CT angiography findings in carotid blowout syndrome and its role as a predictor of 1-year survival.
Carotid blowout is a serious late complication of prior treatment of advanced head and neck cancer. We evaluate the efficacy of CTA in the diagnosis of impending carotid blowout syndrome in patients with head and neck cancer, and its capability to predict clinical outcome. The clinical data of 29 patients with impending carotid blowout who underwent CTA were collected and analyzed. Imaging signs included tissue necrosis, exposed artery, viable perivascular tumor, pseudoaneurysm, and contrast extravasation. DSA was obtained in 20 patients. One-year outcomes were compared based on management. The most common CTA finding was necrosis (94%), followed by exposed artery (73%), viable tumor (67%), pseudoaneurysm (58%), and contrast extravasation (30%). Exposed artery, pseudoaneurysm, and contrast extravasation were the 3 CTA findings related to outcomes. All of the pseudoaneurysm and contrast extravasation cases were associated with an exposed artery. An exposed artery was the most important prognostic predictor and could not be diagnosed on DSA. Patients without the 3 findings on CTA (group 1) had the best survival rate at 1-year follow-up, followed by patients with the 3 findings treated immediately by permanent artery occlusion (group 2). Patients with the 3 findings who had no immediate treatment (group 3) had the worst outcomes (P < .001 in group 1 vs group 3 and group 2 vs group 3; P = .056 group 1 vs group 2). CTA, with its ability to diagnose an exposed artery compared with DSA, may offer important management and prognostic information in patients with impending carotid blowout.


Perceived barriers to psychiatric help-seeking in South Korea by age groups: text mining analyses of social media big data.
The psychiatric treatment gap is substantial in Korea, implying barriers in seeking help. This study aims to explore barriers of seeing psychiatrists, expressed on the internet by age groups. A corpus of data was garnered extensively from internet communities, blogs and social network services from 1 January 2016 to 31 July 2019. Among the texts collected, texts containing words linked to psychiatry were selected. Then the corpus was dismantled into words by using natural language processing. Words linked to barriers to seeking help were identified and classified. Then the words from web communities that we were able to identify the age groups were additionally organized by age groups. 97,730,360 articles were identified and 6,097,369 were included in the analysis. Words implying the barriers were selected and classified into four groups of structural discrimination, public prejudice, low accessibility, and adverse drug effects. Structural discrimination was the greatest barrier occupying 34%, followed by public prejudice (27.8%), adverse drug effects (18.6%), and cost/low accessibility (16.1%). In the analysis by age groups, structural discrimination caused teenagers (51%), job seekers (64%) and mothers with children (43%) the most concern. In contrast, the public prejudice (49%) was the greatest barriers in the senior group. Although structural discrimination may most contribute to barriers to visiting psychiatrists in Korea, variation by generations may exist. Along with the general attempt to tackle the discrimination, customized approach might be needed.


Coronary heart disease risk factors ranked by importance for the individual and community. A 21 year follow-up of 12 000 men and women from The Copenhagen City Heart Study.
The importance of coronary heart disease risk factors may differ between individuals and community and by sex and age. METHODS AND RESULTS The Copenhagen City Heart Study followed for 21 years a random sample of 5599 men and 6478 women aged 30 to 79 years at baseline. The importance of risk factors in individuals and the community were evaluated as relative- and population-attributable risks. We traced 2180 coronary events. In Cox regression analysis with ten risk factors entered simultaneously, relative risks for coronary heart disease in men ranged from 1.69 to 1.20 with the highest risks for diabetes, hypertension, smoking, and physical inactivity. In women, relative risks ranged from 2.74 to 1.19 with the highest risks for diabetes, smoking, hypertension, and physical inactivity. Population-attributable risks in men ranged from 22% to 3% with the highest risks for smoking, hypertension, and no daily alcohol intake. In women, attributable risks ranged from 37% to 3% with the highest risks for smoking, hypertension, and hypercholesterolaemia. Several of these rankings differed by age. The importance of coronary heart disease risk factors may differ for individuals, the community, and by sex and age. Consequently, prevention strategies should be tailored accordingly.


Design, synthesis and anti-inflammatory activity of diterpenoid alkaloids and non-steroidal anti-inflammatory drug hybrids based on molecular hybridization strategy.
Molecular hybridization is a widely employed approach in pharmaceutical chemistry for modifying drugs with the aim of improving pharmacological efficacy and reducing adverse effects. A prime example of this is the case of benorylate, which was created by combining aspirin and acetaminophen, two non-steroidal anti-inflammatory drugs (NSAIDs). Diterpenoid alkaloids, which exhibit potent anti-inflammatory activity, have limitations in their application due to their toxicity and side effects. Thus, we aimed to design new anti-inflammatory lead compounds through the molecular hybridization of the anti-inflammatory active skeletons (lappaconitine, aconorine, and bulleyaconitine A) of diterpenoid alkaloids with classical NSAIDs. In this study, we synthesized 25 diterpenoid alkaloid derivatives with NSAIDs, organized into four series. Among these derivatives, lappaconitine derivative 1e demonstrated the strongest inhibition of lipopolysaccharide (LPS)-induced NO production in RAW 264.7 cells with minimal cytotoxicity. Additionally, 1e effectively suppressed the inflammatory response induced by carrageenan in vivo, with a swelling rate of only 1%. This anti-inflammatory potency was found to be significantly superior to that of naproxen. The molecular docking analysis revealed that the binding affinity of 1e was scored as -10.3 kcal/mol, suggesting that it forms a stable complex with cyclooxygenase-2 (COX-2). Therefore, compound 1e holds potential as a lead anti-inflammatory compound that could be further developed.


Ultrastructural changes of bovine pulmonary artery endothelial cells irradiated in vitro with a 137Cs source.
Bovine pulmonary artery endothelial cells in culture were evaluated by phase-contrast and electron microscopy at various times after being irradiated with 137Cs in vitro. Cells irradiated prior to reaching confluency showed vacuolization aand increased numbers of lysosomes beginning at 48 hr after irradiation with 300-500 rad and at 24 hr after irradiation with 1500-5000 rad. After 7 days the morphological changes appeared to be reversible for cells receiving the lower doses, but were progressive for higher doses of radiation. The same qualitative changes, with a delayed onset, were observed for cells irradiated at confluency. An observed decrease in the endoplasmic reticulum and polysomes occurred only late in the course of radiation injury. There was no observable structural alteration of mitochondria even when there was evidence of otherwise marked cytoplasmic injury. We conclude that structural changes of the lysosomes constitute an early phase of injury by irradiation of the endothelial cell in culture, while decreases in endoplasmic reticulum and polysomes occur relatively late. The mitochondrial structure of the endothelial cell appears to be relatively resistant to radiation. All morphological changes occur subsequent to impaired transport of alpha-aminoisobutyric acid, which is observed within 6 hr as previously reported.


New Insights into the Parasitoid Parvilucifera sinerae Life Cycle: The Development and Kinetics of Infection of a Bloom-forming Dinoflagellate Host.
Parvilucifera sinerae is a parasitoid of dinoflagellates, the major phytoplankton group responsible for harmful algal bloom events. Here we provide a detailed description of both the life cycle of P. sinerae, based on optical, confocal, and transmission electron microscopy observations, and its infection kinetics and dynamics. P. sinerae completes its life cycle in 3-4 days. The zoospore encounters and penetrates the host cell within 24h after its addition to the host culture. Inside the host, the parasitoid develops a trophocyte, which constitutes the longest stage of its life cycle. The trophocyte replicates and divides by schizogony to form hundreds of new zoospores contained within a sporangium. Under laboratory conditions, P. sinerae has a short generation time, a high rate of asexual reproduction, and is highly prevalent (up to 80%) in the Alexandrium minutum population. Prevalence was shown to depend on both the parasitoid inoculum size and host density, which increase the encounter probability rate. The parasitoid infection parameters described in this study are the first reported for the genus Parvilucifera. They show that P. sinerae is well-adapted to its dinoflagellate hosts and may be an important factor in the termination of A. minutum blooms in the natural environment.


Use of Telazol to immobilize female northern sea lions (Eumetopias jubatus) in Alaska.
Twenty-nine female northern sea lions (Eumetopias jubatus) were immobilized using Telazol in dosages ranging from 1.8 to 8.1 mg/kg. Best results were achieved with Telazol dosages ranging between 1.8 and 2.5 mg/kg which resulted in smooth induction and recovery. Optimal injection location was in the muscle mass of the lower back and hip. Dosages greater than 3.5 mg/kg resulted in a tendency toward hypothermia. Six mortalities occurred which were partially caused by the location of drug injection and perhaps the high dosage.


Deep learning-based scan range optimization can reduce radiation exposure in coronary CT angiography.
Cardiac computed tomography (CT) is essential in diagnosing coronary heart disease. However, a disadvantage is the associated radiation exposure to the patient which depends in part on the scan range. This study aimed to develop a deep neural network to optimize the delimitation of scan ranges in CT localizers to reduce the radiation dose. On a retrospective training cohort of 1507 CT localizers randomly selected from calcium scoring and angiography scans and acquired between 2010 and 2017, optimized scan ranges were delimited by two radiologists in consensus. A neural network was trained to reproduce the scan ranges and was tested on two randomly selected and independent validation cohorts: an internal cohort of 233 CT localizers (January 2018-June 2020) and an external cohort from a nearby hospital of 298 CT localizers (July 2020-December 2020). Localizers where a bypass surgery was visible were excluded. The effective radiation dose to the patient was simulated using a Monte Carlo simulation. Scan ranges of radiographers, radiologists, and the network were compared using an equivalence test; likewise, the reduction in effective dose was tested using a superior test. The network replicated the radiologists' scan ranges with a Dice score of 96.5 ± 0.02 (p < 0.001, indicating equivalence). The generated scan ranges resulted in an effective dose reduction of 10.0% (p = 0.002) in the internal cohort and 12.6% (p < 0.001) in the external cohort compared to the scan ranges delimited by radiographers in clinical routine. Automatic delimitation of the scan range can result in a radiation dose reduction to the patient. Fully automated delimitation of the scan range using a deep neural network enables a significant reduction in radiation exposure during CT coronary angiography compared to manual examination planning. It can also reduce the workload of the radiographers. • Scan range delimitation for coronary computed tomography angiography could be performed with high accuracy by a deep neural network. • Automated scan ranges showed a high agreement of 96.5% with the scan ranges of radiologists. • Using a Monte Carlo simulation, automated scan ranges reduced the effective dose to the patient by up to 12.6% (0.9 mSv) compared to the scan ranges of radiographers in clinical routine.


Tetanus and psychiatry: unexpected bedfellows.
Six patients who were admitted with the initial diagnosis of tetanus to a general hospital serving 130 000 people over a 10-year period are reviewed. In three of these patients psychogenic factors played a major part in the presenting pictures. These cases followed a markedly different course from the others. Guidelines to the early differentiation of such atypical cases, and to the way psychogenic factors can be identified and their importance evaluated, are discussed.


Subarachnoid haemorrhage of unknown origin: clinical and tomographical aspects.
65 patients with negative but technically satisfactory 4 vessel angiography - all admitted to our Department in the years 1976-1983 - were evaluated in the present study. CT scan was undertaken in all cases (in 47 cases within 4 days of haemorrhage). Arterial hypertension was present on admission in 9% of cases. The period of follow-up ranged from 4 to 11 years, with a mean of 5.3 years. The study group was compared to a control group, comprising 760 patients with subarachnoid haemorrhage from ruptured aneurysms, admitted during the same period. Clinical grade on admission (Hunt's classification) was better in patients belonging to the study group. The amount of cisternal deposition on CT scan was less significant than in patients with ruptured aneurysms, and the deposition was often atypical (circumpeduncular, ambiental, and/or tentorial). Clinical deterioration associated with vasospasm was observed in 5% of patients in this study and in 27% of patients in the control group. In patients with a consistent or thick cisternal layer (CT scan "at risk") the incidence of clinical vasospasm was 21%, against 47% in controls. One or more rebleedings occurred in 12% of patients in the study group, against 25% of patients in the control group. A significant ventricular dilatation was observed in 15% of patients in the first group (requiring a shunt in 8%), against 25% of patients in the second group (requiring a shunt in 11%). Final outcome was favourable in 95% of patients in this study group and in 63% of patients in the control group, with a mortality rate of 5% in the first group and 32% in the second group.


Transcriptional stochasticity in gene expression.
Due to the small number of copies of molecular species involved, such as DNA, mRNA and regulatory proteins, gene expression is a stochastic phenomenon. In eukaryotic cells, the stochastic effects primarily originate in regulation of gene activity. Transcription can be initiated by a single transcription factor binding to a specific regulatory site in the target gene. Stochasticity of transcription factor binding and dissociation is then amplified by transcription and translation, since target gene activation results in a burst of mRNA molecules, and each mRNA copy serves as a template for translating numerous protein molecules. In the present paper, we explore a mathematical approach to stochastic modeling. In this approach, the ordinary differential equations with a stochastic component for mRNA and protein levels in a single cells yield a system of first-order partial differential equations (PDEs) for two-dimensional probability density functions (pdf). We consider the following examples: Regulation of a single auto-repressing gene, and regulation of a system of two mutual repressors and of an activator-repressor system. The resulting PDEs are approximated by a system of many ordinary equations, which are then numerically solved.


Predicting length of treatment for neonatal abstinence syndrome in methadone-exposed neonates.
The objective of the study was to identify maternal variables predicting length of treatment for neonatal abstinence syndrome (NAS). This was a retrospective cohort study of infants treated for NAS during 2000-2006 whose mothers were on methadone maintenance at delivery. Mixed-effects linear regression was used to examine the interaction of maternal and neonatal variables with length of treatment. Of 204 neonates born to methadone exposed mothers, the average dose at delivery was 127 mg daily (25-340 mg) with median length of treatment 32 days (1-122 days). Trimester of initial exposure (P = .33), methadone dose at delivery (P = .198), body mass index (P = .31), antidepressant use (P = .40), cigarette use (P = .76), race (P = .78), and maternal age (P = .84) did not predict length of treatment. In the multivariate analysis, gestational age at delivery and benzodiazepine use were significant predictors of length of treatment. Later gestational age and concomitant benzodiazepine use were associated with longer treatment.


The transcription factor 7-like 2 (TCF7L2) gene is associated with Type 2 diabetes in UK community-based cases, but the risk allele frequency is reduced compared with UK cases selected for genetic studies.
Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects). When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]. Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects.


[Aspects of pneumocystosis seen in a French pneumonology department in 1987-1988].
Over a 2 years' period, 49 AIDS patients and 3 non AIDS patients were treated for pneumocystosis in our chest department. Forty-six were male and 6 were female. Pneumocystosis was the first opportunistic infection in 77 p 100 of patients. Fever above 38.5 degrees C was the major symptom in 92 p 100. Cough was present in 90 p 100 and dyspnoea in 94 p 100. Clinical symptoms had begun 21.7 +/- 15.7 days before diagnosis. Mean PaO2 value was 50.9 +/- 15.7 mmHg. Forty-eight patients were initially treated by daily intravenous administration of trimethoprim 960 mg and sulfamethoxazole 4,800 mg. Three patients received a pentamidine aerosol and one received DFMO. Treatment was effective in 39 patients; 11 patients died between the 5th and the 29th days of treatment; 2 had an early relapse. Fever disappeared after 9.8 +/- 6.6 days, and blood gases returned to normal within 10.8 +/- 7.7 days. All patients whose PaO2 was above 56 mmHg were cured. Thus, the trimethoprim-sulfamethoxazole combination proved active in the treatment of pneumocystosis. Other treatments are useful in case of side-effects or failure of the initial therapy. Failures can be suspected on the fourth day of treatment and in such cases CMV co-infection must be looked for and treated.


A Fluorescence-Based Reporter Gene Assay to Characterize Nuclear Receptor Modulators.
Reporter gene assays are critical tools of nuclear receptor research for characterizing the effects of ligands on nuclear receptor activity. Common luciferase-based techniques require expensive substrates and are typically performed in endpoint format. Here, we describe a versatile reporter gene assay to observe nuclear receptor activity with fluorescent proteins as reporters. This setting is highly cost-efficient and enables observation of nuclear receptor activity over time with multiple measurements from one plate.


Get back TFIIF, don't let me Gdown1.
In this issue of Molecular Cell, papers by the Price and Roeder labs reveal how the Gdown1 protein antagonizes the general transcription factor TFIIF during RNAPII initiation and elongation and how the Mediator complex intervenes in this molecular tug-of-war to activate RNAPII.


Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation.
A wide array of microRNAs (miRNAs) is differentially expressed in breast tumors and also functions as tumor suppressors. Herein, the current study sought to unravel the function of miR-4731-5p in breast cancer progression. First, breast cancer-related miRNA and mRNA microarray data sets were retrieved for differential analyses. Subsequently, the expression patterns of miR-4731-5p, PAICS, and FAK in breast cancer tissues and cells were determined, in addition to analyses of their roles in glycometabolism, migration, invasion, epithelial-mesenchymal transition (EMT) analyzed through functional assays. Next, the targeting relation between miR-4731-5p and PAICS was validated. Xenograft tumors in nude mice were further established to reproduce and verify the in vitro findings. miR-4731-5p was poorly expressed and PAICS was highly expressed in breast cancer tissues and cells. PAICS was confirmed as a target of miR-4731-5p. Moreover, miR-4731-5p exerted an inhibitory effect on glycolysis, EMT, migration, and invasion in breast cancer cells via regulation of PAICS-dependent phosphorylation of FAK. In vivo assay further validated the significance of the miR-4731-5p/PAICS/FAK axis in vivo tumorigenesis and lung metastasis in breast cancer. Collectively, our findings indicated that miR-4731-5p inhibited breast cancer cell glycolysis and EMT through the reduction of PAICS-induced phosphorylation of FAK.


Morphological Features of the Ascending Aorta Remodeling and Activation of Regeneratory Potential in Intima when Forming Aneurysm.
In patients with an ascending aorta aneurysm, restructuring of all its layers and, first of all, the intima and media was revealed. The thickness of the intima was 79.3±63.1 μm in patients with aortic diameter <55 mm (group Ao<55) and 162.7±177.4 μm (p<0.05) in patients with aortic diameter ⩾55 mm (Ao⩾55 group), the thickness of the aortic media was 1184.0±198.2 and 1144.3±288.4 μm, respectively. In patients of the Ao<55 group, aortic dilatation was accompanied by compensatory thickening of the inner and middle layers of the aorta. In the Ao⩾55 group, thinning of the aortic media, fragmentation of elastic fibers, and its cystic degeneration were revealed. c-kit+ Stem cells were detected in the subendothelium of the thickened intima of the dilated ascending aorta. The appearance of c-kit+ cells correlated with intimal remodeling and its colonization with CD34+ and CD44+ myofibroblast-like cells.


Delayed-onset streptococcus pyogenes endophthalmitis following Ahmed glaucoma valve implantation.
To report a case of delayed-onset Streptococcus pyogenes endophthalmitis following implantation of an Ahmed glaucoma valve. A 10-year-old patient presented with acute endophthalmitis 1 year after Ahmed glaucoma valve implantation. The conjunctiva and Tenon's capsule over the valve plate had been penetrated by one of the polypropylene fixation sutures. The valve was removed, and pars plana vitrectomy was performed. Vitreous specimens and removal of the discharge over the plate revealed Streptococcus pyogenes. This is the first documented case of Streptococcus pyogenes endophthalmitis following Ahmed glaucoma valve implantation. We think the conjunctival buttonhole caused by the polypropylene suture provided an entry site for the infection.


The Identification of Stenotrophomonas maltophilia Contamination in Ultrasound Endoscopes and Reproduction of Decontamination Failure by Deliberate Soiling Tests.
An outbreak of Stenotrophomonas maltophilia was observed in the cultures of bronchial aspirations. After systematic culturing of the scopes and reprocessing the equipment, it turned out to be a pseudo-outbreak caused by a failure of the disinfector to sterilize ultrasound scopes, subsequently resulting in cross infection of the bronchoscopes via the connecting tubes in the dryer. To support the above-mentioned findings and to show how different variables influence the decontamination process. The ultrasound scopes were deliberately contaminated with test soil and subsequently disinfected with peracetic acid (PAA), glutaraldehyde (GA) and hot water. Cultures were taken immediately after disinfection and after 4 days in the drying cabinet. After disinfection with PAA, persistent contamination was observed in the endobronchial ultrasound scope, and after disinfection with PAA and prolonged storage in the drying cabinet, contamination of the endoscopic ultrasound scope persisted. All ultrasound scopes were effectively disinfected with GA. It is concluded that disinfection with PAA fails to decontaminate the small channels of the ultrasound scopes. Prolonged storage in humid conditions seems to enhance the outgrowth of microorganisms. By reassignment of all endoscopes to fixed locations in the drying cabinet, by using disposable connector tubes for the balloon channels, and by using GA instead of PAA, the reprocessing procedure in our hospital was corrected effectively.


Salivation and depression: a role for appetitive factors.
A decrease in salivary flow rate (SFR) is associated with depressive illness although the mechanisms underlying this association are unknown. Appetitive factors are known to influence SFR, but are not adequately considered in the studies of salivation and depression. Diminished SFR in depressive illness may be more closely related to the appetite disturbances commonly associated with depressive illness than to mood disorder or depressive illness per se. The implications for considering SFR as a physiological correlate of depressive illness are discussed in light of this possibility.


Single stage dorsal inlay buccal mucosal graft with tubularized incised urethral plate technique for hypospadias reoperations.
To report the experience with single stage dorsal inlay buccal mucosal grafts using the Snodgrass technique for complex redo cases. From May 2004 to December 2005, a total of 53 patients aged from 3 to 34 years old (average 11.62 +/- 7.18 years) with failed previous hypospadias surgery were included in the present study. Indications included urethral strictures and repair breakdown. The unhealthy urethra was unroofed from the meatus in the ventral midline, a buccal mucosal graft was inlayed between the incised urethral plate and fixed to the corpora cavernosa. The neourethra was tubularized, and covered with subcutaneous (dartos) tissue and penile skin. Glanuloplasty was also performed in all cases. Outcome analysis included clinical follow-up, and endoscopy in 2 selected cases. The buccal mucosal graft was 3.0-7.5 cm in length and 0.7-2.0 cm in width. All patients required glanuloplasty, with buccal mucosal grafts extended to the tip of the glans. After a follow-up of 14-30 months (mean 22.6 months), the total complication rate was 15.1%, with five cases of fistula and three cases of stricture. Inlaying dorsal buccal mucosal grafts applying the Snodgrass technique is a reliable method for creating a substitute urethral plate for tubularization. The recurrent rate of urethral stricture and fistula is at an acceptable level for redo cases. This approach represents an effective, simple and safe option for reoperations.


Assessment of greenhouse technologies on the drying behavior of cocoa beans.
Cocoa beans (Theobroma cacao L.) are the principal raw material for chocolate manufacture. Before cocoa beans are ready for the chocolate industry, farm-based fermentation and drying processes are key determinants of bean quality and hence the price. To improve its value, cocoa beans were dried in a modified greenhouse (MGHD), conventional greenhouse (CGHD), and open sun (OSD) dryers. The drying behavior, kinetics, and quality were evaluated. The MGHD was constructed by modifying a conventional greenhouse with a fleece of black polyester material. Evaluation of air properties of the dryers without and with cocoa beans showed that the MGHD had average temperatures of 2 and 8°C above, and relative humidity of 12.28% and 25.48% below the CGHD and OSD, respectively. The drying data were fitted to four thin layer mathematical models. The Page and Overhult models gave favorable ranges of R 2 (.976 to .987), chi-square (3.7 × 10-4 to 9.9 × 10-4), and root mean square (RMSE; 0.0188 to 0.0307) for the three dryers. The cocoa beans dried in the MGHD took a shorter time to reach the expected 5%-8% moisture content and were of grade one quality.


Reproductive endocrine disruption and gonadal intersex induction in male Japanese medaka chronically exposed to betamethasone at environmentally relevant levels.
The broad utilization of betamethasone in medical treatments may pose a significant ecotoxicological risk to aquatic organisms, yet its potential reproductive toxicity remains unclear. The present study examined the impacts of environmental exposure on male reproduction using Japanese medaka (Oryzias latipes). After 110 days of betamethasone exposure at environmentally relevant concentrations (0, 20 and 200 ng/L), LH/FSH synthesis and release in the pituitary was inhibited, and the production of sex hormones and their signaling pathways in the gonads of male medaka were greatly influenced. This synthetic glucocorticoid restrained testosterone (T) synthesis and gave rise to a significant increase in E2/T and E2/11-KT ratios. Furthermore, chronic betamethasone exposure (20 and 200 ng/L) led to the suppression of androgen receptor (AR) signaling and enhancement of estrogen receptors (ERs) signaling. An increase in hepatic vitellogenin contents was also detected, and testicular oocytes were observed in both 20 and 200 ng/L betamethasone-treated groups. It showed that 20 and 200 ng/L betamethasone could induce male feminization and even intersex, triggering abnormal spermatogenesis in medaka males. With its adverse effects on male fertility, betamethasone could potentially influence the fishery productivity and population dynamics in aquatic ecosystems.


Directional colour encoding of the human thalamus by diffusion tensor imaging.
The potential of diffusion tensor imaging (DTI) in brain imaging in terms of the in vivo mapping of neuroanatomy is generally accepted. Mostly, analyses of deep brain structures were based on complex methodical backgrounds. In the present study, the delineation of groups of thalamic nuclei with similar projection characteristics was investigated in healthy human subjects using a novel differentiated colour encoding approach of DTI data without the use of statistical calculations. With the application of this directional colour encoding of the longest eigenvector of every voxel-specific tensor, at least three functional groups in the thalamus with different projection directions could be differentiated. The method displayed, furthermore, a high symmetry and stability in the analysis of the individual subjects. In summary, substantial neuroanatomical information can be gained for deep subcortical gray matter structures such as the thalamus with an improved detection and directional differentiation of voxel-specific tensors.


Spectroscopic, viscositic and molecular modeling studies on the interaction of 3'-azido-daunorubicin thiosemicarbazone with DNA.
A new daunorubicin has been synthesized and structurally characterized. The interaction of native calf thymus DNA (ctDNA) with 3'-azido-daunorubicin thiosemicarbazone (ADNRT) was investigated under simulated physiological conditions by multi-spectroscopic techniques, viscometric measurements and molecular modeling study. It concluded that ADNRT could intercalate into the base pairs of ctDNA, and the fluorescence quenching by ctDNA was static quenching type. Thermodynamic parameters calculated suggested that the binding of ADNRT to ctDNA was mainly driven by hydrophobic interactions. The relative viscosity of ctDNA increased with the addition of ADNRT, which confirmed the intercalation mode. Furthermore, molecular modeling studies corroborate the above experimental results.


Age, size, and lead factors alone do not predict venous obstruction in children and young adults with transvenous lead systems.
Venous occlusion is a recognized complication of transvenous pacing, and lead cross-sectional area indexed to body surface area (BSA) has been used to predict venous obstruction in children. The aim of this study was to identify the risk factors and incidence of angiographic venous obstruction after transvenous lead implantation in both children and young adults. Contrast venography was obtained in 85 of 90 consecutive patients undergoing repeat pacemaker or ICD procedures from 2002 to 2004 at a single cardiac center. Venograms were graded as complete venous obstruction, significant partial obstruction (>70% with collaterals), or patent. The cohort had a median age of 15.0 years at implant and was divided into two age groups: 3-12 years (n = 35) and 13 years and over (n = 50). After a median interval of 6.5 years, complete obstruction was seen in 11 of 85 patients (13%) and partial obstruction in another 10 patients (12%). No significant differences were seen in the incidence of obstruction between the two age groups although younger patients had a larger lead indexed to BSA ratio (6.82 vs 5.05, P = 0.005). There were no significant differences between obstructed and nonobstructed patients in relation to age, size, growth, or lead factors. Transvenous lead systems implanted in young children have a similar incidence of venous occlusion compared to older patients. Furthermore, patient age, body size, and lead characteristics at implant do not clearly predict venous occlusion.


Whey proteins protect more than red meat against azoxymethane induced ACF in Wistar rats.
Protein type and density have been shown to influence colon cancer risk using a carcinogen-induced rat model. It is suggested that red meat may promote colon cancer risk more than whey proteins. The aim of this study was to evaluate the influence of red meat, whey protein and their density in the diet on the number of aberrant crypt foci (ACF), preneoplastic markers in Wistar rats. The sources of protein, red meat as barbecued kangaroo muscle meat, and whey protein concentrate were fed to rats to provide 8, 16 and 32% protein by weight in a modified AIN-93 diet with low fiber, low calcium and high polyunsaturated fat. Adult Wistar rats (13 weeks of age) were fed these diets for 4 weeks and then two s.c. injections of azoxymethane, 15 mg/kg BW, were administered 1 week apart. Diets were fed for a further 8 weeks, rats were then killed, their colons fixed in formalin saline and stained with methylene blue to quantify ACF number. Fecal samples were collected and the fecal water was isolated for quantification of heme and thiobarbituric acid reactive substances. Increasing red meat density correlated positively, while increasing dairy protein density correlated negatively with rate of weight gain (p<0.05). Dietary intake was not significantly affected by protein type or density. The 32% whey protein group had significantly less ACF in the proximal colon in comparison to the 16 and 32% red meat groups (p<0.05). This reduction in ACF number in the whey protein group may be caused by hormones associated with the reduction in weight gain, and/or by components of whey protein concentrate such as cysteine, lactose and conjugated linoleic acid which have been shown to have anti-cancer effects. Using ACF number as an index, whey protein appeared to be more protective than red meat.


Multi-target regulation of pro-inflammatory cytokine production by transcription factor Blimp-1.
Cytokine storm syndrome is a fatal condition related to infectious and autoimmune diseases. Here, we aim to investigate the regulatory mechanisms of Blimp-1 on multiple cytokine production. The Blimp1 shRNA was transfected into RAW264.7 macrophages, followed by Toll-like receptor (TLR) ligand stimulation. The mRNA and protein levels of cytokines were detected by real-time PCR and flow cytometric bead array. The nuclear translocation of AP-1 and NF-κB p65 was measured by immunofluorescence staining. The transcriptional activity was detected by luciferase reporter assay with 5 × NF-κB reporter or with IL6 promoter reporter. Blimp-1 significantly inhibited the expression and secretion of IL-1β, IL-6, and IL-18 in macrophages during stimulation with a variety of TLR ligands. The immunofluorescence staining results showed that Blimp-1 strictly controlled the nuclear translocation of NF-κB p65 in LPS-challenged macrophages. Furthermore, Blimp-1 directly inhibited the transcriptional activity of NF-κB and the transcription of IL6 gene. Blimp-1 represses the production of multiple pro-inflammatory cytokines by directly binding the genomic region and restricting the nuclear translocation and transcriptional activity of NF-κB. This finding may provide potential therapeutic strategies for the cytokine storm-related diseases.


High mechanical property and antibacterial poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/functional enzymatically-synthesized cellulose biodegradable composite.
Biodegradable materials with antibacterial properties are highly promising. A novel antimicrobial nanocellulose (ECP) was synthesized in one-step by enzyme-catalyzed method to improve the mechanical and antimicrobial properties of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(HB-co-HV)]. The biodegradable nanocomposites were prepared by melt blending and the performance analysis results show that the nanocomposites display enhanced mechanical performances and antibacterial activities. Compared with the neat P(HB-co-HV), the P(HB-co-HV) doped with 0.5 wt%-ECP shows the highest mechanical properties with yield strength/elongation at break of 29.3 MPa, 7.63 %, respectively, an increase of 38 %/59 %, and a clear inhibition zone against Staphylococcus aureus (S. aureus) of approximately 3.0 mm. As a heterogeneous nucleation agent, ECP optimizes nucleation, and the interfacial interaction between phenol group and matrix promotes the compatibility and dispersion of ECP, resulting in superior mechanical properties of ECP-based composites. The P(HB-co-HV)/ECP nanocomposites have great potential in biomedical materials especially for the bone defect filling material.


Study on multielemental speciation analysis of Cr(VI), As(III) and As(V) in water by advanced hyphenated technique HPLC/ICP-DRC-MS. Fast and reliable procedures.
Analytical procedures for multielemental speciation analysis of arsenite - As(III), arsenate - As(V) and hexavalent chromium - Cr(VI) in water using high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC/ICP-DRC-MS) hyphenated technique have been developed. A dynamic reaction cell (DRC) for spectral interferences elimination has been involved in the experiment. Application of oxygen and ammonia as reaction gases in the DRC under various conditions has been verified. Optimization of the following chromatographic conditions: mobile phase composition, concentration of particular components, mobile phase pH and flow rate, injection volume and column temperature, has been conducted. Species separation has been carried out on anion-exchange chromatographic column using isocratic elution with: 22 mM (NH4)2HPO4, 25 mM NH4NO3 (for procedure A) and 22 mM (NH4)2HPO4, 65 mM NH4NO3 (for procedure B) as mobile phases. Detection limits (LD) for procedure A were 0.16 µg L(-1), 0.090 µg L(-1), 0.073 µg L(-1), and for procedure B were 0.14 µg L(-1), 0.062 µg L(-1), 0.15 µg L(-1) for As(III), As(V) and Cr(VI), respectively. Linearity was tested at two concentration ranges of: (0.5-10.0) µg L(-1) for procedure A and (5-50) µg L(-1) for procedure B, and showed correlation coefficients for each of the analytes to be above 0.999. Repeatability values obtained for spiked real water samples were in the range of (4.2-7.6)% and (2.0-2.4)% for procedure A and B respectively. Accuracy was calculated based on the analysis of spiked real water samples at three concentration levels. Obtained recoveries were from 94% to 102%.


Flexible substrata for the detection of cellular traction forces.
By modulating adhesion signaling and cytoskeletal organization, mechanical forces play an important role in various cellular functions, from propelling cell migration to mediating communication between cells. Recent developments have resulted in several new approaches for the detection, analysis and visualization of mechanical forces generated by cultured cells. Combining these methods with other approaches, such as green-fluorescent protein (GFP) imaging and gene manipulation, proves to be particularly powerful for analyzing the interplay between extracellular physical forces and intracellular chemical events.


Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F-MRI and Multispectral Analysis.
The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F-MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B188.8.131.52) was found by MS 19F-MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.


In vivo imaging in autoimmune diseases in the central nervous system.
Intravital imaging is becoming more popular and is being used to visualize cellular motility and functions. In contrast to in vitro analysis, which resembles in vivo analysis, intravital imaging can be used to observe and analyze cells directly in vivo. In this review, I will summarize recent imaging studies of autoreactive T cell infiltration into the central nervous system (CNS) and provide technical background. During their in vivo journey, autoreactive T cells interact with many different cells. At first, autoreactive T cells interact with endothelial cells in the airways of the lung or with splenocytes, where they acquire a migratory phenotype to infiltrate into the CNS. After arriving at the CNS, they interact with endothelial cells of the leptomeningeal vessels or the choroid plexus before passing through the blood-brain barrier. CNS-infiltrating T cells become activated by recognizing endogenous autoantigens presented by local antigen-presenting cells (APCs). This activation was visualized in vivo by using protein-based sensors. One such sensor detects changes in intracellular calcium concentration as an early marker of T cell activation. Another sensor detects translocation of Nuclear factor of activated T-cells (NFAT) from cytosol to nucleus as a definitive sign of T cell activation. Importantly, intravital imaging is not just used to visualize cellular behavior. Together with precise analysis, intravital imaging deepens our knowledge of cellular functions in living organs and also provides a platform for developing therapeutic treatments.


[Population-related and individual prevention. Strategies and effectiveness].
In the German health system up to now prevention takes only a marginal position. To tap the full preventive potential in future population-based and risk group-strategies must be systematically extended, combined with individual strategies in clinical preventive medicine and integrated in health care. This report gives international and national examples for these strategies and shows that such preventive programmes could be effective as well cost-effective.


Comparison of clinical outcomes between patellar resurfacing and patellar non-resurfacing in cruciate retaining total knee arthroplasty.
It is not established whether patellar resurfacing is better than patellar non-resurfacing during total knee arthroplasty (TKA). This study was to compare the clinical outcomes between groups with patellar resurfacing and non-resurfacing during cruciate retaining (CR) TKA. In this retrospective cohort study, subjects undergoing primary CR TKA for osteoarthritis between 2012 and 2019 were included. Of 500 subjects, 250 had patellar resurfacing (group 1) and 250 had patellar non-resurfacing (group 2) CR TKA. Knee society knee score (KSKS), knee society function score (KSFS), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scale, Kujala score, anterior knee pain, patellar compression test and range of motion (ROM) of the replaced knee were assessed and compared between the two groups. There were no significant differences in KSKS, KSFS, WOMAC scale, Kujala score, prevalence of anterior knee pain and ROM of the replaced knee between the two groups at the last follow-up (p > .05). Group 2 had more subjects with positive patellar compression test than group 1 at the last follow-up (p = .010). Clinical and functional outcomes of the replaced knee were not different between patellar resurfacing and non-resurfacing groups. Anterior knee pain was significantly reduced after total knee arthroplasty regardless of patellar resurfacing. Retrospective cohort study, Level III.


Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group.
To define risk factors for complications that occur during warfarin therapy. Retrospective cohort study. Five anticoagulation clinics. Nine hundred twenty-eight consecutive patients receiving 1103 courses of warfarin. Hemorrhagic and thromboembolic complications. In 1950 patient-years of follow-up, there were 1332 bleeding events (4 were classified as fatal, 31 as life-threatening, 226 as serious, and 1071 as minor). The cumulative incidence of fatal bleeding was 1% at 1 year and 2% at 3 years. The cumulative incidences of first episodes of life-threatening and serious bleeding at 1, 2, 4, and 8 years were 1%, 2%, 5%, and 9% and 12%, 20%, 28%, and 40%, respectively. Of 156 patients who had a serious or life-threatening hemorrhage, 32% suffered a recurrence, typically within 1 year. Independent predictors of a first episode of serious bleeding included a mean prothrombin time ratio (PTR) of 2.0 or more during the course of treatment (relative risk, 3.0; 95% CI, 1.9 to 4.7); recent initiation of warfarin therapy (relative risk during the first 3 months compared with the rest of the first year, the second year, and anytime thereafter, 1.9 [CI, 1.3 to 3.0], 3.0 [CI, 1.8 to 4.8], and 5.9 [CI, 3.8 to 9.3], respectively); variability of the PTR over time (relative risk for the highest compared with the lowest tertile, 1.6 [CI, 1.2 to 2.7]); and the presence of 3 or more comorbid conditions (RR, 1.4 [CI, 1.1 to 2.5]). Age, reason for anticoagulation, use of interfering drugs, and hypertension were not associated with risk for bleeding. The risk for a thromboembolic complication at a PTR of less than 1.3 was 3.6 (CI, 2.1 to 6.4) times higher than at a PTR of 1.3 to 1.5. The incidence of warfarin-associated bleeding may be reduced by attending to modifiable risk factors (that is, highly variable PTRs and values greater than 2.0), frequent monitoring early in treatment, and careful patient selection. Older age, in and of itself, is not a risk factor.


Androgen receptor agonist and antagonist reduce response of cytokine-induced killer cells on prostate cancer cells.
Despite many advances, prostate cancer (PCa) is still the second most frequently diagnosed cancer and fifth leading cause of cancer death in men worldwide. So far, the promising field of onco-immunology has not yet provided a satisfactory treatment option for PCa. Here we show that the ex vivo expansion and activation of cytokine-induced killer (CIK) cells isolated from primary peripheral blood mononuclear cells induce immune-mediated apoptosis in both human PCa LNCaP and C4-2 cells. Interestingly, pretreating LNCaP and C4-2 cells with either androgen or the androgen receptor (AR) antagonist enzalutamide mediates resistance to this immunogenic attack. This is associated with a reduction of both total cell loss and apoptosis levels suggesting one possible mechanism blunting onco-immunological activity. The data also suggest that secreted factors from AR ligand-treated PCa cell suppress lymphocyte proliferation. Further, we analysed immune-mediated killing activity using conditioned media from LNCaP and C4-2 treated cells. The obtained data suggest that the conditioned media from PCa treated cells does not influence a measurable lymphocyte-mediated apoptosis. However, analysing clonal expansion of activated lymphocytes, the androgen-derived conditioned media suppresses lymphocyte proliferation/expansion suggesting inhibition of onco-immunological activity by pretreatment of PCa cells with AR ligands.


Cholecystokinin B receptor antagonism enhances the ability of a low dose of morphine to reduce c-Fos expression in the spinal cord of the rat.
Three hours after intraplantar carrageenin (6 mg/150 microliters) Fos-like immunoreactivity was predominantly observed in the superficial and deep laminae of the L4-L5 segments of the dorsal horn of the spinal cord in the rat. The total number of Fos-like immunoreactive neurons was equally divided between the superficial (laminae I-II) and deep laminae (laminae V-VI), 99 +/- 3 and 102 +/- 7 Fos-like immunoreactive neurons per section, respectively. In the absence of carrageenin stimulation a negligible number of Fos-like immunoreactive neurons were observed. Pre-administered systemic morphine (0.3 mg/kg) did not significantly influence the total number of Fos-like immunoreactive neurons 3 h after carrageenin. However, pre-administration of a higher dose of morphine (3 mg/kg) significantly reduced the total number of Fos-like immunoreactive neurons (28 +/- 8% reduction, P < 0.001, as compared with control carrageenin Fos-like immunoreactive expression), with this effect being equally divided between the superficial and deep laminae (29 +/- 5 and 29 +/- 6% reduction, respectively, P < 0.001, as compared with control carrageenin Fos-like immunoreactive expression, for both). Pre-administration of the selective cholecystokinin B receptor antagonist, L-365-260 (0.2 mg/kg), alone did not influence the total number of Fos-like immunoreactive neurons 3 h after carrageenin.(ABSTRACT TRUNCATED AT 250 WORDS)


Supramolecular recognition: on the kinetic lability of thermodynamically stable host-guest association complexes.
A molecular receptor consisting of a spacer bearing two cofacially disposed terpyridyl-palladium-ligand (terpy-Pd-L) units rigidly separated by about 7 A has been investigated for molecular recognition of planar aromatic molecules. It is found that although the receptor forms stable 1:2 host-guest association complexes with 9-methylanthracene (9-MA), the guest undergoes very rapid site exchange within the receptor and with external free 9-MA. A crystal structure of the 2:1 adduct shows one 9-MA in the molecular cleft defined by the two terpy-Pd-L units and the other resides on an outside face of one terpy-Pd-L unit. To establish the site residency time of the guests, a number of tethered molecules were prepared. These involve an anthracene molecule tethered to a pyridine ligand bound to the palladium atoms to form intramolecular host-guest adducts. Rotating-frame Overhauser effects were used to infer the site residency of the anthracene guests in the receptor. Variable-temperature (1)H NMR spectroscopy of the intramolecular host-guest complexes has revealed that the site residency time of the anthracene guests is 1.6 x 10(-5) sec at 20 degrees C and 1.3 sec at -90 degrees C in acetone solution. Whereas the guests are thermodynamically stable, they are kinetically very labile. A crystal structure of one of the tethered host-guest adducts reveals the expected structure which is the same as that determined in solution by (1)H rotating-frame Overhauser enhancement spectroscopy experiments.


HPV16 status might correlate to increasing tumor-infiltrating lymphocytes in hypopharyngeal cancer.
Human papillomavirus (HPV) plays a major etiological role in the increasing number of patients with head and neck squamous cell carcinoma (HNSCC). This study aimed at exploring the relationship between HPV infection and prognosis in patients with hypopharyngeal carcinoma (HPSCC). We retrospectively analyzed 108 consecutive patients diagnosed with HPSCC from 2015 to 2018. Real-time fluorescent quantitative PCR and P16 immunohistochemistry were used to detect HPV infection in tissues of patients with hypopharyngeal carcinoma. The numbers of CD8, CD4 and Foxp3 cells in tumor parenchyma were obtained by immunohistochemical counting. Finally, the analysis was performed according to the clinicopathological variables and prognosis of the patients. Among 108 patients with HPSCC, 18 cases were detected by qPCR, and 16 subtypes accounted for the majority (77.8%). Kaplan-Meier analysis showed that HPV16+, higher CD8+, higher CD4+ and higher FoxP3+ TIL infiltration was strongly associated with superior three-year disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Univariate analysis showed that HPV and CD4+ TIL had higher predictive value for prognosis. HPV16 infection is significantly related to tumor immune infiltrating cells (TILs).


A new perspective of microbial survival and dissemination in a prospectively contaminated air-fluidized bed model.
A major concern of users of air-fluidized beds has been the possibility that such beds might be a source of microbial contamination. The purpose of this series of prospective, controlled experiments was to measure quantitatively the dissemination and survival of Bacillus subtilis, a species of bacterium that forms desiccation-resistant spores, as it was associated with circulating and clumped microbeads after challenge in an air-fluidized bed operating under decontamination conditions of heating at 48 degrees C and microbead agitation by an air flow of 100% at 110 cu ft/min. Microbead samples collected after B. subtilis challenge from predesignated depths and locations within the air-fluidized bed at 0.25, 1, 2, 4, 24, and 48 hours were assayed for colony-forming units (CFU) of challenge bacteria by end point dilution and streak-plate assays. Results of three experiments with an average challenge of 1110 CFU of B. subtilis per gram of microbeads indicated that no more than 0.46 CFU of B. subtilis per gram of circulating microbeads and 0.78 CFU per gram of clumped microbeads were detected after 24 to 48 hours at decontamination conditions. Few microbes were detected during three control (sterile water) challenges of the air-fluidized bed operating at 33 degrees C with 95% to 100% air flow. This study has demonstrated that an air-fluidized bed operating at the described decontamination conditions for 24 to 48 hours caused significant decreases, averaging a thousandfold per gram, in levels of microbead-associated challenge bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)


Demonstration of the interaction of transforming growth factor beta 2 and type X collagen using a modified tandem affinity purification tag.
Like other members of the transforming growth factor beta (TGF-beta) family of growth factors, the biological activity of TGF-beta2 is believed to be regulated by the formation and dissociation of multiprotein complexes. To isolate the molecular complex formed by TGF-beta2 secreted by hypertrophic chondrocytes we have used expression of TGF-beta2 fused with the humanized, tandem affinity purification (hTAP) tag and mass spectrometry for the identification of interacting proteins. The hTAP synthetic gene was assembled by systematically replacing the rare codons of the original TAP tag with codons most preferred in highly expressed human genes to circumvent the poor translation efficiency of the original TAP tag in animal cells. TGF-beta2 was shown to interact with Type X collagen and this interaction confirmed using V5 tagged TGF-beta2. Functional interaction was suggested by the inhibition of TGF-beta2 activity by type X collagen in culture and the influence of a mutation in type X collagen on the distribution of TGF-beta2 in growth cartilage.


A retrospective analysis of the outcome of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck refractory to a platinum-based chemotherapy.
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) develops in around 72,000 people in Europe every year. Treatment options are limited, mainly consisting of platinum-based palliative chemotherapy, with median overall survival times of only 6-8 months. No standard second-line treatment after progression on platinum-based chemotherapy is available. Few data have reported the efficacy of these treatments and the outcome of the patients. In an effort to generate such data, this retrospective study analysed clinical records from 151 patients with SCCHN refractory to platinum-based chemotherapy treated between 1990 and 2000 at seven different centres around Europe. Most patients (45%) received only best supportive care (BSC), and had a median survival of 56 days. A total of 28.5% of the patients received second-line chemotherapies: 16.6% radiotherapy and 9.9% chemoradiotherapy. No objective response was observed with the various second-line chemotherapies. The overall median survival was 103 days (95% confidence interval [CI]: 77-126 days) for the whole cohort. The overall objective response rate (ORR) to second-line treatment in this population was calculated to be 2.6%. These results highlight the need for additional treatment options for this disease. Similar, if not superior, response rates have already been observed in initial clinical studies of novel, targeted anti-cancer agents.


The Circle of Female Sexual Desire-Have We Come a Long Way?
Ever since the release of sildenafil (Viagra) two decades ago to treat erectile dysfunction in men, there has been a conversation around whether there is a need for a "female Viagra." Last year's release of flibanserin (Addyi) was hailed by some as an achievement in women's sexual health. But how effective is this drug in affecting women's sexual desire? And are the things being labeled as women's sexual desire problems really problems to be fixed with a drug?


Zinc and glutamate dehydrogenase in putative glutamatergic brain structures.
A certain topographic parallelism between the distribution of histochemically (TIMM staining) identified zinc and putative glutamatergic structures in the rat brain was demonstrated. Glutamate dehydrogenase as a zinc containing protein is in consideration to be an enzyme synthesizing transmitter glutamate. In a low concentration range externally added zinc ions (10(-9) to 10(-7) M) induced an increase in the activity of glutamate dehydrogenase (GDH) originating from rat hippocampal formation, neocortex, and cerebellum up to 142.4%. With rising molarity of Zn(II) in the incubation medium, the enzyme of hippocampal formation and cerebellum showed a biphasic course of activation. Zinc ions of a concentration higher than 10(-6) M caused a strong inhibition of GDH. The effect of Zn(II) on GDH originating from spinal ganglia and liver led only to a decrease of enzyme activity. These results are discussed in connection with a functional correlation between zinc and putatively glutamatergic system.


Alterations of skeletal muscle in chronic heart failure.
The present study was designed to define the prevalence and characteristics of skeletal muscle alterations in patients with chronic heart failure (CHF) and their relation to exercise capacity. The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry in 57 patients with CHF and 18 healthy controls. The volume density of mitochondria (Vvm) and the surface density (Svmc) of mitochondrial cristae were evaluated as a structural correlate of oxidative capacity of skeletal muscle. Vvm and Svmc were reduced by approximately 20% in patients with severe CHF irrespective of age and etiology. The cytochrome oxidase activity in mitochondria as determined by cytochemistry and subsequent morphometry in a subset of patients (n = 10) was significantly decreased in heart failure (p less than 0.01). The capillary length density of skeletal muscle was reduced in CHF (n = 12, p less than 0.05), and the fiber type distribution was shifted to type II fibers (n = 15, p less than 0.05). Vvm and Svmc were significantly related to peak exercise VO2 (r = 0.56, p less than 0.001, n = 60) and to VO2 at anaerobic threshold (r = 0.535, p less than 0.0001, n = 60). In 16 patients with severe heart failure, Vvm was inversely related to the duration of heart failure (r = 0.545, p less than 0.03). In 11 patients who underwent repeat biopsies after 4 months, a correlation was observed between the change in Vvm and the change in peak exercise VO2 (r = 0.89, p less than 0.001). These findings indicate that patients with CHF develop significant ultrastructural abnormalities of skeletal muscle reflecting a depressed oxidative capacity of working muscle. It appears that these alterations of skeletal muscle contribute to the decreased exercise capacity of these patients but are, in principle, reversible by an effective treatment regimen.


Invasive lumbricid earthworms in North America - different life-histories but common dispersal?
Lumbricid earthworms are invasive across northern North America, causing notable changes in forest ecosystems. During their range expansion they encountered harsher climatic conditions compared to their native ranges in evolutionary short time. This study investigated if (1) dispersal barriers, (2) climatic selection, or (3) anthropogenic activities, such as fishing bait disposal, structure the dispersal of free-living earthworm populations. North America, forest habitats along former Wisconsinan glaciation line. Lumbricus terrestris, L. rubellus. Lumbricus terrestris and L. rubellus co-occur in the same habitats but differ in ecology and use Conservation approach for goblin species were sampled in five transects ranging from the east to the west coast of northern North America, including major dispersal barriers, three different climate zones, and bait shops near sampling locations. Genetic diversity and structure were compared between the two species, and the presence of free-living bait shop genotypes was assessed using four markers (COI, 16S rDNA, 12S rDNA, H3). Populations of both species were genetically diverse with some geographic structure, which was more pronounced in L. terrestris than in L. rubellus. Common haplotypes were present in all regions, but locally restricted haplotypes also occurred. Further, two distinct genetic clades of L. terrestris co-occurred only in the two most distant transects (Alberta and Minnesota). Genotypes identical to bait individuals were omnipresent in field populations of L. terrestris. Genetic diversity was high in both species, and invasive populations represented a genetic subset of European earthworms. Geographic and climatic dispersal barriers affected the less mobile species, L. rubellus, resulting in differences in genetic structure between the two species. Our results indicate common long-distance dispersal vectors and specific vectors affecting only L. terrestris. The roles of climate and anthropogenic activities are discussed, providing additional explanations of dispersal and new insights into establishment of invasive earthworms.


Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells.
MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.


Skin Contour Sutures in Rhinoplasty.
The skin-soft tissue envelope (STE) is a critical component of rhinoplasty and can have a significant impact on the final result. Skin contour sutures (SCSs) can be used to prevent potential complications related to skin detachment and to improve rhinoplasty results. The aim of this study was to assess the efficiency of SCSs for nasal skin approximation. SCSs involve the use of external sutures to stabilize the STE flap based on the principle that the pressure of the sutures helps to approximate the STE to the underlying nasal skeleton. The first study group demonstrated the utilization of SCSs in 459 consecutive rhinoplasty cases between December 2016 and April 2022 which were retrospectively reviewed. The second study group consisted of 30 patients with thick skin who had insertion of SCSs with ultrasonic evaluation both preoperatively and postoperatively. The average postoperative follow-up period in the first study group was 41 months (range, 12-64 months). Any suture site that was visible after removal of the suture disappeared completely after 6 weeks in most patients. No complications were reported. In the second group the ultrasound data indicated that STE healing was faster as its thickness returns to its preoperative state earlier in the healing process when SCSs were used. SCSs appear to help to decrease severe nasal edema, hematomas, loss of tip definition, fibrosis, and pollybeak deformity, thereby improving the results and predictability of rhinoplasty surgery.


Case report. Hypoglossal palsy: computed tomography demonstration of denervation hemiatrophy of the tongue associated with glomus jugulare tumor.
In a patient with left glomus jugulare tumor and left hypoglossal nerve palsy, computed tomography demonstrated focal lucency of the left half of the tongue. This was interpreted to represent postdenervation fibrosis and fatty replacement of the intrinsic and extrinsic lingual muscles supplied by the hypoglossal (XIIth cranial) nerve.


Etoposide and hypoxia do not activate apoptosis of multipotent mesenchymal stromal cells in vitro.
Incubation of multipotent mesenchymal stromal cells from human adipose tissue with etoposide for 24, 48, and 72 h under standard conditions (20% O(2)), at "physiological" oxygen content (5% O(2)), and under hypoxic conditions (1% O(2)) did not induce cell apoptosis and only slightly increased the number of necrotic cells. The absence of growth factors in the culture medium did not potentiate the damaging effect of etoposide on multipotent mesenchymal stromal cells under standard and hypoxic conditions. We concluded that etoposide produced no pro-apoptotic effect on multipotent mesenchymal stromal cells from the human adipose tissue.


Surgical repair of dissection of the upper descending thoracic aorta and discrete ascending aortic aneurysm.
This report describes successful staged surgical repair in 2 patients with dissection of the upper descending thoracic aorta (DeBakey type III) with coexisting discrete Marfan's aneurysms of the ascending aorta. Initial repair of the descending aortic dissection was done through a left thoracotomy using a transverse aorta--femoral artery shunt in 1 patient and a left ventricular apex--femoral artery shunt without systemic heparinization in the other. Emphasis is placed on the need for pharmacological reduction of blood pressure during aortic cross-clamping as well as the use of a shunt to prevent dissection of the ascending aortic aneurysm. In both patients, subsequent repair of the ascending aortic aneurysm was accomplished using composite graft replacement of the aortic valve and ascending aorta. This operation is advised for such patients even in the absence of notable aortic valve incompetence.


Patient satisfaction after open carpal tunnel release correlates with depression.
To test the null hypothesis that depression does not correlate with patient satisfaction after open release of electrodiagnostically confirmed carpal tunnel syndrome when controlling for other demographic, disease-related, and psychosocial factors. Eighty-two survey respondents who had recovered (minimum 2 years after surgery) from a limited incision open carpal tunnel release completed measures of satisfaction, perceived disability, depression, pain catastrophizing, and pain anxiety. Univariate and multivariate analyses sought predictors of satisfaction and perceived disability from among demographic, disease related, and psychological factors. The average satisfaction score was 8 points (range, 0-10) and the average Disabilities of the Arm, Shoulder, and Hand score was 13 points (range, 0-76). Predictors of greater dissatisfaction included greater depression and the categorical electrophysiologic test rating. Predictors of perceived disability included depression, pain catastrophizing, and static numbness. Depression was the dominant predictor of both satisfaction and perceived disability. Dissatisfaction and perceived disability after limited open carpal tunnel release for electrodiagnostically confirmed idiopathic carpal tunnel syndrome is predicted primarily by depression and ineffective coping skills and to a lesser degree by clinical or electrophysiologic evidence of advanced nerve damage. Prognostic II.


Osteopontin expression in the invasive front stroma of colorectal adenocarcinoma is associated with tumor budding and prognosis.
Tumor budding (TB) is an important prognostic factor in colorectal carcinoma (CRC). Osteopontin (OPN) functions in various processes such as immune response, migration and invasion, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis. However, the involvement of OPN and CD44v6, which is a receptor for OPN, in TB has not been clarified. Therefore, we examined the relationship of OPN with TB in CRC and compared the clinicopathological features. We investigated the expression of OPN and CD44v6 in 83 cases of CRC by immunostaining and analyzed the clinicopathological features. OPN expression was observed mostly in the cytoplasm of stromal cells such as macrophages and fibroblasts, and rarely in cancer cells. There was a significant correlation between OPN positivity and the degree of differentiation at the invasive front and TB grade. CD44v6 was positive in cancer cells in 72 cases (86.7 %) and negative in 11 cases (13.3 %). A statistically significant effect on overall survival (OS) was identified between the OPN-positive group [median OS: 1586 (range, 30-2749) days] and the OPN-negative group [median OS: 1901 (range, 8-2665) days] (log-rank test, p = 0.011). OPN analysis in CRC stromal cells may have prognostic implications.


The melatonin receptor antagonist luzindole induces the activation of cellular stress responses and decreases viability of rat pancreatic stellate cells.
In this study, we have examined the effects of luzindole, a melatonin receptor-antagonist, on cultured pancreatic stellate cells. Intracellular free-Ca2+ concentration, production of reactive oxygen species (ROS), activation of mitogen-activated protein kinases (MAPK), endoplasmic reticulum stress and cell viability were analyzed. Stimulation of cells with the luzindole (1, 5, 10 and 50 μm) evoked a slow and progressive increase in intracellular free Ca2+ ([Ca2+ ]i ) towards a plateau. The effect of the compound on Ca2+ mobilization depended on the concentration used. Incubation of cells with the sarcoendoplasmic reticulum Ca2+ -ATPase inhibitor thapsigargin (1 μm), in the absence of Ca2+ in the extracellular medium, induced a transient increase in [Ca2+ ]i . In the presence of thapsigargin, the addition of luzindole to the cells failed to induce further mobilization of Ca2+ . Luzindole induced a concentration-dependent increase in ROS generation, both in the cytosol and in the mitochondria. This effect was smaller in the absence of extracellular Ca2+ . In the presence of luzindole the phosphorylation of p44/42 and p38 MAPKs was increased, whereas no changes in the phosphorylation of JNK could be noted. Moreover, the detection of the endoplasmic reticulum stress-sensor BiP was increased in the presence of luzindole. Finally, viability was decreased in cells treated with luzindole. Because cellular membrane receptors for melatonin have not been detected in pancreatic stellate cells, we conclude that luzindole could exert direct effects that are not mediated through its action on melatonin membrane receptors.


Disorders of sexual desire in a sample of women alcoholics.
A questionnaire study on the sexuality of 55 women alcoholics and a matched sample of 54 non-alcoholics shows that for women alcoholics sexuality and partner relationships are definitely more stressful and conflicting than for the non-alcoholic control group. Women alcoholics describe to a greater extent than controls symptoms which indicate a disorder of sexual desire according to the model of H.S. Kaplan (H.S. Kaplan, Disorders of Sexual Desire, Simon & Schuster, New York, 1979).


Sampling and energy evaluation challenges in ligand binding protein design.
The steroid hormone 17α-hydroxylprogesterone (17-OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17-OHP containing an extended, nonpolar, shape-complementary binding pocket for the four-ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17-OHP with micromolar affinity. A co-crystal structure of one of the designs revealed that 17-OHP is rotated 180° around a pseudo-two-fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same "flipped" orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two-fold symmetry of the molecule.


Cytological Diagnosis and Misdiagnosis of Nodular Fasciitis.
Nodular fasciitis (NF) is a rapidly growing, self-limiting, subcutaneous nodular cytologic exuberant fibroblastic/myofibroblastic proliferation prone to cytological misdiagnosis. This study aimed at finding out the utility of fine needle aspiration cytology (FNAC) from NF patients and to validate the diagnostic features. The study group comprised 11 cases diagnosed as NF on cytology or subsequent histology. Out of 11 cases, 9 were cytologically diagnosed as NF. Two cases were misdiagnosed as sarcoma as proven histologically. Of the 9 cases of NF, spontaneous resolution occurred in 7 cases in 2-16 weeks; excisional biopsy was undertaken in the other 2 cases. On cytology, NF reveals hypercellular, polymorphic, dispersed cell population, which is most commonly misdiagnosed as sarcoma. For this reason, FNAC has to be correlated with clinical data and followed up for the anticipated spontaneous regression.


Multivariate nonlinear regression analysis of trajectory tracking performance using force reflecting joystick in chronic stroke-induced hemiparesis.
Individualizing a neurorehabilitation training protocol requires understanding the performance of subjects with various capabilities under different task settings. We use multivariate regression to evaluate the performance of subjects with stroke-induced hemiparesis in trajectory tracking tasks using a force-reflecting joystick. A nonlinear effect was consistently shown in both dimensions of force field strength and impairment level for selected kinematic performance measures, with greatest sensitivity at lower force fields. This suggests that the form of a force field may play a different "role" for subjects with various impairment levels, and confirms that to achieve optimized therapeutic benefit, it is necessary to personalize interfaces.


Molecular phylogeny of the spiny-surfaced species of the dinoflagellate Prorocentrum with the description of P. thermophilum sp. nov. and P. criophilum sp. nov. (Prorocentrales, Dinophyceae).
Spiny-surfaced species of Prorocentrum form harmful algal blooms, and its taxonomic identity is obscure due to the size and shape variability. Molecular phylogenies reveal two major clades: one for P. cordatum with sequences mainly retrieved as P. minimum, and the other for P. shikokuense with sequences also retrieved as P. dentatum and P. donghaiense. Several closely related clades still need to be characterized. Here, we provide nuclear SSU and LSU rRNA genes, and nuclear ITS region (ITS1-5.8S gene-ITS2) sequences of the strain CCMP3122 isolated from Florida (initially named P. donghaiense) and strains Prorocentrum sp. RCC6871-2 from the Ross Sea, Antarctica. We describe Prorocentrum thermophilum sp. nov. based on the strain CCMP3122, a species also distributed in the open waters of the Gulf of Mexico, New Zealand, and the Arabian Gulf; and Prorocentrum criophilum sp. nov. based on the strain RCC6872, which is distributed in the Antarctic Ocean and Arctic Sea. Prorocentrum thermophilum is roundish (~14 μm long, ~12 μm wide), with an inconspicuous anterior spine-like prolongation under light microscopy, valves with tiny, short knobs (5-7 per μm2 ), and several (<7) large trichocyst pores (~0.3 μm) in the right valve, as well as smaller pores (~0.15 μm). Prorocentrum criophilum is round in valve view (~11 μm long, 10 μm wide) and asymmetrically roundish in lateral view, the periflagellar area was not discernible under light microscopy, valves with very tiny, short knobs (6-10 per μm2 ), and at least 12 large pores in the right valve. Other potentially undescribed species of spiny-surfaced Prorocentrum are discussed.


Infection of immunosuppressed mice with the abomasal nematode parasite of ruminants, Haemonchus contortus.
Infective larvae of Haemonchus contortus established in mice either immunosuppressed with the corticosteroid, dexamethasone, or the cytotoxic drug, cyclophosphamide, or treated with the histamine H2 inhibitor, cimetidine. Infections persisted for as long as the immunosuppressive treatment (7 days) and growth of larvae was similar to that seen in sheep. Virtually no larvae survived in untreated mice. Accordingly, it would appear that adaptive immunity is an important barrier against primary infection by H. contortus in mice and is a determinant of host-range for this parasite. Antibody raised in either sheep or mice against soluble extracts of adult H. contortus precipitated with different but overlapping sets of worm antigens. This suggests that the unique antigens recognized by the mouse compared with the sheep are crucial for the rapid protective responses which prevent primary infection.


Characterizing the fusion order and level-specific rates of arthrodesis in 3-level anterior cervical discectomy and fusion: A radiographic study.
Pseudarthrosis is a well-recognized complication following multi-level ACDF. We aim to characterize the fusion order and level-specific rates of arthrodesis across four time points following 3-level ACDF. Patients who underwent 3-level ACDF by three UCSF spine surgeons from August 2012 to December 2019 were identified. Fusion status at each level was determined by measuring the interspinous motion on flexion and extension radiographs and assessing for evidence of bridging bone. Measurements were performed post-operatively at 6 weeks, 6 months, 12 months, and 18-24 months. A total of 77 patients with 3-level ACDF were identified and included in this study. Specific ACDF levels include C3-C6 (17 patients), C4-C7 (57 patients), and C5-T1 (3 patients). At 6 months, the cranial, middle, and caudal level fusion rates were 17.0%, 34.0%, and 3.8%, respectively. By 24 months, fusion rates were 61.1%, 88.9%, and 27.8% at the cranial, middle, and caudal level, respectively. PEEK cages were associated with lower odds of multi-level arthrodesis. Arthrodesis occurred the quickest at the middle level with an 88.9% fusion rate by 24 months after surgery. The caudal level had the slowest rate of arthrodesis with only a 27.8% fusion rate at 24 months, likely due to increased biomechanical stress at the most caudal level. Allograft was associated with higher odds of multi-level arthrodesis compared to PEEK cages.


Interferon regulatory factor-1 is inducible by prolactin, interleukin-2 and concanavalin A in T cells.
Interferon regulatory factor-1 (IRF-1) gene expression is rapidly upregulated in the prolactin (PRL)-activated Nb2 rat T lymphoma cell line. To further elucidate its role as a T cell activation molecule, IRF-1 gene expression in response to various T cell stimuli was examined. In Nb2 T cells, PRL induced two peaks of IRF-1 gene expression: a rapid, transient peak at 1 h and a sustained peak at 12 h. PRL subsequently induced interferon-gamma (IFN-gamma) gene expression at 3-6 h. However, the early induction of IRF-1 and IFN-gamma does not appear to be interdependent. Interleukin-2 (IL-2) also induced IRF-1 gene expression in Nb2 T cells but only one broad peak at 10 h was observed. In primary mouse splenocytes, concanavalin A induced rapid and transient expression of the IRF-1 gene; maximal expression occurred by 6 h, and then returned to basal levels by 12-15 h. These results provide additional evidence for the importance of IRF-1 in T cell activation.


Correction to: The efficacy of etanercept as anti-breast cancer treatment is attenuated by residing macrophages.
An amendment to this paper has been published and can be accessed via the original article.


Autofluorescence of Parathyroid Glands: A Review of Methods of Parathyroid Gland Identification and Parathyroid Vascular Assessment.
Postoperative hypoparathyroidism may cause significant patient morbidity and even mortality. Emerging technologies centered on autofluorescent properties of parathyroid glands when exposed to near-infrared light hold promise to improve surgical parathyroid gland identification and preservation. Two systems (probe-based and camera-based) are commercially available currently; however, neither system alone provides indication of vascular viability or postoperative parathyroid gland function. The administration of indocyanine green, when combined with near-infrared fluorescence imaging, enables subjective assessment of parathyroid gland perfusion. Additional technologies to assess parathyroid gland perfusion are being developed. The impact of these nascent technologies on relevant clinical outcomes is an area of active investigation.


Autosomal dominant inheritance of sinus node disease.
A family with sinus node disease is presented. The mother was severely affected by sinus bradycardia and required a permanent atrial pacing system. The father is asymptomatic and has no evidence of conduction disturbances. All their offspring (one son and two daughters) are affected with variable degrees of severity. The occurrence of the disease in this family is suggestive of autosomal dominant inheritance with variable penetrance.


Towards diversity in genomics: The emergence of neurogenomics in Africa?
There is a high burden of mental and neurological disorders in Africa. Nevertheless, there appears to be an under-representation of African ancestry populations in large-scale genomic studies. Here, we evaluated the extent of under-representation of Africans in neurogenomic studies in the GWAS Catalog. We found 569 neurogenomic studies, of which 88.9% were exclusively focused on people with European ancestry and the remaining 11.1% having African ancestry cases included. In terms of population, only 1.2% of the total populations involved in these 569 GWAS studies were of African descent. Further, most of the individuals in the African ancestry category were identified to be African-Americans/Afro-Caribbeans, highlighting the huge under-representation of homogenous African populations in large-scale neurogenomic studies. Efforts geared at establishing strong collaborative ties with European/American researchers, maintaining freely accessible biobanks and establishing comprehensive African genome data repositories to track African genome variations are critical for propelling neurogenomics/precision medicine in Africa.


Basophil histamine release and humoral changes during immunotherapy. Dissociation between basophil-bound specific IgE, serum value, and cell sensitivity.
An in vitro pilot study was performed to determine whether basophil cell-bound specific IgE was correlated to serum-specific IgE and to basophil cell sensitivity during immunotherapy with a well-documented treatment. The findings showed a clear dissociation between these three parameters, which is in contrast to the situation before hyposensitization and to our previous study in a comparable group of non-hyposensitized patients, where highly significant correlations were observed. Further investigations are in progress to clarify whether the dissociation is involved in the clinical improvement.


The evidence on the degradation processes in the midgut epithelial cells of the larval antlion Euroleon nostras (Geoffroy in Fourcroy, 1785) (Myrmeleontidae, Neuroptera).
We analysed structural differences between midgut epithelial cells of fed instar antlions' larvae Euroleon nostras and starved ones. In starved larvae the presence of autophagolysosome-like structures was observed, which are characteristic structures associated with autophagy. The results presented here provide insight supporting the role of autophagy as a cell survival mechanism for the periods of food deprivation. Additional structural changes in the cytoplasm were seen in the spherites. The ultrastructure and chemical composition of spherites in the midgut epithelial cells of first, second and third instar larvae were observed with light microscopy and transmission electron microscopy (TEM). A detailed characterization of the elemental composition of the spherites was studied using analytical electron microscopy; a combination of energy dispersive X-ray spectroscopy (EDXS), electron energy-loss spectroscopy (EELS) and energy filtering TEM (EFTEM) was applied. The structure and elemental composition of the spherites changed during the period of larval life. Moreover, changes in chemical composition were found between spherites from fed and starved E. nostras. In fed first instar larvae, the spherites contained an organic matrix, composed of C, N and O. In this matrix, P, Cl, Ca and Fe were detected. In starved first instar larvae, only C, N and P were present. The spherites of fed second instar larvae were rich in organic and inorganic elements and were composed of C, N, O, Na, Mg, P, S, Cl, K, Ca, Mn, Fe and Zn. In starved second instar larvae, the chemical elements N, O, P, Ca and Fe were found. In fed third instar larvae, the spherites contained C, N, O, Na, Mg, P, Cl, K, Ca, Mn, Fe, Co and Zn. In starved third larvae, C, O, Si, Ca, and Fe were detected. Generally, the spherites are exploited in starved larvae. These results suggest that the elemental supply of spherites may provide crucial support for physiological processes during starvation periods amongst E. nostras instar larvae. In some cases in fed second and fed third instar larvae, spherites were seen in the lumen of the midgut. Such spherites could serve as reservoirs for nontoxic waste material that cannot be metabolized.


Robotic approach for pediatric pulmonary resection: preliminary investigation and comparative study with thoracoscopic approach.
Minimal invasive pulmonary resection in children is challenging, irrespective of whether it is conducted using a robot or a thoracoscope. This study presents the preliminary results of pediatric robotic pulmonary resection (RPR) and comparison outcomes with conventional thoracoscopic pulmonary resection (TPR). This is a retrospective study conducted in patients underwent RPR (RPR group; n=30) and TPR (TPR group; n=44). The clinical data, including operative time, post-operative body temperature, surgical complications, surgeon's workload (by NASA-TLX), postoperative hospital stay, and scar score (using the SCAR scale), of both the RPR and TPR groups were collected and compared. Both groups had similar age and weight. The youngest patient belonged to the RPR group and was 6 months old and weighed 8 kg. One case in the RPR group and two in the TPR group were converted to thoracotomy. RPR had a longer total operative time (148.3±36.8 min), but a shorter pure operative time (103.9±28.5 min) than those of the TPR group [118.3±22.5 (P<0.001) and 111.4±18.3 min (P=0.045), respectively]. Compared to the TPR group, fewer patients in the RPR group reported fever postoperatively (2/29 vs. 11/42, P=0.039). The workload of the surgeons was also lower in the RPR group (55.2±4.7 vs. 62.9±6.0, P<0.01). No significant difference was observed in perioperative complications, drainage length, postoperative hospital stays, and scar score of the two groups. The safety and effectiveness of the robotic approach are similar to those of the thoracoscopic surgery for pediatric pulmonary resection in children heavier than 8 kg. In addition, the robotic approach shows improved operative dissection efficiency and accuracy for patients and reduced workload for surgeons. Hence, it is beneficial to both surgeons and patients.


Glycosidase activities of mycoplasmas.
The activities of alpha- and beta-glucosidase, beta-galactosidase and beta-N acetylglucosaminidase were assessed at acidic pH by fluorimetry using the appropriate 4-methylumbelliferyl substrate in four Mycoplasma species (M. pneumoniae, M. gallisepticum, M. hominis and M. capricolum) and in Acholeplasma laidlawii. The glycosidase activities were in a low range (0.1-4.2 nmole per h per mg protein) with the exception of higher activities of beta-N-acetylglucosaminidase in A. laidlawii. The enzyme levels of a virulent and a nonvirulent strain of M. pneumoniae were comparable. Despite the very sensitive assay, neuraminidase activity was not detected in M. pneumoniae and M. gallisepticum. No induction of alpha-glucosidase could be demonstrated for M. pneumoniae or A. laidlawii. At least part of the glycosidase activities was localized in the membrane fraction of all mycoplasmas studied. This may support the hypothesis that pathogenic mycoplasmas, being membrane parasites, may modify, by their glycosidases, some host cell glycoconjugates. However, our study did not distinguish the pathogenic mycoplasmas to possess a characteristic glycosidase profile.


Conformational changes in protein function.
Conformational changes are the hallmarks of protein dynamics and are often intimately related to protein functions. Molecular dynamics (MD) simulation is a powerful tool to study the time-resolved properties of protein structure in atomic details. In this chapter, we discuss the various applications of MD simulation to the study of protein conformational changes, and introduce several selected advanced techniques that may significantly increase the sampling efficiencies, including locally enhanced sampling (LES), and grow-to-fit molecular dynamics (G2FMD).


Halogenated methanesulfonic acids: A new class of organic micropollutants in the water cycle.
Mobile and persistent organic micropollutants may impact raw and drinking waters and are thus of concern for human health. To identify such possible substances of concern nineteen water samples from five European countries (France, Switzerland, The Netherlands, Spain and Germany) and different compartments of the water cycle (urban effluent, surface water, ground water and drinking water) were enriched with mixed-mode solid phase extraction. Hydrophilic interaction liquid chromatography - high resolution mass spectrometry non-target screening of these samples led to the detection and structural elucidation of seven novel organic micropollutants. One structure could already be confirmed by a reference standard (trifluoromethanesulfonic acid) and six were tentatively identified based on experimental evidence (chloromethanesulfonic acid, dichloromethanesulfonic acid, trichloromethanesulfonic acid, bromomethanesulfonic acid, dibromomethanesulfonic acid and bromochloromethanesulfonic acid). Approximated concentrations for these substances show that trifluoromethanesulfonic acid, a chemical registered under the European Union regulation REACH with a production volume of more than 100 t/a, is able to spread along the water cycle and may be present in concentrations up to the μg/L range. Chlorinated and brominated methanesulfonic acids were predominantly detected together which indicates a common source and first experimental evidence points towards water disinfection as a potential origin. Halogenated methanesulfonic acids were detected in drinking waters and thus may be new substances of concern.


[Applicability of QUIKS in conservatively treated tumor inpatients].
Quality improvement in conservative pain management (QUIKS), a module for nonoperative patients in the QUIPS project was tested on a cohort of tumor patients regarding its applicability. Conservatively treated inpatients at the University Hospital of Würzburg (UKW) were prospectively surveyed on the quality of pain management using the QUIKS outcome questionnaire (AZ 129/17, Ethics Committee at UKW). Information on therapy and demographics was taken from the hospital's internal documentation system. During the data collection period 100 conservatively treated inhouse tumor patients from different hospitals were included. Of the patients 74% required assistance in answering the questionnaire. Functional limitations or pain treatment-related side effects were present in 77% of the patients; the average pain level was 6 on the numerical rating scale. The most commonly reported type of pain was back pain and headache. Of the patients 18% received pain therapy with opioids and 26% with nonopioids, adjustment was made in 5% with opioids and in 44% with nonopioids and pain medicine specialists were consulted in 9% of cases. The application of the questionnaire was well accepted by the patients but required a high level of assistance in completing it. A high level of pain was observed during the hospital stay and the adjustment of pain therapy or the involvement of pain medicine specialists was rare. The interpretation of statements regarding the quality of tumor pain may be limited as other (pre-existing) pain entities, such as nontumor-associated pain or chronic tumor pain could not be clearly delineated.