since they also had a relatively low oxygen uptake index (0.10--0.12 mmol. s-1. m-2), the possibility of earlier extubation in these patients is suggested.


A single point mutation within the ED1 gene disrupts correct splicing at two different splice sites and leads to anhidrotic ectodermal dysplasia in cattle.
The ectodysplasin 1 gene ( ED1) encodes a signaling molecule of the tumor necrosis factor family that is involved in fetal development of ectodermal appendages. Mutations in the ED1 gene are responsible for X-linked anhidrotic ectodermal dysplasia characterized by impaired development of hair, teeth, and eccrine sweat glands in human, mouse, and cattle. Two isoforms of ectodysplasin 1, termed ED1-A1 and ED1-A2, arise by alternative splicing and bind to different receptors. We identified a novel ED1 splice site mutation in a cattle family with X-linked anhidrotic ectodermal dysplasia. The point mutation is located within a 5' splice site (splice donor) at the beginning of intron 8 that is used exclusively in the alternatively spliced ED1-A1 transcript. Remarkably, cDNA sequencing demonstrated that both physiological transcripts, i.e., the ED1-A1 and the ED1-A2 splice variant, were affected by this point mutation. In an affected animal, the use of cryptic internal splice donor and acceptor sites within exon 8 lead to the production of a single transcript lacking 51 or 45 bp with respect to the normal ED1-A1 or ED1-A2 transcripts, respectively. The translated protein of the mutated transcript contained a large deletion in the functionally important C-terminal tumor necrosis factor-like domain thus causing the observed phenotype of anhidrotic ectodermal dysplasia. Our findings suggest the presence of a splice enhancer in the ED1 gene in the region of the mutation.


Fibrosarcoma of the right ventricle--a case report.
An unusual case of fibrosarcoma of the right ventricle is described in a 25-year-old man. The diagnosis of a right ventricular tumour was made on the basis of echocardiographic and radionuclide studies and was confirmed by angiocardiography. The surgical management and postoperative course are described together with a brief review of the literature.


Isolation, characterization and chromosomal mapping of an actin gene from the primitive red alga Cyanidioschyzon merolae.
Based on the results of cytological studies, it has been assumed that Cyanidioschyzon merolae does not contain actin genes. However, Southern hybridization of C. merolae cell-nuclear DNA with a yeast actin-gene probe has been suggested the presence of an actin gene in the C. merolae genome. In the present study, an actin gene was isolated from a C. merolae genomic library using a yeast actin-gene probe. The C. merolae actin gene has no intron. The predicted actin is composed of 377 amino acids and has an estimated molecular mass of 42 003 Da. Southern hybridization indicated that the C. merolae genome contains only one actin gene. This gene is transcribed at a size of 2.4 kb. When Southern hybridization was performed with C. merolae chromosomes separated by pulsed-field gel electrophoresis, a band appeared on unseparated chromosomes XI and XII. A phylogenetic tree based on known eucaryote actin-gene sequences revealed that C. merolae diverged after the division of Protozoa, but before the division of Fungi, Animalia and Chlorophyta.


Concentration changes of bile acids in sequential segments of pigeon intestine and their relation to bile acid absorption.
Changes in the concentration of bile acids in sequential segments of pigeon intestine were measured. It was found that the jejunum has the highest concentration of bile acids. When the ratio of bile acids to beta-sitosterol (a non-absorbable dietary marker) was examined in contents of various segments, it was found that the ratio showed a marked decrease (86.6%) from the upper to lower jejunum while the subsequent changes in other segments were not as striking. This indicates that the jejunum is the major site of bile acid absorption in the pigeon, unlike in mammals, where the ileum has been shown to be the major site of bile acid absorption. This notion was confirmed by studies of the effect of ileal bypass in these pigeons. This surgical procedure did not significantly change the fecal excretion of bile acids or neutral sterols indicating that the jejunum is capable of maintaining a normal enterohepatic circulation of bile acids in the absence of the ileum in the pigeons.


MCHergic projections to the nucleus pontis oralis participate in the control of active (REM) sleep.
Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are located in the lateral hypothalamus and incerto-hypothalamic area and project diffusely throughout the central nervous system, including areas that participate in the generation and maintenance of sleep and wakefulness. Recent studies have shown that hypothalamic MCHergic neurons are active during active sleep (AS), and that intraventricular microinjections of MCH induce AS sleep; however, there are no data available regarding the manner in which MCHergic neurons participate in the control of this behavioral state. Utilizing immunohistochemical and retrograde tracing techniques, we examined, in the cat, projections from MCHergic neurons to the nucleus pontis oralis (NPO), which is considered to be the executive area that is responsible for the generation and maintenance of AS. In addition, we explored the effects on sleep and waking states produced by the microinjection of MCH into the NPO. We first determined that MCHergic fibers and terminals are present in the NPO. We also found that when a retrograde tracer (cholera toxin subunit B) was placed in the NPO MCHergic neurons of the hypothalamus were labeled. When MCH was microinjected into the NPO, there was a significant increase in the amount of AS (19.8+/-1.4% versus 11.9+/-0.2%, P<0.05) and a significant decrease in the latency to AS (10.4+/-4.2 versus 26.6+/-2.3 min, P<0.05). The preceding anatomical and functional data support our hypothesis that the MCHergic system participates in the regulation of AS by modulating neuronal activity in the NPO.


Influence of surface roughness and shape on microdamage of the osseous surface adjacent to titanium dental implants.
To assess the relationship between smooth and roughened implant surfaces of straight and narrow configurations with respect to microdamage of the bone surface during placement of dental implants. Straight and tapered, rough and smooth surface Nobel Biocare implants were placed into sheep mandibles. Microdamage within the bone adjacent to the implant surface was quantitated using a semi-automated digitized histomorphometric method. Independent of implant type, microdamage, microcracks, cross-hatch damage and diffuse damage were significantly higher close to the implants compared with far from the implants. Microcracks and cross-hatch damage were higher for the rough cylindrical implants than all the other implant types. Insertion of a rough cylindrical implant type results in an increased fraction of microdamaged bone matrix in comparison to rough tapered, smooth cylindrical and smooth tapered implants.


Amplified photocurrent signal for fabricating photoelectrochemical sulfadimethoxine aptasensor based on carbon nitride photosensitization with visible/near-infrared light responsive zinc phthalocyanine.
Developing effective analytical method for sulfadimethoxine (SDM) detection is highly desirable and vitally crucial for protecting environment safety and human health. Herein, a highly selective and sensitive photoelectrochemical (PEC) aptasensor for accurate detection of SDM was proposed, which employed zinc phthalocyanine/graphitic carbon nitride (ZnPc/CN) nanocomposite as photosensitive material. The ZnPc/CN nanocomposite was constructed by modification of CN nanosheet with visible/near-infrared light responsive photosensitizer ZnPc. The introduction of ZnPc into CN exhibited amplified PEC response, which was 5.7 and 18.3 times than pure ZnPc and CN, attributed to the enhanced light harvesting ability and improved photoelectric conversion efficiency of such nanocomposite. By using ZnPc/CN and sulfadimethoxine (SDM) aptamer as PEC response material and specific probe, a PEC aptasensor was established for SDM detection. The aptamer was connected to the surface of chitosan/ZnPc/CN/ITO through the formation of phosphoramidate bonds between the amino group of the chitosan and phosphate group of the aptamer at 5' end. The fabricated aptasensor displayed good detection linearity of 0.1 ~ 300 nM and low detection limit of 0.03 nM (S/N = 3) under optimized conditions, and the potential applicability of the PEC aptasensor was confirmed by detecting SDM in milk powder samples.


The Mammotome biopsy system is an effective treatment strategy for breast abscess.
Although most breast abscesses can be treated with the current first-line treatment of antibiotics by needle aspiration, the therapeutic duration is lengthy and recurrences often occur. Therefore, we aimed to investigate the clinical efficacy of the Mammotome biopsy system (Johnson & Johnson Corp., New Brunswick, NJ) in a cohort of patients with breast abscesses. Forty lactating and 30 nonlactating breast abscess patients with unfavorable outcomes with antibiotic treatment and/or needle aspiration failure were recruited and treated with the Mammotome biopsy system. Skin inflammation of all patients disappeared within 6 days with no recurrence. The clinical outcomes in patients with an abscess size ≤ 3.5 cm was significantly better than those with an abscess size >3.5 cm (P = .025). The Mammotome biopsy system, an effective treatment strategy that is minimally invasive and less damaging, in combination with appropriate antibiotic therapy can be used safely as the first-line approach to breast abscess management.


Temporal analysis of vaginal proteome reveals developmental changes in lower reproductive tract of gilts across the first two weeks postnatal.
In swine the upper reproductive tract undergoes early postnatal development, however little is known about the lower reproductive tract. Our objective was to measure cytology and proteome of vaginal swab samples taken on postnatal day (PND) 2 and 16 in gilts to determine if temporal changes occurred in cell and protein profiles during the first two weeks after birth. The posterior vagina was swabbed using a cytology brush on PND 0, 2 and 16 and slides were prepared. The proportion of anuclear and superficial cells increased and parabasal decreased (P < 0.05) from PND 0 to 16. Proteins isolated from vaginal swabs taken on PND 2 and 16 from six gilts across three litters were measured using LC-MS/MS. Over 1500 proteins were identified, with 881 differentially expressed (P-adj < 0.05) between PND 2 and 16. One-third of proteins upregulated between days were categorized as secreted, including lipocalins. Categories enriched by downregulated proteins included cell-cell adherens junction, translation and ER to Golgi vesicle-mediated transport, and reflected increased cornification of stratified epithelium and thus mirrored changes in cytology. Changes in cytology and proteome over the first two weeks after birth support that the porcine vagina continues to develop postnatal.


Enhancement of muscle regeneration in the rat gastrocnemius muscle by low energy laser irradiation.
The effect of low-energy laser (He-Ne) irradiation on the rate of skeletal muscle regeneration after partial excision of the rat gastrocnemius muscle was studied using quantitative histological morphometric methods. The injured zones of the experimental rats were subjected to direct He-Ne laser (632.8 nm wavelength) irradiation (6.0 mW for 2.3 min) immediately following injury and once daily thereafter for 5 days. Muscles that were injured as above and subjected to red or room light irradiation served as a control group. The volume fraction (percent of total volume of injured zone) of the mononucleated cells in the injured zone decreased gradually with time after injury, but more rapidly in the laser irradiated muscles than in the control. At 3 days post-injury the myotubes in the laser-irradiated muscles populated a significantly higher percentage (13.9 +/- 1.1%) of the injured area than in the control muscles (7.8 +/- 1.0%). The volume fraction of the young myofibers in the laser irradiated muscles exceeded 30.6 +/- 2.2% and 49.6 +/- 5.6% at 8 and 11 days post-injury, respectively, while in control muscles these structures comprised only 9.6 +/- 1.0% and 27.2 +/- 3.8% of the injured zone at 8 and 11 days after injury, respectively. It is concluded that He-Ne laser irradiation during the regeneration process promotes muscle maturation in the injured zone following partial excision of the rat gastrocnemius muscle.


Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis.
BRCA1 mutated breast cancers are commonly diagnosed as negative for classical hormone receptors i.e. estrogen receptor, progesterone receptor and/or Her2. Due to these common targets being absent the application of anti-endocrine therapies is rather limited and a certain focus has been set on discovering alternative target molecules. We recently highlighted thyroid hormone receptors (TRs) to predict prognosis in breast cancer patients that had been diagnosed a BRCA1 germline mutation. Vitamin D Receptor (VDR), Retinoid X Receptor (RXR) and Peroxisome Proliferator-activated Receptor γ (PPARγ) are known to interact with TRs by forming functional heterodimers. Whether VDR, RXR or PPARγ are expressed in BRCA1 mutated breast cancer or may even be present in case of triple negativity is not known. Hence the current study aimed to investigate VDR, RXR and PPARγ in BRCA1 mut breast cancer and to test whether any of the three may be associated with clinico-pathological criteria including overall survival. This study analyzed VDR, RXR and PPARγ by immunohistochemistry in BRCA1 associated (n = 38) and sporadic breast cancer (n = 79). Receptors were quantified by applying an established scoring system (IR-score) and were tested for association with clinico-pathological variables. VDR, RXR and PPARγ were detected in over 90% of triple negative BRCA1 mut breast cancer and were significantly (VDR: p < 0.001, RXR: p = 0.010, PPARγ: p < 0.001) overexpressed in BRCA1 mutated as compared to sporadic cancer cases. VDR and RXR positivity predicted prolonged overall survival only in BRCA1 mutated cases while such association was not observed in sporadic breast cancer. In conclusion, this is the first study to describe VDR, RXR and PPARγ in BRCA1 mutated breast cancer. Based on the data presented here these receptors may be hypothesized to potentially evolve as interesting markers or even targets in hereditary breast cancer. However, independent studies are indispensable thus to confirm this hypothesis.


Cortical depth profiles of auditory and visual 7 T functional MRI responses in human superior temporal areas.
Invasive neurophysiological studies in nonhuman primates have shown different laminar activation profiles to auditory vs. visual stimuli in auditory cortices and adjacent polymodal areas. Means to examine the underlying feedforward vs. feedback type influences noninvasively have been limited in humans. Here, using 1-mm isotropic resolution 3D echo-planar imaging at 7 T, we studied the intracortical depth profiles of functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signals to brief auditory (noise bursts) and visual (checkerboard) stimuli. BOLD percent-signal-changes were estimated at 11 equally spaced intracortical depths, within regions-of-interest encompassing auditory (Heschl's gyrus, Heschl's sulcus, planum temporale, and posterior superior temporal gyrus) and polymodal (middle and posterior superior temporal sulcus) areas. Effects of differing BOLD signal strengths for auditory and visual stimuli were controlled via normalization and statistical modeling. The BOLD depth profile shapes, modeled with quadratic regression, were significantly different for auditory vs. visual stimuli in auditory cortices, but not in polymodal areas. The different depth profiles could reflect sensory-specific feedforward versus cross-sensory feedback influences, previously shown in laminar recordings in nonhuman primates. The results suggest that intracortical BOLD profiles can help distinguish between feedforward and feedback type influences in the human brain. Further experimental studies are still needed to clarify how underlying signal strength influences BOLD depth profiles under different stimulus conditions.


Teaching group dynamics: a critical evaluation of an experiential programme.
Nursing interventions based on a group approach have increased considerably in recent years. Although more common in mental health settings, group interventions are no longer exclusive to them. In this paper the authors argue that groups are now such a common feature of the experiences of all nurses that it is essential that educational programmes for nurses provide them with an opportunity to become acquainted with the ever-widening body of theory related to this subject. They identify the dissatisfaction and problems generated by the existing strategy for introducing pre-registration students to group dynamics in their college. A new course intended to address this dissatisfaction is described, including an outline of the principles which underpinned its design, and an evaluation of its implementation.