The Phenotypic Variation of a Parkin-Related Parkinson's Disease Family and the Role of Heterozygosity.
Parkinson's disease (PD) is a common neurodegenerative disorder with both sporadic occurrence and Mendelian heredity, as it is true for autosomal recessive parkin-related PD (PARK-parkin). Parkin-related PD is characterized by early onset, slow progression, frequent lower limb dystonia, and a robust response to levodopa. Clinicians are increasingly confronted with heterozygous PD patients mimicking dominant inheritance. Nevertheless, the exact clinical implications of heterozygosity are not fully understood. We present an illustrative PARK-parkin family with 2 affected sisters (compound heterozygous) and their father (heterozygous). One sister expresses the classical phenotype, whereas the other has isolated jerky tremor. The father has left-sided action tremor of the hand with some dystonic posturing without clear bradykinesia and normal DaTSCAN. This case series illustrates the phenotypic variability in parkin-related PD with 1 classical phenotype and 1 patient with isolated jerky tremor. Unilateral hand tremor of the heterozygous father could mislead genetic testing by mimicking dominant inheritance.


Focal epithelial hyperplasia of the oral mucosa. A case report from the United Kingdom.
A case of focal epithelial hyperplasia of the oral mucosa (Heck's disease) is presented, which appears to be the first to be described in the United Kingdom. Virus particles were found in tissue from the lesions studied by electron microscopy, and identified as belonging to the papilloma virus sub-group of the family of papovaviruses.


Hydrogen bonding interactions between adsorbed polymer molecules and crystal surface of acetaminophen.
The objective of this work was to investigate whether or not the hydrogen bonding interaction between polymer and crystal surface can be detected by the etching pattern changes in the presence of polymers. The (010) face of acetaminophen single crystal was used as a model solid surface. The etching patterns on the (010) face of acetaminophen crystal by water are in the directions of a- and c-axes, which are the same as the directions of the dominant attachment energies on the (010) face. In the presence of polymer, the hydrogen bonding interactions between adsorbed polymer and crystal surface can affect surface diffusion of acetaminophen molecules and change the etching patterns in the direction of a-axis, i.e., the direction of one hydrogen bond chain. Studies with 2-hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and poly(vinyl alcohol) (PVA) showed that polymers, which can form hydrogen bonds with acetaminophen crystal surface, can change etching patterns in the direction of a-axis. Study with Dextran suggested that if a polymer cannot form hydrogen bonds with crystal surface due to steric repulsion, it will not change the etching pattern in the direction of a-axis. Studies with poly(ethylene glycol) (PEG) and poly(propylene glycol) (PPG) further confirmed that only if a polymer can form hydrogen bonds with acetaminophen on crystal surface, the etching patterns in the direction of a-axis will be affected. The study results suggest that in the presence of polymers, the etching pattern change in the direction of hydrogen bond chain, the a-axis of acetaminophen crystals, can be used to indicate the existence of the hydrogen bonding interactions between adsorbed polymers and acetaminophen crystal surface.


Detection of Moisture by Fluorescent OFF-ON Sensor in Organic Solvents and Raw Food Products.
Copper complex based on a new class of fluorescence OFF-ON sensor 1.Cu has been reported for the detection of trace amounts of water in various organic solvents such as CH3OH, THF, CH3CN, and acetone by means of fluorescence emission intensity. The probe is highly responsive to water in THF (DL = 0.003 wt %). The dissociation of copper from probe 1.Cu in the presence of water is responsible for the fluorescence change and it was confirmed by electrospray ionization-mass spectrometry (ESI-MS), proton nuclear magnetic resonance (1H-NMR), and fluorescence lifetime studies. Real application of the probe was successfully applied for the detection of moisture content in commercial products such as salt, sugar, wheat, and washing powder.


RNY-derived small RNAs as a signature of coronary artery disease.
Data from next generation sequencing technologies uncovered the existence of many classes of small RNAs. Recent studies reported that small RNAs are released by cells and can be detected in the blood. In this report, we aimed to discover the occurrence of novel circulating small RNAs in coronary artery disease (CAD). We used high-throughput sequencing of small RNAs from human and mouse apoptotic primary macrophages, and analyzed the data by empirical Bayes moderated t-statistics to assess differential expression and the Benjamini and Hochberg method to control the false discovery rate. Results were then confirmed by Northern blot and RT-qPCR in foam cells and in two animal models for atherosclerosis, namely ApoE(-/-) and Ldlr(-/-) mouse lines. Quantitative RT-PCR to detect identified small RNAs, the RNY-derived small RNAs, was performed using sera of 263 patients with CAD compared to 514 matched healthy controls; the Student t-test was applied to statistically assess differences. Associations of small RNAs with clinical characteristics and biological markers were tested using Spearman's rank correlations, while multivariate logistic regressions were performed to test the statistical association of small RNA levels with CAD. Here, we report that, in macrophages stimulated with pro-apoptotic or pro-atherogenic stimuli, the Ro-associated non-coding RNAs, called RNYs or Y-RNAs, are processed into small RNAs (~24-34 nt) referred to as small-RNYs (s-RNYs), including s-RNY1-5p processed from RNY1. A significant upregulation of s-RNY expression was found in aortic arches and blood plasma from ApoE(-/-) and Ldlr(-/-) mice and in serum from CAD patients (P <0.001). Biostatistical analysis revealed a positive association of s-RNY1-5p with hs-CRP and ApoB levels; however, no statistical interaction was found between either of these two markers and s-RNY1-5p in relation to the CAD status. Levels of s-RNY1-5p were also independent from statin and fibrate therapies. Our results position the s-RNY1-5p as a relevant novel independent diagnostic biomarker for atherosclerosis-related diseases. Measurement of circulating s-RNY expression would be a valuable companion diagnostic to monitor foam cell apoptosis during atherosclerosis pathogenesis and to evaluate patient's responsiveness to future therapeutic strategies aiming to attenuate apoptosis in foam cells in advanced atherosclerotic lesions.


Does intraoperative fluoroscopy improve acetabular component positioning and limb-length discrepancy during direct anterior total hip arthroplasty? A meta-analysis.
The positioning of implant components for total hip arthroplasty (THA) is essential for joint stability, polyethylene liner wear, and range of motion. One potential benefit of the direct anterior approach (DAA) for THA is the ability to use intraoperative fluoroscopy for acetabular cup positioning and limb-length evaluation. Previous studies comparing intraoperative fluoroscopy with no fluoroscopy during DAA have reported conflicting results. This meta-analysis aimed to evaluate whether intraoperative fluoroscopy improves component positioning compared to no fluoroscopy during direct anterior total hip arthroplasty. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. We searched Web of Science, EMBASE, PubMed, Cochrane Controlled Trials Register, Cochrane Library, Highwire, CBM, CNKI, VIP, and Wanfang database in May 2023 to identify studies involving intraoperative fluoroscopy versus no fluoroscopy during direct anterior total hip arthroplasty. Finally, we identified 1262 hips assessed in seven studies. There were no significant differences in terms of acetabular cup inclination angle (ACIA, P = 0.21), ACIA within safe zone rate (P = 0.97), acetabular cup anteversion angle (ACAA, P = 0.26); ACAA within safe zone rate (P = 0.07), combined safe zone rate (P = 0.33), and limb-length discrepancy (LLD, P = 0.21) between two groups. Even though intraoperative fluoroscopy was not related to an improvement in cup location or LDD. With fewer experienced surgeons, the benefit of intraoperative fluoroscopy might become more evident. More adequately powered and well-designed long-term follow-up studies were required to determine whether the application of the intraoperative fluoroscopy for direct anterior total hip arthroplasty will have clinical benefits and improve the survival of prostheses.


Nicotine enantiomers and oxidative stress.
Nicotine affects a variety of cellular processes ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of this study was to characterize the toxicity of nicotine enantiomers as well as their ability to induce oxidative stress in an in vitro model using Chinese hamster ovary (CHO) cells. Colony formation assay has demonstrated that (-)-nicotine is the more toxic of the enantiomers. At 6 mM concentrations, (-)-nicotine was found to be approximately 28- and 19-fold more potent than (+)-, and (+/-)-nicotine (racemic), respectively. Results also indicated that the toxicity of (+/-)-nicotine is higher than that of (+)-nicotine. (-)-Nicotine at a 10 mM concentration substantially decreased glutathione (GSH) levels (46% decrease). In addition, a 3-fold increase in malondialdehyde (MDA) level was evident in cells after exposure to 10 mM (-)-nicotine. Increased lactate dehydrogenase (LDH) activities in the media demonstrated that cellular membrane integrity was disturbed in nicotine treated cells. In the presence of superoxide dismutase (SOD) and catalase (CAT), the LDH activities returned to control value in 24 h with all concentrations of (-)-, (+)-, and (+/-)-nicotine. The decreases in LDH activities in the presence of the radical scavenging enzymes SOD and CAT suggest that membrane damage may be due to free radical generation.


A review of the evidence to support electrical stimulation-induced vascularization in engineered tissue.
Tissue engineering presents a promising solution for regenerative medicine and the success depends on the supply of oxygen/nutrients to the cells by rapid vascularization. More and more technologies are being developed to facilitate vascularization of engineered tissues. In this review, we indicated that a regulatory system which influences all angiogenesis associated cells to achieve their desired functional state is ideal for the construction of vascularized engineered tissues in vitro. We presented the evidence that electrical stimulation (ES) enhances the synergistic promotion of co-cultured angiogenesis associated cells and its potential regulatory mechanisms, highlighted the potential advantages of a combination of mesenchymal stem cells (MSCs), endothelial cells (ECs) and ES to achieve tissue vascularization, with particular emphasis on the different biological pathways of ES-regulated ECs. Finally, we proposed the future direction of using ES to reconstruct engineered tissue blood vessels, pointed out the potential advantages and disadvantages of ES application on tissue vascularization.


Consecutive immobilized enzymatic reactions in continuous stirred tank reactor systems.
The performance characteristics of two-enzyme reaction in a continuous stirred tank reactor (CSTR) are analytical investigated in this work. A model is formulated to describe the substrate concentration variations by taking into account the external and internal diffusion resistances. It is found that the reaction system exhibits the characteristics of reaction control or diffusion control depending on the operating conditions. The single CSTR model is also extended to describe the multiple CSTR system. The latter model enables the prediction of the number of CSTRs in series required to achieve a prescribed substrate conversion.


Dysfunctions of mitochondria in close association with strong perturbation of long noncoding RNAs expression in down syndrome.
Trisomy 21 is the most common chromosomal disorder and underlies Down syndrome. Epigenetics, such as DNA methylation and post-translational histone modifications, plays a vital role in Down syndrome. However, the functions of epigenetics-related long noncoding RNAs (lncRNAs), found to have an impact on neural diseases such as Alzheimer's disease, remain unknown in Down syndrome. In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, P<0.05), suggesting that lncRNAs play more important roles in Down syndrome. Through gene set enrichment analysis and bi-clustering, we also found that most of the differential expressed lncRNAs were closely associated with mitochondrial functions (e.g. mitochondrion organization, P=3.21×10-17; mitochondrial ATP synthesis coupled electron transport, P=1.73×10-19 and mitochondrial membrane organization, P=4.04×10-8). PCR-array and qRT-PCR results revealed that almost all genes related to mitochondria were down-regulated in Down syndrome-iPSCs, implying that mitochondria were dysfunctional in Down syndrome (e.g. ATP5B, Fold Change=-8.2317; COX6A1, Fold Change=-12.7788 and SLC25A17, Fold Change=-22.1296). All in all, our study indicated that a stronger perturbation of lncRNAs expression may lead to the dysfunction of mitochondria in Down syndrome.


Hypertension in a Brazilian urban slum population.
Low- and middle-income countries account for the majority of hypertension disease burden. However, little is known about the distribution of this illness within subpopulations of these countries, particularly among those who live in urban informal settlements. A cross-sectional hypertension survey was conducted in 2003 among 5649 adult residents of a slum settlement in the city of Salvador, Brazil. Hypertension was defined as either an elevated arterial systolic (≥140 mmHg) or diastolic (≥90 mmHg) blood pressure. Sex-specific multivariable models of systolic blood pressure were constructed to identify factors associated with elevated blood pressure. The prevalence of hypertension in the population 18 years and older was 21% (1162/5649). Men had 1.2 times the risk of hypertension compared with women (95% confidence intervals (CI), 1.05, 1.36). Increasing age and lack of any schooling, particularly for women, were also significantly associated with elevated blood pressure (p < 0.05). There was also a direct association between men who were black and an elevated blood pressure. Among those who were hypertensive, 65.5% were aware of their condition, and only 36.3% of those aware were actively using anti-hypertensive medications. Men were less likely to be aware of their diagnosis or to use medications (p < 0.01 for both) than women. The prevalence of hypertension in this slum community was lower than reported frequencies in the non-slum population of Brazil and Salvador, yet both disease awareness and treatment frequency were low. Further research on hypertension and other chronic non-communicable diseases in slum populations is urgently needed to guide prevention and treatment efforts in this growing population.


TMT-based quantitative proteomic analysis of spheroid cells of endometrial cancer possessing cancer stem cell properties.
Cancer stem cells (CSCs) play an important role in endometrial cancer progression and it is potential to isolate CSCs from spheroid cells. Further understanding of spheroid cells at protein level would help find novel CSC markers. Spheroid cells from endometrial cancer cell lines, Ishikawa and HEC1A, exhibited increased colony forming, subsphere forming, chemo-drug resistance, migration, invasion ability and tumorigenicity, verifying their cancer stem-like cell properties. The up-regulated CD90, CD117, CD133 and W5C5 expression also indicated stemness of spheroid cells. TMT-based quantitative proteomic analysis was performed to explore the potential alterations between parent cells and cancer stem-like spheroid cells. HK2-siRNA was transfected to Ishikawa and HEC1A cells to explore the roles and molecular mechanism of HK2 in endometrial cancer. We identified and quantified a total of 5735 proteins and 167 overlapped differentially expressed proteins of two cell types, 43 proteins were up-regulated and 124 were down-regulated in spheroid cells comparing with parent cells. KEGG pathway revealed a significant role of HIF-1 pathway in spheroid cells. qRT-PCR and western blot results of GPRC5A, PFKFB3 and HK2 of HIF-1 pathway confirmed their elevated expressions in spheroid cells which were consistent with proteomic results. HK2 promoted cancer stemness in endometrial cancer. These findings indicate that spheroid cells from endometrial cancer cell lines possess cancer stem-like cell properties and enrich CSCs. HIF-1 pathway is activated in endometrial cancer stem-like spheroid cells.


The synergistic tumor growth-inhibitory effect of probiotic Lactobacillus on transgenic mouse model of pancreatic cancer treated with gemcitabine.
Pancreatic cancer is one of the most lethal and chemo-resistant cancers worldwide. Growing evidence supports the theory that the gut microbiota plays an essential role in modulating the host response to anti-cancer therapy. The present study aimed to explore the effect of probiotics as an adjuvant during chemotherapy for pancreatic cancer. An LSL-KrasG12D/--Pdx-1-Cre mouse model of pancreatic ductal adenocarcinoma (PDAC) was created to study the effects of using four-week multi-strain probiotics (Lactobacillus paracasei GMNL-133 and Lactobacillus reuteri GMNL-89) as an adjuvant therapy for controlling cancer progression. At 12 weeks of age, pancreatitis was induced in the mice by two intraperitoneal injection with caerulein (25 μg/kg 2 days apart). Over the next 4 weeks the mice were treated with intraperitoneal injections of gemcitabine in combination with the oral administration of probiotics. The pancreas was then harvested for analysis. Following caerulein treatment, the pancreases of the LSL-KrasG12D/--Pdx-1-Cre transgenic mice exhibited more extensive pancreatic intraepithelial neoplasia (PanIN) formation. Combined treatment with gemcitabine and probiotics revealed a lower grade of PanIN formation and a decrease in the expression of vimentin and Ki-67. Mice that received gemcitabine in combination with probiotics had lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Notably, the use of high-dose probiotics alone without gemcitabine also had an inhibitory effect on PanIN changes and serum liver enzyme elevation. These findings suggest that probiotics are able to make standard chemotherapy more effective and could help improve the patient's tolerance of chemotherapy.


Generation of an induced pluripotent stem cell line NCHi003-A from a 11-year-old male with pulmonary atresia with intact ventricular septum (PA-IVS).
Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare congenital heart defect defined by membranous or muscular atresia of the right ventricular outflow tract where patients display varying degrees of hypoplasia of the right ventricle. This condition results in cyanosis due to an inability of blood to flow from the right ventricle to the pulmonary arteries, thus requiring immediate surgical intervention after birth. An iPSC line was generated from peripheral blood mononuclear cells of a 11-year-old male patient diagnosed with PA-IVS through Sendai virus-mediated reprogramming. This disease-specific iPSC line was characterized by immunocytochemistry, STR analysis, karyotype analysis, and mycoplasma testing.


Association of neurovascular bundle preservation with oncological outcomes in patients with high-risk prostate cancer.
To investigate the oncologic safety of neurovascular bundles (NVB) preservation at radical prostatectomy (RP) in patients with high-risk and/or locally advanced prostate cancer (PCa). Within a two-institutional high-volume center database we identified patients who harbored high-risk PCa at RP (2000-2017). Only patients with D'Amico high-risk PCa were included. Kaplan-Meier and multivariable Cox regression models tested the effect of NVB preservation on biochemical recurrence (BCR), metastasis and overall survival (OS). Subgroup analyses focused on patients with clinical stage T3 and/or biopsy ISUP grade 5 and pathologic stage T3. Of 4351 patients with D'Amico high-risk, 35.7% vs. 38.0% vs. 26.3% underwent bilateral vs. unilateral vs. no NVB preservation, respectively. At 120 months after RP BCR-free, metastasis-free survival and OS rates were 62.2% vs. 44.3% vs. 27.1% (p < 0.001), 83.7% vs. 66.7% vs. 60.3% (p < 0.001), and 91.8% vs. 87.5% vs. 72.3% (p < 0.001) for bilateral vs. unilateral vs. no NVB preservation, respectively. In multivariable Cox regression models, bilateral and unilateral compared to no NVB preservation did not increase the risk for BCR, metastasis or death in the entire cohort and in subgroups with clinical stage T3 and/or biopsy ISUP grade 5, as well as pathologic stage T3. NVB preservation was not associated with worse oncological outcome in patients with high-risk and/or locally advanced PCa and may be offered to well-selected patients who are at risk of harboring nonorgan-confined PCa.


Radiation attenuation properties of chemically prepared MgO nanoparticles/HDPE composites.
Sheets of high-density polyethylene (HDPE) loaded with magnesium oxide in micro and nano were synthesized with different weight percentages of micro-MgO (0,5,10,20 and 30% by weight) and nano-MgO (5 and 30%) and shaped in form of disc and dog bone shape. The morphological, mechanical, and attenuation characteristics of each concentration were determined. The linear attenuation coefficients (LAC) of the prepared discs were calculated using a well-calibrated scintillation detector and five standard gamma-ray point sources (241Am, 133Ba, 137Cs, 60Co and 152Eu). The LAC was theoretically calculated for HDPE/micro-MgO composites using XCOM software. A good agreement between the theoretical and experimental results was observed. The comparison between micro and nano-MgO as a filler in HDPE was evaluated. The results proved that the loaded nano-MgO in different proportions of HDPE produced greater attenuation coefficients than its micro counterpart. The addition of nano MgO with different weight percentage led to a significant improvement in the mechanical properties of HDPE, the ultimate force and ultimate stress increased as the concentration of nano MgO increased, and the young modulus of HDPE also increased with increasing concentration of micro and nano MgO.


Reducing interaural tonotopic mismatch preserves binaural unmasking in cochlear implant simulations of single-sided deafness.
Binaural unmasking, a key feature of normal binaural hearing, can refer to the improved intelligibility of masked speech by adding masking that facilitates perceived separation of target and masker. A question relevant for cochlear implant users with single-sided deafness (SSD-CI) is whether binaural unmasking can still be achieved if the additional masking is spectrally degraded and shifted. CIs restore some aspects of binaural hearing to these listeners, although binaural unmasking remains limited. Notably, these listeners may experience a mismatch between the frequency information perceived through the CI and that perceived by their normal hearing ear. Employing acoustic simulations of SSD-CI with normal hearing listeners, the present study confirms a previous simulation study that binaural unmasking is severely limited when interaural frequency mismatch between the input frequency range and simulated place of stimulation exceeds 1-2 mm. The present study also shows that binaural unmasking is largely retained when the input frequency range is adjusted to match simulated place of stimulation, even at the expense of removing low-frequency information. This result bears implications for the mechanisms driving the type of binaural unmasking of the present study and for mapping the frequency range of the CI speech processor in SSD-CI users.


Flexible control of biohythane composition and production by dual cathodes in a bioelectrochemical system.
Flexible control of CH4/H2 ratio in biohythane is important to its applications but remains a challenge. Herein, a dual-cathode bioelectrochemical system (BES) was developed for achieving biohythane production with controllable composition through adjusting external resistance. The BES was started as a microbial electrolysis cell to produce hydrogen in both cathodes ("H2-cathode") and then evolved to produce methane production in one cathode with inoculation of anaerobic sludge ("CH4-cathode"). When increasing the external resistance of the H2-cathode from 10 to 330 Ω, its H2 production decreased from 173 ± 11 to 8 ± 2 L m-3 d-1. This redistribution of electrons has benefited the CH4-cathode that had an increased CH4 production from 25 ± 3 to 90 ± 5 L m-3 d-1. The CH4/H2 ratio increased from 0.14 to 11, making biohythane more applicable to natural gas engines. Those results will help to formulate a BES-based approach to accomplish controllable biohythane production.


Exposure study to examine chemosensory effects of formaldehyde on hyposensitive and hypersensitive males.
Main objective of this study was to examine the chemosensory effects of formaldehyde on hyposensitive and hypersensitive males at concentrations relevant to the workplace. Attention focused on objective effects on and subjective symptoms of the mucous membranes of the eyes, the nose, the upper respiratory tract and olfactory function. Forty-one male volunteers were exposed for 5 days (4 h per day) in a randomised schedule to the control condition (0 ppm) and to formaldehyde concentrations of 0.5 and 0.7 ppm and to 0.3 ppm with peak exposures of 0.6 ppm, and to 0.4 ppm with peak exposures of 0.8 ppm, respectively. Peak exposures were carried out four times a day over a 15-min period of time. Subjective pain perception induced by nasal application of carbon dioxide served as indicator for sensitivity to sensory nasal irritation. The following parameters were examined before and after exposure: subjective rating of symptoms and complaints (Swedish Performance Evaluation System), conjunctival redness, eye-blinking frequency, self-reported tear film break-up time and nasal flow rates. In addition, the influence of personality factors on the volunteer's subjective scoring was examined (Positive And Negative Affect Schedule). Formaldehyde exposures to 0.7 ppm for 4 h and to 0.4 ppm for 4 h with peaks of 0.8 ppm for 15 min caused no significant sensory irritation of the measured conjunctival and nasal parameters. No differences between hypo- and hypersensitive subjects were seen. Nevertheless, statistically significant differences were noted for olfactory symptoms, especially for the 'perception of impure air'. These subjective complaints were more pronounced in hypersensitive subjects. Formaldehyde concentrations of 0.7 ppm for 4 h and of 0.4 ppm for 4 h with peaks of 0.8 ppm for 15 min did not cause adverse effects related to irritation, and no differences between hypo- and hypersensitive subjects were observed.


Chronicles of foam films.
The history of the scientific research on foam films, traditionally known as soap films, dates back to as early as the late 17th century when Boyle and Hooke paid special attention to the colours of soap bubbles. Their inspiration was transferred to Newton, who began systematic study of the science of foam films. Over the next centuries, a number of scientists dealt with the open questions of the drainage, stability and thickness of foam films. The significant contributions of Plateau and Gibbs in the middle/late 19th century are particularly recognized. After the "colours" method of Newton, Reinold and Rücker as well as Johhonnot developed optical methods for measuring the thickness of the thinner "non-colour" films (first order black) that are still in use today. At the beginning of the 20th century, various aspects of the foam film science were elucidated by the works of Dewar and Perrin and later by Mysels. Undoubtedly, the introduction of the disjoining pressure by Derjaguin and the manifestation of the DLVO theory in describing the film stability are considered as milestones in the theoretical development of foam films. The study of foam films gained momentum with the introduction of the microscopic foam film methodology by Scheludko and Exerowa, which is widely used today. This historical perspective serves as a guide through the chronological development of knowledge on foam films achieved over several centuries.


[18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.
Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.


Prevalence and effect of fever on outcome following resuscitation from cardiac arrest.
Evaluate the prevalence of fever in the first 48 h after cardiac arrest and its effect on outcomes. Review of patients treated between 1/1/2005 and 6/30/2010. Fever was defined as T ≥ 38.0°C. We classified categories of post-cardiac arrest illness severity as (I) awake, (II) coma+mild cardiopulmonary dysfunction (SOFA cardiac+respiratory score <4), (III) coma+moderate-severe cardiopulmonary dysfunction, and (IV) deep coma. Associations between fever and survival or good neurologic outcome were examined between hypothermia (TH) and non-TH groups. In 336 patients, mean age was 60 years (SD 16), 63% experienced out-of-hospital cardiac arrest and 65% received TH. A shockable rhythm was present in 40%. Post arrest illness severity was category II in 38%, category III in 20%, and category IV in 42%. Fever was present in 42% of subjects, with a post-arrest median onset of 15 h in the non-TH cohort and 36 h in TH cohort. Fever was not associated with survival within the whole cohort (OR 0.32, CI 0.15, 0.68) or TH cohort (OR 1.21, CI 0.69, 2.14), but was associated with survival in non-TH cohort (OR 0.47, CI 0.20, 1.10). Fever was not associated with good outcomes in the whole cohort (OR 0.83, CI 0.49, 1.40), TH cohort (OR 1.09, CI 0.56, 2.12) or non-TH cohort (OR 0.34, CI 0.11, 1.06). The development of fever within the first 48 h after ROSC is common. Fever is associated with death in non-TH patients. TH treatment appears to mitigate this effect, perhaps by delaying fever onset.


Paradoxical GH increase after oral glucose load in subjects with and without acromegaly.
A paradoxical GH rise after the glucose load (GH-Par) is described in about one-third of acromegalic patients. Here, we evaluated the GH profile in subjects with and without acromegaly aiming to refine the definition of GH-Par. Observational case-control study. Our cohort consisted of 60 acromegalic patients, and two groups of subjects presenting suppressed GH (< 0.4 µg/L) and high (non-acro↑IGF-1, n = 116) or normal IGF-1 levels (non-acro, n = 55). The distribution of GH peaks ≥ 120% from baseline, insulin, and glucose levels were evaluated over a 180-min time interval after glucose intake. A similar proportion of subjects in all three groups shows a GH ratio of ≥ 120% starting from 120 min. Re-considering the definition of paradoxical increase of GH within 90 min, we observed that the prevalence of GH peaks ≥ 120% was higher in acromegaly than in non-acro↑IGF-1 and non-acro (respectively 42%, 16%, and 7%, both p < 0.001). In patients without GH-Par, a late GH rebound was observed in the second part of the curve. Higher glucose peak (p = 0.038), slower decline after load, 20% higher glucose exposure (p = 0.015), and a higher prevalence of diabetes (p = 0.003) characterized acromegalic patients with GH-Par (with respect to those without). GH-Par response may be defined as a 20% increase in the first 90 min after glucose challenge. GH-Par, common in acromegaly and associated with an increased prevalence of glucose metabolism abnormalities, is found also in a subset of non-acromegalic subjects with high IGF-1 levels, suggesting its possible involvement in the early phase of the disease.


Abdominal applications of fast MR imaging: a comparison of fast field echo (FFE) and spin echo (SE) pulse sequences.
Fast gradient echo (GE) MR imaging during breathhold was performed in 73 abdominal MR examinations in order to determine the value of GE technique in the reduction of movement artefacts and improvement of image quality. The results were compared with conventional spin-echo (SE) technique. T1-weighted SE images consistently demonstrated normal anatomy and pathology. T2*-weighted and intermediate GE technique proved to be superior to T2-weighted SE technique in a considerable number of cases providing not only better delineation of normal structures but also better lesion detection. At this stage GE technique should be considered as an adjunct to T1-weighted SE technique. If the artefacts presently inherent to GE imaging could be reduced or compensated for, this technique of rapid MR imaging during suspended respiration could become an important tool being one of the fastest techniques for abdominal MR imaging.


Inverted left atrial appendage presenting as a large left atrial mass.
Inverted left atrial appendage (ILAA) is a rare phenomenon. We describe a patient with mitral stenosis who presented with a homogenous mass in the left atrium, mimicking a large thrombus. The patient was sent to surgery and no thrombus was found; intraoperative examination by the surgeon revealed an ILAA. We briefly discuss the main features of this entity and also some aspects of the differential diagnosis.


The reproducibility of cytomorphometrical grading of bladder tumours.
The reproducibility of cytomorphometrical nuclear area measurements on transitional cell carcinoma is studied. The inter-individual consistency is low (r = 0.55, P = 0.0005) when nuclei for measurement are chosen at random. When we use a systematic analysis based on cell situation and cytological features of malignancy to select the 50 nuclei for measurement per slide, the consistency between two technicians appears to be significantly higher (r = 0.90, P = 0.015). Not only interindividual consistency increases using the selection, but the correlation with histological tumour grade also improves significantly for both technicians. The results show that cytomorphometry is a method of grading bladder carcinoma when an accurate selection of nuclei to measure is used. Cytomorphometrical studies should contain a clear description of the way the nuclei for measurement are chosen.


Surgical Ablation of Ventricular Tachycardia.
Surgery for ventricular tachycardia (VT) is indicated in patients in whom pharmacotherapy or catheter ablation is ineffective or frequent VT attacks are not suppressed or with frequent activation of implantable cardioverter defibrillator. In ischemic VT, resection of fibrous endocardium combined with encircling cryothermia at the border between the infarcted and normal myocardium is performed. In surgery for VT associated with cardiomyopathy, close collaboration between the physician and surgeon is important and intraoperative mapping using electro-anatomic mapping system is helpful. In VT associated with cardiac tumors, cryothermia of the thinned subepicardial myocardium at the edge of the tumor is recommended in addition to resection of tumors.


Long term storage of Pleurotus ostreatus and Trametes versicolor isolates using different cryopreservation techniques and its impact on laccase activity.
The strain Pleurotus ostreatus Florida f6, its 45 basidiospore-derived isolates (both monokaryons and dikaryons prepared in our laboratory), Trametes versicolor strain CCBAS 614 and 22 other T. versicolor isolates obtained from the sporocarps collected in distant localities were successfully preserved for 12 y using perlite and straw cryopreservation protocols. All tested isolates survived a 12-year storage in liquid nitrogen (LN) and their laccase production and Poly B411 decolorization capacity was preserved. Also mycelium extension rate and the types of colony appearance of individual isolates remained unchanged. Different cryopreservation techniques were also tested for the short time (24 h) and the long time (6 m) storage of the culture liquid with extracellular laccase produced by T. versicolor strain CCBAS 614. The results showed that 10 % glycerol was the most suitable cryopreservant. The absence of the cryopreservant did not cause high loss of laccase activity in the samples; the presence of DMSO (5 or 10 %) in LN-stored samples caused mostly a decrease of laccase activity. For the preservation of laccase activity in the liquid culture the storage in the freezer at -80 °C is more convenient than the storage in liquid nitrogen.


Reversible pure word deafness due to inferior colliculi compression by a pineal germinoma in a young adult.
We report a clinical case of a 19-year-old male patient who developed pure word deafness due to the local compressive effect of a pineal germinoma on the inferior colliculi of the quadrigeminal plate. After percutaneous radiation therapy the size of the tumor decreased significantly, while audiometry demonstrated a complete regression of the auditory deficit. Since pure word deafness is commonly attributed to temporal lesions, the inferior colliculi represent an exceptional site for these symptoms. The pathophysiological background and the scarce literature on pure word deafness, especially the one related to neoplasms of the tectal region, are briefly discussed.


Pattern of acute MI admissions in India during COVID-19 era: A Cardiological Society of India study - Rationale and design.
COVID-19 pandemic has affected around 20million patients worldwide and 2.0 million cases from India. The lockdown was employed to delay the pandemic. However, it had an unintentional impact on acute cardiovascular care, especially acute myocardial infarction (AMI). Observational studies have shown a decrease in hospital admissions for AMI in several developed countries during the pandemic period. We aimed to evaluate the impact of COVID-19 on the AMI admissions patterns across India. In this multicentric, retrospective, cross-sectional study, we included all AMI cases admitted to participating hospitals during the study period 15th March to 15th June 2020 and compared them using a historical control of all cases of AMI admitted during the corresponding period in the year 2019. Major objective of the study is to analyze the changes inthe number of hospital admissions for AMI in hospitals across India. In addition, we intend to evaluate the impact of COVID-19 on the weekly AMI admission rates, and other performance measures like rates of thrombolysis/primary percutaneous interventions (PCI), window period, door to balloon time, and door to needle time. Other objectives include evaluation of changes in the major complications and mortality rates of AMI and its predictors during COVID-19 pandemic. This CSI-AMI study will provide scientific evidence about the impact of COVID-19 on AMI care in India. Based on this study, we may be able to suggest appropriate changes to the existing MI guidelines and to educate the public regarding emergency care for AMI during COVID-19 pandemic.


Studies on inositol-mediated expression of MAL gene encoding maltase and phospholipid biosynthesis in Schizosaccharomyces pombe.
In this study, the effects of inositol addition on expression of the MAL gene encoding maltase and phosphatidylinositol (PI) biosynthesis in Schizosaccharomyces pombe (a naturally inositol-requiring strain) were examined. We found that specific maltase activity was at its maximum when the concentration of added inositol reached 6 microg ml(-1) in a synthetic medium containing 2.0% (w/v) glucose. When the concentration of added inositol was 1 microg ml(-1) in the medium, repression of MAL gene expression occurred at glucose concentration higher than 0.2% (w/v). However, when S. pombe was cultured in the synthetic medium containing 6 microg ml(-1), repression of maltase gene expression occurred only at initial glucose concentration above 1.0% (w/v). More mRNA encoding maltase was detected in the cells grown in the medium with 6 microg ml(-1) inositol than in those grown in the same medium with 1 microg ml(-1) inositol. These results demonstrate that higher inositol concentrations in the synthetic medium could derepress MAL gene expression in S. pombe. PI content of the yeast cells grown in the synthetic medium with 6 microg ml(-1) of inositol was higher than that of the yeast cells grown in the same medium with 1 microg ml(-1) of inositol. This means that PI may be involved in the derepression of MAL gene expression in S. pombe.


Influence of opioids on central thermoregulatory mechanisms.
Of the effects of morphine and endogenous opioid peptides on thermoregulation, the one which is most likely to be of physiologic significance is hyperthermia. This increase in body temperature is the result of coordinated changes in both physiological and behavioral thermoregulatory activities and, like fever, reflects an increase in the level about which body temperature is regulated. Morphine, endogenous opioid peptides and other opioids such as pentazocine all cause hyperthermia, but the considerable variation in the dose of naloxone required to antagonize the different agonists indicates that more than one type of opiate receptor is involved in these pharmacologic responses. The minimal effect of naloxone and naltrexone on normal body temperature and on pyrogen-induced fever indicates that endogenous opioid peptides are unlikely to act physiologically via stimulation of receptors specifically sensitive to morphine. However, methionine-enkephalin is less readily antagonized by naloxone and could have a physiologic role in thermoregulation through stimulation of another type of opiate receptor.


Treatment patterns and clinical outcomes in patients with metastatic breast cancer treated with palbociclib-based therapies: real-world data in the Han population.
This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+) metastatic breast cancer in routine clinical practice. The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially for various combination regimens. The efficacy of palbociclib-based therapy in patients with prior everolimus treatment was also assessed. A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups ( P = 0.566): 10.0 months (95% confidence interval [CI] 3.8-16.1) in the +exemestane group, 9.7 months (95% CI 6.3-13.1) in the +letrozole group, 7.8 months (95% CI 5.5-10.2) in the +fulvestrant group, 7.2 months (95% CI 3.2-11.3) in the +toremifene group, and 6.1 months (95% CI 1.2-11.0) in the +anastrozole group. Thirty-four patients (18.3%) had received everolimus for their metastatic disease before the prescription of palbociclib. The disease control rate was significantly lower in patients who had received previous everolimus than in the everolimus-naïve group (50.0% vs . 82.2%, P < 0.001). Patients pre-treated with everolimus had significantly worse PFS than those in the everolimus-naïve group (3.4 months vs . 8.8 months, P = 0.001). After propensity score matching, patients pre-treated with everolimus had similar PFS (4.4 months, 95% CI 0.5-8.2) compared with everolimus-naïve patients (6.1 months, 95% CI 4.7-7.5, P = 0.439). Various palbociclib-based regimens have promising efficacy in ER+ metastatic breast cancer in real-world settings, even in patients who had been pre-treated with everolimus.


Global spatiotemporal transmission dynamics of measles virus clade D genotypes in the context of the measles elimination goal 2020 in India.
Measles viruses (MeV) circulating in India mainly belong to genoypes D4 and D8 of clade D. In the context of measles elimination goal 2020 in India, molecular clock and phylogeography studies would help to identify the timescales of evolution and track the transmission pathways of MeV. We used nucleoprotein gene sequences (n = 756) from GenBank, representing 86 countries (1973-2016), to study the spatiotemporal transmission dynamics of clade D. Genotype D4 was introduced into India around 1991 and genotype D8 around 1994. Recent transmissions of the D4 genotype of measles virus (MeV) were noted from India to the United States of America and East Asia region while D8 genotype importations from North America were noted in recent years.


Reliability and Validity of the Adolescence Stress Scale (ADOSS) for Indian Adolescents.
Stress levels increase tremendously in adolescence. Indian adolescents derive much of their stress from school and family pressures. Developing a standardized tool to assess adolescent stress can help early diagnosis. This article aimed to assess the reliability and validity of the ADOlescence Stress Scale (ADOSS). ADOSS was administrated by trained interviewers to 100 adolescents (10-17 years) of both sexes in Chennai, South India. Salivary cortisol was used as an objective measure of stress in 40 adolescents. Reliability was assessed within a two weeks interval. Exploratory factor analysis was done for the baseline ADOSS scores. The internal consistency (Cronbach's alpha and spilt-half correlation), test-retest agreement (Kappa value), and inter-rater reliability (ICC) were assessed. Pearson correlation between salivary cortisol and ADOSS score was done. The inter-factor correlation between the inherent four ADOSS factors (personal, academic, family, and social) was between 0.73 and 0.87, and split-half correlation was between 0.70 and 0.83, showing that the factors are reliable and coherent. Test-retest agreement was Kappa: 0.63, P = 0.001, and ICC was 0.84. Pearson correlation showed a statistically significant positive correlation between cortisol levels and ADOSS scores (r = 0.87, P = 0.001). ADOSS is a reliable and valid tool to assess the overall stress of Indian adolescents in the age group of 10-17 years.


Forecasting daily confirmed COVID-19 cases in Algeria using ARIMA models.
COVID-19 has become a threat worldwide, affecting every country. This study aimed to identify COVID-19 cases in Algeria using times series models for forecasting the disease. Confirmed COVID-19 daily cases data were obtained from 21 March 2020 to 26 November 2020 from the Algerian Ministry of Health. Forecasting was done using the Autoregressive Integrated Moving Average (ARIMA) models (0,1,1) with Minitab 17 software. Observed cases during the forecast period were accurately predicted and placed within prediction intervals generated by ARIMA. Forecasted values of COVID-19 positive cases, recoveries and deaths showed an accurate trend, which corresponded to actual cases reported during 252, 253 and 254 days. Results were strengthened by variations of less than 5% between forecast and observed cases in 100% of forecasted data. ARIMA models with optimally selected covariates are useful tools for predicting COVID-19 cases in Algeria.


Comparison of two devices for the treatment of keloid scars with the use of intralesional cryotherapy: An experimental study.
Intralesional (IL) cryotherapy is a new technique for the treatment of keloid scars, in which the scar is frozen from inside. Two cryodevices are available, which were recently evaluated. Both devices showed promising results, but differed in clinical outcome. To explain these differences, more understanding of the working mechanism of both devices is required. This experimental study was designed to investigate and compare the thermal behavior of an argon gas- and a liquid nitrogen-based device. Thermal behavior constitutes: (1) minimum tissue temperature (°C), (2) the freezing rate (°C/min). The thermal behavior was measured inside and on the outer surface of the scar. Both devices were tested ex vivo and in vivo. Ex vivo, when determining the maximum freezing capacity, the argon gas device showed a higher end temperature compared to the liquid nitrogen device (argon gas: -120°C, liquid nitrogen: -140°C) and a faster freezing rate (argon gas: -1300°C/min, liquid nitrogen: -145°C/min). In vivo, measured inside the keloid, the argon gas device showed a lower end temperature than the liquid nitrogen device (argon gas: -36.4°C, liquid nitrogen: -8.1°C) and a faster freezing rate (argon gas: -14.7°C/min, liquid nitrogen: -5°C/min). The outer surface of the scar reached temperatures below -20°C with both devices as measured with the thermal camera. In conclusion, the argon gas device displayed a lower end temperature and a faster freezing rate in vivo compared to the liquid nitrogen device. Although this resulted in lower recurrence rates for the argon gas device, more hypopigmentation was seen compared to the liquid nitrogen device following treatment. Finally, the low outer surface temperatures measured with both devices, suggest that some hypopigmentation following treatment is inevitable.


Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan.
PINK1 is the second most predominant gene associated with autosomal recessive Parkinson's disease. Homozygous mutations in this gene are associated with an early onset of symptoms. Bradykinesia, tremors, and rigidity are common features, while dystonia, motor fluctuation, and non-motor symptoms occur in a lower percentage of cases and usually respond well to levodopa. We investigated 14 individuals with parkinsonism and eleven symptom-free siblings from three consanguineous Sudanese families, two of them multigenerational, using a custom gene panel screening 34 genes, 27 risk variants, and 8 candidate genes associated with parkinsonism. We found a known pathogenic nonsense PINK1 variant (NM_032409.3:c.1366C>T; p.(Gln456*)), a novel pathogenic single base duplication (NM_032409.3:c.1597dup; p.(Gln533Profs*29)), and another novel pathogenic insertion (NM_032409.3:c.1448_1449ins[1429_1443; TTGAG]; p.(Arg483Serfs*7)). All variants were homozygous and co-segregated in all affected family members. We also identified intrafamilial and interfamilial phenotypic heterogeneity associated with PINK1 mutations in these Sudanese cases, possibly reflecting the nature of the Sudanese population that has a large effective population size, which suggests a higher possibility of novel findings in monogenic and polygenic diseases in Sudan.


Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat.
At doses of 5-10 mg kg-1, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) produces in rats acute immobility, retropulsion, straub tail, piloerection, exophthalmos, salivation and clonic movements of the forepaws. It does not produce analgesia as measured by the tail test, nor does it produce permanent motor impairment after chronic or intranigral administration. The acute retropulsion and immobilizing effects can be blocked by methysergide. Administered acutely, NMPTP doubles levels of serotonin in the raphe nucleus and substantia nigra. At the same time, levels of dopamine increase in the caudate nucleus and decrease in the substantia nigra. The NMPTP-induced decrease in dopamine content of the substantia nigra persists in chronically treated rats, but there is no significant decrease in striatal dopamine. After chronic administration of NMPTP, striatal levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased by about 50%. Intranigral administrations of NMPTP (10 micrograms daily for 5 days) failed to produce a 6-hydroxydopamine-like lesion in the nigrostriatal system. These results indicate that NMPTP in the rat does not cause selective destruction of dopaminergic neurons, but it does produce acute tryptamine-like effects.


2-(125I) iodomelatonin binding sites in rat adrenals: pharmacological characteristics and subcellular distribution.
Specific binding sites for 2-[125I] iodomelatonin, a selective radiolabeled melatonin receptor ligand, were detected and characterized in rat adrenal membranes. Saturation studies demonstrated that 2-[125I]iodomelatonin binds to a single class of sites with an affinity constant (Kd) of 541 pM and a total binding capacity (Bmax) of 3.23 fmol/mg protein. Competition experiments revealed that the relative order of potency of compounds tested was as follows: 6-chloromelatonin greater than 2-iodomelatonin greater than melatonin greater than 5-methoxytryptamine greater than 5-methoxytryptophol. The highest density of binding sites was found in membranes from nuclear (0.76 fmol/mg protein) and mitochondrial (1.82 fmol/mg protein) subcellular fractions.


Effects of L-leucine on the properties of spray-dried swellable microparticles with wrinkled surfaces for inhalation therapy of pulmonary fibrosis.
Swellable microparticles (SMs) provide a potential strategy for achieving sustained inhalation therapy. However, spray dried SMs are highly hygroscopic, exhibiting poor flowability and dispersibility properties. This study aimed at determining whether L-leucine (LL) can improve aerosolization performance of SMs with wrinkled surface and its potential mechanisms. Cryptotanshinone was co-spray dried with chitosan and LL (0-40%, mass fraction in carrier materials), after which the production yield, particle size, density, encapsulation efficiency, morphology, cohesion, crystallinity, surface LL distribution, hygroscopicity, water content and in vitro aerosolization performance of the developed formulations were characterized. In addition, we determined whether LL, as a hydrophobic amino acid, would impair swellability and macrophage phagocytosis of SMs. The possible impact of LL on in vitro drug release, cytotoxicity and anti-fibrosis effects on MRC-5 cells was also investigated. As the LL content increased, LL began to crystallize. At 7.5% LL, water content and hygroscopicity of the SMs were at their lowest. Moreover, at 7.5% LL, surface enrichment increased rapidly after which it achieved a comparatively complete coverage at 20-40% LL. However, LL ≥ 20% caused the formation of over-wrinkled, even dimpled or hollow particles, which significantly deteriorated powder properties. Optimum aerosolization performance was obtained at 10% LL, irrespective of its crystallization behavior, accompanied by the lowest cohesion, optimal flowability and production yield, and without impaired swellability, macrophage uptake and anti-fibrosis efficacy. The optimal formulation did not exhibit optimum surface LL coverage, implying that improvement of aerosolization performance of wrinkled SMs by LL not simply depended on its surface enrichment, but its significant influence on morphology and on related powder properties as well.


Predicting Recurrence in Endometrial Cancer Based on a Combination of Classical Parameters and Immunohistochemical Markers.
The aim of this study was to establish a nomogram to predict the recurrence of endometrial cancer (EC) by immunohistochemical markers and clinicopathological parameters and to evaluate the discriminative power of this model. The data of 473 patients with stages I-III endometrial cancer who had received primary surgical treatment between October 2013 and May 2018 were randomly split into two sets: a training cohort and a validation cohort at a predefined ratio of 7:3. Univariate and multivariate Cox regression analysis of screening prognostic factors were performed in the training cohort (n=332) to develop a nomogram model for EC-recurrence prediction, which was further evaluated in the validation cohort (n=141). Univariate analysis found that FIGO stage, histological type, histological grade, myometrial invasion, cervical stromal invasion, postoperative adjuvant treatment, and four immunohistochemical markers (Ki67, ER, PR, and p53) were associated with recurrence in EC. Multivariate analysis showed that FIGO stage, histological type, ER, and p53 were superior parameters to generate the nomogram model for recurrence prediction in EC. Recurrence-free survival was better predicted by the proposed nomogram, with a C-index value of 0.79 (95% CI 0.66-0.92) in the validation cohort. This nomogram model involving immunohistochemical markers can better predict recurrence in FIGO stages I-III EC.


1-(2-Pyrimidinyl)piperazine antagonizes GABA-activated currents in cultured spinal neurones of the rat.
Buspirone is an anxiolytic drug with an unknown mechanism of action. We have addressed the proposal that its therapeutic effect is due to a metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), increasing the open probability of gamma-aminobutyric acid (GABA)-activated channels. By making whole-cell recordings from cultured spinal neurones we demonstrated that 1-PP, in contrast to flurazepam, actually antagonizes GABA- and glycine-activated currents. These observations are inconsistent with this proposed mechanism of action for buspirone.


Adsorption behavior of O2 on U-Nb surface: a first-principles study.
Oxygen is a chemically active gas. Metal uranium will be rapidly oxidized when exposed to oxygen directly, forming a complex and uncompacted oxide layer on the surface. The U-O2 reaction system is a very complex metal oxidation system. The surface oxidation reaction of uranium-niobium alloy is more complex, and it is also the main corrosion form of uranium-niobium alloy. Exploring the microscopic mechanism of surface oxidation corrosion of uranium-niobium alloy is of great significance for understanding the surface corrosion phenomenon in practical applications. The adsorption of O2 on U-Nb (5at.%) surface was investigated by first-principles calculation using a periodic slab model within the density functional theory (DFT). The effect of different levels of Nb doping on O adsorption was investigated, and the stability of O-U and O-Nb adsorption was studied in conjunction with the Bader charge distribution, differential charge density map, electron density of states, and surface work function. The results showed that physical adsorption happens when O2 is vertically adsorbed at the top site of Nb atom, whereas dissociative adsorption happened in all other configurations considered here. The interaction between adsorbed O2 and U-Nb surface was essentially the hybridization between the O/2p orbital electrons and the U/6d, U/5f, Nb/4p, Nb/5s, and Nb/4d orbital electrons to form a relatively stable ionic bond. When Nb was doped into the second layer of the surface, the most stable O2 adsorption configuration was top-site horizontal adsorption. The adsorption energy was - 22.38 eV, which was more negative than the adsorption energy of - 21.38 eV for the first doped layer horizontal adsorption at hollow-site. The interaction was essentially the hybridization between O/2p orbital electrons and U/6d and U/5f electrons and between O/2s orbital electrons and U/6p orbital electrons to form a relatively stable ionic bond. In this paper, the adsorption and dissociation of oxygen molecules on the surface of U-Nb system were systematically studied by first-principles calculations, in order to explore the surface oxidation corrosion mechanism of uranium-niobium alloy from the micro level. The VASP program uses PAW pseudopotential, which belongs to the density functional method, and uses DSP.


Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms.
The mouse model for familial adenomatous polyposis, Apc(Min/+) mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc(Min/+) mice. Apc(Min/+) and Apc+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, beta-catenin, p53, and nitrotyrosine, and mutations of beta-catenin and K-ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female Apc(Min/+) mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc(Min/+) mice but did not develop in Apc+/+ mice. Adenocarcinomas developed in Apc(Min/+) mice that received DSS showed loss of heterozygosity of Apc and no mutations in the beta-catenin and K-ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc(Min/+) mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of beta-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc(Min/+) mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc(Min/+) mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development.


Comparative efficacy of social media delivered health education on glycemic control: A meta-analysis.
To compare outcomes associated with patient education about glycemic control via group chat versus patient education as usual among individuals with diabetes in China. We searched the following databases both in English and in Chinese languages: PubMed, CNKI, Wanfang database, VIP database, and CBM for articles published up to Jan 1, 2018. The studies were screened by two independent reviewers. Using criteria from the risk of bias assessment tool developed by Cochrane Collaboration to assess the risk of bias of eligible studies. A meta-analysis of studies was performed using comprehensive meta-analysis version 3.0. Twenty-five unique randomized clinical trials, including 2,838 patients, were identified. The education delivered via group chat had large overall pooled effect sizes in improving glucose control measured by hemoglobin A1c [Hedges' g = -0.81, 95% CI: (-0.98, -0.64)], fasting blood glucose [Hedges' g = -1.11, 95% CI: (-1.37, -0.85)], and 2 h postprandial blood glucose [Hedges' g = -0.98, 95% CI: (-1.20, -0.76)]. Additionally, patient education delivered via group chat has shown consistently superior outcomes in glucose control in short-term (0-3 months), mid-term (3-6 months) and longer-term (6-12 months). Educational interventions via group chat had a superior outcome in blood glucose control compared to education as usual in China. Educational interventions via group chat had superior short-term, mid-term, and longer-term outcomes in blood glucose control compared to education as usual in China.


Development and preclinical evaluation of an alphavirus replicon vaccine for influenza.
We used a propagation-defective, single-cycle, alphavirus replicon vector system to produce virus-like replicon particles (VRP) expressing the hemagglutinin (HA) and neuraminidase (NA) proteins from influenza A/Wyoming/03/2003 (H3N2). Efficient production methods were scaled to produce pilot lots of HA VRP and NA VRP and clinical lots of HA VRP. HA VRP-induced high-titered antibody responses in mice, rabbits and rhesus macaques, as measured by ELISA or hemagglutination inhibition (HI) assays, and robust cellular immune responses in mice and rhesus macaques, as measured by IFN-gamma ELISPOT. NA VRP also induced cellular immune responses in mice. A toxicology study with HA VRP and NA VRP in rabbits showed no adverse effects in any parameter. These studies support clinical testing of alphavirus replicon vaccines for influenza.


The postulated innocuity of lifetime exposure to aluminium should be reappraised.
Because of its chemical versatility and abundance in nature, aluminium is employed in a myriad of frequently used products - including cosmetics and food additives - and applications - drinking water purification procedures being an example. Despite what its widespread use might suggest, aluminium's harmlessness is a matter of debate in the scientific community. In this article we trace the lines of a growing questioning about the potential mutagenic effects of this metal, due to the data produced over the recent years, and with an eye to the discussions currently underway in this regard between the scientific community, industry, and regulatory bodies.


Fiscal Decentralization and Local Environmental Pollution in China.
Fiscal decentralization is one of the tools for the central government to engage local governments in environment management. However, its effects are inconclusive. This paper aims to examine the impact of fiscal decentralization on environmental pollution and the role of government environmental preference in China's provinces. The results show that fiscal revenue decentralization exacerbates local environmental pollution more seriously than expenditure decentralization. This negative environmental effect of fiscal decentralization could be moderated by government environmental preference. Based on our findings, it is recommended that China's local governments should improve environmental preference so that fiscal decentralization can create a win-win situation for the economy and environment. Furthermore, the different effects of fiscal revenue and expenditure decentralization create a necessity for differentiated management of fiscal decentralization by the central and local governments.


Preoperative thrombocytosis as a prognostic factor in endometrioid-type endometrial carcinoma.
The impact of preoperative thrombocytosis as a prognostic factor in endometrial carcinoma (EC) remains uncertain and has never been examined in Saudi Arabia. To determine the prevalence of preoperative thrombocytosis (platelet count > 400 000/ μL), and its prognostic significance for clinicopathological factors and survival in Saudi patients with endometrioid-type EC. A retrospective cross-sectional study from January 2010 to December 2013. A referral tertiary healthcare institute. Patients who underwent staging surgery for primary endometrioid-type EC were retrospectively analyzed for perioperative details: age, preoperative platelet count, International Federation of Gynecology and Obstetrics (FIGO) stage, endometrioid grade, recurrence, disease-free survival (DFS) and overall survival (OS). Survival analysis was conducted using Kaplan-Meier estimates and a Cox proportional hazards model. Prevalence of preoperative thrombocytosis, DFS and OS. In 162 patients who met inclusion criteria, the frequency of preoperative thrombocytosis was 8.6% (n=14). Patients with advanced FIGO disease (stages III-IV) and recurrence had significantly higher mean preoperative platelet counts than patients with early FIGO disease (stages I-II) and no recurrence (P=.0080 and P=.0063, respectively). Patients with thrombocytosis had statistically significant higher rates of advanced FIGO stages III-IV disease, unfavorable grades II-III endometrioid histology and recurrence than patients with preoperative platelet counts.


Common problems associated with necrotic and sloughy wounds.
Effective wound management is dependent on the removal or control of causative factors, implementation of systemic support and application of appropriate wound management. This article examines the management of necrotic and sloughy wounds.


Receptor binding occurrence and plasma levels of natriuretic peptides in response to sympathectomy.
In the present investigation the relationship between the sympathetic nervous system and the endocardial levels of receptor binding sites for natriuretic peptides and the plasma content of atrial natriuretic peptide were analyzed in rats. In order to destruct the cardiac sympathetic nerve terminals, chemical sympathectomy with 6-hydroxydopamine was made in parallel with intravenous measurements of blood pressure and heart frequency. By use of immunohistochemical and enzyme-linked-immunosorbent techniques the expression of tyrosine hydroxylase-positive sympathetic nerve terminals and plasma levels of pro-atrial natriuretic peptide were determined, respectively. The occurrence of receptor binding sites for natriuretic peptides was examined by in vitro receptor autoradiography. In contrast to the marked occurrence of natriuretic peptide receptor binding sites seen in the ventricular endocardium of control rats, the sympathectomized rats exhibited a decreased number of binding sites for natriuretic peptides in the endocardium of both the right and left chambers. Interestingly, this was found in parallel with a significant decrease of systolic and diastolic blood pressure and increased plasma levels of pro-atrial natriuretic peptide in the treated group of rats. These findings, together with those in previous studies, give support to an idea that one part of the blood pressure-decreasing effects, seen in patients treated with beta-adrenergic blockade, might be through a reduction of the natriuretic clearance receptor C, then giving rise to increased levels of atrial natriuretic peptide.


Optically stimulated luminescence in forensics.
Tracking the former location of a radioactive source represents an attractive attribute in today's society, where the threat of a radiological dispersal device (RDD) is considered high. Development of a novel, retrospective detection technique based on optically stimulated luminescence is underway. This will allow confirmation of the former location of a radioactive source. Materials near the source's former location may be probed for information on accumulated dose by taking advantage of radiation-induced charge trapping that occurs in many common materials. The prototype detector design and analysis techniques are described.


Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes.
ADPKD is one of the most common inherited disorders, with high risk for end-stage renal disease. Numerous patients, however, have no relatives in whom this disorder is known and are unsure whether they may transmit the disease to their offsprings. The aim of this study was to evaluate whether germline mutation analysis adds substantial information to clinical symptoms for diagnosis of ADPKD in these patients. Clinical data included renal function and presence of liver or pancreas cysts, heart valve insufficiency, intracranial aneurysms, colonic diverticles, and abdominal hernias. Family history was evaluated regarding ADPKD. Germline mutation screening of the PKD1 and PKD2 genes was performed for intragenic mutations and for large deletions. A total of 324 adult patients with ADPKD including 30 patients without a family history of ADPKD (sporadic cases) were included. PKD1 mutations were found in 24/30 and PKD2 mutations in 6 patients. Liver cysts were present in 14 patients and intracranial aneurysms in 2 patients. Fourteen patients (45%) had no extrarenal involvement. Compared to the 294 patients with familial ADPKD, the clinical characteristics and the age at the start of dialysis were similar in those with sporadic ADPKD. The clinical characteristics of patients with sporadic and familial ADPKD are similar, but sporadic ADPKD is often overlooked because of the absence of a family history. Molecular genetic screening for germline mutations in both PKD1 and PKD2 genes is essential for the definitive diagnosis of ADPKD.


Racial inequities and addiction research.
What accounts for variation across racial and ethnic groups in drug use and harms related to substance use? While explanatory mechanisms for racial and ethnic disparities include differential access to and use of health services, a myriad of other factors, including racism and historical trauma, contribute to drug-related disparities. Furthermore, the addiction scientific workforce, like the full biomedical research enterprise, lacks diversity. This deficit undercuts U.S. scientific leadership and is a major challenge for the field. To address these entrenched problems, the National Institute on Drug Abuse (NIDA) is prioritizing research on health disparities and supporting multiple efforts to enhance scientific workforce diversity. Studies on substance use trends and emerging threats must measure disparities and track progress in reducing disparities, but also acknowledge the limitations of race and ethnicity-based data. Researchers must take the bold step of proposing studies that elucidate causal mechanisms which have the potential to be ameliorated by novel policies and practices. Critically, the impact of racism on all aspects of the substance use trajectory must be assessed to better tailor prevention, harm reduction, treatment, and recovery-support interventions to the specific circumstances of those who need them. Particular attention should be given to people who are incarcerated, who are experiencing homelessness, and who have a history of adverse childhood experiences. Training the next generation of the addiction science workforce needs to address structural barriers to participation with partnerships between funders, such as NIDA, and grantee organizations.


The transamidosome: a dynamic ribonucleoprotein particle dedicated to prokaryotic tRNA-dependent asparagine biosynthesis.
Asparagine, one of the 22 genetically encoded amino acids, can be synthesized by a tRNA-dependent mechanism. So far, this type of pathway was believed to proceed via two independent steps. A nondiscriminating aspartyl-tRNA synthetase (ND-DRS) first generates a mischarged aspartyl-tRNAAsn that dissociates from the enzyme and binds to a tRNA-dependent amidotransferase (AdT), which then converts the tRNA-bound aspartate into asparagine. We show herein that the ND-DRS, tRNAAsn, and AdT assemble into a specific ribonucleoprotein complex called transamidosome that remains stable during the overall catalytic process. Our results indicate that the tRNAAsn-mediated linkage between the ND-DRS and AdT enables channeling of the mischarged aspartyl-tRNAAsn intermediate between DRS and AdT active sites to prevent challenging of the genetic code integrity. We propose that formation of a ribonucleoprotein is a general feature for tRNA-dependent amino acid biosynthetic pathways that are remnants of earlier stages when amino acid synthesis and tRNA aminoacylation were coupled.


Critique and cure: a dream of uniting psychoanalysis and philosophy.
Critical theory, whose aim was to historicize philosophy through integrating it with the social sciences, turned to psychoanalysis to find its way through an accounting of philosophy after the Second World War. Over 50 years after this initial project, the rift between philosophy and psychoanalysis has never been greater. If Jacques Lacan could be considered one of the few psychoanalysts to maintain and foster links to philosophical thought in the latter half of the 20th century, his work has sadly remained marginal in the clinical field throughout America and Europe. Both critical theory and Lacan remain skeptical of the direction taken by psychoanalysis after Freud. Reflecting on the history of these two disciplines, as well as through an examination of Theodor Adorno's posthumously published dream journal, critique and cure emerge as two dialectically intertwined themes that gain momentum in the dream of the unification of the philosophical and psychoanalytic projects.


Knockdown of circ_0003928 ameliorates high glucose-induced dysfunction of human tubular epithelial cells through the miR-506-3p/HDAC4 pathway in diabetic nephropathy.
Previous data have indicated the importance of circular RNA (circRNA) in the pathogenesis of diabetic nephropathy (DN). The study is designed to investigate the effects of circ_0003928 on oxidative stress and apoptosis of high glucose (HG)-treated human tubular epithelial cells (HK-2) and the underlying mechanism. The DN cell model was established by inducing HK-2 cells using 30 mmol/L D-glucose. RNA expression of circ_0003928, miR-506-3p and histone deacetylase 4 (HDAC4) was detected by quantitative real-time polymerase chain reaction. Cell viability and proliferation were investigated by cell counting kit-8 and 5-Ethynyl-29-deoxyuridine (EdU) assays, respectively. Oxidative stress was evaluated by commercial kits. Caspase 3 activity and cell apoptotic rate were assessed by a caspase 3 activity assay and flow cytometry analysis, respectively. Protein expression was detected by Western blotting analysis. The interactions among circ_0003928, miR-506-3p and HDAC4 were identified by dual-luciferase reporter and RNA pull-down assays. Circ_0003928 and HDAC4 expression were significantly upregulated, while miR-506-3p was downregulated in the serum of DN patients and HG-induced HK-2 cells. HG treatment inhibited HK-2 cell proliferation, but induced oxidative stress and cell apoptosis; however, these effects were reversed after circ_0003928 depletion. Circ_0003928 acted as a miR-506-3p sponge, and HDAC4 was identified as a target gene of miR-506-3p. Moreover, the circ_0003928/miR-506-3p/HDAC4 axis regulated HG-induced HK-2 cell dysfunction. Circ_0003928 acted as a sponge for miR-506-3p to regulate HG-induced oxidative stress and apoptosis of HK-2 cells through HDAC4, which suggested that circ_0003928 might be helpful in the therapy of DN.


Improving Timely Antibiotic Administration for Pediatric Oncology Patients With Neutropenic Fever Seen in the Emergency Department.
To improve the care for pediatric oncology patients with neutropenic fever who present to the emergency department (ED) by administering appropriate empiric antibiotics within 60 minutes of arrival. We focused on improving the care for pediatric oncology patients at risk of neutropenia who presented to the ED with concern for fever. Our baseline adherence to the administration of empiric antibiotics within 60 minutes for this population was 53% (76/144) from January 1, 2010, to December 21, 2014. During 2015, we reviewed data monthly, finding 73% adherence. We used the Lean methodology to identify the process waste, completed a value-stream map with input from multidisciplinary stakeholders, and convened a root cause analysis to identify causes for delay. The 4 causes were as follows: (1) lack of staff awareness; (2) missing patient information in electronic medical record; (3) practice variation; and 4) lack of clear prioritization of laboratory draws. We initiated Plan-Do-Study-Act cycles to achieve our goal of 80% of patients receiving appropriate empiric antibiotics within 60 minutes of arrival in the ED. Five Plan-Do-Study-Act cycles were completed, focusing on the following: (1) timely identification of patients by utilizing the electronic medical record to initiate a page to the care team; (2) creation of a streamlined intravascular access process; (3) practice standardization; (4) convenient access to appropriate antibiotics; and (5) care team education. Timely antibiotic administration increased from 73%-95% of patients by 2018. More importantly, the adherence was sustained to greater than 90% through 2021. A structured and multifaceted approach using quality improvement methodologies can achieve and sustain improved patient care outcomes in the ED.


Substrate protein folds while it is bound to the ATP-independent chaperone Spy.
Chaperones assist in the folding of many proteins in the cell. Although the most well-studied chaperones use cycles of ATP binding and hydrolysis to assist in protein folding, a number of chaperones have been identified that promote folding in the absence of high-energy cofactors. Precisely how ATP-independent chaperones accomplish this feat is unclear. Here we characterized the kinetic mechanism of substrate folding by the small ATP-independent chaperone Spy from Escherichia coli. Spy rapidly associates with its substrate, immunity protein 7 (Im7), thereby eliminating Im7's potential for aggregation. Remarkably, Spy then allows Im7 to fully fold into its native state while it remains bound to the surface of the chaperone. These results establish a potentially widespread mechanism whereby ATP-independent chaperones assist in protein refolding. They also provide compelling evidence that substrate proteins can fold while being continuously bound to a chaperone.


Distributed-observer-based cooperative control for synchronization of linear discrete-time multi-agent systems.
This paper considers output synchronization of discrete-time multi-agent systems with directed communication topologies. The directed communication graph contains a spanning tree and the exosystem as its root. Distributed observer-based consensus protocols are proposed, based on the relative outputs of neighboring agents. A multi-step algorithm is presented to construct the observer-based protocols. In light of the discrete-time algebraic Riccati equation and internal model principle, synchronization problem is completed. At last, numerical simulation is provided to verify the effectiveness of the theoretical results.


Impact of the Thrombectomy Trials on the Management and Outcome of Large Vessel Stroke: Data From the Lyon Stroke Center.
Introduction: Randomized trials (RT) have recently validated the superiority of thrombectomy over standard medical care, including intravenous thrombolysis (IVT). However, data on their impact on routine clinical care remains scarce. Methods: Using a prospective observational registry, we assessed: (1) the clinical and radiological characteristics of all consecutive patients treated with thrombectomy; (2) the outcome of all patients with M1 occlusion (treated with thrombectomy or IVT alone). Two periods were compared: before (2013-2014) and after (2015-2016) the publication of RT. Results: Endovascular procedures significantly increased between the two periods (N = 82 vs. 314, p < 0.0001). In 2015-2016, patients were older (median [IQR]: 69 [57-80]; vs. 66 [53-74]; p = 0.008), had shorter door-to-clot times (69 [47-95]; vs. 110 [83-155]; p < 0.0001) resulting in a trend toward shorter delay from symptom onset to reperfusion (232 [185-300]; vs. 250 [200-339]; p = 0.1), with higher rates of reperfusion (71 vs. 48%; p = 0.0001). Conversely, no significant differences in baseline NIHSS scores, ASPECTS, delay to IVT or intracranial hemorrhage were found. In 2015-2016, patients with M1 occlusion were treated with thrombectomy more often than in 2013-2014 (87 vs. 32%, respectively; p < 0.0001), with a significant improvement in clinical outcome (shift analysis, lower modified Rankin scale scores: OR = 1.68; 95% CI: 1.10-2.57; p = 0.017). Conclusion: Following the publication of RT, thrombectomy was rapidly implemented with significant improvements in intrahospital delay and reperfusion rates. Treatment with thrombectomy increased with better clinical outcomes in patients with M1 occlusion.


Worksite-screenings for hypertension with follow-up: experiences from the Munich Blood Pressure Program.
In 1983/84, the Munich Blood Pressure Program (MBP) performed worksite screenings for arterial hypertension at 18 Munich companies. A participation of 51% (n = 7310) was achieved. After duplicate measurements of casual blood pressure 1084 participants were suspected of having actual hypertension. All suspected cases were invited for a reexamination to reduce the number of false-positive hypertensives. Individuals with persisting hypertension after this two-step-screening were predominantly male, on the average younger than 50 years and showed a low level of antihypertensive drug treatment. About 75% of all detected hypertensives saw a family physician subsequent to the screenings for further management. Referrals and patient compliance were frequently reinforced by a computer based reminder system. A follow-up examination was performed among the MBP participants after two years. It showed that in 417 confirmed hypertensives of the primary screenings a marked increase in the proportion of treated and controlled hypertensives had occurred. This was true for younger and older hypertensives.


Binary Mixtures of Some Active Pharmaceutical Ingredients with Fatty Alcohols-The Criteria of Successful Eutectic Formation and Dissolution Improvement.
Pharmaceutical eutectics are solid mixtures, where the crystals of active pharmaceutical ingredients (APIs) are finely divided in the phase-separated microstructures. The size reduction makes the eutectic formation a viable option to improve the dissolution rate of the poorly soluble APIs. In the present study, ibuprofen, naproxen, and sorafenib were investigated in terms of their phase behaviors with fatty alcohols, such as tetradecanol, octadecanol, and docosanol. Among the studied APIs, only ibuprofen was able to form eutectics with the fatty alcohols, and this was in agreement with the feasibility prediction based on the van 't Hoff equation and solubility parameters. In vitro release behavior was significantly improved for the ibuprofen/octadecanol eutectic mixture, although the practical insolubility of octadecanol in water was the opposite of the outstanding hydrophilicity of usual eutectic formers. The feasibility prediction and the choice of eutectic formers in the present study will be useful in advancing the utility of the pharmaceutical eutectics.


Iron Status of Preadolescents Without Clinical Pallor Attending a Tertiary Care Hospital in South India- A Cross-Sectional Analytical Study.
To determine the prevalence of Iron Deficiency (ID) in children without clinical pallor using serum ferritin and the new parameters, soluble transferrin receptor (sTfR) & the ratio of sTfR/log10 serum ferritin (sTfR-F index), as suggested by WHO. Also to assess whether these new parameters could individually predict the presence of ID. Consecutive 230 healthy children aged 9-11 y without clinical pallor underwent estimation of Hemoglobin (Hb), C-Reactive Protein (CRP), serum ferritin, sTfR, and sTfR-F index levels in their blood. The abilities of the sTfR and sTfR-F index in predicting ID were determined by comparing with the gold standard (normal CRP and less serum ferritin), plotting Receiver-operating characteristic (ROC) curve, and noting the area under the curve (AUC). The blood reports of 114 boys and 106 girls (total = 220) were available for analysis. Overall, 57 (31 girls, 26 boys) children had ID; among children with low CRP, 45 had ID, as suggested by low serum ferritin levels. Among children with high CRP, 12 had evidence of ID as evidenced by elevated sTfR and/or sTfR-F index. The positive predictive values of both sTfR and sTfR-F were low (32.9% and 35.9%, respectively) than the negative predictive values (85.6% and 95.3%, respectively). The proportion of children identified to have ID using serum ferritin, sTfR, and sTfR-index was 25.9%. sTfR and/or sTfR-F index are unlikely to be ideal individual predictors of ID.


Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis.
In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n = 17); Group 2, hormone-sensitive and metastatic Pca (n = 33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n = 18); and Group 4, CRPC with chemotherapy (n = 27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p = 0.045), but decreased from Group 3 through to Group 4. AR splice variant 7 (ARV7) and glucocorticoid receptor (GR) transcript levels significantly increased from Group 1 through to Group 4 (p = 0.002 and 0.049, respectively). Kaplan-Meier curve revealed that the high transcript level of these three receptors resulted in significantly poorer cancer-specific survival (CSS) than that by low transcript level, although Cox regression analysis revealed that the ARV7 level alone was an independent prognostic factor for CSS in CRPC patients (high vs. low: hazard ratio, 1.897; 95% confidence interval, 1.102-3.625; p = 0.042). In conclusion, ARV7 and GR transcript levels significantly increase as Pca progresses to CRPC.


Pharmacokinetics of homoharringtonine in dogs.
We studied the pharmacokinetics and distribution of homoharringtonine (HHT), an antitumor alkaloid, in anesthetized dogs using chromatographic and radiochemical techniques. Uniformly tritiated HHT was administered i.v. to five dogs at doses of 0.05 to 0.34 mg/kg, 200 microCi per animal. Unchanged HHT disappeared in a triphasic manner from the plasma with an initial plasma t1/2 of 9.4 +/- 4.2 min, an intermediary t1/2 of 1.4 +/- 0.5 h, and a terminal t1/2 of 40.6 +/- 4.6 h. The plasma clearance was 114.0 +/- 20.1 ml/kg-1 h-1 and the steady-state volume of distribution was 6.2 +/- 0.7 1/kg. In 72 h, 40.1% +/- 4.0% of the administered radioactivity was excreted in the urine, 17.8% +/- 2.7% of which was unchanged HHT. HHT was metabolized extensively to one major and two minor metabolites. Biliary excretion of total radioactivity was 14.4% in 5 h, 2% of which was HHT. HHT concentration in the CSF was highest 4 h after drug administration, about 40% of the concentration in the concurrent plasma. At autopsy 5 h after dosing, the highest percentage of HHT was in the liver (7.4%), followed by the small intestine (2.5%), stomach (1.0%), pancreas (0.8%), kidneys (0.8%), and lungs (0.7%). The heart, spleen, large intestine, and brain each retained less than 0.5%. However, 24 h after dosing, 4% of the HHT still remained in the liver, 1% in the small intestine, and less than 1% in the other organs. HHT seems to be extensively metabolized in dogs and partially retained in the body.


Sexual function after surgery for early-stage cervical cancer: is there a difference in it according to the extent of surgical radicality?
Approximately 15% of all cervical cancers are found in women under the age of 40. Sexual function is a matter of great importance for these women. However, the impact of the surgical radicality for cervical cancer on sexual function has not been established. The aim of this study is to estimate the difference in postoperative sexual function in women with surgically treated early-stage cervical cancer according to the extent of surgical radicality. One hundred and five women with early-stage cervical cancer treated by cervical conization (CC), radical trachelectomy (RT), and radical hysterectomy (RH) between January 2006 and December 2009 were asked to answer a validated questionnaire, the Female Sexual Function Index (FSFI). FSFI score. Eighty-one completed questionnaires from 39 (48.2%) women in the CC group, 18 (22.2%) in the RT group, and 24 (29.6%) in the RH group were studied. The FSFI total score for the CC group was 30.72 ± 3.39, suggesting no sexual dysfunctioning. The FSFI total score for the RT and RH groups (21.78 ± 4.17 and 22.40 ± 4.09, respectively) demonstrated a globally compromised sexuality, based on a FSFI total score of 26.55 as the clinical cut-off for sexual dysfunction. The FSFI total scores in the RT and RH groups were significantly decreased compared to the CC group (P < 0.001). However, there were no significant differences between the RT and RH groups. The RT and RH groups, unlike the CC group, had compromised sexual function after the treatment of early-stage cervical cancer.


Two and three dimensional display of myocardial ischemic "border zone" in dogs.
It is intuitively apparent that the ultimate fate of reversibly damaged, peri-ischemic "border zone" tissue should relate to individual patient survival. The purpose of this study was: (1) to describe a technique of assessing the adequacy of epicardial and myocardial oxygenation, and (2) to examine the extent and character of the peri-ischemic "border zone" in the dog after coronary arterial ligation. A diagonal branch of the left anterior descending coronary artery was ligated in four anesthetized open chest, neurohormonally intact dogs. The same diagonal coronary artery was ligated in six isolated perfused canine heart preparations in which coronary partial pressures of oxygen and carbon dioxide, pH, blood flow and temperature were fixed. The ischemic zones were rapidly frozen and reduced nicotinamide adenine dinucleotide (NADH) fluorescence photographs were taken of the epicardium and at 0.5 mm depths into the myocardium. The distinction between perfused and ischemic myocardium is not apparent with the naked eye or natural light photography. Epicardial and myocardial oxidation-reduction status is well seen with NADH fluorophotography. In both the intact and perfused heart preparations the NADH-fluorescent (ischemic) border is jagged along all edges. Islands of perfused nonfluorescent tissue appear within the ischemic border. The transition between NADH-fluorescent ischemic cells and adjacent non-fluorescent tissue is less than 0.1 mm. The ischemic border is narrow. The distance between homogeneously NADH-fluorescent tissue and homogeneously nonfluorescent tissue (across the zone of island normoxia or microheterogeneity) may be as wide as 6 to 8 mm.


Attentionally modulated effects of cortisol and mood on memory for emotional faces in healthy young males.
Heightened cortisol levels due to stress or acute administration seem to enhance memory for emotional material, independently of emotional valence. An arousal-driven neurobiological mechanism involving the amygdala has been proposed. The relation between pre-task salivary measures of cortisol (by convention named 'basal levels') and emotionally modulated memory has not been investigated yet. Given the association between higher basal levels of cortisol and indices of low mood, valence-specific effects on emotionally modulated memory could be expected (e.g. mood-congruent or stimulus-specific forms of processing). This study was designed to investigate the relationship between basal levels of salivary cortisol, self-reported mood and spatial memory for neutral, happy and angry facial expressions in healthy young volunteers (N=31). Memory performance was indexed using a modified version of a computerized object-relocation task, using emotional facial expressions as stimuli. Results showed a significant relation between cortisol and depressive mood. More importantly, both the levels of cortisol and depressive mood were inversely related to the memory performance for the happy facial expressions, while a similar relationship between cortisol and memory performance on angry faces neared significance. An explanation in terms of the down-regulation of social behavior by elevated basal cortisol levels is postulated.


Organization and chromosomal localization of the gene for the human bombesin receptor subtype expressed in pregnant uterus.
The gene encoding the human homologue of the guinea pig uterine bombesin receptor [(1992) Eur. J. Biochem. 208, 405] was isolated from a genomic lambda library by the PCR/homology screening approach. The gene spans more than 4 kb and consists of 3 exons and 2 introns. The deduced amino acid sequence shows about 86% identity to that of guinea pig bombesin receptor. This subtype of bombesin receptor is expressed in the pregnant uterus and in two human tumour cell lines, T47D (ductal breast carcinoma) and A431 (epidermal carcinoma). PCR analysis of genomic DNA from human-mouse cell hybrids allows the cloned gene to be localized to the region q26-q28 on chromosome X.