Ultrasound gel causes fine needle aspiration artifact? A clear choice.
Ultrasound-guided fine needle aspiration (FNA) is a commonly employed tool in cytopathologic practice. Artifacts resulting in misinterpretation of specimens have been noted with various ultrasound gel media. Our purpose was to perform a prospective human cadaveric study of this phenomenon to identify a low-cost solution that eliminates the artifact. Three separate ultrasound-guided FNAs were performed on the thyroid and parotid glands in situ of a fresh human cadaver using three different types of ultrasound gel media. Slides were prepared in standard fashion (Quik-Diff and Papanicolaou stains). Two cytopathologists subsequently analyzed the slides for the presence of any artifact interfering with their ability to visualize and interpret the cellular aspirate material. Two of the three gel media revealed significant artifacts mimicking apoptosis, necrosis or colloid, making it difficult to visualize the cellular components and differentiate the artifact from the thyroid colloid. One gel medium did not show any significant artifact, and there was no discernable difference in its quality with regard to the ultrasound image during FNA procedures. Ultrasound gels can be associated with a significant artifact in FNA specimens. To eliminate this artifact, which may alter the adequacy, diagnosis or cytologic appearance, we confirm a specific gel type that is useful for ultrasound-guided FNAs.


Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids.
This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors.


Stabilisation of sagittal split set-back osteotomies with miniplates: a prospective, multicentre study with 2-year follow-up.
The aim of this study was to assess post-operative stability of bilateral sagittal split set-back osteotomies using two miniplates and clinical parameters including nerve function, TMJ function, occlusal relapse and patient satisfaction. The stability was measured on cephalometric radiographs and possible condylar alterations on orthopantomograms. This prospective study implied a 2-year follow-up on a group of 24 patients. The same protocol was used at six participating institutions at which the patients were treated. A stable occlusion without appreciable relapse was seen in 91% after 2-year follow-up. Only two patients in this study had mild occlusal relapse. The mean skeletal horizontal relapse at pogonion of the whole group, after 2 years was 1.1mm and appeared to be directed backwards. At occlusal level, however, the mean relapse was 1.2mm forwards. The function of the inferior alveolar nerve 2 years post-operatively was reported to be normal in approximately 70% of the patients, yet 80% had no complaints about nerve dysaesthesia. In approximately 21% of the patients, signs and symptoms of TMJ dysfunction had disappeared. Another group (10%), however, without pre-operative signs and symptoms of TMJ dysfunction developed these signs or symptoms post-operatively. No condylar remodelling or resorption was seen in this group of patients. The sagittal split set-back osteotomy fixed with miniplates appeared to be a relatively save and reliable procedure giving rise to adequate results and a high degree of patients satisfaction.


Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity.
Curcumin has been demonstrated to have many neuroprotective properties, including improvement of cognition in humans and neurogenesis in animals, yet the mechanism of such effects remains unclear. We assessed behavioural performance and hippocampal cell proliferation in aged rats after 6- and 12-week curcumin-fortified diets. Curcumin enhanced non-spatial and spatial memory, as well as dentate gyrate cell proliferation as compared to control diet rats. We also investigated underlying mechanistic pathways that might link curcumin treatment to increased cognition and neurogenesis via exon array analysis of cortical and hippocampal mRNA transcription. The results revealed a transcriptional network interaction of genes involved in neurotransmission, neuronal development, signal transduction, and metabolism in response to the curcumin treatment. The results suggest a neurogenesis- and cognition-enhancing potential of prolonged curcumin treatment in aged rats, which may be due to its diverse effects on genes related to growth and plasticity.


Utilization of the embryonated egg for in vivo evaluation of the anti-influenza virus activity of neuraminidase inhibitors.
Previous studies have shown that embryonated egg provides a convenient and easy to use system for in vivo screening of anti-influenza virus inhibitors. However, it is not known whether this model is suitable for testing neuraminidase (NA) inhibitors, too. Therefore, the present study describes the evaluation of the ion-channel blockers amantadine and rimantadine in comparison with the NA inhibitors oseltamivir and zanamivir by using the influenza A virus hen's egg model. The treatment was started immediately before or after the challenge dose was placed on the chorioallantoic membrane (CAM). Differences between the survival rate of treated and untreated chick embryos infected with influenza A virus were analyzed statistically. As result, the survival rate of chick embryos could be significantly increased when the treatment with amantadine, rimantadine, oseltamivir, or zanamivir was started before the CAM was inoculated with one egg infective dose 50% (EID50) influenza A virus. When the drugs were administered shortly after viral inoculation, significant antiviral efficacy was shown for rimantadine, oseltamivir, and zanamivir. Antiviral efficacy could be demonstrated exclusively for both oseltamivir and zanamivir after the embryos were infected with higher challenge doses of 10(2) EID50 influenza A virus. In conclusion, the NA inhibitors oseltamivir and zanamivir have a significantly better antiviral activity against influenza A virus than amantadine and rimantadine tested in embryonated hen's eggs. Therefore, this model can be a valuable alternative approach for in vivo pre-testing anti-influenza virus activity of NA inhibitors.


An Introduction to Chemogenomics.
Chemogenomics is an innovative approach in chemical biology that synergizes combinatorial chemistry and genomic and proteomic biology to systematically study the response of a biological system to a set of compounds, which can aid the identification and validation of biological targets as well as biologically active small-molecule agents responsible for a phenotypic outcome. Central to this strategy is a collection of chemically diverse compounds, a so-called chemogenomics library. Selection and annotation of vastly available chemogenomic compound candidates for an inclusion in such set present a challenge, but optimal compound selection is critical for success of chemogenomics. The library can be used in a wide variety of research applications from biological mechanism deconvolution to drug discovery. However, phenotypic screening methods are typically required to be high-throughput and equipped with a systematic analysis of complex biological-chemical interactions. This chapter provides a general outline to the chemogenomics approach, including concept and critical steps in all stages of this innovative chemical biology strategy.


Expert opinions on good practice in evaluation of health promotion and primary prevention measures related to children and adolescents in Germany.
Determining what constitutes "good practice" in the measurement of the costs and effects of health promotion and disease prevention measures is of particular importance. The aim of this paper was to gather expert knowledge on (economic) evaluations of health promotion and prevention measures for children and adolescents, especially on the practical importance, the determinants of project success, meaningful parameters for evaluations, and supporting factors, but also on problems in their implementation. This information is targeted at people responsible for the development of primary prevention or health promotion programs. Partially structured open interviews were conducted by two interviewers and transcribed, paraphrased, and summarized for further use. Eight experts took part in the interviews. The interviewed experts saw evaluation as a useful tool to establish the effects of prevention programs, to inform program improvement and further development, and to provide arguments to decision making. The respondents' thought that determinants of a program's success were effectiveness with evidence of causality, cost benefit relation, target-group reach and sustainability. It was considered important that hard and soft factors were included in an evaluation; costs were mentioned only by one expert. According to the experts, obstacles to evaluation were lacking resources, additional labor requirements, and the evaluators' unfamiliarity with a program's contents. It was recommended to consider evaluation design before a program is launched, to co-operate with people involved in a program and to make use of existing structures. While in in this study only a partial view of expert knowledge is represented, it could show important points to consider when developing evaluations of prevention programs. By considering these points, researchers could further advance towards a more comprehensive approach of evaluation targeting measures in children and adolescents.


The prognostic value of global myocardium strain by CMR-feature tracking in immune checkpoint inhibitor-associated myocarditis.
Immune checkpoint inhibitor (ICI)-associated myocarditis is a potentially fatal complication. Sparse published researches evaluated the prognostic value of cardiovascular magnetic resonance feature tracking (CMR-FT) for ICI-associated myocarditis. In the single-center retrospective study, 52 patients with ICI-associated myocarditis and CMR were included from August 2018 to July 2021. The ICI-associated myocarditis was diagnosed by using the clinical criteria of the European Society of Cardiology guidelines. Major adverse cardiovascular events (MACE) were comprised of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. During a median follow-up of 171 days, 14 (27%) patients developed MACE. For patients with MACE, the global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) were significantly worse and native T1 values and late gadolinium enhancement (LGE) extent were significantly increased, compared with patients without MACE (p < 0.05). The GLS remained the independent factor associated with a higher risk of MACE (hazard ratio (HR): 2.115; 95% confidence interval (CI): 1.379-3.246; p = 0.001) when adjusting for LVEF, LGE extent, age, sex, body mass index, steroid treatment, and prior cardiotoxic chemotherapy or radiation. After adjustment for LVEF, the GLS remained the independent risk factor associated with a higher rate of MACE among patients with a preserved LVEF (HR: 1.358; 95% CI: 1.007-1.830; p = 0.045). GLS could provide independent prognostic value over GCS, GRS, traditional CMR features, and clinical features in patients with ICI-associated myocarditis. • The global circumferential strain (GCS), global radial strain (GRS), and global longitudinal strain (GLS) by cardiovascular magnetic resonance feature tracking were significantly impaired in patients with an immune checkpoint inhibitor (ICI)-associated myocarditis. • GLS was still significantly impaired in patients with preserved left ventricular ejection fraction. • The worse GLS was an independent risk factor over GCS, GRS, traditional CMR features, and clinical features for predicting major adverse cardiovascular events in patients with ICI-associated myocarditis.


Expansive arterial remodeling of the carotid arteries and its effect on atherosclerotic plaque composition and vulnerability: an in-vivo black-blood 3T CMR study in symptomatic stroke patients.
Based on intravascular ultrasound of the coronary arteries expansive arterial remodeling is supposed to be a feature of the vulnerable atheroslerotic plaque. However, till now little is known regarding the clinical impact of expansive remodeling of carotid lesions. Therefore, we sought to evaluate the correlation of expansive arterial remodeling of the carotid arteries with atherosclerotic plaque composition and vulnerability using in-vivo Cardiovascular Magnetic Resonance (CMR). One hundred eleven symptomatic patients (74 male/71.8 ± 10.3y) with acute unilateral ischemic stroke and carotid plaques of at least 2 mm thickness were included. All patients received a dedicated multi-sequence black-blood carotid CMR (3Tesla) of the proximal internal carotid arteries (ICA). Measurements of lumen, wall, outer wall, hemorrhage, calcification and necrotic core were determined. Each vessel-segment was classified according to American Heart Association (AHA) criteria for vulnerable plaque. A modified remodeling index (mRI) was established by dividing the average outer vessel area of the ICA segments by the lumen area measured on TOF images in a not affected reference segment at the distal ipsilateral ICA. Correlations of mRI and clinical symptoms as well as plaque morphology/vessel dimensions were evaluated. Seventy-eight percent (157/202) of all internal carotid arteries showed atherosclerotic disease with AHA Lesion-Type (LT) III or higher. The mRI of the ICA was significantly different in normal artery segments (AHA LT I; mRI 1.9) compared to atherosclerotic segments (AHA LT III-VII; mRI 2.5; p < 0.0001). Between AHA LT III-VII there was no significant difference of mRI. Significant correlations (p < 0.05) of the mRI with lumen-area (LA), wall-area (WA), vessel-area (VA) and wall-thickness (WT), necrotic-core area (NC), and ulcer-area were observed. With respect to clinical presentation (symptomatic/asymptomatic side) and luminal narrowing (stenotic/non-stenotic) no relevant correlations or significant differences regarding the mRI were found. Expansive arterial remodeling exists in the ICA. However, no significant association between expansive arterial remodeling, stroke symptoms, complicated AHA VI plaque, and luminal stenosis could be established. Hence, results of our study suggest that expansive arterial remodeling is not a very practical marker for plaque vulnerability in the carotid arteries.


UVB damage onset and progression 24 h post exposure in human-derived skin cells.
The focus of this research was on UVB radiation (280-320 nm) responsible for cellular changes in skin of acute and chronically exposed individuals. This study investigated the acute cellular damages triggered by UVB exposure of cultured human fibroblasts and keratinocyte cells immediately and 24 h post exposure in order to understand damage onset and progression. The study evaluated a number of cellular parameters including mitochondria, lysosomes, cell membrane, DNA damages as well as pro and anti-apoptotic protein expression levels. Cellular organelle damages were assessed by a battery of in vitro toxicological assays using MTS and Neutral red cytotoxicity assays. Cell membrane damages were also assessed by measuring lactate dehydrogenase (LDH) enzyme leakage from UVB exposed cells. Lastly DNA damages was assessed using the comet assay while protein expression was evaluated using Western Blot. In this study we reported in all our assay systems (MTS, NR and LDH) that cellular damages were UVB dose dependent with damages amplified 24 h post exposure. Our results also indicated that incubation of exposed cells for a period of 24 h increased the sensitivity of the assay systems used. The increased sensitivity in detecting early cytotoxic damages was manifested though organelle damage measurement at very low doses which were not manifested immediately post exposure. The data also indicated that HaCaT cells were most sensitive in detecting UVB triggered damages immediately and 24 h post exposure using the MTS assay. We also established upregulation and downregulation of various apoptotic proteins at various time points post exposure. The presented data clearly indicated the need for a comprehensive assessment of UVB damages 4 and 24 h post exposure due to the different assay sensitivities in addition to various signaling mechanisms activated at different time points post exposure.


Novel, recyclable Brønsted acidic deep eutectic solvent for mild fractionation of hemicelluloses.
Acidic deep eutectic solvents (DESs) are promising media for lignin valorization and cellulose conversion due to their good ability in efficient deconstruction of plant cell wall. However, hemicellulose extraction from lignocellulose using acidic DESs remains a challenge. Herein, novel and green Brønsted acidic DESs (BDESs) were synthesized from natural organic acids and common polyols and successively adopted to deconstruct corncob for mild fractionation of hemicelluloses. Oxalic acid (OA)-based BDESs were preferred for corncob processing due to the high solubility of xylan. The results revealed that the suitable acidity of DESs and mild temperature effectively avoided the over-degradation of hemicelluloses. The chemical composition and structural features of the recovered hemicelluloses were investigated systematically. Moreover, after ethylene glycol (EG)-OA BDES was recycled and reused three times, the extraction still resulted in a satisfactory hemicellulose yield. The novel and eco-friendly processing offers a practical and sustainable route for hemicellulose extraction in acidic condition.


An evidence-based review of optimal perioperative practices in minor hand surgery.
Like many surgical subspecialties, there have been frequent advancements and discoveries in the field of hand and upper extremity surgery. With a rapidly growing literature base, it can be difficult to remain updated on the latest recommendations. A comprehensive literature search was completed on PubMed using MeSH terms. Topics included nutrition management, anticoagulation, immunosuppressive medication management, antibiotic use, skin preparation, splinting, tourniquet use, and suture choice. Data from articles with a level of evidence 1A-3 C were included. A total of 42 articles were identified and reviewed to provide evidence for recommendations regarding various aspects of pre-, intra-, and post-operative care. The objective of this manuscript is to serve as a resource for evidence-based recommendations by the findings of recent evidence related to perioperative care in elective hand surgery. Additional studies are required in certain areas of the literature in order to provide stronger recommendations.


Multivariate statistical methods for evaluating biodegradation of mineral oil.
Two methods were developed for evaluating natural attenuation and bioremediation of mineral oil after environmental spills and during in vitro experiments. Gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode was used to obtain compound-specific data. The chromatographic data were then preprocessed either by calculating the first derivative, retention time alignment and normalization or by peak identification, quantification and calculation of diagnostic ratios within homologue series of polycyclic aromatic compounds (PACs). Finally, principal component analysis (PCA) was applied to the preprocessed chromatograms or diagnostic ratios to study the fate of the oil. The methods were applied to data from an in vitro biodegradation experiment with a North Sea crude oil exposed to three mixtures of bacterial strains: R (alkane degraders and surfactant producers), U (PAC degraders) and M (mixture of R- and U-strains) over a 1-year-period with five sampling times. Assessment of variation in degradability within isomer groups of methylfluorenes (m/z 180), methylphenanthrenes (m/z 192) and methyldibenzothiophenes (m/z 198) was used to evaluate the effects of microbial degradation on the composition of the oil. The two evaluation methods gave comparable results. In the objective pattern matching approach, principal component 1 (PC1) described the general changes in the isomer abundances, whereas M samples were separated from U and R samples along PC2. Furthermore, in the diagnostic ratio approach, a third component (PC3) could be extracted; although minor, it separated R samples from U and M samples. These results demonstrated that the two methods were able to differentiate between the effects due to the different bacterial activities, and that bacterial strain mixtures affected the PAC isomer patterns in different ways in accordance with their different metabolic capabilities.


Erratum: Flow Navigation by Smart Microswimmers via Reinforcement Learning [Phys. Rev. Lett. 118, 158004 (2017)].
This corrects the article DOI: 10.1103/PhysRevLett.118.158004.


Lymph node ratio-based the ypTNrM staging system for gastric cancer after neoadjuvant therapy: a large population-based study.
The lymph node ratio (LNR) has been considered a better prognostic factor than traditional N staging in patients with gastric cancer (GC), but its accuracy is unclear for those who receive neoadjuvant therapy (NAT). We aimed to compare the node ratio (Nr) staging with the ypN staging and to thereby develop a modified staging system incorporating Nr staging. A total of 1791 patients who underwent gastrectomy after NAT in the Surveillance, Epidemiology, and End Results database were retrospectively analyzed. ypTNrM staging was established based on the overall survival (OS). The Nr staging was generated using 0.2 and 0.5 as the cutoff values of LNR and represented patients with more homogeneous OS compared with ypN staging. The 5-year OS rates for ypTNrM stages IA, IB, II, IIIA, and IIIB were 70.2%, 54.2%, 36.0%, 21.2%, and 6.6%, respectively, compared with 58.8%, 39.1%, and 21.6% for ypTNM stages I, II, and III, respectively. Compared with the ypTNM staging system, the ypTNrM staging system had a lower misclassification rate (3.0% vs. 50.9%) and better prognostic predictive power (C-index: 0.645 vs. 0.589, P < 0.001). The ypTNrM staging system incorporating Nr staging may provide a more accurate assessment in the clinical decision-making process for GC after NAT.


Aberrant reward dynamics in depression with anticipatory anhedonia.
Previous studies have shown that anticipatory anhedonia is linked to abnormal reward processing. The present study aimed to explore the underlying neural mechanism of the influence of anticipatory anhedonia symptoms on reward processing. Electrophysiological activities in the anticipatory and consummatory phase were recorded during the Monetary Incentive Delay (MID) task in 24 depressed high anticipatory anhedonia (HAA) patients, 25 depressed low anticipatory anhedonia (LAA) patients, and 29 healthy controls (HC). We suggested a significant condition × group interaction effect on feedback-related negativity (FRN) amplitudes during the consummatory phase, a smaller FRN in reward cue trails compared with neutral cue trail was revealed in the HC and LAA group, but such reward-related effect was not found in the HAA group. In addition, we found significant correlations between FRN, fb-P3 and cue-N1, cue-N2 in the HC group, besides, significant correlations between FRN, fb-P3 and cue-P2 was also revealed in the HC and LAA group. However, no significant correlation was found in HAA patients. Our results suggest that the link between the anticipatory and consummatory phase was interrupted in depressed HAA patients, which may be driven by the aberrant consummatory reward processing. The current study is the first one to demonstrate the influence of anticipatory anhedonia symptom on the association between anticipatory and consummatory phase of reward process.


Dual chamber pacing mode in an atrial antitachycardia pacing device without a ventricular lead - A necessary evil.
We present a case of a single chamber atrial pacemaker implanted for sinus node dysfunction and treatment of macroreentrant atrial tachycardias with atrial antitachycardia pacing. The patient presented with sustained atrial tachycardia above the detection rate, however, the device was unable to detect the tachycardia and did not deliver the programmed therapy. We discuss the nuances of the atrial tachyarrhythmia detection algorithms, and the programming strategies to maximize detection of atrial arrhythmias in a single chamber atrial pacemaker.


Enzymic reduction of cystine and glutathione in cultivated human fibroblast from normal subjects and patients with cystinosis.
Cystine glutathione transhydrogenase, cystine-reductase, and glutathion reductase activities were studied in cultivated skin fibroblasts of control subjects and of three patients with cystinosis. Specific activity, pH optima, electrophoretic mobility, and kinetic parameters were described. Evidence for two isoenzyme forms of cystine-glutathione transhydrogenase was obtained. No difference was detected in activity of biochemical characteristics of these enzymes between cells of cystinotic and normal subjects.


TMpro web server and web service: transmembrane helix prediction through amino acid property analysis.
TMpro is a transmembrane (TM) helix prediction algorithm that uses language processing methodology for TM segment identification. It is primarily based on the analysis of statistical distributions of properties of amino acids in transmembrane segments. This article describes the availability of TMpro on the internet via a web interface. The key features of the interface are: (i) output is generated in multiple formats including a user-interactive graphical chart which allows comparison of TMpro predicted segment locations with other labeled segments input by the user, such as predictions from other methods. (ii) Up to 5000 sequences can be submitted at a time for prediction. (iii) TMpro is available as a web server and is published as a web service so that the method can be accessed by users as well as other services depending on the need for data integration. http://linzer.blm.cs.cmu.edu/tmpro/ (web server and help), http://blm.sis.pitt.edu:8080/axis/services/TMProFetcherService (web service).


Validation of the Liver Imaging Reporting and Data System Treatment Response Criteria After Thermal Ablation for Hepatocellular Carcinoma.
Single hepatocellular carcinoma (HCC) tumors can be successfully eradicated with thermal ablation (TA). We assessed the validity of the Liver Imaging Reporting and Data System Treatment Response (LR-TR) criteria with a retrospective analysis of a single-center database of patients with small HCC tumors (<3 cm in diameter) who underwent both laparoscopic TA and liver transplantation (LT) from 2004 to 2018. Postablation MRIs were assigned LR-TR categories (nonviable, equivocal, and viable) for ablated lesions and Liver Imaging Reporting and Data System (LI-RADS) categories (probable or definite HCC) for untreated lesions. Interpretations were compared with the histopathology of the post-LT explanted liver. There were 45 patients with 81 tumors (59 ablated and 22 untreated; mean size, 2.2 cm), and 23 (39%) of the ablated tumors had viable HCC on histopathology. The sensitivity/specificity of LR-TR categories (nonviable/equivocal versus viable) of ablated tumors was 30%/99%, with a positive predictive value (PPV)/negative predictive value (NPV) of 93%/69%. The sensitivity varied with residual tumor size. The sensitivity/specificity of LI-RADS 4 and 5 diagnostic criteria at detecting new HCC was 65%/94%, respectively, with a PPV/NPV of 85%/84%. The interrater reliability (IRR) was high for LR-TR categories (90% agreement, Cohen's ĸ = 0.75) and for LI-RADS LR-4 and LR-5 diagnostic categories (91% agreement, Cohen's ĸ = 0.80). In patients with HCC <3 cm in diameter, LR-TR criteria after TA had high IRR but low sensitivity, suggesting that the LR-TR categories are precise but inaccurate. The low sensitivity may be secondary to TA's disruption in the local blood flow of the tissue, which could affect the arterial enhancement phase on MRI. Additional investigation and new technologies may be necessary to improve imaging after ablation.


Nerve conduction study of the association between glycemic variability and diabetes neuropathy.
It remains unclear whether glycemic variability is related to diabetes microvascular disease, especially diabetes peripheral neuropathy (DPN). We investigated the association between glycemic variability and DPN with type 1 or 2 diabetes. Forty patients (23 males and 17 females; aged 34-79 years) underwent continuous glucose monitoring (CGM) and a nerve conduction study (NCS). Glycemic variability was estimated by mean amplitude of glycemic excursions (MAGE) in CGM. DPN was quantitatively evaluated by NCS in the median, tibial, sural and medial plantar nerves. MAGE had a significantly positive correlation with disease duration and low-density lipoprotein cholesterol level (r = 0.462, p = 0.003; and r = 0.40, p = 0.011, respectively), and a significantly negative correlation with BMI and medial plantar compound nerve action potential amplitude (r = - 0.39, p = 0.012; and r = - 0.32, p = 0.042, respectively). Multivariate linear regression analysis with adjustment for clinical background showed that MAGE (β = - 0.49, p= 0.007) was independently associated with a higher risk of medial plantar neuropathy. Glycemic variability may be an independent risk factor for DPN.


Is crow's feet sign a reliable indicator of corneal injury in facial burns?
Facial burns occur commonly, although they rarely result in serious ophthalmological injuries. Despite this, failure to identify and manage minor eye injuries can have serious consequences. When the blink reflex is forcibly suppressed, the cornea is left exposed, resulting in serious injury. One indicator of possible corneal injury is the absence of 'Crow's feet sign'. Crow's feet sign describes the sparing of the skin creases or crow's feet around the eye with forced eyelid closure. The implication is that the patient was conscious at the time of injury and therefore able to protect the eye from ocular injury. We present a consecutive series of 145 people with facial burns attending the burns unit at Selly Oak Hospital, Birmingham over a 2-year period. Demographics, cause, presence of inhalational injury and outcome were examined for all patients. Eleven patients were diagnosed with ocular injury, and none of these patients had crow's feet sign. To date, we have found 100% correlation between the presence of crow's feet sign and the absence of ocular injury. We would recommend that clinicians are alert to the absence of this sign as a marker of possible eye injury.


Effect of progesterone on monoamine turnover in the brain of the estrogen-primed rat.
The effect of progesterone (P) on monoamine levels and turnover was evaluated in 8 brain nuclei in estrogen-primed rats. Animals were subcutaneously (SC) injected with P or vehicle 21 hours after SC treatment with 5 micrograms of estradiol benzoate (EB). EB-primed animals treated with P showed high levels of lordosis behavior and an LH surge three hours later. Initial concentrations of norepinephrine (NE), dopamine (DA), serotonin (5HT) and 5-hydroxyindole acetic acid were determined in EB-saline treated controls 3 hours after P or vehicle. NE and DA turnover was estimated from the exponential decline of these amines 2 hours after IP injection of alpha-methyl-p-tyrosine (5 hours after P or vehicle). The accumulation of 5HT 20 min following IP injection of pargyline was used as an index of 5HT turnover. P did not affect the initial NE, 5HT or 5HIAA concentrations in any of the brain nuclei studied, but decreased DA content in the arcuate-median eminence region (Ar-ME). The DA rate constant was elevated in the nucleus of the diagonal band of Broca and the DA turnover rate was decreased in the Ar-ME. In the periventricular region (PVE, anterior hypothalamic level) the NE turnover rate (K, pg/microgram protein/hr) and rate constant (k, hr-1) decreased following P treatment. Progesterone treatment decreased the accumulation of 5HT in the ventromedial hypothalamus (VMN, pars lateralis) and the dorsal midbrain central grey (MCG). Progesterone effects on monoamine turnover were not found in the lateral septal, medial preoptic, anterior hypothalamic or dorsal raphe nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of a herbal formulation, KGC3P, and its individual component, nepetin, on coal fly dust-induced airway inflammation.
Coal fly dust (CFD)-induced asthma model is used as an ambient particulate matter model of serious pulmonary damage. We aimed to evaluate the effects of a combination of ginseng and Salvia plebeia R. Br extract (KGC-03-PS; KG3P) and its individual components (hispidulin, nepetin and rosmarinic acid) in a CFD-induced mouse model of airway inflammation (asthma). We also evaluated signal transduction by KG3P and its individual components in the alveolar macrophage cell line, MH-S cells. In vitro, KG3P and its individual components inhibited nitric oxide production and expression of pro-inflammatory mediators and cytokines (iNOS, COX-2, IL-1β, IL-6 and TNF-α) through the NF-κB and MAPK pathways in coal fly ash (CFA)-induced inflammation in MH-S cells. Moreover, in the CFD-induced asthma model in mice, KG3P and its predominant individual component, nepetin, inhibited Asymmetric Dimethyl arginine (ADMA) and Symmetric Dimethyl arginine (SDMA) in serum, and decreased the histopathologic score in the lungs. A significant reduction in the neutrophils and immune cells in BALF and lung tissue was demonstrated, with significant reduction in the expression of the pro-inflammatory cytokines. Finally, IRAK-1 localization was also potently inhibited by KG3P and nepetin. Thus, KG3P extract can be considered as a potent candidate for amelioration of airway inflammation.


Recurrence of renal tuberculosis 29 years after therapy.
A case of renal tuberculosis in a man when he was 23 years old is reported. He was treated with streptomycin and reported routinely for followup examinations. When the patient was 52 years old, 29 years after treatment, he had a positive urine culture from the remaining kidney. Triple drug therapy was administered and has been effective. The need for lifelong examination of patients with renal tuberculosis is justified.


RNAa-mediated overexpression of WT1 induces apoptosis in HepG2 cells.
Recent studies have reported that double-stranded RNA (dsRNA) can activate gene expression by targeting promoter sequence in a process termed RNA activation. The present study was conducted to evaluate the potential of WT1 induction by small activating RNA targeting the WT1 promoter (dsWT1) in the treatment of hepatocellular carcinoma. The human hepatocellular carcinoma cell line HepG2 was transfected with dsRNA by liposomes. The expression of mRNA and protein in cells were investigated using real-time reverse real-time quantitative PCR and Western blot, respectively. Cell viability and clonogenicity were determined by MTT assay and clonogenicity assay, respectively. Cell apoptosis was evaluated by flow-cytometric analysis. Expressions of WT1 mRNA and protein in dsWT1 treated HepG2 cells were significantly elevated. Inhibition of cell viability by dsWT1 was dose-dependent and time-dependent. Reduction of the number and size of colonies formed were found in dsWT1 treated cells. dsWT1 induced significant apoptosis in HepG2 cells. The decreased anti-apoptotic protein Bcl-2 and elevated pro-apoptotic protein Bak expression were detected in dsWT1 treated cells. The level of pro-caspase-3 remarkably decreased and cleaved caspase-3 and PARP fragment were also detected in dsWT1 treated cells. These data show that RNAa-mediated overexpression of WT1 may have therapeutic potential in the treatment of hepatocellular carcinoma.


An electrochemical aptasensor based on intelligent walking DNA nanomachine with cascade signal amplification powered by nuclease for Mucin 1 assay.
Intelligently walking DNA nanomachines have sprung up an upsurge in various nucleic acid testing, but the rapid and sensitive test methods toward disease biomarker proteins based on the signal amplification strategy of DNA nanomachines were still ongoing development. In this work, an electrochemical aptasensor coupling the magnetic separation technique with the nuclease-powered walking DNA nanomachine was established for Mucin 1 (MUC1) detection. The magnetic beads (MBs) were modified by MUC1 aptamer hybridized with blocker DNA probe (BDP). After reacting with MUC1 proteins, the BDP was released from MBs to trigger the opening of capture hairpin DNA on Au nanoparticle (Au NPs)/MXene-modified electrode surface. In the presence of exonuclease III (Exo III), the BDP as a DNA walker is activated to autonomously move on the electrode. Then, lots of residual DNA fragments can still stay on electrode, further hybridizing with hairpin DNA, which can capture more UiO-66-NH2 metal-organic frameworks (MOFs). The amounts of ligands in MOFs can generate enhanced differential pulse voltammetry (DPV) signal probes. Furthermore, the concentrations of MUC1 can convert into the amplified DPV signals by introducing the signal amplification between the BDP as DNA walkers and Exo III as driven forces. This proposed electrochemical aptasensor achieved MUC1 detection ranging from 5 pg/mL to 50 ng/mL with detection limit of 0.72 pg/mL. Consequently, the designed and nuclease-powered walking DNA nanomachine provided an efficient strategy for the quantitative analysis of proteins by the interconversion between protein and BDP as a walker, which exhibited practical applicability of MUC1 detection in human serum.


Mapping Out Autoimmunity Control in Primary Immune Regulatory Disorders.
There is a growing understanding of the clinical overlap between primary immune deficiency and autoimmunity. An atypical or treatment-refractory clinical presentation of autoimmunity may in fact signal an underlying congenital condition of primary immune dysregulation (an inborn error of immunity). Detailed profiling of the family history is critical in the diagnostic process and must not be limited to the occurrence of frequent or atypical infections, but additionally should include inquiries into chronic forms of autoimmunity, hyperinflammation, and malignancy. A genetic and a functional diagnostic approach are complementary and nonoverlapping methods of identifying and validating an inborn error of immunity. Extended immune phenotyping of both affected and unaffected family members may provide insight into disease mode of inheritance, penetrance, and secondary inherited or environmentally acquired modifiers. Clinical care of a family with an inborn error of immunity may require local and national expertise in addition to cross-disciplinary care from the disciplines of pediatrics and internal medicine. Physician communication across subspecialties as well as distinct medical institutes can facilitate the appropriate disclosure of genetic testing results toward their prompt incorporation into patient care. Targeted immunomodulation based directly on genetic and functional immune phenotyping has the potential to reduce unnecessary immunosuppression and provide more exacting therapeutic benefit to our patients.


Midwifery workforce challenges in Victoria, Australia. A cross-sectional study of maternity managers.
In Australia, there is a lack of accurate data on midwifery workforce staffing and skill mix, which in turn hinders workforce policy and planning. To describe the current staffing levels of the midwifery workforce in Victoria, Australia, explore workforce challenges and assess the impact of COVID-19 pandemic on staffing. Cross-sectional. Midwifery managers in all public and private maternity services in Victoria, Australia were invited to complete a survey exploring midwifery staffing numbers and adequacy. Topics explored included midwifery turnover, recruitment, and skill mix. Descriptive statistics were used. The survey was open March to October 2021, and 56 % (38/68) of managers responded. Of these, 76 % reported inadequate midwifery staff levels, with deficits ranging from one to 19 estimated Full-Time Equivalent (EFT) midwives, with a combined total deficit of 135 EFT. In the 12 months prior to the survey, 73 % of services had found it difficult to recruit midwives, with increased difficulty during the COVID-19 pandemic. Managers were concerned about retaining and recruiting 'experienced' midwives due to an ageing workforce and high turnover due to work/life imbalance and job dissatisfaction. These issues have led to a predominantly early career midwifery workforce and created concern about skill mix. Victorian maternity services have a midwifery workforce shortage and are experiencing significant skill mix issues. The pandemic has exacerbated these considerable gaps in the workforce. Urgent implementation of retention and recruitment schemes are needed, along with strategies to improve the working conditions for the current workforce.


Prognostic value of cell proliferation (Ki-67 antigen) and nuclear DNA content in clinically resectable, distal bile duct carcinoma.
The aim of this study was to investigate the prognostic value of cell proliferation (Ki-67 antigen) and DNA content in patients resected for distal bile duct carcinoma (DBDC). Formalin-fixed tumor specimens of 35 patients with resected DBDC and a long-term clinical follow-up were analyzed. MIB-1 antibody was used for Ki-67 antigen detection to determine the proportion of proliferating cells. DNA content was measured using flow cytometry. A significant correlation was found between a low MIB-1 index (<20%) and survival (P <.05). Of the 35 tumor specimens, 34 specimens were evaluable by flow cytometry: 22 carcinomas were diploid (65%), and 12 were aneuploid (35%). The median DNA index of aneuploid tumors was 1.36 (range, 1.09 to 1.76). No correlation of DNA-ploidy with survival time was found. In contrast to DNA-ploidy pattern, Ki-67 antigen expression showed prognostic significance in resectable DBDC. A Ki-67 positive ratio of > or =20% was associated with decreased survival time.


Bacterial gastroenteritis.
Acute diarrhea is a major cause of childhood morbidity. Important advances in the understanding of bacterial gastroenteritis have been made in the past two decades. This article reviews the epidemiology, pathogenesis, and methods of diagnosis of bacterial gastroenteritis. Bacterial enteric pathogens common to North America are discussed in more detail.


Radial keratotomy and corneal permeability in Owl Monkey.
Radial keratotomy was performed on Owl Monkey corneas using 8 incisions with sparing of a 3.5mm central pupillary area. Cornea endothelial membrane permeabilities were determined at 2 days, and 4 weeks, following the procedure using simultaneous flux determinations of 3H-labeled inulin and 14C-labelled dextran. Inulin permeability was increased 27% two days following the procedure, and had returned to levels comparable to the unoperated eye 4 weeks following the procedure. Dextran permeability was unaltered at both 2 days, and 4 weeks, following the procedure. This study has shown that radial keratotomy causes a transient reduction in endothelial barrier function with the production of physiologically significant 'holes' in the membrane in the immediate post-operative period. The relationship of this physiological alteration to ultimate endothelial cell function is, at the present time, unknown.


FGF2/EGF contributes to brain neuroepithelial precursor proliferation and neurogenesis in rat embryos: the involvement of embryonic cerebrospinal fluid.
At the earliest stages of brain development, the neuroepithelium works as an interdependent functional entity together with cerebrospinal fluid, which plays a key regulatory role in neuroepithelial cell survival, replication and neurogenesis; however, the underlying mechanism remains unknown in mammals. We show the presence of fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF), in 13.5-day rat embryo cerebrospinal fluid (eCSF). Immunohistochemical detection of FGF2 expression localized this factor inside neuroepithelial precursors close to the neuroepithelial-CSF interface, suggesting that FGF2 from eCSF could originate in the neuroepithelium by apical secretion. The colocalization of FGFR1 and FGF2 in some neuroepithelial cells close to the ventricular surface suggests they are target cells for eCSF FGF2. Brain neuroepithelium EGF expression was negative. By using a neuroepithelial organotypic culture, we demonstrate that FGF2 and EGF from eCSF plays a specific role in triggering the self-renewal and are involved in neurogenetic induction of mesencephalic neuroepithelial precursor cells during rat development. We propose eCSF as an intercommunication medium for neuroepithelial precursor behavior control during early rat brain development, and the neuroepithelial regulation of FGF2 and EGF presence in eCSF, as a regulative mechanism controlling precursor proliferation and neurogenesis.


Acid glycosaminoglycans (mucopolysaccharides) in the differential diagnosis of pleural effusion.
Pleural fluid glycosaminoglycans (GAG) in 64 patients with various diseases were isolated by anion-exchange chromatography after proteolysis, and characterised by spectrophotometric, electrophoretic and enzymatic techniques. GAG concentrations ranged from 7 to 1178 microng hexuronate/ml pleural fluid. The highest values (1178, 161 and 160 micron/ml) were found in patients with diffuse mesothelioma. Over 90% of the pleural fluid GAG consisted of hyaluronic acid (HA) in these patients. In other types of pleural effusion the relative HA content varied from 42 to 70% of the total GAG. Determination of pleural fluid HA consequently appears extremely valuable in the diagnosis of the form of mesothelioma producing HA. The mean GAG concentration of pleural fluid was significantly higher in tuberculous pleurisy than in hydrothorax (P less than 0.01), secondary malignant pleural effusion (P less than 0.0005) and idiopathic pleurisy (Pless than 0.03). It was impossible to demonstrate definite correlations between GAG and protein, and GAG and glucose concentrations of pleural fluid.


Sugar tongs get a grip on the starch granule in barley alpha-amylase 1.
A novel polysaccharide binding site is identified in domain C of barley alpha-amylase 1 from the X-ray structure of the enzyme/tetrasaccharide complex.


LINE-1: an emerging initiator of cGAS-STING signalling and inflammation that is dysregulated in disease.
The cGAS-STING (cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)) axis integrates DNA damage and cellular stress with type I interferon (IFN) signalling to facilitate transcriptional changes underlying inflammatory stress responses. The cGAS-STING pathway responds to cytosolic DNA in the form of double-stranded DNA, micronuclei, and long interspersed nuclear element 1 (L1) retroelements. L1 retroelements are a class of self-propagating non-long terminal repeat transposons that have remained highly active in mammalian genomes. L1 retroelements are emerging as important inducers of cGAS-STING and IFN signalling, which are often dysregulated in several diseases, including cancer. A key repressor of cGAS-STING and L1 activity is the exonuclease three prime repair exonuclease 1 (TREX1), and loss of TREX1 promotes the accumulation of L1. In addition, L1 dysregulation is a common theme among diseases with chronic induction of type I IFN signalling through cGAS-STING, such as Aicardi-Goutières syndrome, Fanconi anemia, and dermatomyositis. Although TREX1 is highly conserved in tetrapod species, other suppressor proteins exist that inhibit L1 retrotransposition. These suppressor genes when mutated are often associated with diseases characterized by unchecked inflammation that is associated with high cGAS-STING activity and elevated levels of L1 expression. In this review, we discuss these interconnected pathways of L1 suppression and their role in the regulation of cGAS-STING and inflammation in disease.


Latent-time estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study.
In this paper, an analysis of the fractionation sensitivity and latency of subcutaneous fibrosis and telangiectasia in a clinical series is presented. The series comprised 163 breast cancer patients who, from 1978 to 1980, received postmastectomy irradiation delivered in 12 fractions, with 2 fractions per week over a period of 37 to 46 days. The total dose was specified either as a maximum absorbed dose of 51.36 Gy, or as a minimum target dose of 36.6 Gy specified at the level of the mid-axilla. From 1981 to 1982, 66 patients received a minimum target dose of 40.92 Gy in 22 fractions administered as 5 fractions per week over 29 to 35 days. Late complications were evaluated prospectively at a single follow-up after a minimum observation time of 16 months. The clinical endpoints analyzed were subcutaneous fibrosis and telangiectasia. The data were analyzed using a mixture model that incorporates both dose fractionation and latency effects. The length of time to expression of 90% of the ultimate frequency of moderate or severe complications was 3.2 years (95% confidence limits (c.l.) [2.3,3.9] years) and 4.7 years (95% c.l. [4.0,4.8] years) for fibrosis and telangiectasia respectively, while the alpha/beta ratios were 1.9 Gy (95% c.l. [0.8,3.0] Gy) and 3.7 Gy (95% c.l. [0.2,47] Gy), respectively. For subcutaneous fibrosis the time to reach a specific grade of reaction increases with the grade, thus being consistent with the clinical impression that fibrosis progresses in severity over time. If latency and censoring effects are unaccounted for, serious underestimates of the ultimate frequency of radiation complications in groups with incomplete follow-up may result.


Isoniazid Induced Metabolic Acidosis and Renal Dysfunction in an Elderly Patient with Chronic Renal Disease.
Metabolic acidosis is one of the common manifestations of Isoniazid toxicity but rare with normally used doses of the drug. Among anti tubercular drugs, rifampicin, streptomycin and capreomycin are commonly implicated in renal injury. Here we report the first case of metabolic acidosis and renal injury caused by isoniazid at normal prescribed dose.


Assessment of craniospinal arteriovenous malformations at 3T with highly temporally and highly spatially resolved contrast-enhanced MR angiography.
Patients with arteriovenous malformation (AVM) are known to have an elevated risk of complications with conventional catheter angiography (CCA) but nonetheless require monitoring of hemodynamics. Thus, we aimed to evaluate both anatomy and hemodynamics in patients with AVM noninvasively by using contrast-enhanced MR angiography (CE-MRA) at 3T and to compare the results with CCA. Institutional review board approval and informed consent were obtained for this Health Insurance Portability and Accountability Act-compliant study. Twenty control subjects without vascular malformation (6 men, 18-70 years of age) and 10 patients with AVMs (6 men, 20-74 years of age) underwent supra-aortic time-resolved and high-spatial-resolution CE-MRA at 3T. Large-field-of-view coronal acquisitions extending from the root of the aorta to the cranial vertex were obtained for both MRA techniques. Image quality was assessed by 2 specialized radiologists by using a 4-point scale. AVM characteristics and nidus size were evaluated by using both CE-MRA and CCA in all patients. In patients, 96.6% (319/330) of arterial segments on high-spatial-resolution MRA and 87.7% (272/310) of arterial segments on time-resolved MRA were graded excellent/good. MRA showed 100% specificity for detecting feeding arteries and venous drainage (n = 8) and complete obliteration of the AVM in 2 cases (concordance with CCA). Nidus diameters measured by both MRA and CCA resulted in a very strong correlation (r = 0.99) with a mild overestimation by MRA (0.10 cm by using the Bland-Altman plot). By combining highly temporally resolved and highly spatially resolved MRA at 3T as complementary studies, one can assess vascular anatomy and hemodynamics noninvasively in patients with AVM.


Species-dependent expression patterns of DNA methyltransferase genes in mammalian oocytes and preimplantation embryos.
DNA methyltransferases (DNMTs) comprise a family of proteins involved in the establishment and maintenance of DNA methylation patterns in the mammalian genome. DNA methylation involves the transfer of the methyl group of the coenzyme S-adenosyl-L-methionine to the 5 position of cytosine residues within CpG dinucleotides. DNA methylation is implicated in the control of imprinted genes expression, X chromosome silencing, development of certain types of cancer, and embryonic development. DNA methylation is also believed to protect the genome from parasitic elements such as transposons, retrotransposons, and viruses. The aim of this study was to analyze the expression patterns of DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L genes in rhesus macaque (Macaca mulatta) oocytes and preimplantation stage embryos from fertilization to the hatched blastocyst stage, and to compare these results with the expression profiles in the mouse and other mammalian species. We describe species-dependent differences as well as similarities in expression patterns of DNMT genes among mammals.


Statistical investigation of mandibular dimensions for the planning of a series of mandibular corpus replacements.
The mandibular corpus height, the width measured at the height of the foramina mental and at a distance of 3 mm from the base, the mandibular corpus length and the mandibular angle were examined in 368 (185 male, 167 female, and 34 uncertain) intact, European anthropologic skulls. The differences between the left and right sides and the two sexes were evaluated. No significant difference was found between the two sides. The differences between males and females did prove statistically significant, but was considered unimportant with regard to the aim of planning a series of mandibular prostheses. The experimental data were broken down into five classes, and the class medians were taken to be the dimensions for the replacements. For a five-piece series, the relative percentage distribution of the class medians suggests the following proportions for production (mean -2SD and mean +2SD 6%, mean -SD and mean +SD 25% and mean 38%). Mandibles with these average dimensions can be chosen from the anthropologic collection, wax models of which may facilitate the planning of a series of mandibular corpus prostheses.


Intimate Partner Violence Victimization and Perpetration Among U.S. Adults During the Earliest Stage of the COVID-19 Pandemic.
The objective of this study was to evaluate the association between COVID-19 related conditions and the perpetration or experience of intimate partner violence (IPV) in the earliest stage of the pandemic. This cross-sectional study analyzed data collected via an internet-based survey in the spring of 2020 from an online sample of noninstitutionalized adults in the United States (N = 2,045). More than half of the sample self-identified as being in an intimate relationship at the time of the study (58.2%, n = 1,183) and were used in the analysis. A four-item tool was used to assess IPV perpetration and victimization during the earliest stage of the pandemic. Respondents self-reported demographic data and recent health histories, including COVID-19 tests results, related symptoms, and degree of personal social distancing. We hypothesized that COVID-19 related factors would increase risks of IPV. Descriptive, correlational, and generalized linear modeling analysis techniques were employed. COVID-19 impacted respondents had an increased risk of IPV victimization and perpetration. Among those who reported having symptoms consistent with COVID-19 but were denied access to testing, the odds of being a victim of psychological IPV was three times more likely than those who did not have symptoms. Respondents who reported testing positive to COVID-19 were two to three times more likely to experience or perpetrate psychological and physical IPV against an intimate partner. People who lost their job due to the pandemic were three to four times more likely to perpetrate IPV compared to those who remained employed. Especially during this COVID-19 pandemic period, our results emphasize the need for an ongoing public-health response to IPV. Continued surveillance via effective screening, intervention development, and implementation is needed.


Survival following pancreatic carcinoma: a follow-up study of all cases recorded in Malmö, Sweden, 1977-1991.
The aim of this follow-up study was to assess whether there has been any increase in the percentage of patients offered attempted curative surgery for pancreatic carcinoma and whether the overall survival rate has improved, during the time period 1977-1991. Details of new cases of pancreatic carcinoma arising in the population of Malmö during the study period were retrieved from the Local Tumour Register in Lund, Sweden. In all, 740 patients were found; 575 of these were diagnosed before death. Kaplan-Meier analysis was used to calculate overall survival rates, and Cox regression analysis was used to assess survival in relation to year of diagnosis after adjustment for sex, age at diagnosis and stage of disease. Cytological or histopathological evidence of the disease was given in 95 per cent of cases. The overall 5-year survival rate was 0.5 per cent (three of 575). Curative surgery was attempted in 24 patients (4.2 per cent); the proportion undergoing curative surgery increased in the last part of the study. Two of the 24 patients in this group survived for 5 years. The prognosis in pancreatic carcinoma remains dismal. Attempted curative surgery still is the only hope for cure, but the group of patients that can be offered this possibility is very limited. In this study, an increase was found in the proportion of patients who were offered attempted curative surgery, but there was no statistically significant increase in the 5-year survival rate following surgery.


Treatment pattern and changes in oral glucocorticoid dose after tocilizumab treatment in patients with adult Still's disease: An analysis of a Japanese claims database.
Intravenous tocilizumab (TCZ-IV) was approved for the treatment of adult Still's disease (ASD) in Japan in May 2019 based on its efficacy and safety in a phase III randomized controlled trial. This study determined treatment patterns in patients with ASD and assessed oral glucocorticoid (GC) dose changes after TCZ-IV administration in Japanese clinical practice. Patients in the Medical Data Vision database aged 16 years or older with one or more of International Classification of Diseases, 10th revision codes M061 (ASD) or M082 (systemic juvenile idiopathic arthritis) during January 2017-March 2021 (cohort 1) and those initiating TCZ-IV during May 2019-March 2021 (cohort 2) were included. In cohort 1, the proportion of patients who were prescribed interleukin-6 inhibitors (mainly TCZ-IV) increased from 10.8% (January-April 2019 [before TCZ-IV approval]; n = 2002) to 18.3% (January-March 2021 [after TCZ-IV approval]; n = 2008). In cohort 2 (n = 193), 84.5% of patients were on oral GCs (≤5 mg/day: 23.8%) at index date (initial TCZ-IV prescription date); 46/70 (65.7%) were on oral GC at 5 mg/day or higher 12 months after TCZ-IV treatment (primary outcome). After 12 months of treatment, the TCZ-IV retention rate was 73.6% and the TCZ-IV administration interval was every 4 weeks and every 2 weeks in 31.9% and 27.7% of patients, respectively. The use of interleukin-6 inhibitors increased by 7.5% points in Japanese patients with ASD ~2 years after TCZ-IV approval, suggesting that an unmet medical need existed. This study suggests the potential GC-sparing effect of TCZ-IV in patients with ASD in clinical practice.


Stem cell-derived exosomes: Role in the pathogenesis and treatment of atherosclerosis.
Atherosclerosis (AS) is a chronic inflammatory vascular disease characterized by the accumulation of lipids and inflammatory debris in large arteries, high morbidity, and AS-related disease mortality. AS is a complex process, involving endothelial cell dysfunction and inflammation, smooth muscle cell proliferation, and macrophage activation. However, the currently available therapies for AS are not ideal, thus requiring development of novel treatment strategies. Exosomes are bi-lipid membranous extracellular containing multifarious cargo, such as proteins, lipids, micro ribonucleic acid (miRNAs), messenger RNAs, and long non-coding RNAs. Moreover, exosomes reportedly participate in various AS processes. Specifically, stem cell-derived exosomes can regulate the occurrence and development of AS, exhibiting the ability to overcome the limitations associated with AS treatment and stem cell therapy. In this paper, we review the pathological mechanism of AS and discuss the role of exosomes and stem cell-derived exosomes in AS progression. We conclude by suggesting new therapeutic strategies for treating AS with stem cell-derived exosomes in the hope of improving the clinical treatment of AS.


Effect of Cigarette Smoking on Risk for Adverse Events in Patients With Heart Failure and Preserved Ejection Fraction.
Smoking is an important risk factor in the development of heart failure with preserved ejection (HFpEF), and previous reports have identified smoking as a significant predictor of death in this population. However, the relation between smoking and heart failure-specific outcomes has not been examined in patients with HFpEF. This analysis included 1,717 patients (mean age = 71 ± 10 years; 50% men; 78% white) with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial from the Americas. Smoking was ascertained by self-reported history and categorized as never, former, or current. Multivariable Cox regression was used to examine the risk of hospitalization for heart failure, death, and cardiovascular death across smoking categories. There were 116 current smokers (7%), 871 former smokers (51%), and 729 never smokers (42%) in this analysis. Current smoking was associated with an increased risk of hospitalization for heart failure (never: hazard ratio [HR] 1.0; former: HR 1.25, 95% confidence interval [CI] 0.99 to 1.57; current: HR 1.68, 95% CI 1.08 to 2.61), death (never: HR 1.0; former: HR 1.02, 95% CI 0.81 to 1.29; current: HR 1.82, 95% CI 1.19 to 2.78), and cardiovascular death (never: HR 1.0; former: HR 1.00, 95% CI 0.74 to 1.35; current: HR 1.85, 95% CI 1.09 to 3.24) compared with former or never smokers in a multivariable model adjusted for cardiovascular risk factors. A similar increased risk of hospitalization for heart failure (former: HR 1.0; current: HR 1.54, 95% CI 1.01, 2.36), death (former: HR 1.0; current: HR 1.81, 95% CI 1.19, 2.75), and cardiovascular death (former: HR 1.0; current: HR 1.76, 95% CI 1.04, 2.98) was observed for current smokers when we limited the analysis to those with a history of smoking. In conclusion, current smoking is associated with an increased risk for adverse outcomes in HFpEF, including hospitalization for heart failure. Smoking cessation strategies possibly have a role to reduce the risk for adverse cardiovascular outcomes in patients with HFpEF.


Short-term effect of reclaimed wastewater quality gradient on soil microbiome during irrigation.
To investigate the effect of wastewater (WW) treatment on soil bacterial communities, water of different quality was used to irrigate eight lettuces per tank: raw municipal wastewater (RWW), WW treated with an aerated constructed wetland (CWW) and WW treated with a membrane bioreactor (MBW), and tap water (TW). The physicochemical and microbiological characteristics (quality indicators) of these water types were characterized, and the water and soil bacterial communities were monitored by quantitative PCR (qPCR) and 16S rRNA gene sequencing. Despite marked differences in microbial load and diversity of waters, soil communities remained remarkably stable after irrigation. Microbial biomass was increased only in soils irrigated with RWW. At the end of the irrigation period (day 84), soil and water shared a large fraction of their bacterial communities, from 43 % to 70 %, depending on the water quality, indicating a transfer of bacterial communities from water to soil. Overall, the relative abundance of Proteobacteria and Acidobacteria was increased and that of Actinobacteria was decreased in soils irrigated with MBW, CWW and even more with RWW. Multivariate ordination clearly separated soils in three groups: soils irrigated with the cleanest water (TW), with treated WW (MBW and CWW), and with untreated WW (RWW). Nitrifying, denitrifying, and nitrogen-fixing bacteria were quantified by qPCR targeting amoA, narG, and nifH, respectively. Nitrifying bacteria were the most affected by the water quality, as indicated by amoA copy number increase in RWW-irrigated soil and decrease in CWW-irrigated soil. Overall, the abundance of all three genes was positively influenced by RWW treatment. In conclusion, the 84 days of irrigation influenced the soil microbial communities, and the impact depended on the quality of the used water.


Studies of the plasma membrane during maturation of the mammalian erythrocyte.
Plasma membranes were obtained from a homogeneous population of rabbit red blood cells at different maturation periods. Minor modifications in membrane proteins and membrane phospholipids and significant decreases in membrane glycoproteins and total lipids were observed with the age of the cell. The ouabain inhibited (Na+K+)-ATPase and the adenylate cyclase decreased with maturation but acetylcholinesterase and 5'-nucleotidase remained almost unchanged. The apparent activation energy of the ATPase increased with maturation. The results indicate that structural and functional modifications of the plasma membrane occur concomitantly with the ageing processes of the red cell.


Solubilization of A1 adenosine receptor from pig brain: characterization and evidence of the role of the cell membrane on the coexistence of high- and low-affinity states.
The present solubilization strategy recognizes the important role of detergent cocktails in the solubilization and subsequent stability of adenosine A1, receptors from pig brain cortical membranes. The 3-[3-(cholamidopropyl)dimethylammonio]-1-propane-sulfonate-digitonin mixture produced the extraction of up to 52% of the receptor with an enrichment of 1.2-fold with respect to crude membranes. The binding activity of the soluble extract was very stable even in the absence of glycerol. In crude membranes the existence of high- and low-affinity states was detected, but in the soluble extract and in the detergent-treated membranes only the high-affinity state was detected. Association-dissociation curves showed that in crude membranes no interconversion between high- and low-affinity sites is produced by the association of the ligand [3H]R-N6-phenylisopropyladenosine. These results suggest that the high- and low-affinity states are different conformations induced by the structure of the membrane. The modulation of the binding activity by (Gpp(NH)p) 5'-guanylylimidodiphosphate and Mg2+ was studied. In crude membranes Gpp(NH)p shifted the high-affinity state to the low-affinity state, whereas the contrary occurred when Mg2+ was used. The effect of both Mg2+ and Gpp(NH)p was also assayed with the soluble extract and with the detergent-treated membranes. In addition to a decrease of the overall binding capacity, Gpp(NH)p promoted a conversion to all low-affinity states in the detergent-treated membranes or to all very-low-affinity sites in the soluble extract. Mg2+ and Gpp(NH)p counteracted their effects in intact membranes, whereas Mg2+ could not reverse the uncoupling effect of Gpp(NH)p with solubilized or detergent-treated membranes. Thus, it is suggested that Mg2+ acts at sites other than guanine-nucleotide-sensitive sites. If high-affinity states correspond to receptor/G protein complexes and low-affinity states correspond to the uncoupled receptor, we should conclude that Mg2+, as well as the loss of membrane integrity, favours the interaction of A1 receptor molecule with G protein.


A novel TLR4 binding protein, 40S ribosomal protein S3, has potential utility as an adjuvant in a dendritic cell-based vaccine.
Dendritic cells (DCs) are professional antigen presenting cells (APCs), which can activate antigen-specific CD8+ T cell immunity, resulting in tumor clearance. Immature DCs are usually stimulated by various adjuvants through their immune receptors. Among them, Toll-like receptor 4 (TLR4) has an important role in activating DCs to cause their maturation. In fact, TLR4 is well-known to induce innate and adaptive immune responses against various external microbial or internal damage associated molecular patterns (DAMP). LPS is widely regarded as a strong stimulator of TLR4 signaling. However, LPS is inappropriate for use in humans since it is an endotoxin. Unfortunately, other TLR4 ligands such as HMGB1 or heat shock proteins have weak adjuvant effects. Therefore, there is a need to identify novel, biocompatible, strong, TLR4 ligands. 40S ribosomal protein S3 (RPS3) was screened through pull-down assay using TLR4. BMDCs from wild type (WT) and TLR4 knock-out mice were treated by RPS3 to identify the activation and maturation of DCs. T cell generation including memory T cells, tumor prevention, and treatment experiments were performed with BMDCs based vaccination. Also, human DCs originated from patients were treated by RPS3 to confirm the activation and maturation of DCs. In this study, we identified 40S ribosomal protein S3 (RPS3) through a pull-down assay using a variety of human cancer cell-derived proteins that could bind to TLR4. RPS3 was released from tumor cells following treatment with an anticancer drug, and it was shown that the released RPS3 binds to TLR4. Recombinant RPS3 induced maturation and activation of DCs, and following pulsing with tumor specific antigens, these DCs could be used as a vaccine to significantly increase tumor specific CD8+IFN-γ+ T cells, and provide both tumor prevention and tumor treatment effects. The effect of RPS3 on DC maturation and its utility as a vaccine were shown to be dependent on TLR4 using TLR4 knockout mice. This study therefore proved that human cancer cell-derived RPS3, a novel TLR4 ligand, has great potential as an adjuvant in tumor-specific antigen DC-based vaccines.


Improvement in rejection, engraftment rate and survival without increase in graft-versus-host disease by high marrow cell dose in patients transplanted for aplastic anaemia.
Two hundred and fifty-two consecutive patients with severe aplastic anaemia were conditioned by cyclophosphamide and given marrow transplants from HLA-identical siblings or parents. The results were analysed to examine the influence of marrow cell dose on graft rejection, speed of engraftment, survival and acute and chronic graft-versus-host disease (GVHD). Sixty patients received a corrected marrow cell dose below 2.2 x 10(8) nucleated cells per kg body weight, 73 patients between 2.2 and 3.2 x 10(8) cells/kg, 60 patients between 3.3 and 4.2 x 10(8) cells/kg, and 59 patients more than 4.2 x 10(8) cells/kg. The significant association between high marrow cell dose and low risk of graft rejection previously reported was confirmed. In addition, high marrow cell dose resulted in small but statistically significant reductions in time to granulocyte and platelet recoveries in patients with sustained engraftment. High marrow cell dose was also associated with a significant improvement in patient survival, a result solely due to the reduction in the incidence of graft rejection. Neither acute nor chronic GVHD were influenced by marrow cell dose. We conclude that the maximum marrow cell dose should be transplanted in patients with severe aplastic anaemia. Maximum marrow cell doses are likely to decrease the incidence of graft rejection, shorten the time to engraftment thereby decreasing the need for blood products and antibiotic support, and improve overall patient survival.


Changes in nationwide use of preoperative radiotherapy for rectal cancer after revision of the national colorectal cancer guideline.
The rate of preoperative radiotherapy (RT) for rectal cancer in the Netherlands has been the highest among European countries. Revision of the national guideline on colorectal cancer, officially published in 2014, specifically focussed on the indication for RT and MRI criteria to evaluate mesorectal lymph nodes. The objective of this study was to evaluate implementation of the revised guideline using a national audit. Data of the Dutch Surgical Colorectal Audit (DSCA) between 2009 and 2014 were used to evaluate RT use and RT regimen for relevant subgroups of cM0 rectal cancer patients, as well as accuracy of pre-operative MRI. 14,018 patients were included for analysis. Overall RT use in cT1-4N0-2M0 stage ranged from 81.4% to 84.2% between 2009 and 2013, and decreased to 64.4% in 2014. The absolute decrease in RT use from 2013 to 2014 for cT1N0, cT2N0 and cT3N0 stage was 32.8%, 43.5% and 31.6%, respectively. Short course RT with delayed surgery was used as an alternative to chemoradiotherapy up to 2013 in 30.6% of patients over 80 years, and in 12.1% of patients with an ASA score >2; these percentages increased to 45.8% and 19.9% in 2014, respectively. Specificity of MRI for N-stage decreased from 82.9% in 2009 to 62.9% in 2013, with an increase to 73.2% in 2014. The revised national guideline on colorectal cancer was rapidly implemented in the Netherlands with a substantial decrease in RT use for low risk resectable rectal cancer, and increased specificity of MRI for N-staging.


Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models.
The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.


2,2-Bis[3,5-bis-(di-methyl-amino)-phen-yl]-1,1,1,3,3,3-hexa-methyl-tris-ilane.
The title compound, C26H48N4Si3, was synthesized by the reaction of 2,2-di-chloro-tris-ilane with 3,5-bis-(di-methyl-amino)-phenyl-lithium. In the mol-ecule, the dihedral angle between the benzene rings is 57.57 (7)° and the Si-Si-Si bond angle is 110.08 (2)°. In the crystal, mol-ecules are linked via an SiC-H⋯π(ar-yl) inter-action, forming a chain along the c-axis direction.


Attributable risk of household solid fuel use and second-hand smoke associated with under-5 mortality in 46 low- and lower-middle-income countries, 2010-2020.
Household solid fuel use (including indoor and outdoor) and second-hand smoke (SHS) are considered to be major contributors of under-5 mortality (U5M) in low- and lower-middle-income countries (LMICs). This study provides a comprehensive assessment of their odds ratios and attributable mortality in LMICs. We used the Demographic Health Surveys data for under-5 children in 46 LMICs (n = 778,532) from 2010 to 2020. Mixed effect multilevel logistic regressions were conducted to estimate the pooled adjusted odds ratio (aOR) for U5M due to solid fuel use, SHS and their combination compared to no exposure to them in 46 LMICs. The attributable mortality of solid fuel use, SHS, and their combination were assessed for each LMIC. The pooled aOR of solid fuel use and SHS for U5M was estimated to be 1.27 (95% Confidence Interval (CI): 1.19-1.36) and 1.13 (95%CI: 1.06-1.25), respectively, whereas those of their combination was 1.40 (95%CI: 1.31-1.50). U5M attributable to indoor and outdoor solid fuel use was the highest in Myanmar (18.0%) and the Gambia (16.5%), respectively, while those attributable to SHS was the highest in Indonesia (9.8%). U5M attributable to the combination of solid fuel use and SHS was the highest in Timor-Leste (22.7%). The combined effect of exposure to solid fuel and SHS had a higher risk of U5M than the individual risk. The use of clean fuel and tobacco control measures should be integrated with other child health promotion policies. This research was partially supported by a research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (21H03203).


Assessing readiness to change binge eating and compensatory behaviors.
The purpose of this study was to evaluate whether assessing motivation to change binge eating and compensatory behaviors separately would better describe concurrent bulimic symptomatology compared with a general measure of readiness to change eating behaviors. Participants completed the Eating Disorder Diagnostic Scale [EDDS: Stice, Telch, & Rizvi, in Psychol. Assess. 12 (2000) 123] to assess binging and compensatory behaviors, as well as three measures of readiness to change based on the University of Rhode Island Change Assessment Scale (URICA; McConnaughy, DiClemente, Prochaska, & Velicer (1989)): a general measure, which asked about eating behaviors in general, and two behavior specific measures, one asking about binging behavior only and the other asking about compensatory behaviors only. Results revealed that assessing readiness to change binge eating and compensatory behaviors separately accounted for greater variance in bulimic behaviors than a general measure of readiness to change. Results also provided discriminate validity for measuring readiness to change binge eating and compensatory behaviors separately. Results highlight the utility of assessing readiness to change bulimic symptomatology and the importance of measuring motivation to change binging and compensatory behaviors separately.


Trends in incidence of and mortality from invasive cancer of the uterine cervix in Scotland (1975-1994).
I. To identify major trends in the incidence of and mortality from invasive cancer of the cervix uteri in Scotland during the twenty year period 1975-1994; II. to consider the extent to which these trends may have been shaped by the introduction of systematic cervical screening. Analysis of annual age standardised and age specific rates for incidence and mortality, based on data collected by the Scottish Cancer Registry and the General Register Office for Scotland. Scotland. Women registered with the Scottish Cancer Registry as having developed invasive cancer of the cervix during the period of interest. Annual all ages incidence rates of invasive cervical cancer show little overall change over the period 1975-1989, but exhibit a pronounced decline from 1990 onwards. All-ages mortality rates show clear evidence of decline during the period 1975-1994, the rate for 1994 being some 30% lower than that for 1975. Annual age-specific incidence rates show different patterns by age group, with clear evidence of decreasing trends in the age range 50-64 years but different patterns in younger and older age groups. Most age groups show steep declines in incidence from 1990 onwards. Age specific mortality rates for 1975-1994 exhibit the most pronounced decreasing trends in the age range 50-64 years. The trends identified are broadly similar to those experienced in England and Wales over an approximately comparable period. The overall (all ages) incidence of invasive cervical cancer in Scotland changed little during the period 1975-1989, but declined sharply from 1990 onwards. The most pronounced decline in incidence across the period 1975-1994 appears to have taken place in the age range 50-64 years. This decline has been accompanied by a commensurate fall in mortality in the same age range. These reductions in incidence and mortality may be attributable in part to increased coverage of cervical screening programmes during the period of interest. Evidence from other studies suggest that, without the increased coverage of cervical screening achieved during this period incidence rates in Scotland might have been seen to increase.


Lactate modulates microglia polarization via IGFBP6 expression and remodels tumor microenvironment in glioblastoma.
Lactic acidosis has been reported in solid tumor microenvironment (TME) including glioblastoma (GBM). In TME, several signaling molecules, growth factors and metabolites have been identified to induce resistance to chemotherapy and to sustain immune escape. In the early phases of the disease, microglia infiltrates TME, contributing to tumorigenesis rather than counteracting its growth. Insulin-like Growth Factor Binding Protein 6 (IGFBP6) is expressed during tumor development, and it is involved in migration, immune-escape and inflammation, thus providing an attractive target for GBM therapy. Here, we aimed at investigating the crosstalk between lactate metabolism and IGFBP6 in TME and GBM progression. Our results show that microglia exposed to lactate or IGFBP6 significantly increased the Monocarboxylate transporter 1 (MCT1) expression together with genes involved in mitochondrial metabolism. We, also, observed an increase in the M2 markers and a reduction of inducible nitric oxide synthase (iNOS) levels, suggesting a role of lactate/IGFBP6 metabolism in immune-escape activation. GBM cells exposed to lactate also showed increased levels of IGFBP6 and vice-versa. Such a phenomenon was coupled with a IGFBP6-mediated sonic hedgehog (SHH) ignaling increase. We, finally, tested our hypothesis in a GBM zebrafish animal model, where we observed an increase in microglia cells and igfbp6 gene expression after lactate exposure. Our results were confirmed by the analysis of human transcriptomes datasets and immunohistochemical assay from human GBM biopsies, suggesting the existence of a lactate/IGFBP6 crosstalk in microglial cells, so that IGFBP6 expression is regulated by lactate production in GBM cells and in turn modulates microglia polarization.


Stimulus Frequency Otoacoustic Emission Delays and Generating Mechanisms in Guinea Pigs, Chinchillas, and Simulations.
According to coherent reflection theory (CRT), stimulus frequency otoacoustic emissions (SFOAEs) arise from cochlear irregularities coherently reflecting energy from basilar membrane motion within the traveling-wave peak. This reflected energy arrives in the ear canal predominantly with a single delay at each frequency. However, data from humans and animals indicate that (1) SFOAEs can have multiple delay components, (2) low-frequency SFOAE delays are too short to be accounted for by CRT, and (3) "SFOAEs" obtained with a 2nd ("suppressor") tone ≥2 octaves above the probe tone have been interpreted as arising from the area basal to the region of cochlear amplification. To explore these issues, we collected SFOAEs by the suppression method in guinea pigs and time-frequency analyzed these data, simulated SFOAEs, and published chinchilla SFOAEs. Time-frequency analysis revealed that most frequencies showed only one SFOAE delay component while other frequencies had multiple components including some with short delays. We found no systematic patterns in the occurrence of multiple delay components. Using a cochlear model that had significant basilar membrane motion only in the peak region of the traveling wave, simulated SFOAEs had single and multiple delay components similar to the animal SFOAEs. This result indicates that multiple components (including ones with short delays) can originate from cochlear mechanical irregularities in the SFOAE peak region and are not necessarily indicative of SFOAE sources in regions ≥2 octaves basal of the SFOAE peak region. We conclude that SFOAEs obtained with suppressors close to the probe frequency provide information primarily about the mechanical response in the region that receives amplification, and we attribute the too-short SFOAE delays at low frequencies to distortion-source SFOAEs and coherent reflection from multiple cochlear motions. Our findings suggest that CRT needs revision to include reflections from multiple motions in the cochlear apex.


De novo network analysis reveals autism causal genes and developmental links to co-occurring traits.
Autism is a complex neurodevelopmental condition that manifests in various ways. Autism is often accompanied by other conditions, such as attention-deficit/hyperactivity disorder and schizophrenia, which can complicate diagnosis and management. Although research has investigated the role of specific genes in autism, their relationship with co-occurring traits is not fully understood. To address this, we conducted a two-sample Mendelian randomisation analysis and identified four genes located at the 17q21.31 locus that are putatively causal for autism in fetal cortical tissue (LINC02210, LRRC37A4P, RP11-259G18.1, and RP11-798G7.6). LINC02210 was also identified as putatively causal for autism in adult cortical tissue. By integrating data from expression quantitative trait loci, genes and protein interactions, we identified that the 17q21.31 locus contributes to the intersection between autism and other neurological traits in fetal cortical tissue. We also identified a distinct cluster of co-occurring traits, including cognition and worry, linked to the genetic loci at 3p21.1. Our findings provide insights into the relationship between autism and co-occurring traits, which could be used to develop predictive models for more accurate diagnosis and better clinical management.


[Familial adenomatous polyposis from the ophthalmologic viewpoint].
Familial adenomatous polyposis is dominant autosomal heritable and pre-cancerous. Characteristic changes of ocular fundus, multiple and bilateral retinal dysplasias, permit diagnosis in presymptomatic stage, significant especially not at least for sporadic cases of polyposis recti and coli, which are 40 per-cent of all. Contrary to often wellknown risk-families this group can't be realized epidemiologically, but complications are the same.


Publisher Correction: Generation of a Jurkat-based fluorescent reporter cell line to evaluate lipid antigen interaction with the human iNKT cell receptor.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


[Unwanted Events Caused by Incorrectly Conducted Psychotherapy - A Pilot Study of the Inventory for the Assessment of Malpractice and its Consequences in Psychotherapy].
A pilot study was conducted to test a newly developed inventory for the assessment of malpractice in psychotherapy and its consequences. We aimed to examine the frequency of boundary crossings and violations in the context of psychotherapy from a patient's perspective and the resulting burden as well as to identify potential predictors. Data assessment was realized in an online-based survey. The final sample existed of N = 165 patients who underwent prior psychotherapeutic treatment. Patients reported M = 16.21 events which can be interpreted in terms of malpractice resulting in a mediocre level of distress. While malpractice summarized as "inadequate use of diagnostics/techniques" was reported most frequently, sexual boundary violations were associated with the highest levels of distress. The results demonstrate the need of a differential and systematic assessment of malpractice in psychotherapy. The new inventory especially seems to be suited for research purposes.


Homology of the D-galactose-specific lectins from Artocarpus integrifolia and Maclura pomifera and the role of an unusual small polypeptide subunit.
The Maclura pomifera agglutinin (MPA) was purified by affinity chromatography from a seed extract and its properties were compared with those of the Artocarpus integrifolia lectin, jacalin. Reverse-phase high-performance liquid chromatography showed both proteins had multiple forms of a small approximately 20-residue polypeptide chain in addition to the major 12,000 Mr subunit. The amino acid sequences of the small chains and the N-terminal sequences of the large subunits showed considerable similarity between the two proteins, approximately 60% identical residues. The homology of the proteins was confirmed by the similarity of their circular dichroism and fluorescence emission spectra. MPA showed much greater spectral changes upon binding methyl alpha-D-galactoside, suggesting it has complete activity rather than the partial activity found for jacalin. The binding of methyl alpha-D-galactoside by MPA was measured by fluorescence titration; the KA was 1.9 X 10(4) M-1 compared to 3.4 X 10(4) M-1 for jacalin. MPA also precipitated human IgA1 in the same manner as jacalin. The spectra indicate the involvement of tryptophan and tyrosine residues in the binding site of these lectins. Since a tryptophan residue is conserved in all the small subunits, they may form part of the binding site.


Synthesis, in vitro and in vivo biological evaluation of novel graveolinine derivatives as potential anti-Alzheimer agents.
A novel series of graveolinine derivatives were synthesized and evaluated as potential anti-Alzheimer agents. Compound 5f exhibited the best inhibitory activity for acetylcholinesterase (AChE) and had surprisingly potent inhibitory activity for butyrylcholinesterase (BuChE), with IC50 values of 0.72 μM and 0.16 μM, respectively. The results from Lineweaver-Burk plot and molecular modeling study indicated non-competitive inhibition of AChE by compound 5f. In addition, these derivatives showed potent self-induced β-amyloid (Aβ) aggregation inhibition. Moreover, 5f didn't show obvious toxicity against PC12 and HepG2 cells at 50 μM. Finally, in vivo studies confirmed that 5f significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, these graveolinine derivatives should be thoroughly and systematically studied for the treatment of Alzheimer's disease.


In silico approach to probe the binding affinity between OMVs harboring the ZEGFR affibody and the EGF receptor.
There is a growing interest in designing a nanocarrier containing an EGFR targeting affibody to direct toward cancer cells. Here, cytolysin A was cloned at the N-terminus of ZEGFR:1907 affibody to guarantee its surface presentation on the OMVs while targeting the epidermal growth factor receptors (EGFRs). A separate construct including a fusogenic peptide (GALA) was also designed for the endosomal escape of the nanocarrier. Binding of the two constructs ClyA-affiEGFR and ClyA-affiEGFR-GALA to domain III of EGFR was investigated using molecular docking and molecular dynamic simulations. The higher stability of the ClyA-affiEGFR-GALA/EGFR as compared to the ClyA-affiEGFR/EGFR complex was evident. The ClyA-affiEGFR-GALA structure showed a higher RMSD during the first half of the simulation time implying a much less stable behavior. Plateau state of the radius of gyration plot of ClyA-affiEGFR-GALA confirmed a well-folded structure in the presence of the GALA sequence. Solvent accessible surface area for both proteins was in the same range. The data obtained from hydrogen bond analysis revealed a more equilibrated and stable form of the ClyA-affiEGFR-GALA structure upon interaction with EGFR. The data provided here was a requisite for our biological evaluation of the synthesized constructs as a component of a novel drug delivery system.


A randomized, patient/evaluator-blinded, split-face study to compare the efficacy and safety of polycaprolactone and polynucleotide fillers in the correction of crow's feet: The latest biostimulatory dermal filler for crow's feet.
No data on the clinical results and safety profiles of the polycaprolactone (PCL) -based dermal filler for crow's feet correction have been published. This study was designed to compare the efficacy and safety of a novel PCL-based dermal filler, DLMR01, with that of RJR, a purified polynucleotide dermal filler. A total of 30 subjects with symmetric crow's feet of 2-4 points on the Crow's Feet Grading Scale (CFGS) were enrolled in this randomized, patient/evaluator-blinded, split-face study. Each subject was randomized to receive injections of DLMR01 or RJR in their right or left crow's feet. At 4 and 12 weeks, all participants were evaluated via CFGS, Global Aesthetic Improvement Scale (GAIS), and PRIMOS software system. No significant difference in CFGS, GAIS, and Ra value was detected between DLMR01 side and RJR at 12 weeks (improvement rate in CFGS from baseline at week 12-DLMR01: 48.28% [14/29], RJR: 41.38% [12/29]). The novel PCL-based dermal filler DLMR01 shows suitable efficacy and safety, widening the selection possibilities for clinicians and patients in the treatment crow's feet.


The future of pediatric epilepsy surgery. Signposts and science.
Many of the advances in pediatric epilepsy surgery should reflect scientific, technical, and conceptual issues identical to those seen with adult epilepsy surgery. However, there are certainly some unique issues involving the developing brain, and these aspects require significant input from the discipline of developmental neurobiology and the study of cortical plasticity. These developmental disciplines may prove as critical as more traditional areas of electrophysiology thought to be key to the advancement of epilepsy surgery. Pediatric epilepsy surgery may turn out to be the major beneficiary of the basic scientific advancements in these burgeoning fields.


The effectiveness of radiotherapy in the treatment of head and neck mucosal melanoma: Systematic review and meta-analysis.
Mucosal melanoma (MM) is a rare condition with a poor prognosis. Surgery is the corner stone of treatment, however, radiotherapy has been commonly employed as a treatment strategy and recent studies suggesting that survival outcomes may be improving are emerging. A systematic review and meta-analysis comparing risk ratios of radiotherapy and surgery and radiotherapy (SRT) with surgery for 5-year overall survival, local recurrence and distant metastasis in head and neck mucosal melanoma (HNMM). SRT has a lower risk of death compared to surgery [RR 0.93 [95% CI = 0.87, 0.98] (P = .01)] and a reduced risk of local recurrence [RR 0.63 [95% CI = 0.48, 0.82] (P = .005)]. SRT has no effect on distant metastasis. Radiotherapy has worse survival when compared to surgery [RR 1.2 [95% CI = 1.03, 1.33] (P = .0006)]. SRT confers a moderate survival advantage in HNMM compared to surgery. This is most likely secondary to reduced local recurrence.


Polyploidization of G2M phase cells separated from aerobically and anaerobically grown Ehrlich ascites tumor cells.
G2-enriched fractions of Ehrlich ascites tumor cells (up to 80%-85% G2 cells) separated from anaerobically and aerobically cultured asynchronous populations by centrifugal elutriation revealed the same growth characteristics after recultivation under standard conditions: a significant proportion of cells with increased DNA (DNA content greater than 4C) emerged. Interruption of DNA synthesis by deprivation of oxygen may account for polyploidization (over-replication) of DNA but other mechanisms must be taken into consideration.