In vitro immune responses of bovine mammary epithelial cells induced by Escherichia coli, with multidrug resistant extended-spectrum β-lactamase, isolated from mastitic milk.
Bovine mastitis is an inflammatory condition of mammary glands causing huge economic losses for dairy industries. Infection with extended-spectrum β-lactamase (ESBL)-producing sequence types (ST) 410-Escherichia coli (ESBL-ST410 E. coli) is considered a leading cause of bovine mastitis in China. However, pathogenic effects of these strains in an in vitro model, e.g. bovine mammary epithelial cells (bMECs), are unknown. Therefore, our objectives were to explore pathogenesis (adhesion and invasion, inflammation, oxidative stress and apoptosis) of ESBL-E. coli (highly prevalent in bovine mastitis) in bMECs. Non-pathogenic E. coli DH5α and a prototypical E. coli P4 were included as negative and positive controls, respectively. The bMECs were infected with our isolated ST410 strains, plus DH5α and P4, with assessment of the following end points: adhesive and invasive capabilities; lactate dehydrogenase (LDH) activities; inflammatory responses, including concentrations of interleukin-1β (IL-1β), IL-6, IL-10 and tumor necrosis factor-α; oxidative stress including intracellular reactive oxygen species production, malondialdehyde concentrations, activities of glutathione peroxidase and superoxide dismutase; and apoptosis. All ST410 strains had greater adhesive and invasive capabilities and increased LDH release, with varying degrees of inflammatory responses, oxidative stress and apoptosis compared to blank and DH5α groups, similar to P4-infected bMECs. In particular, ST410(4) was more likely than the other 3 isolates to adhere to and invade bMECs and increase LDH activities, cytokine release, oxidative stress and apoptosis. Thus, ST410 isolates had pathogenic manifestations of adhesive and invasive capabilities; furthermore, they induced inflammation, oxidative stress and apoptosis in bMECs. Finally, ST410(4) was the most pathogenic strain.


Molecular methods in the diagnosis of infections in the immunocompromised host.
Despite recent developments, infection remains a major obstacle to a successful outcome in transplantation. Molecular methods have allowed for earlier diagnosis and have proven to be powerful tools for analysing the epidemiology of infectious diseases. More recently, some of these molecular methods have been commercialized, enabling standardized diagnostic techniques to be used in multicentre trials.


Stress reactivity and corticolimbic response to emotional faces in adolescents.
Adolescence is a critical period in the development of lifelong patterns of responding to stress. Understanding underpinnings of variations in stress reactivity in adolescents is important, as adolescents with altered stress reactivity are vulnerable to negative risk-taking behaviors including substance use, and have increased lifelong risk for psychopathology. Although both endocrinological and corticolimbic neural system mechanisms are implicated in the development of stress reactivity patterns, the roles of these systems and interactions between the systems in reactivity to social stimuli in adolescents are not clear. We investigated the relationship between cortisol response to a laboratory-based social stressor and regional brain responses to emotional face stimuli in adolescents. Changes in cortisol levels following the Trier Social Stress Test-Child version (TSST-C) were measured in 23 disadvantaged and chronically stressed adolescents who also participated in functional magnetic resonance imaging during processing of emotional faces and structural magnetic resonance imaging. The relationships between changes in cortisol following the TSST-C with regional brain activation during face processing, as well as with regional brain morphology, were assessed. Cortisol change on the TSST-C showed a significant inverse relationship with left hippocampus response to fearful faces (p < .05, corrected); significant associations with volume were not observed. Increased cortisol response to the Trier social stressor was associated with diminished response of the left hippocampus to faces depicting fear. This suggests that HPA-corticolimbic system mechanisms may underlie vulnerability to maladaptive responses to stress in adolescents that may contribute to development of stress-related disorders.


Nanomedicine from amphiphilizedprodrugs: Concept and clinical translation.
Nanomedicines generally consisting of carrier materials with small fractions of active pharmaceutical ingredients (API) have long been used to improve the pharmacokinetics and biodistributions, augment the therapeutic efficacies and mitigate the side effects. Amphiphilizing hydrophobic/hydrophilic drugs to prodrugs capable of self-assembly into well-defined nanostructures has emerged as a facile approach to fabricating nanomedicines because this amphiphilized prodrug (APD) strategy presents many advantages, including minimized use of inert carrier materials, well-characterized prodrug structures, fixed and high drug loading contents, 100% loading efficiency, and burst-free but controlled drug release. This review comprehensively summarizes recent advances in APDs and their nanomedicines, from the rationale and the stimuli-responsive linker chemistry for on-demand drug release to their progress to the clinics, clinical performance of APDs, as well as the challenges and perspective on future development.


Interleukin 4/13 receptors: An overview of genes, expression and functional role in teleost fish.
In superior vertebrates, Interleukin 4 (IL-4) and Interleukin 13 (IL-13) play key and diverse roles to support immune responses acting on cell surface receptors. When stimulated, receptors activate intracellular signalling cascades switching cell phenotypes according to stimuli. In teleost fish, Interleukin 4/13 (IL-4/13) is the ancestral family cytokine related to both IL-4 and IL-13. Every private and common receptor subunit for IL-4/13 have in fish at least two paralogues and, as in mammals, soluble forms are also part of the receptor system. Reports for findings of fish IL-4/13 receptors have covered comparative analysis, transcriptomic profiles and to a lesser extent, functional analysis regarding ligand-receptor interactions and their biological effects. This review addresses available information from fish IL-4/13 receptors and discusses overall implications on teleost immunity, summarized gene induction strategies and pathogen-induced gene modulation, which may be useful tools to enhance immune response. Additionally, we present novel coding sequences for Atlantic salmon (Salmo salar) common gamma chain receptor (γC), Interleukin 13 receptor alpha 1A chain (IL-13Rα1A) and Interleukin 13 receptor alpha 1B chain (IL-13Rα1B).


The determination of binding parameters when the total and free substrate concentrations are not approximately equal.
By using a standard graphical method values of Km and V may be found that are independent of the conditions and assumptions that the total substrate concentration approximates to its free concentration and that Km is much larger than the enzyme concentration. The procedure is also applicable to the determination of equilibrium binding parameters of a ligand to a macromolecule.


Dynamic Transcriptional Regulation of Fis in Salmonella During the Exponential Phase.
Fis is one of the most important global regulators and has attracted extensive research attention. Many studies have focused on comparing the Fis global regulatory networks for exploring Fis function during different growth stages, such as the exponential and stationary stages. Although the Fis protein in bacteria is mainly expressed in the exponential phase, the dynamic transcriptional regulation of Fis during the exponential phase remains poorly understood. To address this question, we used RNA-seq technology to identify the Fis-regulated genes in the S. enterica serovar Typhimurium during the early exponential phase, and qRT-PCR was performed to validate the transcriptional data. A total of 1495 Fis-regulated genes were successfully identified, including 987 Fis-repressed genes and 508 Fis-activated genes. Comparing the results of this study with those of our previous study, we found that the transcriptional regulation of Fis was diverse during the early- and mid-exponential phases. The results also showed that the strong positive regulation of Fis on Salmonella pathogenicity island genes in the mid-exponential phase transitioned into insignificant effect in the early exponential phase. To validate these results, we performed a cell infection assay and found that Δfis only exhibited a 1.49-fold decreased capacity compared with the LT2 wild-type strain, indicating a large difference from the 6.31-fold decrease observed in the mid-exponential phase. Our results provide strong evidence for a need to thoroughly understand the dynamic transcriptional regulation of Fis in Salmonella during the exponential phase.


The effects of routine oxytocic administration in the management of the third stage of labour: an overview of the evidence from controlled trials.
Recent claims that routine active management of the third stage of labour increases rather than decreases maternal and neonatal morbidity have prompted us to conduct a systematic review of the relevant controlled trials. In this paper we have analysed data derived from a total of nine published reports of controlled trials in which an oxytocic drug was compared with either a placebo or no routine prophylactic. Oxytocic drugs used routinely appear to reduce the risk of postpartum haemorrhage by about 40% (typical odds ratio 0.57, 95% confidence interval 0.44-0.73) implying that for every 22 women given such an oxytocic, one postpartum haemorrhage could be prevented. The available data are insufficient to assess the possible effects of this policy on the incidence of retained placenta, hypertension and other possible adverse effects.


Human mucosal CD4+ T cells but not blood CD4+ T cells respond vigorously towards CD28 engagement.
Human lamina propria T lymphocytes (LPT) possess functional properties profoundly different from those of peripheral blood T lymphocytes (PBT). While they are characterized by a low proliferative response to T cell receptor (TCR)/CD3 stimulation in vitro their responsiveness to activation through the 'co-stimulatory' CD2-receptor is enhanced when compared to PBT. In this study, we demonstrate that engagement of another co-stimulatory receptor on both LPT and PBT, namely CD28, by a single monoclonal antibody (mAb), respectively, strongly activates the former but not the latter through a PI3-kinase dependent signalling pathway leading to the production of inflammatory cytokines such as interleukin (IL)-2, tumour necrosis factor (TNF)-α, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition to the high sensitivity of LPT to CD2 stimulation, this finding supports the notion that 'non-specific/innate' mechanisms to activate T lymphocytes play a predominant role vis-à-vis'TCR driven/adaptive' responses in the intestinal mucosa. Furthermore, it suggests that results from preclinical tests for therapeutic antibodies performed with human blood derived T cells are probably insufficient to predict reactivities of tissue-resident immune cells, which--given their quantitative predominance--may critically determine the in-vivo response to such compounds.


Inhibition of bacterial degradation of EtG by collection as dried urine spots (DUS).
Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are direct alcohol consumption markers widely used nowadays for clinical and forensic applications. They are detectable in blood and urine even after consumption of trace amounts of ethanol and for a longer time frame, being detectable even when no more ethanol is present. The instability of EtG against bacterial degradation in contaminated urine samples and/or the possible postcollection synthesis of this metabolite in samples containing, e.g., Escherichia coli and ethanol, may cause false identification of alcohol uptake. Therefore, it is of paramount importance to constrict these error sources by inhibition of any bacterial growth causing hydrolization or synthesis of EtG. This study evaluates a new method of collecting urine samples on filter paper, dried urine spots (DUS), for simultaneous detection of EtG, EtS and creatinine, having the great advantage of inhibiting bacterial activity. In addition, a method validation for the determination of EtG and EtS in DUS was performed according to the FDA guidelines. Sterile-filtered urine was spiked with EtG and EtS, inoculated with E. coli and incubated. Liquid and dried urine samples were collected after various time intervals up to 96 h. Liquid samples were frozen immediately after collection, whereas aliquots for DUS were pipetted onto filter paper, allowed to dry and stored at RT until analysis 1 week after. The specimens were analyzed by LC-ESI-MS/MS. As expected, degradation of EtG, but not of EtS, was observed in contaminated liquid urine samples. However, the specimens collected on filter paper and stored at RT showed no degradation during storage. Therefore, collecting urine samples on filter paper for EtG and EtS analysis turns out to be a reliable method to avoid bacterial degradation of EtG and EtS, and consequently, stabilization of these ethanol metabolites is achieved. In addition, simultaneous measurement of creatinine content as an indicator of urine dilution helps to interpret the results. Method validation for EtG and EtS in DUS was satisfactory, showing the linearity of the calibration curves in the studied concentration range, good precision, accuracy and selectivity.


Emphysematous cholecystitis: sonographic findings.
Emphysematous cholecystitis (EC) is a rare but life-threatening complication of acute cholecystitis, and an early diagnosis is required to prevent delay in patient management. Because sonography (US) is the first choice for diagnosing gallbladder diseases, US findings of EC should be understood more precisely. We reviewed US findings of 11 surgically proven cases of EC (with small amounts of gas in three cases and large amounts in eight cases) and compared those with patients' clinical data. (1) In cases with small amounts of gas, US showed an echogenic line with a distinct ring-down artifact or a "powder snow-like" speckled posterior echo. (2) In cases with large amounts of gas, US showed a wide spiculated echogenic band with a powder snow-like speckled posterior echo or a speckled acoustic shadowing. In all cases, the presence of gas prevented visualization of the gallbladder wall. (3) US did not differentiate gas localized to the gallbladder wall and gas extending to the surrounding hepatic tissue. (4) Two diabetic cases showed gas throughout the intrahepatic bile ducts. In those cases, the time from diagnosis to recovery was relatively long. Our series showed some characteristic US patterns of EC. A good understanding of its US findings and appropriate emergent management will reduce the serious morbidity and mortality rates caused by EC.


Intracellular survival of Campylobacter jejuni in human monocytic cells and induction of apoptotic death by cytholethal distending toxin.
Campylobacter jejuni 81-176 is capable of extensive replication within human monocytic cell vacuoles and induces apoptotic death via cytolethal distending toxin.


Thematic Reclassifications and Emerging Sciences.
Over time, various thematic classifications have been put forward to organize science into a coherent system of specialized areas of research. From an analysis of the historical evolution of the criteria used to distinguish the sciences from one another, I propose in this paper a quadripartite typology for the different thematic classification systems propounded by scholars throughout the centuries. Basically, I argue that the criteria used to differentiate the sciences have been alternately drawn from their respective subject matters, kinds of knowledge, methods and aims. Then, I show that several reclassifications occurred in the thematic structure of science. Finally, I argue that such changes in the structure of learning displaced the modalities of contact between the objects, knowledge, methods and aims of the various branches of science, with the result of outlining reshaped intellectual territories conducive to the emergence of new areas of research.


Parents' perspectives on preparing for parenthood: a qualitative study on Greenland's universal parenting programme MANU 0-1 year.
The transition to parenthood has received increasing attention in research, partly due to evidence pointing out the crucial developmental period of a child's first thousand days. Parenting programmes aim to prepare and support families in their transition and distress. For a programme to be implemented successfully it is important to consider parents' needs and resources. Bringing parents' perspectives and experiences to the forefront of the implementation of the Greenlandic parenting programme MANU 0-1 Year (MANU) is important for determining if the programme can meet its aim of contributing to thriving families. This study aims to investigate how parents' notions and experiences of parenthood are reflected and challenged in MANU. Data were collected in three of Greenland's five municipalities. Qualitative interviews were held with 38 mothers and 12 fathers either individually or as couples: a total of 40 interviews. Additionally, a Sharing Circle with three fathers was held. Interviews were in Greenlandic or Danish. A thematic, inductive analysis was applied. In their transition to parenthood, participants experienced a reprioritisation of their life and changes in their network. It is important to parents that their child experiences security and care, and participants describe this in contrast to their own childhood. Community is the most important value in child-rearing. Conversations and advice from family members and friends are mentioned as a means to prepare for birth and parenthood. Additionally, conversations with midwives and MANU sessions were also used for preparation. Parents appreciated learning from and listening to other parents in MANU sessions. However, accessing MANU depends on the individual parent's interest and ability to attend sessions. Parents' notions and experiences of parenthood are addressed in the programme, but the use of MANU depends on the parents' attendance and how it is organised and locally offered. The study suggests that MANU has the possibility to create a space for parents to reflect and prepare. However, for MANU to be universal as intended and to reach both mother and father the facilitation of sessions could be revisited.


The Genetics of Febrile Seizures.
Investigators from Virginia Commonwealth University, Norwegian Center for Epilepsy and University of Southern Denmark carried out twin studies to analyse the genetic influence of developing epilepsy after febrile seizures.


Risperidone interacts with serum albumin forming complex.
The aim of the work is to study the mechanisms of the interaction of risperidone with human and bovine serum albumins using the fluorescence quenching technique. Risperidone is an atypical antipsychotic drug used to treat many psychiatric disorders. We selectively excited the fluorescence of tryptophan residues with a 290 nm wavelength light, and observed quenching by titrating human and bovine serum albumin solutions with risperidone. Emission spectra were recorded in the range from 300 to 450 nm for each quencher addition. Stern-Volmer graphs were plotted and quenching constants were estimated. Results showed that the drug quenches the fluorescence of the human serum albumin by the formation of a complex risperidone-albumin. Association constants calculated from Stern-Volmer equation for low concentrations (lower than 1:10 ratio risperidone/albumin) were of 2.56 × 10(5)M(-1), at 25 °C, and 1.43 × 10(5)M(-1), at 37 °C. As the quenching intensity of bovine serum albumin, which contains two tryptophan residues, was found to be higher than that of human serum albumin, which contains only one tryptophan residue. Hence, we suggest that the primary binding site for risperidone in albumin should be located in sub domain IB.


Spatial turnover of soil viral populations and genotypes overlain by cohesive responses to moisture in grasslands.
Viruses shape microbial communities, food web dynamics, and carbon and nutrient cycling in diverse ecosystems. However, little is known about the patterns and drivers of viral community composition, particularly in soil, precluding a predictive understanding of viral impacts on terrestrial habitats. To investigate soil viral community assembly processes, here we analyzed 43 soil viromes from a rainfall manipulation experiment in a Mediterranean grassland in California. We identified 5,315 viral populations (viral operational taxonomic units [vOTUs] with a representative sequence ≥10 kbp) and found that viral community composition exhibited a highly significant distance-decay relationship within the 200-m2 field site. This pattern was recapitulated by the intrapopulation microheterogeneity trends of prevalent vOTUs (detected in ≥90% of the viromes), which tended to exhibit negative correlations between spatial distance and the genomic similarity of their predominant allelic variants. Although significant spatial structuring was also observed in the bacterial and archaeal communities, the signal was dampened relative to the viromes, suggesting differences in local assembly drivers for viruses and prokaryotes and/or differences in the temporal scales captured by viromes and total DNA. Despite the overwhelming spatial signal, evidence for environmental filtering was revealed in a protein-sharing network analysis, wherein a group of related vOTUs predicted to infect actinobacteria was shown to be significantly enriched in low-moisture samples distributed throughout the field. Overall, our results indicate a highly diverse, dynamic, active, and spatially structured soil virosphere capable of rapid responses to changing environmental conditions.


High FAAP24 expression reveals poor prognosis and an immunosuppressive microenvironment shaping in AML.
As a core member of the FA complex, in the Fanconi anemia pathway, FAAP24 plays an important role in DNA damage repair. However, the association between FAAP24 and patient prognosis in AML and immune infiltration remains unclear. The purpose of this study was to explore its expression characteristics, immune infiltration pattern, prognostic value and biological function using TCGA-AML and to verify it in the Beat AML cohort. In this study, we examined the expression and prognostic value of FAAP24 across cancers using data from TCGA, TARGET, GTEx, and GEPIA2. To further investigate the prognosis in AML, development and validation of a nomogram containing FAAP24 were performed. GO/KEGG, ssGSEA, GSVA and xCell were utilized to explore the functional enrichment and immunological features of FAAP24 in AML. Drug sensitivity analysis used data from the CellMiner website, and the results were confirmed in vitro. Integrated analysis of the TCGA, TARGET and GTEx databases showed that FAAP24 is upregulated in AML; meanwhile, high FAAP24 expression was associated with poor prognosis according to GEPIA2. Gene set enrichment analysis revealed that FAAP24 is implicated in pathways involved in DNA damage repair, the cell cycle and cancer. Components of the immune microenvironment using xCell indicate that FAAP24 shapes an immunosuppressive tumor microenvironment (TME) in AML, which helps to promote AML progression. Drug sensitivity analysis showed a significant correlation between high FAAP24 expression and chelerythrine resistance. In conclusion, FAAP24 could serve as a novel prognostic biomarker and play an immunomodulatory role in AML. In summary, FAAP24 is a promising prognostic biomarker in AML that requires further exploration and confirmation.


Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer.
Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan-Meier estimator, log-rank test, and Cox regression. Our analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05). Our gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application.


Intraperitoneal chemotherapy for ovarian carcinoma.
Investigators at several centers have begun to explore the potential utility of the intraperitoneal administration of chemotherapeutic agents as therapy for advanced ovarian carcinoma. Recent pharmacokinetic modeling studies have suggested and initial clinical trials have confirmed an advantage for cavity exposure to certain drugs compared to systemic exposure when the agents are delivered directly into the peritoneal cavity. While objective responses have been observed in patients with refractory disease, there are both practical and theoretical problems with this approach to the treatment of ovarian carcinoma. Eventually randomized controlled trials will be required to define a role for this innovative therapeutic technique.


Purification and characterization of heat-tolerant protease produced by Bacillus polyfermenticus SCD.
A protease produced by Bacillus polyfermenticus SCD was purified and characterized as a new detergent material. The protease was purified from supernatant produced by B. polyfermenticus SCD, by ammonium sulfate precipitation, ion-exchange chromatography on a DEAE-Sephadex A-50, and finally gel filtration chromatography on Sephadex G-50. The molecular mass of this enzyme was 44 kDa based on SDS-PAGE. The optimum temperature and pH were 50°C and pH 8.0. The ranges of its stability to the pH and temperature were 7.0 to 9.0 and under 40°C, respectively. The enzyme was highly stable in the presence of the surfactants like Triton X-100 (0.1%), showing a 2-fold increase in its proteolytic activity. However, the enzyme was slightly inhibited by the chelating agent EDTA (1 mM). The enzyme has a maximum activity at 50°C and the activity can be increased by surfactants such as Triton X-100 and Tween 80.


Reproducibility and validity of ambulatory ST segment monitoring in patients with chronic stable angina pectoris.
Transient ST segment changes are thought to be an indicator of intermittent myocardial ischemia in patients with chronic stable angina pectoris, and ambulatory ECG monitoring is a potentially useful means of quantifying these changes. In order to evaluate their repeatability, the automated analytical system developed in our department was carefully validated. Ambulatory ST segment monitoring was then performed on two occasions, 6 weeks apart, in 16 patients with established chronic stable angina pectoris of at least 1 year's duration. Both periods of monitoring were undertaken after administration of placebo for 2 weeks, and two bipolar ECG leads (CM5 and CC5) were monitored on both occasions. The total number (mean +/- SEM) of episodes of ST segment depression greater than 1 mm and of 3 minutes' duration or more in 24 hours was 4.9 +/- 1.0 and 5.1 +/- 1.0 on the first and second recordings (p = NS), and the total duration of ST segment depression in 24 hours was 83.6 +/- 27.7 minutes and 78.9 +/- 20.8 minutes, (p = NS) respectively. The maximal depth of ST segment depression observed during 24 hours was 3.5 +/- 0.3 mm and 3.4 +/- 0.2 mm, respectively, in lead CM5 (p = NS), with similar findings from lead CC5. These results demonstrate that ambulatory ST segment depression observed during uncontrolled normal daily activity in patients with established chronic stable angina pectoris is reproducible. This technique could provide a valuable method for assessment of antianginal drugs and patterns of ST segment changes during normal daily activities, provided that manual checks to ensure artifact exclusion are used to supplement the automated analysis.


Lymphoid Papillary Hyperplasia Arising from the Upper Portion of the Left Palatine Tonsil: A Case Report and Literature Review.
Lymphoid papillary hyperplasia of the tonsils is a rare, benign lesion and is characterized by a papillomatous appearance with reactive follicular hyperplasia. Our case was unique because the lesion involved the unilateral and focal palatine tonsil, as the lesion usually involves the bilateral and entire palatine tonsils.


Predictive values of post-clopidogrel platelet reactivity assessed by different platelet function tests on ischemic events in East Asian patients treated with PCI.
Abstract An accumulating number of studies are revealing that platelet reactivity above specific cut-off scores leads to exponentially increased rates of post-percutaneous coronary intervention (PCI) ischemic events. To evaluate the optimal predictive values for three different platelet function measurement assays of platelet reactivity on early clinical outcomes in Korean patients undergoing PCI, we enrolled 228 patients receiving clopidogrel prior to PCI. Platelet reactivity was measured by light transmittance aggregometry (LTA), VerifyNow P2Y12 assay, and multiple electrode platelet aggregometry (MEA). The primary endpoint was the 30-day occurrence of ischemic events after PCI. MACE occurred in 36 patients (15.8%), including 35 patients (15.4%) with periprocedural MI and the death of one patient (0.4%). ADP-induced LTA and VerifyNow values (pre- and post-PCI) were significantly higher in patients with the subsequent occurrence of periprocedural MI, but the MEA assay data (PCI and post-PCI) displayed no significant differences (pre-PCI p=0.25 and post-PCI p=0.33). ROC curve analysis demonstrated HPR values for LTA (pre-PCI, >66% and post-PCI, >53 %, all p<0.001), VerifyNow (pre-PCI, >347 PRU and post-PCI >272 PRU, all p<0.001) and MEA (pre-PCI, >50 U and post-PCI >39 U, all p>0.05). The platelet reactivity measurements by LTA and the VerifyNow assay can discriminate the risk of 30-day ischemic events after PCI. The predictive cut-off values for adverse events are dependent on sampling time.


[Use of an outpatient treatment center for cannabis abuse].
There has been an increase of cannabis-related disorders in Germany during the last 10 years. According treatments are being established, however little is known about the treatment populations. The population of an outpatient treatment program for diagnosis and therapy of cannabis-related disorders was investigated using a structured interview (based on EuropASI, SCID-I) regarding sociodemographic variables, history of addiction, consumption patterns, and psychiatric comorbidity. The 90 patients studied had a mean age of 27.5+/-6.6 years; 82% were male. They claimed averages of cannabis consumption for 11+/-7 years and current amount at 1.9 g per day. Alcohol problems were also common in this sample. High percentages were shown regarding unemployment, living alone, and problems with the law. Comorbid psychiatric disorders were diagnosed in 42% of patients. The patients were chronic users of cannabis with extensive psychosocial problems. Therapy of cannabis-related disorders should therefore include treatment for comorbidities and social care besides the treatment for addictive behavior.


Uncoupled iron homeostasis in type 2 diabetes mellitus.
Diabetes mellitus is frequently associated with iron overload conditions, such as primary and secondary hemochromatosis. Conversely, patients affected by type 2 diabetes mellitus (T2DM) show elevated ferritin levels, a biomarker for increased body iron stores. Despite these documented associations between dysregulated iron metabolism and T2DM, the underlying mechanisms are poorly understood. Here, we show that T2DM patients have reduced serum levels of hepcidin, the iron-regulated hormone that maintains systemic iron homeostasis. Consistent with this finding, we also observed an increase in circulating iron and ferritin levels. Our analysis of db/db mice demonstrates that this model recapitulates the systemic alterations observed in patients. Interestingly, db/db mice show an overall hepatic iron deficiency despite unaltered expression of ferritin and the iron importer TfR1. In addition, the liver correctly senses increased circulating iron levels by activating the BMP/SMAD signaling pathway even though hepcidin expression is decreased. We show that increased AKT phosphorylation may override active BMP/SMAD signaling and decrease hepcidin expression in 10-week old db/db mice. We conclude that the metabolic alterations occurring in T2DM impact on the regulation of iron homeostasis on multiple levels. As a result, metabolic perturbations induce an "iron resistance" phenotype, whereby signals that translate increased circulating iron levels into hepcidin production, are dysregulated. T2DM patients show increased circulating iron levels. T2DM is associated with inappropriately low hepcidin levels. Metabolic alterations in T2DM induce an "iron resistance" phenotype.


Morphometric analysis, at electron microscope level, combined with hormone assay of nonfunctioning adrenocortical adenomas: comparison with aldosterone-producing adenomas.
We performed electron microscopic studies of eight nonfunctioning adrenocortical adenomas (NFA) and nine aldosterone-producing adenomas (APA) obtained from surgical specimens. A comparison of these two types of adenomas was conducted by morphometric analysis of random electron micrographs. The organelles measured included mitochondria (M), smooth-surfaced endoplasmic reticulum (SER), rough-surfaced endoplasmic reticulum (RER), lipid vacuoles (LV), and lysosomes (Ly). The content of steroid hormones, including 17-alpha hydroxyprogesterone (17-OHP), aldosterone (Ald), and other steroid hormones, was measured in adenoma tissue from six NFA and eight APA. The percentages of the areas of the organelles M, SER, and RER per total cell area in the NFA were significantly lower than those in the APA. The average content of Ald in adenoma tissues in APA was markedly higher than that in the NFA, while the mean content of 17-OHP in the NFA was significantly higher than that in APA. In conclusion, NFA are morphometrically characterized by a reduction in organelles such as M, SER, and RER, compared with findings in APA. From the quantitative analysis of steroid hormones, it was suggested that NFA produce more precursor substances with less hormone activity than APA and that steroidgenesis in NFA is shifted to a glucocorticoid pathway, as indicated by the elevated 17-OHP concentration.


Arrector pili muscle: evidence of proximal attachment variant in terminal follicles of the scalp.
There is general agreement that the proximal attachment site of the arrector pili (AP) muscle, via elastic tendons, is the bulge region, where follicular stem cells are situated. A variant of this insertion, in which the AP muscle surrounds the follicle circumference, has been described in human facial vellus hair follicles. To investigate whether terminal hair follicles of the human scalp may also present this variant of proximal insertion of the AP muscle. Histological and immunohistochemical methods were used. At the bulge level, bundles of the AP muscle were seen to encircle the entire hair follicle. Terminal follicles of the human scalp may also present this variant of proximal insertion of the AP muscle.


Continuous flow method for determination of erythrocyte osmotic fragility.
A simple and accurate micromethod for the determination of erythrocyte osmotic fragility is introduced. The method uses a laminar parabolic flow pattern, together with gravity, to retain cells in a long, small-diameter tube while a solution with decreasing osmolarity is passed through the tube. As the cells hemolyze, hemoglobin released from the cells is quickly removed by the axial flow pattern and monitored with a 547 nm optical detector for recording the hemolysis curve. Consequently, a continuous curve is obtained, with a peak occurring at the salt concentration that produces the maximum hemolysis rate. The advantages of this method are simplicity, accuracy, and small sample size (2 microliters of whole blood). The small sample size is of particular importance for infants. A comparison is made with the Parpart method using samples from 18 normal adults. Results are also given for a few abnormal adults and for a series of 26 normal newborns.


Duplicate origin of left vertebral artery.
A verified case of duplicate origin of the left vertebral artery in association with a large aneurysm arising from the aortic arch immediately distal to the left subclavian artery is presented. An anomalous left vertebral artery arises directly from the aortic arch between the left common carotid and subclavian arteries, and joins with the normal left vertebral artery in the transverse foramen of the fifth cervical vertebra.


Bilateral intraocular lens implantation.
A study of 1796 consecutive cataract patients in a posterior chamber intraocular lens implant (IOL) series revealed 373 patients (20.8%) who had bilateral IOLs. Visual acuity was 20/40 or better in 87% of first eyes operated and 90% in second eyes. The major cause of vision less than 20/40 was senile macular choroidal degeneration in both first and second eyes. The surgical reintervention rate was 11.8% in first eyes and 3.7% in second eyes. Ninety-two percent of patients had an interval of six months or more between surgery on the first and second eyes.


Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer.
The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells. We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases. p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.


Preparation and Characterization of Coaxial Electrospun Fibers Containing Triclosan for Comparative Study of Release Properties with Amoxicillin and Epicatechin.
The optimal conditions for the fibers preparation of cellulose acetate (CA) and poly(vinyl pyrrolidone) (PVP) containing triclosan within the fiber were successfully found; the physicochemical characteristics of these fibrous membranes were corroborated by FTIR spectroscopy, thermal analysis, mechanical tests, SEM , and TEM analysis. The formation of composite fibers of CA and PVP containing triclosan at the core of the fiber was evidenced. A comparative study of the release properties of amoxicillin, epicatechin or triclosan embedded into fibers CA/PVP/CA was performed. As more interactions of the drug with CA or PVP occur, slower release of the drug into the release medium takes place. Regarding the drug delivery system design, it is important to consider the possible molecular interactions between the material components and predict how fast or slow the drug will be delivered into the corresponding medium.


Calcium/calmodulin-dependent protein kinase II and arrestin phosphorylation in Limulus eyes.
In rhabdomeral photoreceptors, light stimulates the phosphorylation of arrestin, a protein critical for quenching the photoresponse, by activating a calcium/calmodulin-dependent protein kinase (CaM PK). Here we present biochemical evidence that a CaM PK that phosphorylates arrestin in Limulus eyes is structurally similar to mammalian CaM PK II. In addition, cDNAs encoding proteins homologous to mammalian and Drosophila CaM PK II in the catalytic and regulatory domains were cloned and sequenced from a Limulus lateral eye cDNA library. The Limulus sequences are unique, however, in that they lack most of the association domain. The proteins encoded by these sequences may phosphorylate arrestin.


[Quantitative indices of mitral valve regurgitation].
The assessment of the degree of mitral regurgitation has always been difficult and subject to errors. With the growing impetus on surgery in asymptomatic patients, the quantitation of mitral regurgitation has become a crucial part of the assessment of these patients. Several new methods have been developed that are currently utilized and allow the measurement of the lesion severity (Effective regurgitant orifice) and the volume overload (regurgitant volume and fraction) of mitral regurgitation.


The antagonism of bombesin in the CNS by substance P analogues.
The ability of substance P analogues to inhibit the action of bombesin in the CNS was investigated using receptor binding and biological assays. The putative substance P antagonists inhibited binding to central receptors for both substance P and bombesin-like peptides. Spantide, which was the most potent analogue tested, reversed the bombesin induced hypothermia and grooming. Therefore the putative substance P antagonists may also antagonize the actions of bombesin in the CNS.


Impact of COVID-19 on maternal health and child care behavior: Evidence from a quasi-experimental study of vulnerable communities in Boa Vista, Brazil.
COVID-19 related distress has been shown to have negative associations with family well-being. To determine the immediate impact of acute COVID-19 infection on maternal well-being and parenting practices among Brazilian families. We studied 2'579 mothers (29'913 observations) of young children from vulnerable neighborhoods in Boa Vista, Brazil over 12 months. We monitored family health and caregiving behavior including the incidence of COVID-19 infections in the surveyed households through bi-weekly phone interviews over 50 weeks, from June 2020 to May 2021. Primary outcomes were home-based child stimulation, positive parenting behavior, and parenting stress. We used fixed effects panel regressions to estimate the impact of household COVID-19 infections on parenting outcomes. Over the study period, 441 participants (17.1%; 831 (3.0%) observations) reported at least 1 positive COVID-19 infection in their household. Household COVID-19 infections significantly reduced home-based stimulation by 0.10 SDs (95%CI: -0.18, -0.01), positive parenting behaviors by 0.14 SDs (-0.21, -0.01), and increased parenting stress by 0.07 SDs (0.02, 0.12). The impact on home-based stimulation was most pronounced when the mother herself had a COVID-19 infection (-0.16; -0.29, -0.04). Parenting stress responded most strongly to mother or child COVID-19 infections. Effects were relatively short-lived, only children's infections' on parental stress was still detectable 2 weeks after initial infection. Our findings suggest that COVID-19 infections cause substantial disruptions in children's home environments - additional short-term support for families with acute infections could attenuate the negative impact on children's home environment during the pandemic.


Site-specific mutations of conserved C-terminal residues in aminoglycoside 3'-phosphotransferase II: phenotypic and structural analysis of mutant enzymes.
In order to test the biological importance of amino acids in the C-terminal quarter of aminoglycoside 3'-phosphotransferase II enzyme, seven of the highly conserved residues in this region, His-188, Asp-190, Asp-208, Gly-210, Arg-211, Asp-216 and Asp-220, were changed via site-directed mutagenesis. The phenotype of each mutant was compared to wildtype in terms of antibiotic susceptibilities and enzymatic activities. All of the substitutions either abolished or significantly reduced the resistance of the resulting strains to kanamycin, neomycin, butirosin, ribostamycin, paromomycin, gentamicin A, and G-418. Similarly, enzyme activities in crude extracts were substantially reduced for the mutant strains. Affinity of the enzyme for Mg+2-ATP decreased with His-188, Asp-190, Asp-216 and Asp-220 substitutions as revealed by Km measurements. Secondary structure analysis predicted that substitutions at the conserved residues caused severe conformational distortions at the corresponding regions of the protein.


Local control and vertebral compression fractures following stereotactic body radiotherapy for spine metastases.
We aimed to retrospectively assess the incidence of vertebral compression fractures (VCF), examine clinicopathologic factors potentially associated with VCF, and evaluate treatment response in patients who received stereotactic body radiotherapy (SBRT) for spine metastases (spMets). We identified 78 patients with 125 spMets at baseline and subsequent assessments. Patients received SBRT doses of 16 or 18 Gy. Patients with pre-existing VCF and co-existing local progression were excluded. Spine instability neoplastic score (SINS) was used for spMets categorization. Response to SBRT and VCF were assessed according to the Positron Emission tomography Response Criteria In Solid Tumors (PERCIST) and Genant scores, respectively. Kaplan-Meier analyses were used to assess local control of disease and vertebral compression fracture-free survival (FFS). We treated 103 cases with single spMets and 11 cases involving double spMets with SBRT. Progressive disease was reported in 3.2% and 8.2% of the cases in the first and last PET/CT reports, respectively. The distribution of treatment response in the remaining patients was: complete response in 30.6% of patients, partial response in 47.1% of patients, and stable disease in 22.3% of patients in the first PET/CT; complete response in 62.3% of patients, partial response in 16.7% of patients, and stable disease in 21% of patients at the last monitoring. Local failures were observed in 15 (12%) of cases. Median SINS was 5 (range: 1-13); majority of patients in our cohort (70.4%) were categorized as stable according to SINS, five (4%) patients had Grade 3 VCF at a median time of 16 months after SBRT (range: 2-22 months), and 60% of VCF occurred after an interval of at least 12 months after SBRT. No bisphosphonate usage was significantly associated with VCF (r = -0.204; p = 0.022). Median FFS was 21 months. Univariate analyses indicated that female gender (p < 0.001), bisphosphonate use (p = 0.005), >6 months of bisphosphonates use (p = 0.002), and the lowest vertebral body collapse score (p = 0.023) were associated with higher FFS. Female gender (p = 0.007), >6 months of bisphosphonates usage (p = 0.018), and the lowest vertebral body collapse score (p = 0.044) retained independent significance. This study demonstrated that spine SBRT with doses of 16-18 Gy promises good local control of disease with acceptable VCF rates. Lowest vertebral body collapse score, female gender, and >6 months of bisphosphonate use were significantly associated with longer FFS.


High end-of-life incidence of seizures and status epilepticus in patients with primary and secondary brain tumors.
Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings. This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period. Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients. In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported.


Inversion of chromosome 16 and eosinophilia in refractory anemia with ring sideroblasts: report of a case.
A 72-year-old male who was admitted to our hospital with severe anemia was diagnosed as refractory anemia with ring sideroblasts (RARS), according to the French-American-British (FAB) classification of myelodysplastic syndromes (MDS). The patient showed persistent eosinophilia with no definite signs of either allergy or a parasitic infection. Chromosomal analysis of bone marrow cells revealed inv(16)(p13q22), a known characteristic of M4Eo acute myeloid leukemia (AML) in the FAB classification. This patient didn't exhibit leukemic transformation during his 20-month clinical course, nor was any found at autopsy. Therefore, this is the first case of RARS to speculate that the chromosomal characteristic inv(16)(p13q22) might be specific for eosinophilia rather than AML.


[Influence of ergot feeding on piglets and chicken].
Two preliminary tests were conducted with piglets and chicken to study the influence of feeding ergot, which was specified concerning alkaloid content and pattern, on growth performance and health parameters. Treatments were 5 ergot concentrations in the diets (0; 0.05; 0.1; 0.2; 0.4%) which were fed to 5×16 piglets for 35 days and 5×28 chicken for 21 days. A content of 0.4% ergot in the diet decreased feed intake and growth performance of piglets significantly. Contents of 0.1% and 0.2% ergot in the diet showed a tendency towards improved weight gain as compared to controls. Feed to gain ratio was found to be the lowest in the group with 0.2% ergot in the diet. In the study conducted with chicken significant effects of ergot feeding on growth performance were not detected. With increased ergot concentrations in the diet the weight of hearts decreased, which proved to be significant only at a level of 0.2 % ergot in the diet. Moderate to severe inflammations were found in the proximal duodenum of the ergot fed groups, which, however, were not dosedependent. Further studies with ergot from other sources differing in alkaloid content and pattern are necessary to evaluate toxic alkaloid levels for the various animal species or categories.


Six C21 steroidal glycosides from Cynanchum wallichii Wight roots and their multidrug resistance reversal activities.
Six unidentified C21 steroidal glycosides, cynwallosides A-F, as well as twenty-two known compounds, were isolated from the roots of Cynanchum wallichii Wight. The structures of cynwallosides A-F were determined by spectroscopic analysis and acidic hydrolysis. Most of these twenty-eight compounds were found to significantly reverse drug resistance in both the MCF-7/ADR and HepG2/ADM cell lines by suppressing P-gp protein expression. Further investigation revealed that three compounds suppressed P-gp expression by significantly inactivating the JNK and NF-κB pathways.


Preventing methicillin-resistant Staphylococcus aureus infection in joint replacements: a new problem requiring old solutions.
To analyse prospectively the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation and infection in wounds and surgical vacuum drains. The study group was 100 patients undergoing primary total hip and total knee replacements in a single orthopaedic unit. Two patients had undergone revision joint surgery within the same unit in the year prior to the study due to confirmed MRSA infection. Following a change in the unit's infection control policy, joint replacement surgery continued within the unit even when there were cases of active MRSA present on the same ward. None of the patients undergoing joint replacement grew MRSA in their postoperative drain tips or wound cultures. It is safe to continue with joint replacement surgery when other patients on the same ward have active MRSA as long as strict infection control measures are followed as outlined.


Catheter-induced pulmonary artery perforation: pathologic and pathogenic features.
Perforation of the pulmonary artery due to insertion of a balloon-tipped, flow-directed (Swan-Ganz) catheter is described in four cases. These cases were found in a consecutive series of 270 autopsies done over a 1.5-year period and suggest that the incidence of this complication may be greater than the number of clinically reported cases implies. In three instances, a focal parenchymal hematoma or thrombotic nodule identified the site of rupture. Other pathologic features and the pathogenesis of the perforation are discussed. Difficulties in postmortem diagnosis include distinguishing perforation from hemorrhage due to trauma, thromboembolism, and coagulation abnormalities.


The penetration of 2,3,7,8-tetrachlorodibenzo-p-dioxin into viable and non-viable porcine skin in vitro.
Freshly harvested, full thickness porcine skin was kept metabolically viable at 4 degrees C in a minimal essential medium for at least 48 h, as judged by the formation of lactate or 14CO2 from 14C-labeled glucose. In vitro topical exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 65 ng/cm2) for up to 1000 min did not affect the viability of skin. The penetration and distribution of TCDD into porcine skin was studied in an in vitro system under a variety of conditions, such as viability status, different vehicles or concentrations, or artificial removal of the stratum corneum. Loss of viability of the skin increased the rate of penetration of TCDD by about 60%. Removal of the stratum corneum to mimic lesioned skin increased the rate of dermal penetration of TCDD about 3-fold. The use of acetone as the vehicle, simulating dermal exposure to TCDD as a dust or from a volatile solvent, resulted in higher rates of penetration than the use of mineral oil as the vehicle, which simulates the situation of industrial accidents. The percentage of dose absorbed was independent of the dose of TCDD (65 or 6.5 ng/cm2) administered to the surface of skin. Rates of dermal penetration of TCDD ranged form 14 to 985 pg/cm2 skin per h, or 0.2-1.5% of the dose/h, depending on the conditions of exposure. These rates of penetration are comparable with results obtained by others in several other species, with both in vitro and in vivo systems including human skin in vitro. Full thickness porcine skin, viable or previously frozen, is therefore a valid in vitro model to estimate dermal penetration of TCDD in humans.


Self-assembling Bioadhesive Inspired by the Fourth Repetitive Sequence of Balanus albicostatus Cement Protein 20 kDa (Balcp-20 k).
Barnacle cement proteins are multi-protein complexes composed of a series of functionally related synergistic proteins that enable barnacles to adhere strongly and consistently to various underwater substrates. There is no post-translational modification of barnacle cement proteins, which provides a possibility for the synthesis of similar adhesive materials. Balcp-20 k has four repetitive sequences with multiple conserved cysteine groups. Whether these repeats are separate functional units and the role of cysteine in adhesion is not clear. In order to investigate the adhesion properties of Balcp-20 k, we amplified and expressed R4 (DHLACNAKHPCWHKHCDCFC)4, which is a quadruple repeat of Balcp-20 k's fourth repetitive sequence, and S0R4 (DHLASNAKHPSWHKHSDSFS)4, all cysteine of R4 replaced by serine. Analysis showed that R4 had a similar structure to Balcp-20 k, and the amyloid fibrils structure formed by self-assembly of R4 played an important role in improving the adhesion strength. The absence of disulfide bonds in S0R4 prevents self-assembly, and the failure of self-assembly after the reduction of disulfide bonds of R4 by DTT indicates that disulfide bonds play an important role in self-assembly. With adhesion and coating analysis, it was found that R4 has good adhesion on different materials surfaces, which is better than Balcp-20 k, while S0R4 has weak adhesion, which is only better than BSA.


Importance of the unique cationic residues arginine 12 and lysine 49 in the activity of the cardiotonic polypeptide anthopleurin B.
Sea anemone toxins are potentially important tools for understanding the pharmacology of voltage-sensitive sodium channels. We have previously described a bacterial expression system capable of producing large amounts of one such toxin, anthopleurin B (ApB), which delays channel repolarization (Gallagher, M. J., and Blumenthal K. M. (1992) J. Biol. Chem. 267, 13958-13963). It has been suggested that cationic residues are a major determinant of anemone toxin binding. In this paper, we describe characterization of three mutants at each of two unique cationic sites of ApB, Arg-12 and Lys-49. The activities of all mutants on cardiac and neuronal sodium channels have been compared with that of wild-type ApB. Mutation of Lys-49 has relatively minor effects on toxicity, whereas the mutant R12A, but not R12S or R12K, is severely impaired. These results indicate that cationic residues per se are not absolutely required at either position, but that polar side chains at position 12 contribute significantly to binding affinity. Furthermore, Arg-12 appears to be involved in the toxin's ability to discriminate between neuronal and cardiac sodium channels.


The effects of the thermal prephase transition and salts on the coagulation and flocculation of phosphatidylcholine bilayer vesicles.
Absorbance measurements of sonicated dipalmitoyl phosphatidylcholine vesicles reveal two aggregation processes: flocculation and coagulation. Flocculation is only observed for samples in monovalent cationic salt solutions or in salt-free suspensions. This process is abolished in the presence of di- or trivalent cations. It is also found to be strongly temperature dependent, occurring only below the thermal prephase transition of the lipid. Dispersal of the flocculates is rapid but they re-form at a rate dictated by the hysteresis in the prephase transition. In contrast, coagulation is slow. The extent of coagulation does not seem to be strongly dependent on the temperature, the nature of the electrolyte or its concentration. The relation of the coagulated state to vesicle-vesicle fusion is briefly discussed.


A review on the toxicity of silver nanoparticles against different biosystems.
Despite significant progress made in the past two decades, silver nanoparticles (AgNPs) have not yet made it to the clinical trials. In addition, they showed both positive and negative effects in their toxicity from unicellular organism to well-developed multi-organ system, for example, rat. Although it is generally accepted that capped (bio)molecules have synergistic bioactivities and diminish the toxicity of metallic Ag core, convincing evidence is completely lacking. Therefore, in this review, we first highlight the recent in vivo toxicity studies of chemically manufactured AgNPs, biologically synthesized AgNPs and reference AgNPs of European Commission. Then, their toxic effects are compared with each other and the overlooked factors leading to the potential conflict of obtained toxicity results are discussed. Finally, suggestions are given to better design and conduct the future toxicity studies and to fast-track the successful clinical translation of AgNPs as well.


Ontogenetic transitions, biomechanical trade-offs and macroevolution of scyphozoan medusae swimming patterns.
Ephyrae, the early stages of scyphozoan jellyfish, possess a conserved morphology among species. However, ontogenetic transitions lead to morphologically different shapes among scyphozoan lineages, with important consequences for swimming biomechanics, bioenergetics and ecology. We used high-speed imaging to analyse biomechanical and kinematic variables of swimming in 17 species of Scyphozoa (1 Coronatae, 8 "Semaeostomeae" and 8 Rhizostomeae) at different developmental stages. Swimming kinematics of early ephyrae were similar, in general, but differences related to major lineages emerged through development. Rhizostomeae medusae have more prolate bells, shorter pulse cycles and higher swimming performances. Medusae of "Semaeostomeae", in turn, have more variable bell shapes and most species had lower swimming performances. Despite these differences, both groups travelled the same distance per pulse suggesting that each pulse is hydrodynamically similar. Therefore, higher swimming velocities are achieved in species with higher pulsation frequencies. Our results suggest that medusae of Rhizostomeae and "Semaeostomeae" have evolved bell kinematics with different optimized traits, rhizostomes optimize rapid fluid processing, through faster pulsations, while "semaeostomes" optimize swimming efficiency, through longer interpulse intervals that enhance mechanisms of passive energy recapture.


The intrinsic vascularization of human peripheral nerves: structural and functional aspects.
A combination of microangiographic and histological methods was used to analyse the intrinsic microvascular system of human peripheral nerves of freshly amputated arms. Special attention was paid to perineurial and intrafascicular vascular systems. The human nerves present a microvascular system analogous to the intraneural system of experimental animals. The fascicles are vascularized segmentally by epineurial vessels, and each fascicle presents a well-defined fascicular vascular organization composed of endoneurial and perineurial microvascular systems in combination. The possible effects of intraneural dissection on intrafascicular blood flow are discussed. It is suggested that intraneural dissection produces considerable trauma to the nerve and an inflammatory reaction in extrafascicular layers, but that due to the barrier function of the perineurium the effects on intrafascicular tissues can be limited.


[Primary tumors of the spine. Initial oncologic aspects: epidemiology, anatomo-prognostic and therapeutic classification].
Primary tumors of the vertebral column are rare: 20 per cent of all primary tumors of the spinal column. The distribution by type of tumor shows that the three most frequent primary tumors considered to be "radio and/or chemo resistant lesions" are the chordoma (15.5 to 24.5%), the chondrosarcoma (20%) and the giant cell tumor (10%). A second group with "chemo and/or radiosensitive lesions" include the Ewing sarcoma, primary lymphoma and plasmocytoma (5%). We consider a third group with the benign tumor: osteochondroma, chondroma, osteoid osteoma, osteoblastoma, aneurysmal bone cyst, hemangioma and eosinophilic granuloma (2 to 3%). The last tumoral group agrees with sarcomatous tumors: osteogenic sarcoma, fibrosarcoma, malignant fibro-histiocytoma, angiosarcoma and hemangio-pericytoma (1 to 3% of primary tumors of the vertebral column); they are most frequently secondary to Paget's disease, giant cell tumor or to radiation therapy and their prognosis is poor.


[Lymphomatoid papulosis: clinical and pathological findings in 18 patients].
Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative skin disease that has been described in association with Hodgkin lymphoma. It has also been reported to progress to mycosis fungoides or cutaneous anaplastic large-cell lymphoma. To study the clinical and histologic features of LyP and response to treatment in a patient series. For this retrospective, descriptive, observational study of patients with histologically confirmed LyP and sufficient follow-up data on record, we extracted histologic findings on skin biopsy, clinical presentation, clinical course, and response to treatments. Eighteen patients (10 male, 8 female) were identified. Most biopsies (14/18, 78%) showed a wedge-shaped lymphocytic infiltrate with CD30(+), CD3(+), and CD56(-) cells. A type A histologic pattern was present in the biopsies of 83% of the patients. The most common presentation (83%) consisted of papules on the trunk; for 62% LyP resolved after a single episode. Twelve percent of the patients developed mycosis fungoides (mean follow-up, 7 years); no other associations were noted. Although few series of patients with LyP have been published in recent years, the findings reported generally coincide with our observations. LyP is typically a CD30(+) lymphoproliferative disorder that usually runs a benign course and responds well to treatment.


Development of an AT2-deficient proximal tubule cell line for transport studies.
Angiotensin II is a major regulatory peptide for proximal tubule Na(+) reabsorption acting through two distinct receptor subtypes: AT(1) and AT(2). Physiological or pathological roles of AT(2) have been difficult to unravel because angiotensin II can affect Na(+) transport either directly via AT(2) on luminal or peritubular plasma membranes of proximal tubule cells or indirectly via the renal vasculature. Furthermore, separate systemic and intratubular renin-angiotensin systems impart considerable complexity to angiotensin's regulation. A transport-competent, proximal tubule cell model that lacks AT(2) is a potentially useful tool to assess cellular angiotensin II regulation. To this end, AT(2)-receptor-deficient mice were bred with an Immortomouse, which harbors the thermolabile immortalization gene SV40 large-T antigen (Tag), and AT(2)-receptor-deficient [AT(2) (-/-)], Tag heterozygous [Tag (+/-)] F(2) offspring were selected for cell line generation. S1 proximal tubule segments were microdissected, and epithelial cell outgrowth was expanded in culture. Cells that formed confluent, electrically resistive monolayers were selected for cryopreservation, and one isolate was extensively characterized for conductance (2 mS/cm(2)), short-circuit current (Isc; 0.2 microA/cm(2)), and proximal tubule-specific Na3(+) - succinate (DeltaIsc = 0.8 microA/cm(2) at 2 mM succinate) and Na3(+) - phosphate cotransport (DeltaIsc = 3 microA/cm(2) at 1 mM phosphate). Light microscopy showed a uniform, cobblestone-shaped monolayer with prominent cilia and brush borders. AT(2) receptor functionality, as demonstrated by angiotensin II inhibition of ANF-stimulated cGMP synthesis, was absent in AT(2)-deficient cells but prominent in wild-type cells. This transport competent cell line in conjunction with corresponding wild type and AT(1)-deficient lines should help explain angiotensin II signaling relevant to Na(+) transport.


[Routes of administration of drugs for severe acute asthma].
Beta2-mimetics represent the primary treatment for acute severe asthma. Their route of administration are nebulizer inhalation and inhalation chamber, or direct intratracheal route in patients receiving artificial ventilation. The subcutaneous route remains useful while awaiting implementation of nebulizer routine. The intravenous route is indicated in cases of non-rapid improvement in patients' receiving inhaled treatment.


Mind God's mind: History, development, and teaching.
We dispute the target article that belief in Big Gods facilitated development of large societies and suggest that the direction of causality might be inverted. We also suggest that plain theory of mind (ToM), although necessary, is not sufficient to conceive Big Gods. Grasp of other aspects of the mind is required. However, this theory is useful for the teaching of religion.


Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients.
Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparable CNI blood concentrations frequency and severity of adverse effects vary considerably among individual patients. Determining the RGE of NFAT-regulated genes in leukocytes is a new pharmacodynamic approach to measure directly the functional consequences of calcineurin inhibition in T-lymphocytes. We compared clinical outcome parameters and RGE of activated T-cells after pLtx. We measured prospectively RGE of NFAT regulated genes in 33 pLTX recipients in the maintenance period after pLTX. CsA-treated patients with recurrent infections had significantly lower RGE rates (27%) than children without recurrent infections (50%; p = 0.04), whereas pharmacokinetic parameters of CsA and the concomitant immunosuppressive therapy were comparable between both groups. In patients on tacrolimus-based IS therapy NFAT RGE was only slightly reduced (90%). Pharmacodynamic monitoring of CsA by measurement of RGE in T-lymphocytes has the potential to identify over-immunosuppressed pediatric liver transplant recipients on a CsA-based IS therapy, while in children on low-dose tacrolimus therapy, RGE measurement does not provide additional clinically useful information.


Corrigendum: Antiviral and Immunomodulatory Effects of Pelargonium sidoides DC. Root Extract EPs® 7630 in SARS-CoV-2-Infected Human Lung Cells.
[This corrects the article DOI: 10.3389/fphar.2021.757666.].


Crystal structure of N-(3-oxo-butano-yl)-l-homoserine lactone.
The structure and absolute configuration of the title compound, C8H11NO4, which is a known quorum-sensing modulator, have been determined. The mol-ecule exhibits signs of an intra-molecular attractive carbon-yl-carbonyl n→π* inter-action between the amide and lactone ester groups, specifically - a short contact of 2.709 (2) Å between the amide oxygen atom and ester carbon atom, approach of the amide oxygen atom to the ester carbonyl group along the Bürgi-Dunitz trajectory, at 99.1 (1)°, and pyramidalization of the ester carbonyl group by 1.1 (1)°. Moreover, a similar n→π* inter-action is observed for the amide carbonyl group approached by the ketone oxygen donor. These inter-actions apparently affect the conformation of the uncomplexed mol-ecule, which adopts a different shape when bound to protein receptors. In the crystal, the mol-ecules form translational chains along the a axis via N-H⋯O hydrogen bonds.


Nonsurgical treatment of sinusitis.
Acute infections of the paranasal sinuses is an infrequent complication of viral upper respiratory infections. Prolonged or repeated episodes of acute sinusitis may lead to irreversible changes in the mucosa, resulting in chronic sinusitis. In hospitalized and immunocompromised patients sinusitis may be caused by unusual and resistant bacteria or fungi. Although sinusitis is often considered as merely an annoyance, complications can be associated with significant morbidity and mortality. Therapy of acute sinusitis is often empiric and directed against the most common pathogens. Fungal infections of the sinuses often require surgery as well as amphotericin-B therapy. In hospitalized or immunocompromised patients therapy should be directed at suspected nosocomial pathogens or be based on appropriate culture material.


Application of asymmetric Sharpless aminohydroxylation in total synthesis of natural products and some synthetic complex bio-active molecules.
This report illustrates the applications of Asymmetric Sharpless Aminohydroxylation (ASAH) in the stereoselective synthesis of vicinal amino alcohols as important intermediates in the total synthesis of complex molecules and natural products with significant biological activities. The ASHA allows the regio- syn-selective synthesis of 1,2-amino alcohols via reaction of alkenes with salts of N-halosulfonamides, -amides and -carbamates employing osmium tetroxide (OsO4) as an efficient catalyst. In this reaction, chirality is induced via the addition of dihydroquinine- and dihydroquinidine as derived chiral ligands.


Perforated peptic ulcer.
Peptic ulcer disease has declined significantly since 1950 in industrialized nations. However, the number of patients with perforated and bleeding ulcers has been constant or has declined only slightly, except for older patients, in whom the frequency has increased. In patients with perforated ulcers, operative management is preferable to non-operative treatment. The operative choices are simple closure of the perforation or definitive surgery. Patients who have significant risk factors should undergo simple closure. Closure of the ulcer with parietal cell vagotomy is the author's first choice for definitive operative treatment when this procedure can be performed.


[Tolerance of a new intravenously applied immunoglobulin preparation and its effect on serum globulin levels].
In a controlled prospective study, 212 patients were evaluated in 13 different hospitals with regard to the clinical tolerance of a new gammaglobulin preparation which can be administered intravenously. The age of the patients ranged from one day to 83 years. Patients with a primary or secondary immunoglobulin deficiency and patients with normal serum immunoglobulin concentrations were included in the study. In 811 infusions a total of 7128 g gammaglobulin were applied; the maximum dosage was 30 g/day. We saw a transient, recurrent and spontaneously reversible fever reaction in one patient with long-term substitution because of a primary immunodeficiency syndrome. Otherwise, no serious side-effects were seen in clinical or laboratory controls. Patients controlled for their serum gammaglobulin concentrations before and after the infusions showed a significant rise of 112.5 mg/100 ml for each infusion of 3 g gammaglobulin. The new preparation also showed an estimated half-life of 23 days, thus making it a good possibility for long-term substitution in immunodeficient patients.


Retarded growth of cladoceran zooplankton in the presence of a copepod predator.
Various instars of four different cladoceran species representing a wide spectrum of body size were grown at high food availability in the presence and in the absence of natural densities of an invertebrate predator, a cyclopoid copepod Acanthocyclops robustus (G.O. Sars). Daily weight increments calculated from individual weights at the end and at the beginning of each 1, 2 or 4 day experiment, showed that individual growth was more or less drastically retarded in the presence of the predator as well as when exposed to water in which the predator had been feeding. The data also showed that the effect of this invertebrate predator was more pronounced in small prey instars and small prey species that were more vulnerable to predation than large prey.


Bilateral chiasm and optic nerve micro-decompression in a child with extensive cranial fibrous dysplasia: how I do it.
Surgical decompression to the optic-chiasmatic region in craneofacial fibrous dysplasia (CFD) must be performed safely to improve or stabilize visual loss. We describe a technical nuance when facing on a huge, deformed skull with potentially imbricated dura mater. Craniectomy was performed in concentric arches allowing to expose surgical field and elevated step by step. Bilateral micro-decompression was performed after without difficulties. Decompressing both optic nerves using this technique is safe and relatively simple to perform.


Long-term effects of a combination of D-penicillamine and zinc salts in the treatment of Wilson's disease in children.
The aim of this study was to investigate the effectiveness of a high-dose zinc sulfate and low-dose D-penicillamine combination in the treatment of pediatric Wilson's disease (WD). A retropective chart review of 65 patients with WD was conducted. These patients received D-penicillamine (8-10 mg/kg/day) and zinc sulfate as the primary treatment. The pediatric dose of elemental zinc is 68-85 mg/day until 6 years of age, 85-136 mg/day until 8 years of age, 136-170 mg/day until 10 years of age and then 170 mg/day, in 3 divided doses 1 h before meals. After clinical and biochemical improvement or stabilization, zinc sulfate alone was administered as the maintenance therapy. Under treatment, the majority of patients (89.2%) had a favourable outcome and 3 patients succumbed due to poor therapy compliance. No penicillamine-induced neurological deterioration was noted and side-effects were observed in <11% of patients over the entire follow-up period. Benefical results on the liver and neurological symptoms were reported following extremely long-term treatment with a combination of low-dose D-penicillamine and high-dose zinc sulfate. Therefore, this regimen is an effective and safe treatment for children with WD.


Recent advances in direct cardiac reprogramming.
Human adult cardiomyocytes have limited regenerative capacity resulting in permanent loss of cardiomyocytes in the setting of many forms of heart disease. In an effort to replace lost cells, several groups have reported successful reprogramming of fibroblasts into induced cardiomyocyte-like cells (iCMs) without going through an intermediate progenitor or stem cell stage in murine and human models. This direct cardiac reprogramming approach holds promise as a potential method for regenerative medicine in the future and for dissecting the regulatory control of cell fate determination. Here we review the recent advances in the direct cardiac reprogramming field and the challenges that must be overcome to move this strategy closer to clinical application.


Specific binding of parathyroid hormone to living osteoclasts.
We show that osteoclasts bind parathyroid hormone (PTH) in a manner that displays the properties of receptor-dependent hormone binding, that is, saturability, time dependence, temperature dependence, and hormone specificity. Osteoclasts were isolated from the endosteum of 2 to 3 week chick tibiae and maintained in culture for 4-6 days. Bovine PTH-(1-84) was biotinylated with N-hydroxysuccinimidobiotin. Biotinyl-PTH (btPTH, 10(-5)-10(-11) M) was added to the cultured osteoclasts for 2-20 minutes. After rinsing away unbound btPTH, fluorescein isothiocyanate-labeled avidin (FITC-avidin) at a concentration of 66 micrograms/ml was applied. Receptor binding characteristics were assessed: (1) saturation occurred at around 10(-6) M btPTH; (2) competition of excess unlabeled PTH was found, namely, a 10-fold excess abolished fluorescence; (3) specificity was shown by adding other polypeptide hormones (insulin, glucagon, and calcitonin) in 10- to 100-fold excess--no effect on PTH binding was observed; and (4) affinity of btPTH for its binding site was indicated by half-maximal binding approximately equal to 10(-7) M for both osteoclasts and osteoblasts. Biotin (10(-5) M) or FITC-avidin (66 micrograms/ml) alone did not cause fluorescence. The time course of btPTH on the cell exterior was short: at 2 and 5 minutes dots of fluorescence were randomly dispersed over the cell surface, by 10 minutes most of the fluorescence was clustered in one region of the membrane, and by 20 minutes most of the hormone was no longer present on the surface of the cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Metabolic alkalosis following administration of an organophosphorus compound, O,S,S-trimethyl phosphorodithioate.
The oral administration of a single dose of O,S,S-trimethyl phosphorodithioate (OSSMe) to rats was found to result, 24 hours after treatment, in a dose-related metabolic alkalosis. Non-invasive indices of kidney damage revealed that during the first 4 hours after OSSMe administration there was a fourfold increase in urine flow with increases in albumin, beta 2-microglobulin and N-acetyl-glucosaminidase excretion. These results suggest that OSSMe-induced metabolic alkalosis may result from early renal functional disturbances.


Promoters of Mycoplasma capricolum ribosomal RNA operons: identical activities but different regulation in homologous and heterologous cells.
The 5' region of the rRNA operon, rrnA, of M. capricolum was cloned. Sequence analysis revealed two tRNA genes, tRNA(leu) and tRNA(lys), upstream to the promoter of the rRNA operon. The in vivo transcription start sites of the rRNA operon and of the tRNA genes were mapped. The same promoters used by M. capricolum RNA polymerase are also recognized by E. coli RNA polymerase both in vivo and in vitro. We find that high levels of ppGpp in E. coli, resulting from amino acid starvation or from spoT mutation, activate rather than repress the transcription of the mycoplasma rrnA operon.


Axillary lymphadenopathy 17 years after digital silicone implants: study with x-ray microanalysis.
Axillary lymphadenopathy developed in a patient with rheumatoid arthritis 17 years after the placing of Swanson implants in the hand. Foreign material in the lymph nodes was identified as silicone by energy-dispersive x-ray microanalysis. This emphasizes the long latent period that may be associated with this clinical phenomenon which may mimic other, more serious, diseases.


Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.
Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.


The Pediatric Outcomes Data Collection Instrument for a Polish sample with juvenile idiopathic arthritis: psychometric properties of proxy version.
The aims of the study were to investigate the psychometric properties of the Pediatric Outcomes Data Collection Instrument (PODCI) for parents of children aged 2-10 years, in a Polish sample of juvenile idiopathic arthritis and to compare the results from children with chronic arthritis to the results from a normative sample. The sample consisted of the parents of 29 (72.5%) girls and 11 (27.5%) boys. The ages of the children ranged from 2 to 10 years (mean 6.50, standard deviation [SD] 2.63). Disease course was classified as oligoarticular (n = 26, 65%) and polyarticular (n = 14, 35%). Parents who took part in the intrarater reliability study completed the Polish version of PODCI twice. The PODCI consists of the following subscales: Upper Extremity and Physical Function, Transfer and Mobility Tasks, Sports/Physical Functioning, Pain/Comfort, and Happiness. A Global Functioning Scale consists of the mean of the 'mean of items' values for the first four scales. The mean standarized Global Functioning Scale was 81.79 (SD 13.45), whereas the mean normative Global Functioning Scale score equaled 33.65 (SD 18.19). Cronbach's alpha value of the Global Functioning Scale was excellent and equaled 0.81. The effect size concerning the Global Functioning Scale equaled 0.123. Test-retest reliability equaled 0.98, whereas intrarater reliability (intraclass correlation coefficient) equaled 0.99. The translation and cross-cultural adaptation of the PODCI questionnaire provides a Polish equivalent to assess physical function in children with chronic arthritis.


Arthroscopic resection as a rapid recovery treatment for Os acetabuli in soccer players who had undergone hip arthroscopy: a case series with 1-year follow-up.
Os acetabuli (OSA) is defined as a radiopaque structure located around the acetabular rim highly related to Femoroacetabular Impingement (FAI). Its treatment depends on the perspective of post-surgical joint instability. Ossicle resection is recommended if the femoral head is covered enough by the labrum. Previous research has described the results of this technique in general population. The aim of this study is to describe the outcomes and the time and rate of return to play (RTP) after hip arthroscopy and OSA removal in soccer players. This study is a retrospective analysis of a prospective database containing all the consecutive soccer players who had undergone hip arthroscopy between 2018 and 2019. The subjects diagnosed with OSA and a center-edge angle (CEA) > 25 ° were included in the analysis. All the patients were treated with arthroscopic removal of the OSA and femoral osteoplasty. Hip function was assessed using the Modified Harris Hip Score (MHHS) before and at 3 and 12 months after surgery. Rate of RTP and competitive level at RTP were assessed at a 1-year follow-up. Between 2018 and 2019, 90 soccer players were treated with hip arthroscopy in our facilities. Six of them (6.6%) were diagnosed with OSA. Mean (SD) MHHS values were 69.7 (12.1) before the surgery, 89.7 (6.7) at 3 months post-surgery and 95.7 (5.1) at 12 months post-surgery. All the subjects reported significant improvements in their MHHS scores at 3 and 12 months post-surgery compared with pre-surgery levels (p < 0.01). Non-significant differences were found between 3 and 12 months post-surgery (p > 0.05). All the subjects (100%) returned to previous competitive levels. After surgery, all the soccer players returned to previous competitive level. Preoperative MHHS improved significantly at 3 months maintained for up to 12 months.


The use of tracheotomy in oral and maxillofacial surgery.
Tracheotomy is discussed as a method of airway management required in various clinical situations. The anatomy and operative technique involved have been well-established. This paper reviews additional aspects of the procedure: indications, complications, the physiologic effects on tracheolaryngeal function, and postoperative care.


Mid-infrared hyperchaos of interband cascade lasers.
Chaos in nonlinear dynamical systems is featured with irregular appearance and with high sensitivity to initial conditions. Near-infrared light chaos based on semiconductor lasers has been extensively studied and has enabled various applications. Here, we report a fully-developed hyperchaos in the mid-infrared regime, which is produced from interband cascade lasers subject to the external optical feedback. Lyapunov spectrum analysis demonstrates that the chaos exhibits three positive Lyapunov exponents. Particularly, the chaotic signal covers a broad frequency range up to the GHz level, which is two to three orders of magnitude broader than existed mid-infrared chaos solutions. The interband cascade lasers produce either periodic oscillations or low-frequency fluctuations before bifurcating to hyperchaos. This hyperchaos source is valuable for developing long-reach secure optical communication links and remote chaotic Lidar systems, taking advantage of the high-transmission windows of the atmosphere in the mid-infrared regime.


An artificial intelligence model predicts the survival of solid tumour patients from imaging and clinical data.
The need for developing new biomarkers is increasing with the emergence of many targeted therapies. Artificial Intelligence (AI) algorithms have shown great promise in the medical imaging field to build predictive models. We developed a prognostic model for solid tumour patients using AI on multimodal data. Our retrospective study included examinations of patients with seven different cancer types performed between 2003 and 2017 in 17 different hospitals. Radiologists annotated all metastases on baseline computed tomography (CT) and ultrasound (US) images. Imaging features were extracted using AI models and used along with the patients' and treatments' metadata. A Cox regression was fitted to predict prognosis. Performance was assessed on a left-out test set with 1000 bootstraps. The model was built on 436 patients and tested on 196 patients (mean age 59, IQR: 51-6, 411 men out of 616 patients). On the whole, 1147 US images were annotated with lesions delineation, and 632 thorax-abdomen-pelvis CTs (total of 301,975 slices) were fully annotated with a total of 9516 lesions. The developed model reaches an average concordance index of 0.71 (0.67-0.76, 95% CI). Using the median predicted risk as a threshold value, the model is able to significantly (log-rank test P value < 0.001) isolate high-risk patients from low-risk patients (respective median OS of 11 and 31 months) with a hazard ratio of 3.5 (2.4-5.2, 95% CI). AI was able to extract prognostic features from imaging data, and along with clinical data, allows an accurate stratification of patients' prognoses.


Increased renal reflectivity in sickle cell disease: prevalence and characteristics.
Renal ultrasound appearances have been examined in 315 patients with sickle cell disease aged 10-20 years, followed in a cohort study from birth. There were three different echo patterns. A normal appearance (type 1) occurred in 235 (75%) of all subjects, and in 159/179 (89%) with homozygous sickle cell (SS) disease. A diffuse increase in reflectivity throughout the kidney (type 2), similar to that of adjacent liver, occurred in 17 patients (5%). Widespread confluent or focal increase in reflectivity confined to the renal medulla (type 3) occurred in 63 (20%) of the total group, and was much more common in the mild genotypes of sickle cell-haemoglobin C disease (41/111, 37%) and sickle cell-beta+ thalassaemia (15/19, 79%) than in SS disease (5/179, 3%). We speculate that type 2 changes may reflect diffuse glomerular and interstitial fibrosis, and that type 3 resembles changes seen in sub-clinical nephrocalcinosis, and could be due to iron deposition.


A new method for detecting hepatitis B surface antigen in liver by silver staining.
Staining of tubular and circular structures within the cisternae of the endoplasmic reticulum of the cytoplasm of liver cells infected with hepatitis B virus was enhanced by the use of 1% aqueous silver proteinate.


The CENP-T/-W complex is a binding partner of the histone chaperone FACT.
The CENP-T/-W histone fold complex, as an integral part of the inner kinetochore, is essential for building a proper kinetochore at the centromere in order to direct chromosome segregation during mitosis. Notably, CENP-T/-W is not inherited at centromeres, and new deposition is absolutely required at each cell cycle for kinetochore function. However, the mechanisms underlying this new deposition of CENP-T/-W at centromeres are unclear. Here, we found that CENP-T deposition at centromeres is uncoupled from DNA synthesis. We identified Spt16 and SSRP1, subunits of the H2A-H2B histone chaperone facilitates chromatin transcription (FACT), as CENP-W binding partners through a proteomic screen. We found that the C-terminal region of Spt16 binds specifically to the histone fold region of CENP-T/-W. Furthermore, depletion of Spt16 impairs CENP-T and CENP-W deposition at endogenous centromeres, and site-directed targeting of Spt16 alone is sufficient to ensure local de novo CENP-T accumulation. We propose a model in which the FACT chaperone stabilizes the soluble CENP-T/-W complex in the cell and promotes dynamics of exchange, enabling CENP-T/-W deposition at centromeres.


Overview of Sleep and Circadian Rhythm Disorders in Parkinson Disease.
Sleep disorders are common among PD patients and affect quality of life. They are often under-recognized and under-treated. Mechanisms of sleep disorders in PD remain relatively poorly understood. Improved awareness of common sleep problems in PD. Tailored treatment and evidence for efficacy are lacking. The purpose of this review is to provide an overview and update on the most common sleep disorders in PD. We review specific features of the most common sleep disorders in PD, including insomnia, excessive daytime sleepiness, sleep-disordered breathing, restless legs syndrome, circadian rhythm disorders and REM sleep behavior disorders.


Wnt signalling via the epidermal growth factor receptor: a role in breast cancer?
Recent data have suggested the epidermal-growth-factor receptor (EGFR) as a point of convergence for several different classes of receptor. Civenni and colleagues have now demonstrated crosstalk between Wnt signalling and the EGFR, showing that in breast epithelial cells Wnts activate downstream targets of the EGFR, including cyclin D1. Given the role of members of these pathways in the aetiology of breast cancer and as markers of outcome and potential therapeutic targets in breast cancer, this observation has a number of potential implications important for both the basic biology of breast cancer and the clinical management of the disease.


Pre-power-stroke cross-bridges contribute to force transients during imposed shortening in isolated muscle fibers.
When skeletal muscles are activated and mechanically shortened, the force that is produced by the muscle fibers decreases in two phases, marked by two changes in slope (P₁ and P₂) that happen at specific lengths (L₁ and L₂). We tested the hypothesis that these force transients are determined by the amount of myosin cross-bridges attached to actin and by changes in cross-bridge strain due to a changing fraction of cross-bridges in the pre-power-stroke state. Three separate experiments were performed, using skinned muscle fibers that were isolated and subsequently (i) activated at different Ca²⁺ concentrations (pCa²⁺ 4.5, 5.0, 5.5, 6.0) (n = 13), (ii) activated in the presence of blebbistatin (n = 16), and (iii) activated in the presence of blebbistatin at varying velocities (n = 5). In all experiments, a ramp shortening was imposed (amplitude 10%L₀, velocity 1 L₀•sarcomere length (SL)•s⁻¹), from an initial SL of 2.5 µm (except by the third group, in which velocities ranged from 0.125 to 2.0 L₀•s⁻¹). The values of P₁, P₂, L₁, and L₂ did not change with Ca²⁺ concentrations. Blebbistatin decreased P₁, and it did not alter P₂, L₁, and L₂. We developed a mathematical cross-bridge model comprising a load-dependent power-stroke transition and a pre-power-stroke cross-bridge state. The P₁ and P₂ critical points as well as the critical lengths L₁ and L₂ were explained qualitatively by the model, and the effects of blebbistatin inhibition on P₁ were also predicted. Furthermore, the results of the model suggest that the mechanism by which blebbistatin inhibits force is by interfering with the closing of the myosin upper binding cleft, biasing cross-bridges into a pre-power-stroke state.