MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.


Combinatorial therapy for triple negative breast cancer using hyperstar polymer-based nanoparticles.
We report the ability of a novel combinatorial therapy obtained from nanoparticles of hyperstar polymers encompassing drugs to selectively target triple negative breast cancer (TNBC) cell proliferation through STAT3 and topoisomerase-II pathways. This nano-cocktail was at least two to four fold better than the individual drugs and 6-20 times more selective than the parent drugs.


Insidious Onset Multifocal Chest Wall and Spinal Abscess Caused by Previous Candidemia: A Case Report.
Abscess formation due to Candida albicans infection is extremely rare. Radiological diagnosis of an atypical abscess at an uncommon site is challenging. In this study, we present a case of insidious onset multifocal chest wall and spinal abscess after candidemia in a young woman in the intensive care unit due to postpartum bleeding.


Native bird breeding in a chronosequence of revegetated sites.
Restoration of degraded landscapes through replantings of native vegetation has been proceeding in response to habitat loss and fragmentation and plummeting biodiversity. Little is known about whether the investments in ecological restoration have resulted in biodiversity benefits. We evaluated the potential of restored sites to support populations by assessing bird breeding activity. We surveyed 21 revegetated sites of various ages (9-111 years) in the box-ironbark region of Victoria, Australia. Sites differed in landscape context, patch features and in-site characteristics. The latter, including whether sites were grazed, amounts of fallen timber and numbers of remnant trees, were most important in affecting overall bird breeding activity. Patch-configuration (e.g., shape, area) was of secondary importance. Landscape context appeared to have little effect on bird breeding except for one species. While these results suggest that in-site habitat structure is the predominant driver, we caution against dismissing the importance of patch characteristics and landscape context for two reasons. First, the available sites covered a relatively small range of areas (<54 ha), and we could not provide a broad range of landscape-contextual contrasts given that we could only use existing plantings. Second, much of the breeding activity was by bird species known to be tolerant of smaller woodland areas or of the open countryside. We show that there is very little breeding activity in replantings by species that have declined dramatically in rank abundance between large 'reference' areas and fragmented landscapes. It seems likely that most replantings provide habitat configurations unsuited for dealing with declines of species most vulnerable to habitat loss and fragmentation.


Breastfeeding initiation for Aboriginal and Torres Strait Islander women in Victoria: analysis of routinely collected population-based data.
Increasing breastfeeding rates is one way of improving the short and long term health of Aboriginal and Torres Strait Islander children (hereafter referred to as Aboriginal). Despite the benefits of breastfeeding and recommendations for strategies to increase breastfeeding among Aboriginal people, there is a lack of available population data. To use population-based data from Victoria, Australia to compare breastfeeding initiation for Aboriginal and non-Aboriginal women and to explore factors associated with breastfeeding initiation of Aboriginal women. Routinely collected infant feeding data obtained from the Victorian Perinatal Data Collection (VPDC) was used. The VPDC is a mandatory, population-based system where maternal and infant data on all Victorian births are collected. Compared with non-Aboriginal women, Aboriginal women were less likely to attempt to breastfeed their baby (87.2% vs 95.3%; p<0.001); more likely to give formula in hospital (39.6% vs 30.6%; p<0.001) and less likely to give the last feed prior to discharge exclusively from the breast (64.4% vs 75.0% p<0.001). For Aboriginal women, factors associated with not initiating breastfeeding were being single, multiparous, smoking and length of stay. Infant factors were gestation less than 37 weeks and low birthweight (<2,500g). In Victoria, breastfeeding initiation is lower for Aboriginal women compared with non-Aboriginal women. Further research is needed to explore the effectiveness of interventions that may increase breastfeeding for Aboriginal women.


[Splanchnic artery aneurysms].
Splanchnic artery aneurysms are uncommon but important vascular entity because nearly 25% of all cases present as surgical emergency. The purpose of our study was to present nine patients operated on at the Institute of cardiovascular diseases, as well as literature review of clinical presentation of the disease. There were three splenic artery aneurysms, two celiac trunk aneurysms, and one aneurysm of the hepatic, superior mesenteric, inferior mesenteric and gastroduodenal artery. All patients were males, mean aged 67.5 years (60-73). In four patients, splanchnic artery aneurysm was discovered accidentally during routine ultrasonographic and angiographic examinations of the abdominal aorta. At that time, arteriovenous fistula was diagnosed in a patient No 1; it was formed after rupture of the splenic artery aneurysm into the splenic vein. Three aneurysms were manifested by abdominal pain and palpable pulsating abdominal mass. Two patients were admitted as urgent cases in the state of hemorrhagic shock and signs of intraabdominal bleeding due to rupture of the splenic and hepatic arteries. In 7 cases, diagnosis was made preoperatively by means of ultrasonography and angiography; in two patients, accurate diagnosis was confirmed during surgery. Proximal and distal ligation of the artery was performed in a patient with rupture of the splenic aneurysm into the splenic vein that caused arteriovenous fistula. Gastroduodenal artery aneurysm was treated by trans-aneurysmatic ligation of its "entering" and "exiting" branches. Aneurysms of distal part of the superior mesenteric and splenic artery were resected without further reconstruction. Partial resection of the aneurysm and endoaneurysmorrhaphy was carried out in one case of celiac trunk aneurysm, and in another, after aneurysm resection, the restoration of blood flow through the hepatic and lienal artery was achieved by Dacron grafts. In a patient with the inferior mesenteric artery aneurysm, the resection of aneurysm was followed by reimplantation of medial part of the artery into bifurcated Dacron graft which replaced abdominal aorta. In 5 patients, some of additional surgical procedures were performed. There were 4 reconstructive procedures of abdominal aorta and one splenectomy. The patient with ruptured hepatic artery aneurysm died during surgery due to uncontrolled hemorrhage. In other patients, there was neither morbidity nor mortality in the early postoperative period (first 30 days after surgery). Mean follow up was 1 to 5 years (mean 3.4 years). One patient died after 5 years due to myocardial infarction. Although the introduction of precise diagnostic procedures (computerized tomography, magnetic resonance imaging, spiral scan) make diagnosis easier, the splanchnic artery aneurysms are still difficult to detect due to their uncommon clinical presentations.


Regulation of las and rhl quorum sensing in Pseudomonas aeruginosa.
The production of several virulence factors by Pseudomonas aeruginosa is controlled according to cell density through two quorum-sensing systems, las and rhl. The las system is comprised of the transcriptional activator protein LasR and of LasI, which directs the synthesis of the autoinducer PAI-1. Similarly, the rhl system consists of the transcriptional activator protein RhlR and of RhlI, which directs synthesis of the autoinducer PAI-2 (formerly referred to as factor 2). To study the interrelation between the two P. aeruginosa quorum-sensing systems, we fused a lacZ reporter gene to lasR, rhlR, and rhlA and monitored expression of these three genes under various conditions. Our data indicate that lasR and rhlR are expressed in a growth-dependent manner, with activation of each gene occurring during the last half of log-phase growth. We also show that the las quorum-sensing system controls the rhl quorum-sensing system in two ways. First, we found that LasR and PAI-1 activated rhlR transcription. Second, we showed that PAI-1 blocked PAI-2 from binding to RhlR, thereby inhibiting the expression of rhlA. Our data thus indicate that the las system exerts two levels of control on RhlR, transcriptional and posttranslational.


Pediatric Mycoplasma pneumoniae Infection Presenting with Acute Cholestatic Hepatitis and Other Extrapulmonary Manifestations in the Absence of Pneumonia.
Mycoplasma pneumoniae infections mainly involve respiratory tract; however, also can manifestate other symptoms by site involved. Extrapulmonary manifestations of M. pneumoniae infection are rarely known to occur without pneumonia. Herein we report a case of a 9-year-old boy who presented with acute cholestatic hepatitis in the absence of pneumonia. Rhabdomyolysis, skin rash, and initial laboratory results suspicious of disseminated intravascular coagulopathy were also observed in this patient. M. pneumoniae infection was identified by a 4-fold increase in immunoglobulin G antibodies to M. pneumoniae between acute and convalescent sera by enzyme-linked immunosorbent assay. This is the first pediatric case in Korea of M. pneumoniae infection presenting with acute cholestatic hepatitis in the absence of pneumonia.


Hydrogen adsorption on nitrogen and boron doped graphene.
Hydrogen adsorption on boron and nitrogen doped graphene is investigated in detail by means of first-principles calculations. A comprehensive study is performed of the structural, electronic, and magnetic properties of chemisorbed hydrogen atoms and atom pairs near the dopant sites. The main effect of the substitutional atoms is charge doping which is found to greatly affect the adsorption process by increasing the binding energy at the sites closest to the substitutional species. It is also found that doping does not induce magnetism despite the odd number of electrons per atom introduced by the foreign species, and that it quenches the paramagnetic response of chemisorbed H atoms on graphene. Overall, the effects are similar for B and N doping, with only minor differences in the adsorption energetics due to different sizes of the dopant atoms and the accompanying lattice distortions.


Notch pathway regulates female germ cell meiosis progression and early oogenesis events in fetal mouse.
A critical process of early oogenesis is the entry of mitotic oogonia into meiosis, a cell cycle switch regulated by a complex gene regulatory network. Although Notch pathway is involved in numerous important aspects of oogenesis in invertebrate species, whether it plays roles in early oogenesis events in mammals is unknown. Therefore, the rationale of the present study was to investigate the roles of Notch signaling in crucial processes of early oogenesis, such as meiosis entry and early oocyte growth. Notch receptors and ligands were localized in mouse embryonic female gonads and 2 Notch inhibitors, namely DAPT and L-685,458, were used to attenuate its signaling in an in vitro culture system of ovarian tissues from 12.5 days post coitum (dpc) fetus. The results demonstrated that the expression of Stra8, a master gene for germ cell meiosis, and its stimulation by retinoic acid (RA) were reduced after suppression of Notch signaling, and the other meiotic genes, Dazl, Dmc1, and Rec8, were abolished or markedly decreased. Furthermore, RNAi of Notch1 also markedly inhibited the expression of Stra8 and SCP3 in cultured female germ cells. The increased methylation status of CpG islands within the Stra8 promoter of the oocytes was observed in the presence of DAPT, indicating that Notch signaling is probably necessary for maintaining the epigenetic state of this gene in a way suitable for RA stimulation. Furthermore, in the presence of Notch inhibitors, progression of oocytes through meiosis I was markedly delayed. At later culture periods, the rate of oocyte growth was decreased, which impaired subsequent primordial follicle assembly in cultured ovarian tissues. Taken together, these results suggested new roles of the Notch signaling pathway in female germ cell meiosis progression and early oogenesis events in mammals.


Hospital-based surveillance for HTLV-1/2 infections in Spain.
In Western countries, HTLV-1 infection is recognized mainly among foreigners coming from endemic areas. In contrast, HTLV-2 is found predominantly in native intravenous drug users (IDUs). Spain has experienced a large wave of immigration, which could have influenced the current prevalence and distribution of HTLV-1 and HTLV-2 infection. A 1-day cross-sectional survey was carried out in May 2005 in 13 hospitals distributed across Spain. A total of 2873 outpatient subjects were screened for HTLV-1/2 antibodies. Although the majority of the study population consisted of native Spaniards, 206 (7.2%) were immigrants. Two cases of HTLV-1 and one of HTLV-2 infection were found (overall prevalence, 0.1%). The two individuals with HTLV-1 were immigrants from endemic areas and the single case of HTLV-2 infection was a former Spaniard IDU coinfected with HIV-1. In summary, the current prevalence of HTLV-1/2 infection in Spain is low, with no evidence of spread beyond the classical risk groups. However, a rapidly growing population of immigrants from HTLV-1-endemic areas in Spain could modify this pattern and periodic surveillance studies including both natives and immigrants are warranted.


Serotypes and genotypes of erythromycin-resistant group B streptococci in Korea.
Among 78 erythromycin-resistant group B streptococcus (GBS) isolates from Korea, ermB was detected in 58 (74.4%), mefA was detected in 14 (17.9%), and ermTR was detected in 6 (7.7%). The most prevalent serotypes of erythromycin-resistant GBS were V (detected in 34 isolates [43.6%]) and III (detected in 33 isolates [42.3%]). All serotype V erythromycin-resistant GBS harbored the ermB gene.


Isolation and Characterization of a Distinct Subpopulation from the WM115 Cell Line That Resembles In Vitro Properties of Melanoma Cancer Stem Cells.
Despite key advances in cancer therapies, malignant tumors, such as melanoma, continue to be one of the leading causes of mortality. Recent debate on whether cancer can originate from a tumor-initiating subpopulation has permeated oncology and stem cell research. It has been well established that primary and immortalized tumor cells consist of heterogeneous cell populations. The profound effect of tumor heterogeneity on tumor growth and drug resistance remains elusive, but it is highly likely that subpopulations of cancer cells have different capabilities of self-renewal and drug resistance. Discrepancies between excellent in vitro potency and efficacy and poor patient response have been observed on multiple cancer therapeutics. Although this observation can be attributed to many factors, a better understanding of the contribution from subpopulations within a cancer will help bridge the gap between in vitro assay results and patient prognosis. To comprehend this impact, it is critical to isolate and characterize cancer subpopulations that possess higher growth and drug resistance properties so that novel therapeutics can be developed to eventually eradicate all cancer cells. In this article, we describe a method to enrich a subpopulation, CB4, from the melanoma cell line WM115. CB4 exhibited higher anchorage-independent growth, higher survival under serum starvation condition, and lower drug sensitivity to commonly used melanoma treatment compared with WM115. Details of functional properties and gene expression of CB4 compared with WM115 are reported. Our study demonstrates that it is feasible to isolate and enrich a subpopulation that exhibits higher growth capacity and treatment resistance from an immortalized tumor cell line.


The effect of miR-10b on growth hormone in pituitary cells of Yanbian yellow cattle by somatostatin receptor 2.
This study aimed to evaluate the effect of miR-10b on growth hormone (GH) in pituitary cells of Yanbian yellow cattle. According to analysis of GH and somatostatin receptor 2 (SSTR2) mRNA and protein expression levels, we found that miR-10b targeted 3'UTR of SSTR2. Compared with the negative control (NC) group, GH mRNA transcription and protein expression in pituitary cells of Yanbian yellow cattle were significantly increased by adding miR-10b mimics (p < .01), while these were significantly decreased by adding miR-10b inhibitor (p < .05); compared with the NC group, SSTR2 mRNA transcription and protein expression were significantly inhibited by the addition of miR-10b mimics (p < .01), while these were significantly increased by the addition of miR-10b inhibitor compared with the iNC group (p < .05). This study suggested that miR-10b could regulate GH level by regulating SSTR2 gene expression in pituitary cells of Yanbian yellow cattle.


[Airborne contact allergy provoked by kathon in water-based plastic paint].
We describe two cases of airborne contact allergy to plastic paint containing Kathon. Two women with known kathon allergy, aged 33 and 50 years, developed severe dermatitis and systemic reactions after painting their homes with water-based plastic paint with Kathon as preservative. Both required treatment with systemic steroids. On return to their homes, the symptoms immediately recurred, and they were forced to stay away for several weeks afterwards. Patients allergic to Kathon should be informed of the risk of airborne contact allergy when exposed to paints preserved with Kathon.


[Synopsis of Chinese food hygiene situation from 1912 to 1927].
The primary food hygiene work had been conducted from 1912-1927 in China. Some scholars advocated learning from the West to pay attention to food hygiene. There were a few administrative agencies and regulations of food hygiene in China. Due to the restriction of politics, economy, culture and science, the work of food hygiene was in its young stage. The food born-diseases were one of the main causes of death. Guangzhou's work of food hygiene was better, because of its superior geographical position. Most areas of China were worse on food hygiene. Scholars appealed to society to pay more attention to food hygiene, make regulations which were in conformity with Chinese conditions and train more public hygiene specialists.


Expression of factors involved in dental pulp physiopathological processes by nemotic human pulpal fibroblasts.
To investigate in human dental pulp fibroblasts (HDPF) the expression of factors involved in dental pulp physiopathological processes and in an experimental model of cell activation called nemosis, and to compare the behaviour of pulp cell activation with sound lung fibroblast MRC5, employed as a reference model for nemosis. Nemotic response was induced in three-dimensional cultures of HDPF and lung fibroblasts. The expressions of molecules involved in physiological (alkaline phosphatase, type I collagen) and in inflammatory processes (IL-6, CXCL8, CCL20, COX-2) were studied using real-time PCR. Concentrations of IL-6 and CXCL8 were analysed during 4 days with ELISA. Nonparametric tests were used to determine statistical differences between groups. A significant decrease (P < 0.001) in type I collagen and alkaline phosphatase was observed in MRC5 and HDPF nemotic responses. Although the amounts of mRNA differed between these cell types, there was an increase in CCL20, CXCL8 and COX-2 expression (P < 0.001). Unlike HDPF, MRC5 spheroids displayed significant amounts of IL-6 concentrations and mRNA expression. Notably, increased concentrations of CXCL8 were recorded in all three-dimensional cultures compared with monolayers as a function of time (P < 0.05). Although the nemotic responses observed were not identical in the pulpal and lung fibroblasts, similarities occurred in the expression of chemokines and cyclooxygenase-2. Nemotic reactions and inflammatory processes in pulp diseases share similarities in terms of the expression of factors. Thus, this in vitro model could constitute a powerful tool to study intercellular relations within the dental pulp and to develop new local treatments to counteract the inflammatory reaction that occurs during pulpitis.


The risk of hearing loss associated with occupational exposure to organic solvents mixture with and without concurrent noise exposure: A systematic review and meta-analysis.
This study is a meta-analysis of the previous epidemiological studies which investigated the quantitative estimates of the association between independent or combined exposure to noise and mixed organic solvents and hearing loss until October 2014. Overall, 15 studies with information on 7530 individuals (6% female) were included. Having assessed - by puretone audiometry - the adjusted odds ratio estimates for the association between solvents mixture exposure and the risk of developing hearing loss stood at 2.05 (95% confidence interval (CI): 1.44-2.9). Similarly, for subjects who were concurrently exposed to noise and solvents mixture, an OR of 2.95 (95% CI: 2.1-4.17) was obtained. There was some evidence of heterogeneity within each of the 2 exposure groups (p heterogeneity < 0.001). This heterogeneity was not explained by differences in strength of effect between duration of exposure, the number of solvent and exposure index in subgroups of solvents mixture exposure. Based on the available data, our analysis has provided the evidence of increased risk of developing hearing loss for workers exposed to organic solvents even at quite low concentration. Moreover, if such exposure is accompanied by noise, it will exacerbate the extent of hearing loss. Int J Occup Med Environ Health 2017;30(4):521-535.


Separation albumin-PEG: transmission of PEG through ultrafiltration membranes.
Transmission of polyethylene glycol (PEG) through ultrafiltration membranes has been studied under various operating conditions of pressure, crossflow, and concentration, using different membranes cut-offs and two module designs with the aim of understanding the separation of PEG from BSA. The influence of protein adsorption and fouling of the choice of a membrane has also been considered. Retention depends in general on the molecule to average pore size ratio, as expected, but also on concentration polarization. Accordingly, all operating and design parameters favoring concentration polarization lead to higher transmission. At high fluxes, flexible macromolecules can pass through the membrane, even if the random coil is larger than the apparent average pore. From a process selectivity point of view, the best way to separate PEG from BSA would be to use a membrane totally retaining BSA and to enhance concentration polarization of PEG. Unfortunately, such conditions also increase fouling and concentration polarization by BSA, which limits flux and thus PEG concentration polarization and transmission. Consequences of such conditions on separation efficiency are discussed.


Gemcitabine enhances the transport of nanovector-albumin-bound paclitaxel in gemcitabine-resistant pancreatic ductal adenocarcinoma.
The mechanism for improved therapeutic efficacy of the combination therapy with nanoparticle albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of (1) encapsulating nAb-PTX in multistage nanovectors (MSV); (2) effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX + gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX + gem also caused a substantial increase in tumor PTX accumulation, significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by (1) gem through up-regulation of caveolin-1 and (2) MSV through increasing accumulation of nAb-PTX in the tumor.


Myeloid suppressor cells regulate the lung environment--letter.
4T1 murine mammary carcinoma cells implanted in syngeneic Balb/c mice are increasingly being used in metastasis research, with some groups using this model to study tumor-induced accumulation of bone marrow-derived cells in metastatic target organs. Bone marrow-derived cells (including CD11b(+)Gr-1(+) myelomonocytic cells) are thought to modify the local lung microenvironment to facilitate subsequent colonization by metastatic tumor cells. While quantification of metastatic 4T1 tumor cells in various tissues can be done using ex vivo colony-forming assays, detection of metastatic 4T1 cells is often facilitated by expressing fluorescent proteins in the tumor cells prior to implantation. We found that Balb/c mice mount a potent immune response against 4T1 cells expressing green fluorescent protein (GFP) that includes the generation of anti-GFP antibodies in the circulation. Importantly, the number of bone marrow-derived CD11b(+)Gr-1(+) cells and metastatic tumor cells that accumulate in the lungs is significantly decreased in mice implanted with 4T1 cells expressing GFP compared with mice bearing wild-type 4T1 tumors. Taken together, our data caution against the use of GFP-expressing tumor cells in the Balb/c mouse strain, particularly for studying the influence of immunomodulatory cells on tumor cell metastasis.


Biweekly docetaxel and vinorelbine as first-line chemotherapy in metastatic breast cancer.
This study was designed to evaluate the antitumor activity and tolerance of biweekly docetaxel plus vinorelbine as first-line chemotherapy in patients with metastatic breast cancer (MBC). Forty-one patients with measurable disease and no prior chemotherapy for MBC were treated with docetaxel 60 mg/m(2) plus vinorelbine 30 mg/m(2) on day 1, every 2 weeks for a maximum of 12 courses. Median age was 58 years (range, 23-75). Fourteen patients (34.1%) were premenopausal and 27 (65.9%) were postmenopausal. Most patients had received prior neoadjuvant/adjuvant chemotherapy (n = 27, 65.9%), radiation therapy (n = 22, 53.6%), and hormone therapy (n = 21, 51.2%). The most frequent sites of metastasis were bone (n = 18, 43.9%), pleuropulmonary (n = 16, 39%), and liver (n = 14, 34.1%). Twenty-seven patients (65.9%) had more than one site of metastasis. Three hundred and thirty-nine courses were given (median, 8 courses per patient; range, 1-12). Median relative dose intensity was 85% for both docetaxel and vinorelbine. Grade 3/4 toxicities included neutropenia (14 patients, 34.1%), febrile neutropenia (n = 14, 34.1%), and stomatitis (n = 4, 9.8%). No treatment-related deaths were reported. All patients were assessed for response in an intent-to-treat analysis. Four patients (9.8%) had a complete response and 19 (46.3%) had a partial response (overall response rate, 56.1%; 95% CI, 42%-70%). Six patients (14.6%) had stable disease and 12 patients (29.3%) had progressive disease. With a median follow-up of 15.1 months or until death, median duration of response is 12.6 months. Median time to progression is 12.4 months. Median survival time is 19.6 months. This biweekly combination of docetaxel plus vinorelbine is feasible and active as first-line chemotherapy in patients with MBC. This regimen is safe and well tolerated.


[Acute subdural empyema due to peptostreptococcus].
A very rare case of acute subdural empyema due to peptostreptococcus was reported. A 11-year-old-girl was admitted to our hospital with high grade fever, unconsciousness and rt hemiparesis. CT scans showed the mass effect caused by the subdural empyema over the left frontotemporal region. Subdural empyema was evacuated by the craniotomy. Peptostreptococcus was found in the pus obtained during the operation. However, CT scans 10 days after the operation revealed another subdural empyema in the left frontal base and interhemispheric fissure, which was removed again by the craniotomy using coronal incision 14 days after the first operation. Frontal sinusitis was also demonstrated by CT scan. Killian's operation to the frontal sinusitis was performed by otorhinolaryngologists at the same time. Six weeks after the second operation, she was discharged without any neurological deficits. Peptostreptococcus is one of the indigenous microflora of the oral cavity, skin, gastrointestinal tract and genitourinary system and may be a causative microorganism in every type of human infection due to its abnormal localization. There is a controversy concerning surgical management subdural empyema. Both the burr hole drainage of pus and the craniotomy are advocated. Associated otorhinologic lesions must not be overlooked. Otorhinologic consultation should immediately be obtained so that the drainage of an infected paranasal or mastoid sinus can be performed at the time of craniotomy. This is critical to prevent the recurrence of the subdural empyema from further extension of the extracranial disease.


Recombinant human interleukin-12 is the second example of a C-mannosylated protein.
The beta-chain of human interleukin 12 (IL-12) contains at position 319-322, the sequence Trp-x-x-Trp. In human RNase 2 this is the recognition motif for a new, recently discovered posttranslational modification, i.e., the C-glycosidic attachment of a mannosyl residue to the side chain of tryptophan. Analysis of C-terminal peptides of recombinant IL-12 (rHuIL-12) by mass spectrometry and NMR spectroscopy revealed that Trp-319beta is (partially) C-mannosylated. This finding was extended by in vitro mannosylation experiments, using a synthetic peptide derived from the same region of the protein as an acceptor. Furthermore, human B-lymphoblastoid cells, which secrete IL-12, were found to contain an enzyme that carries out the C-mannosylation reaction. This shows that nonrecombinant IL-12 is potentially C-mannosylated as well. This is only the second report on a C-mannosylated protein. However, the occurrence of the C-mannosyltransferase activity in a variety of cells and tissues, and the presence of the recognition motif in many proteins indicate that more C-mannosylated proteins may be found.


Oscillation death in asymmetrically delay-coupled oscillators.
Symmetrically coupled oscillators represent a limiting case for studying the dynamics of natural systems. Therefore, we here investigate the effect of coupling asymmetry on delay-induced oscillation death (OD) in coupled nonlinear oscillators. It is found that the asymmetrical coupling substantially enlarges the domain of the OD island in the parameter space. Specifically, when the intensity of asymmetry is enhanced by turning down the value of the coupling asymmetry parameter α, the OD island gradually expands along two directions of both the coupling delay and the coupling strength. The expansion behavior of the OD region is well characterized by a power law scaling, R=α(γ) with γ≈-1.19. The minimum value of the intrinsic frequency, for which OD is possible, monotonically decreases with decreasing α and saturates around a constant value in the limit of α→0. The generality of the conducive effect of coupling asymmetry is confirmed in a numerical study of two delay-coupled chaotic Rössler oscillators. Our findings shed an improved light on the understanding of dynamics in asymmetrically delay-coupled systems.


Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition.
Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241-5253). We investigated the mechanisms by which SPRY regulates epithelial-mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3' untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1(-/-) and Spry2(-/-) double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.


Asystole and ventricular fibrillation associated with cocaine intoxication.
We discuss a patient with cocaine intoxication in whom the initial presentation was that of asystole and ventricular fibrillation. Cocaine has a direct toxic action on the heart and also sensitizes cardiac tissue to the action of catecholamines. Cocaine intoxication should be considered in any patient with unexplained cardiac arrest or ventricular arrhythmias.


[Comparison of head-chest lead electrocardiogram and routine lead electrocardiogram in diagnosis of acute posterior wall myocardial infarction].
To compare the value of head-chest lead electrocardiogram (HCECG) and routine lead electrocardiogram (RLECG) in diagnosis of acute positive posterior myocardial infarction. HCECGs and RLECGs were recorded simultaneously in 68 normal individuals and 32 patients with acute posterior wall myocardial infarction confirmed by coronary angiography and echocardiography. Each HCECG and RLECG was analyzed by two senior physicians specialized in clinical electrophysiology who were blinded to the results. The HCECG- and RLECG-based diagnostic results were compared with the results of coronary angiography, and the coincidence rates and false positive rates of diagnosis based on HCECGs and RLECGs were calculated. The coincidence rate was 93.8% (30/32) for RLECGs and 100% (32/32) for HCECGs in the diagnosis of acute posterior wall myocardial infarction, showing no significant difference between them (P>0.05). RLECGs-based diagnosis, however, resulted in a significantly higher false positive rate than HCECGs [13.2% (9/68) vs 0% (0/68), P<0.05]. Head-chest lead system is superior to routine lead system for its low false positive rates in the diagnosis of acute posterior wall myocardial infarction.


[Progress on epigenetic regulation of iron homeostasis].
Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.


pH-sensitive multiwalled carbon nanotube dispersion with silk fibroins.
Multiwalled carbon nanotubes (MWCNTs) are considered to be ideal multifunctional materials for biorelated applications, but there is still some controversy regarding their toxicity. In addition, the poor dispersibility of MWCNTs in either water or organic solvents has limited their practical applications. Therefore, obtaining a good dispersion is one of the key issues in their applications. In this study, MWCNTs were dispersed in an aqueous solution using silk fibroin without chemical modification. An optical analyzer, Turbiscan, was used to confirm the stability of the MWCNT aqueous dispersion. Transmission electron microscopy showed individual MWCNTs coated with silk fibroin molecules. Silk fibroin in the sol state can interact with nanotubes through hydrophobic interactions. Therefore, silk fibroin molecules coat the nanotubes, which allow their dispersion in water. Under basic conditions (pH 12.0), an aqueous dispersion of MWCNTs with silk fibroin was stable without sedimentation or gelation. However, the MWCNT/silk fibroin dispersion was unstable under acidic conditions (pH 4.0). In addition, the MWCNT dispersion showed reversible changes with variations in pH. Under acidic conditions, the MWCNTs settled due to conformation changes in the silk fibroin. However, the stability of the MWCNTs had recovered fully under basic conditions. It is believed that silk fibroin has sol-like behavior under basic conditions and gel-like behavior under acidic conditions. Ultraviolet circular dichroism was used to determine the conformation of the silk fibroin molecules with pH. Overall, the pH-sensitive properties of the carbon nanotubes dispersed with silk fibroin can lead to a new class of novel biomaterials for cancer detection and treatment.


A novel cobalt(II) coordination polymer with an unusual four-connected 4(2).6(3).8 topology.
In the cobalt(II) coordination polymer poly[[(mu(2)-benzene-1,3-dicarboxylato){mu(2)-1,1'-[2,2'-oxybis(ethane-2,1-diyl)]di-1H-imidazole}cobalt(II)] monohydrate], {[Co(C(10)H(14)N(4)O)(C(8)H(4)O(4))].H(2)O}(n), two crystallographically distinct Co(II) cations are four-coordinated by N(2)O(2) donor sets in distorted tetrahedral geometries. The Co(II) centers are connected by benzene-1,3-dicarboxylate (m-BDC) anions, giving two types of linear chains, which are further joined via meso-helical 1,1'-[2,2'-oxybis(ethane-2,1-diyl)]di-1H-imidazole ligands to yield a thick two-dimensional slab. The compound displays a two-dimensional four-connected 4(2).6(3).8 topology, which is unprecedented in coordination polymers.


IL-2 induces expression of serine protease enzymes and genes in natural killer and nonspecific T killer cells.
The expression of serine protease genes was examined in murine NK cells that were purified by panning spleen cells with PMA. Although unstimulated NK cells were cytolytic, they were found not to express the C11 (chymotrypsin-like) mRNA. Culturing these cells in IL-2 (500 to 800 U/ml) for 5 to 7 days induced both the lytic activities and the protease enzymes by 20- to 30-fold. Concomitant to these activation events, the total steady state mRNA of both C11 and HF (trypsin-like) genes were also elevated. The activation of lysis, serine protease enzymes, and C11 and HF mRNA all peaked around day 5 in culture and was dose dependent. In order to exclude the possibility that PMA synergizes with IL-2 in this system, spleen cells from SCID mice, which contained mainly NK cells, were cultured under the same conditions (800 U/ml IL-2, with or without PMA) and PMA did not appear to enhance the expression of these mRNA. Similarly, IL-2 also induced the lytic activities, enzyme levels, and mRNA in the non-Ag-specific T killer cells isolated from spleens of normal mice. Lytic activity of T killer cells was not as high as the NK cells, however, the addition of PHA into the lytic assay resulted in enhanced lysis comparable to that of NK cells. These results showed that lytic activity increased along with protease enzyme levels and mRNA expression in both NK and resting T cells. Therefore, elevated levels of the protease enzymes could be one mechanism involved in optimal lytic activity of IL-2-induced lymphokine activated killer cells.


(Acetyl-acetonato-κO,O')(2-bromo-4-chloro-6-{[2-(dimethyl-amino)-ethyl-imino]-meth-yl}phenolato-κN,N',O)oxidovanadium(IV).
The V(IV) atom in the title complex, [V(C(11)H(13)BrClN(2)O)(C(5)H(7)O(2))O], is six-coordinated by one phenolate O, one imino N and one amino N atom of the tridentate anionic Schiff base ligand, by one oxide O atom, and by two O atoms of an acetyl-acetonate anion, forming a distorted cis-VN(2)O(4) octa-hedral coordination geometry. The deviation of the V atom from the plane defined by the three donor atoms of the Schiff base ligand and one O atom of the acetyl-acetone ligand towards the oxide O atom is 0.256 (2) Å.


Increased Resting-State Cerebellar-Cerebral Functional Connectivity Underlying Chronic Tinnitus.
Purpose: Chronic subjective tinnitus may arise from aberrant functional coupling between the cerebellum and the cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to illuminate the functional connectivity network of the cerebellar regions in chronic tinnitus patients and controls. Methods: Resting-state fMRI scans were obtained from 28 chronic tinnitus patients and 29 healthy controls (well matched for age, sex and education) in this study. Cerebellar-cerebral functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting cerebellar functional connectivity measures were correlated with each clinical tinnitus characteristic. Results: Chronic tinnitus patients demonstrated increased functional connectivity between the cerebellum and several cerebral regions, including the superior temporal gyrus (STG), parahippocampal gyrus (PHG), inferior occipital gyrus (IOG), and precentral gyrus. The enhanced functional connectivity between the left cerebellar Lobule VIIb and the right STG was positively correlated with the Tinnitus Handicap Questionnaires (THQ) score (r = 0.577, p = 0.004). Furthermore, the increased functional connectivity between the cerebellar vermis and the right STG was also associated with the THQ score (r = 0.432, p = 0.039). Conclusions: Chronic tinnitus patients have greater cerebellar functional connectivity to certain cerebral brain regions which is associated with specific tinnitus characteristics. Resting-state cerebellar-cerebral functional connectivity disturbances may play a pivotal role in neuropathological features of tinnitus.


Type 2 diabetic patients with resistant hypertension should be screened for primary aldosteronism.
BP control in diabetic patients is often poor. The contribution of secondary hypertension due to undiagnosed PA in hypertensive type 2 diabetic patients is not well studied. We prospectively screened 100 consecutive Asian type 2 diabetic patients with difficult-to-control or resistant hypertension for PA. PAC (pmol/L) to PRA (ng/mL/h) ratio was measured; those with PAC-to-PRA ratio >550 (corresponding PAC >415) underwent intravenous 0.9% SLT. Patients with PAC >/=140 following SLT had CT adrenals and bilateral AVS. Thirteen patients (13%) were confirmed to have PA, and all had resistant hypertension. Eight had a surgically correctable form of PA. Patients with PA had higher mean (SD) systolic [159.0 (10.6) vs. 146.0 (10.7) mmHg, p=0.001] and diastolic BP [94.6 (6.0) vs. 87.6 (5.9) mmHg, p=0.001], lower serum potassium [3.5 (0.6) vs. 4.3 (0.5) mmol/L, p=0.001], and higher PAC [679.3 (291.0) vs. 239.5 (169.4) pmol/L, p=0.001]. Identification and institution of definitive treatment for PA resulted in better BP control and in a reduction in the use of antihypertensive medications. Our findings demonstrate a high prevalence of PA in type 2 diabetic patients with resistant hypertension. Systematic screening for PA in this select group is recommended, as targeted treatment improves BP control.


Association of adiponectin levels with polycystic ovary syndrome among Indian women.
Polycystic Ovary Syndrome (PCOS) is a hormonal condition where women reproductive hormones are out of endocrinal balance. Women with PCOS frequently exhibit obesity, which causes irregularities in the levels of adipocytes like adiponectin. It is hypothesized that the altered adiponectin levels also play a role in the endocrine and metabolic abnormalities seen in PCOS women. We aimed to study the association of adiponectin levels with PCOS women. This case control study included 60 PCOS women under 30 age, and BMI matched healthy controls were recruited. For all the subjects Biochemical and serum adiponectin were determined. The serum adiponectin shows significantly decreased in PCOS women when compared to healthy controls (P <0.001**). This levels were inversely associated with BMI and total cholesterol, triglycerides in women with PCOS (P<0.001**). The significantly decreased levels of serum adiponectin can be useful for diagnostic and prognostic tool for PCOS in women and its application can be used for the success of specific emerging treatment modalities where the follow up shows improvement of levels of adiponectin.


Tiny percutaneous needle biopsy: An efficient method for studying cellular and molecular aspects of skeletal muscle in humans.
Needle biopsy is widely used to obtain specimens for physiological, anatomical and biochemical studies of skeletal muscle (SM). We optimized a procedure which we termed tiny percutaneous needle biopsy (TPNB), to efficiently gather good numbers of human satellite cells and single dissociated fibers for the functional study of skeletal muscle; these samples permit isolation of high-quality RNA and sufficient amounts of proteins to allow molecular analysis. Moreover, TPNB showed a clear advantage in that the technique was easier than other procedures used on healthy volunteers in human trials. TPNB is a very safe minor surgical procedure. It is less traumatic than needle aspiration biopsy, and significant complications are improbable. TPNB should become established as an important tool in the investigation of SM and may be employed to study various physiological aspects of SM in human subjects. We suggest that TPNB should also be used in the study of muscle diseases and disorders including muscular dystrophy, congenital myopathy, and metabolic defects.


Resting state synchrony in long-term abstinent alcoholics: Effects of a current major depressive disorder diagnosis.
Alcoholism is characterized by a lack of control over an impulsive and compulsive drive toward excessive alcohol consumption despite significant negative consequences; our previous work demonstrated that successful abstinence is characterized by decreased resting-state synchrony (RSS) as measured with functional magnetic resonance imaging (fMRI), within appetitive drive networks and increased RSS in emotion regulation and inhibitory executive control networks. Our hypothesis is that LTAA (Long-Term Abstinent Alcoholics) with a current major depressive disorder (MDD) drank primarily to deal with the negative affect associated with their MDD and not because of a heightened externalizing diathesis (including heightened appetitive drive), and consequently, in achieving and maintaining abstinence, such individuals would not exhibit the RSS adaptations characteristic of pure alcoholics. We studied 69 NSAC (Non Substance Abusing Controls) and 40 LTAA (8 with current MDD, 32 without a current MDD) using resting-state fMRI and seed based connectivity analyses. In the inhibitory executive control network (nucleus accumbens vs. left dorsolateral prefrontal cortex), LTAA with a current MDD showed increased synchrony compared to NSAC. In the emotion regulation executive control network (subgenual anterior cingulate cortex vs. right dorsolateral prefrontal cortex), LTAA with current MDD did not show increased RSS. In the appetitive drive networks (nucleus accumbens vs, aspects of the caudate nucleus and thalamus), LTAA with a current MDD did not show a reduction of RSS compared to NSAC, but LTAA without a current MDD did. These results suggest different pathways to their alcohol dependence in LTAA with vs. without a current MDD, and different patterns of brain activity in long-term abstinence, suggesting different treatment needs.


Effect of chimeric antigen receptor T cells against protease-activated receptor 1 for treating pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year survival rate of 6% following a diagnosis, and novel therapeutic modalities are needed. Protease-activated receptor 1 (PAR1) is abundantly overexpressed by both tumor cells and multiple stroma cell subsets in the tumor microenvironment (TME), thereby offering a suitable immunotherapy target. A chimeric antigen receptor (CAR) strategy was applied to target PAR1 using a human anti-PAR1 scFv antibody fused to the transmembrane region with two co-stimulatory intracellular signaling domains of cluster of differentiation 28 (CD28) and CD137 (4-1BB), added to CD3ζ in tandem. The engineered PAR1CAR-T cells eliminated PAR1 overexpression and transforming growth factor (TGF)-β-mediated PAR1-upregulated cancer cells by approximately 80% in vitro. The adoptive transfer of PAR1CAR-T cells was persistently enhanced and induced the specific regression of established MIA PaCa-2 cancer cells by > 80% in xenograft models. Accordingly, proinflammatory cytokines/chemokines increased in CAR-T-cell-treated mouse sera, whereas Ki67 expression in tumors decreased. Furthermore, the targeted elimination of PAR1-expressing tumors reduced matrix metalloproteinase 1 (MMP1) levels, suggesting that the blocking of the PAR1/MMP1 pathway constitutes a new therapeutic option for PDAC treatment. Third-generation PAR1CAR-T cells have antitumor activity in the TME, providing innovative CAR-T-cell immunotherapy against PDAC.


PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene.
cDNAs representing the alpha subunit of polyomavirus enhancer binding protein 2 (PEBP2; also called PEA2) were isolated. The products of the cDNAs are highly homologous to that of Drosophila segmentation gene runt (run) for an N-proximal 128-amino acid region showing 66% identity. The run homology region encompasses the domain capable of binding to a specific nucleotide sequence motif and of dimerizing with the companion beta subunit. The human AML1 gene related to t(8;21) acute myeloid leukemia also had a run homology region. Together with the beta subunit, which increases the affinity of the alpha subunit to DNA without binding to DNA by itself, PEBP2 represents a newly discovered family of transcription factor. The major species of PEBP2 alpha mRNA was expressed in T-cell lines but not in B-cell lines tested. Evidence indicated that PEBP2 functions as a transcriptional activator and is involved in regulation of T-cell-specific gene expression.


Accuracy of patient reporting as an indication of headgear compliance.
Orthodontists struggle daily with the issue of patient compliance. Often, we must rely on patient cooperation with headgear to correct Class II malocclusions. Because there is no way to objectively and accurately gauge headgear cooperation, we must look for clues in assessing compliance. One clue that we use is the patient's own reporting of headgear wear. This study was aimed at determining the accuracy of patient reporting. Twenty patients in a private orthodontic practice were supplied with electronic timing headgears that enabled the author to compare their reported hours of headgear use with electronically measured actual usage. In this sample, 69% of the patients reported their headgear use at an accuracy level of 84% or greater, while 31% reported their use at an accuracy level of 58% or less. If fully one third of our patients are significantly inaccurate in reporting headgear use, this has clear implications in patient education, expected treatment results, and informed consent. Some may consider the timing headgear a useful adjunct in promoting better patient compliance.


The Application of Artificial Neural Networks and Logistic Regression in the Evaluation of Risk for Dry Eye after Vitrectomy.
Supervised machine-learning (ML) models were employed to predict the occurrence of dry eye disease (DED) after vitrectomy in this study. The clinical data of 217 patients receiving vitrectomy from April 2017 to July 2018 were used as training dataset; the clinical data of 33 patients receiving vitrectomy from August 2018 to September 2018 were collected as validating dataset. The input features for ML training were selected based on the Delphi method and univariate logistic regression (LR). LR and artificial neural network (ANN) models were trained and subsequently used to predict the occurrence of DED in patients who underwent vitrectomy for the first time during the period. The area under the receiver operating characteristic curve (AUC-ROC) was used to evaluate the predictive accuracy of the ML models. The AUCs with use of the LR and ANN models were 0.741 and 0.786, respectively, suggesting satisfactory performance in predicting the occurrence of DED. When the two models were compared in terms of predictive power, the fitting effect of the ANN model was slightly superior to that of the LR model. In conclusion, both LR and ANN models may be used to accurately predict the occurrence of DED after vitrectomy.


Effect of the in vivo treatment with the synthetic steroid 17 beta-methoxy-17-methyl-(5 alpha)-1 H'-androstane-(3,2-c) pyrazole (17MM) on the in vitro formation of DHT in the epididymis of the rat.
Adult male Sprague-Dawley rats were injected subcutaneously (s.c.) for 21 days either with the synthetic steroid 17 beta-methoxy-17-methyl-(5 alpha)-1 H'-androstane-(3,2-c) pyrazole (17MM) at two dose levels (0.1 and 1 mg/kg/day) or with the vehicle used to dilute the steroid. At autopsy, caput epididymes and ventral prostates were removed and incubated in vitro. The effect on the 5 alpha-reductase (5 alpha-R) activity was evaluated by measuring the amounts of DHT formed from 14C-testosterone (14C-T) used as the substrate. The in vivo administration of 17MM at the dose of 0.1 mg/kg/day resulted in a significant decrease in the formation of DHT at the level of the epididymis, while there was no effect on the prostate. The dose of 1 mg/kg/day did not induce any modification in the formation of DHT in either organ. The determination of serum LH showed that the treatment with either dose did not alter serum LH titers. These findings suggest that the in vivo treatment with 17MM lowers the in vitro formation of DHT from T at the epididymal, but not at the prostatic level and consequently suggests a selective inhibitory effect of 17MM on the 5 alpha-R present in the epididymis.


Cardiomyopathies and Congenital Heart Disease in Pregnancy.
Pregnancy-associated diseases of the cardiovascular system occur in up to 10% of all pregnancies and the incidence is increasing. Besides congenital heart disease or pre-existing cardiomyopathy in the mother, the clinical focus has moved especially to peripartum cardiomyopathy (PPCM) because of the condition's dramatic clinical course and the identification of the underlying mechanisms. This review article concentrates therefore on PPCM, which occurs either in the last month of pregnancy or in the first 6 months following delivery in women with previously healthy hearts. The global incidence is estimated today at roughly 1 : 1000 pregnancies. The condition is heterogeneous, ranging from mild disease to severe acute heart failure with cardiogenic shock and sudden cardiac death of the mother. Important risk factors are pregnancy-associated hypertensive complications, multiple pregnancy and greater maternal age. The pathogenesis comprises cleavage, induced by increased oxidative stress, of the lactation hormone prolactin into a toxic hormone fragment that damages blood vessels, known as the 16-kDalton protein fragment. The lactation-blocking drug bromocriptine prevents prolactin release and promotes healing of PPCM in combination with pharmacological heart failure therapy; it appears to prevent recurrence in subsequent pregnancies. Uncomplicated pregnancy is possible in most patients with congenital heart disease. The foetal complications include an increased abortion rate, prematurity and smallness for gestational age, as well as an increased risk of cardiac malformations. The maternal risk comprises mainly arrhythmias, progressive heart failure and thrombembolic complications, with the risk of vessel dissection with a low mortality risk of < 1% in the case of aortopathies. Individual risk assessment and corresponding close monitoring of the pregnancy are required.


Electrostatic Charges Regulate Chemiluminescence by Electron Transfer at the Liquid-Solid Interface.
The role of the electrostatic environment in chemical reactions has long been an important research field, but most studies have focused on the influence of external electric fields on chemical processes, while the effect from the intrinsic electrostatic charges on the solution itself has been ignored. How an electrostatic field generated by contact electrification affects the solvent environment in a chemical reaction and then the chemical reactivity is still ambiguous. Here, based on the inspiration of the droplet triboelectric nanogenerator, electrostatic interactions between a statically charged luminol droplet and the surrounding directional electrostatic field were analyzed, and we demonstrate a relationship between the sign of the luminol sample (negatively or positively charged) and its effect on the reaction reactivity. Our results show that the increased reaction activity and the enhanced chemiluminescence (CL) only occurred when the luminol droplet yields positive charges, while a negatively charged luminol, on the contrary, tends to inhibit the CL, which brings direct evidence of the charge carriers of triboelectricity being electrons at the liquid-solid interface. This work provides a strategy for electrostatically regulating CL by simply statically charging a reaction solution with a dielectric solid and also carries a cautionary message on what to consider when preparing a sample for a chemical reaction.


[Bilateral anterior shoulder dislocation fracture after an epileptic seizure. A case report].
Fractures can occur during violent muscular violence such as occur in the course of epileptic seizures, though this is rare (0.3%). The proximal part of the humerus is most frequently affected. The typical lesion is bilateral posterior dislocation or fracture-dislocation. We present a rare case of bilateral anterior fracture-dislocation of the shoulder sustained as the result of an epileptic fit. The treatment given was open reduction, refixation of the anterior labrum and screw fixation of the fragments. A review of the literature revealed only 18 cases of bilateral anterior dislocations caused by convulsive seizures.


Design of a mechanism for converting the energy of knee motions by using electroactive polymers.
Harvesting energy from human body motions has become a promising option to prolong battery life for powering medical devices for autonomy. Up to now, different generating principles including dielectric electroactive polymers (DEAPs) have been suggested for energy conversion. However, there is a lack of mechanisms that are specifically designed to convert energy with DEAPs. In a proof of concept study, a mechanical system was designed for stretching DEAPs in those phases of the gait cycle, in which the muscles mainly perform negative work. Rotational movements of the knee joint are transformed into linear movements by using a cable pull. The DEAP can be charged during the stretching phase and discharged during releasing and allows for the conversion of kinetic energy into electric energy. To evaluate the concept, tests were conducted. It was found that the developed body energy harvesting (BEH) system has a performance in the range of 24-40 μW at normal walking speed. The converted energy is sufficient for powering sensors in medical devices such as active orthoses or prostheses.


Increasing Incidence of Concussion: True Epidemic or Better Recognition?
To provide updated estimates of the incidence of concussion from all causes diagnosed by all physicians in a large jurisdiction, as previous studies have examined only single causes of injury or from smaller specific populations. Physician Billing and National Ambulatory Care Reporting System (NACRS) databases were used to identify all Ontario residents with a diagnosis of concussion (ICD-9 850.0 and ICD-10 S06.0) made by physicians between 2008 and 2016, excluding those with moderate to severe traumatic brain injury. In total, 1 330 336 people were diagnosed with a concussion between 2008 and 2016. The annual average was 147 815, and 79% were diagnosed in the emergency department. The average annual incidence was 1153 per 100 000 residents. Incidence varied by age, sex, and geography; children younger than 5 years had the highest incidence of concussion, more than 3600 per 100 000 individuals of that age group. Males had higher incidence than females except in older than 65 years age groups. There was a Pearson correlation (+0.669) between sustaining a concussion and living in rural locations. The annual incidence of approximately 1.2% of the population is the highest rate of concussion ever reported thorough sampling methods and may represent a closer estimate of the true picture of concussion. Findings may inform future concussion treatment and healthcare planning.


Infection control among professional tattooists in Minneapolis and St. Paul, MN.
This study investigated infection control knowledge, beliefs, and practices of professional tattooists. In a cross-sectional study of professional tattooists (N = 61), a self-administered questionnaire measured knowledge and beliefs related to blood-borne pathogen transmission and control and self-reported infection control procedures. The study also involved direct observation of the infection control practices of 25 tattoo artists. All respondents believed that bloodborne pathogens could be transmitted via tattooing, and most denied that trouble or expense were barriers to infection control. Knowledge about infection transmission and control was high and was positively associated with learning about infection control from a health official. Subjects were observed implementing an average of 44 of 62 recommended procedures. The percentage of recommended procedures used was negatively associated with years of tattooing experience. Tattooists have an understanding of the risks associated with exposure to blood, but this knowledge is not fully operationalized in the workplace. Interventions should focus on needle disposal, handwashing, cross-contamination, and cleaning prior to sterilization. Tattooists with > or = 10 years of experience are most in need of intervention. National guidelines for tattooing infection control and strategies for collaboration between public health officials and tattooists are needed.


Unprecedentedly High Level of Intracellular Vitamin C and DNA Epigenetic Marks in Prostate: Relevant for Male Fertility?
Seminal plasma composition is affected by the physiological state of the prostate, the major male reproductive gland. Semen components, like vitamin C, can modulate sperm function. Vitamin C is an effective scavenger of free radicals and is an essential component of enzymes such as TET proteins involved in the DNA demethylation process. In the present study, a broad range of parameters which may influence the metabolic state of the prostate gland were analysed including blood and prostate tissue vitamin C, epigenetic DNA modifications and 8-oxo-7,8-dihydro-2'-deoxyguanosine in DNA of leukocytes and prostate tissues. The experimental material were tissue samples from patients with benign prostatic hyperplasia (BPH), normal/marginal prostate tissues from prostate cancer patients, leukocytes from healthy donors, and blood plasma from BPH patients and healthy donors. We applied ultra-performance liquid chromatography methods with mass spectrometry and/or UV detection. We found an unprecedentedly high level of intracellular vitamin C in all analysed prostatic tissues (benign prostatic hyperplasia and normal, marginal ones), a value much higher than in leukocytes and most human tissues. DNA epigenetic patterns in prostate cells are similar to other soft tissues like the colon, however, its uniqueness is the unprecedentedly high level of 5-(hydroxymethyl)-2'-deoxyuridine and a significant increase in 5-formyl-2'-deoxycytidine value compared to aforementioned tissues. Moreover, the level of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an established marker of oxidative stress, is significantly higher in prostate tissues than in leukocytes and many previously studied soft tissues. Our results pointed out that prostatic vitamin C (regarded as the main supplier of the vitamin C to seminal plasma) and the DNA modifications (which may be linked to the regeneration of prostate epithelium) may play important role to maintain the prostate health.


A two-scale Weibull approach to the failure of porous ceramic structures made by robocasting: possibilities and limits.
This paper introduces our approach to modeling the mechanical behavior of cellular ceramics, through the example of calcium phosphate scaffolds made by robocasting for bone-tissue engineering. The Weibull theory is used to deal with the scaffolds' constitutive rods statistical failure, and the Sanchez-Palencia theory of periodic homogenization is used to link the rod- and scaffold-scales. Uniaxial compression of scaffolds and three-point bending of rods were performed to calibrate and validate the model. If calibration based on rod-scale data leads to over-conservative predictions of scaffold's properties (as rods' successive failures are not taken into account), we show that, for a given rod diameter, calibration based on scaffold-scale data leads to very satisfactory predictions for a wide range of rod spacing, i.e. of scaffold porosity, as well as for different loading conditions. This work establishes the proposed model as a reliable tool for understanding and optimizing cellular ceramics' mechanical properties.


Effect of Finishing Procedures on the Surface Roughness of Resin-modified Glass-Ionomer Materials.
This study examined the influence of finishing procedures on the surface roughness of different formulations of resin-modified glass ionomers (RMGIs) available in capsules compared with standard resin composites (RCs). Disc samples of three RMGIs and two RCs were fabricated using a metal mold (5 mm x 1.5 mm). Samples were randomly divided into seven groups (N = 10) and subjected to finishing and polishing procedures using a combination of carbide or diamond burs, followed by either rubber points or aluminum-oxide discs. Three different regions of each sample were analyzed using a contact profilometer to determine the average roughness (Ra). The main surface roughness was calculated using a two-way analysis of variance (ANOVA) and the Bonferroni correction for multiple comparisons. A dual-stage combination of a fine carbide bur followed by the use of the finest two grits of aluminum-oxide discs was found to produce the smoothest finished and polished surface. the smoothest surfaces were found to be on the two RCs and one of the RMGIs.


Study on ground water characteristics and the effects of discharged effluents from textile units at Karur District.
A study was made on the physico-chemical characteristics of water samples mixed with effluent discharged from textile industries at Chellandipalayam (Site--I), Senaparatti (Site--II) and Pasupathipalayam (Sites--III and IV) revealed the elevated levels of Ca, Mg, Na, Cr, K, Ni, Cu, Zn, CO3, SO4, NO3 and Cl- . The concentrations of these ions exceeded the limit prescribed by ISI. The increase in the concentrations of ions was revealed by higher values of electrical conductivity (EC). Water at these sites was found to be hard, brackish and unsuitable for drinking purpose. In all these sites, the seed germination of rice alone was significantly affected among the other crops tested. Irrigation of crops with ground water notably lowered the quantity of reserve food in rice, wheat (starch), and sugarcane (sugar), indicating the interference of their metabolic pathway by polluted ground water.


Use of a mixture of gadolinium and iodinated contrast for angiography.
The purpose of this study was to determine if the image quality of gadolinium digital subtraction angiography (DSA) can be improved by the addition of small quantities of iodinated contrast to gadolinium. The optical density (OD) of a mixture of four parts gadolinium-based contrast to one part iodinated contrast was measured through a phantom study and compared to that of full-strength gadolinium, full strength iodinated contrast, and a 20% solution of iodinated contrast. We also compared the clinical image quality of the mixture of gadolinium-based contrast and iodinated contrast relative to full-strength gadolinium and full strength iodinated contrast during DSA. The DSA image quality of the gadolinium-iodinated contrast mixture was significantly improved relative to images obtained with full-strength gadolinium and compared favorably to that obtained with full-strength iodinated contrast. The phantom data showed that the OD of the gadolinium-iodinated contrast mixture was much greater than that of full strength gadolinium and the 20% iodinated contrast solution. The increase in OD was greater than that expected from a simple additive effect of the OD of the contrast agents. Adding a small amount of iodinated contrast to gadolinium results in a significant improvement in the radiographic density and DSA image quality of gadolinium. This simple technique appears to overcome one of the major limitations of gadolinium-based angiography-poor radiographic density-while continuing to minimize the volume of administered iodinated contrast.


Genetic variations in the matrix metalloproteinase-1 promoter and risk of susceptibility and/or severity of chronic periodontitis in the Czech population.
Matrix metalloproteinase-1 (MMP-1) is a potent enzyme degrading extracellular matrix that was implicated in the pathogenesis of chronic periodontitis. Therefore, the aim of our study was to examine the association between three promoter polymorphisms of the MMP-1 gene and chronic periodontitis susceptibility and/or severity in a Czech population. A total of 329 Caucasian subjects were enrolled in this study. They were 133 patients with mild to severe chronic periodontitis and 196 unrelated control subjects. MMP-1 promoter polymorphisms (-1607 1G/2G, -519A/G, and -422A/T) were genotyped using standard polymerase chain reaction-restriction fragment length product methods. Genotype analysis of the three single nucleotide polymorphisms across 27 different combinations showed significant association with chronic periodontitis (p<0.05). Analyses of individual polymorphisms showed no differences in distribution of the -519A/G and -422A/T variants between periodontitis and control groups. However, a trend to increased frequency of the -1607 1G allele was observed in patients with chronic periodontitis compared with the controls (p=0.054). When the groups were further stratified by smoking status, the 1G allele was associated with chronic periodontitis among non-smokers but not among smokers (p=0.033). On the contrary, the distribution of genotype frequencies of the MMP-1 -422A/T polymorphism was different between the patient and control smokers with respect to heterozygotes (73.91% versus 50.91%; p=0.017). Our results demonstrate that the polymorphisms in the MMP-1 promoter may have only a small effect on the etiopathogenesis of chronic periodontitis.


Asialoorosomucoid degradation by normal and diabetic rat hepatocytes.
Using high concentrations of extracellular [3H]asialoorosomucoid we obtained the steady-state level of [3H]asialoorosomucoid endocytosis by isolated hepatocytes from normal and streptozotocin diabetic rats. At the steady-state of the overall reaction, the intracellular amount of [3H]asialoorosomucoid did not change with time, the apparent overall rate of [3H]asialoorosomucoid degradation was close to that of [3H]asialoorosomucoid internalization, in both normal and diabetic rat hepatocytes. Although in diabetic cells the intracellular amount of [3H]asialoorosomucoid was about three-times lower than in normal cells, the same fraction of intracellular asialoorosomucoid was degraded per time interval by both normal and diabetic cells. The apparent first-order rate constant of steady-state degradation was about 0.011 min-1 for both normal and diabetic cells. In diabetic rat hepatocytes, the decrease of the clearance of serum asialoglycoproteins was directly correlated to the variation of cell surface receptor number, without any modification of internalization and degradation steps.


Direct square-wave voltammetry of superoxidized [4Fe-4S]3+ aconitase and associated 3Fe/4Fe cluster interconversions.
We report a direct square-wave voltammetric study of the iron-sulfur enzyme, aconitase, at the pyrolytic graphite edge electrode. New and established redox driven reactions were observed and the equilibrium reduction potential for each couple was determined: E0'[3Fe-4S]1+/0 = -268 mV, E0'[4Fe-4S]2+/1+ = -450 mV, E0'[4Fe-4S]3+/2+ = +100 mV, E0'Linear Form = -281 mV, and putatively, E0'[3Fe-4S]0/2- congruent to -1000 mV, all versus normal hydrogen electrode. Most importantly we have directly observed the superoxidized [4Fe-4S]3+ form of aconitase (originally proposed by Emptage, M. H., Dreyer, J.-L., Kennedy, M. C., and Beinert, H. (1983) J. Biol. Chem. 258, 11106-11111) and directly followed its conversion to the [3Fe-4S]1+ form; this intermediate is required for the deactivation of aconitase. Without exogenous ferrous iron, [3Fe-4S]0 aconitase is apparently super-reduced at very negative potentials to the [3Fe-4S]2- form and the concomitant formation of [4Fe-4S]2+ aconitase was followed over time. It is the apparent decomposition of super-reduced [3Fe-4S]2- aconitase that provides the source of ferrous iron for the interconversion of [3Fe-4S]0 aconitase to the [4Fe-4S]2+ form. Voltammetry of free and substrate bound [4Fe-4S]2+ aconitase showed that the latter is less susceptible to oxidation but, surprisingly, has the same E0'[4Fe-4S]3+/2+.


PURTSCHER RETINOPATHY AS A MANIFESTATION OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS.
The authors describe a woman diagnosed with hemophagocytic lymphohistiocytosis and found to have retinal examination findings consistent with Purtscher retinopathy. A 52-year-old woman underwent multimodal imaging, including color fundus photography and spectral-domain optical coherence tomography, to confirm the diagnosis. The ophthalmic examination and imaging confirmed the findings of Purtscher retinopathy with significant inner retinal thickening on spectral-domain optical coherence tomography. Throughout a hospital course complicated by multi-organ failure, she continued to have profoundly limited visual acuity, likely resulting from inner retinal ischemia affecting the posterior pole of both eyes. The authors describe a patient with hemophagocytic lymphohistiocytosis, a disease characterized by disruption of normal natural killer cell activity with subsequent uncontrolled cytokine release, who presented with Purtscher retinopathy confirmed with spectral-domain optical coherence tomography.


Case Sequencing of Diagnostic Imaging Studies Performed Under General Anesthesia or Monitored Anesthesia Care During Nights and Weekends.
General anesthesia or monitored anesthesia care sometimes is provided in nonoperating room (OR) locations during nights and weekends (e.g., for magnetic resonance imaging [MRI] or computerized tomography [CT]). Rational and consistent scheduling and sequencing decisions for these diagnostic imaging procedures, including coordination with OR cases, cannot be done without knowing how long each case can wait to be started without risking a worsening of the patient's condition. We reviewed the medical records of the 81 patients who underwent diagnostic imaging procedures (78 = MRI, 3 = CT scan) under general anesthesia or monitored anesthesia care either on weekends or between 6 pm and 6 am at the University of Iowa Hospitals between March 2012 and February 2014. For 77.8% of patients, the indications could have changed clinical management within 4 hours (N = 63/81). Among the 63 imaging studies with potential immediate impact, there was documentation of results having been communicated to the treating team within 4 hours of the completion of imaging for 39 of the patients. Among the 39 patients, 15 promptly received medications or underwent procedures based on the imaging results. Thus, 15 of the 81 patients had a change in care (18.5%, 95% lower confidence limit = 11.2%). Our results are important since we showed previously that it is not possible to make rational and consistent decisions in case sequencing without knowing how long each case (including diagnostic imaging procedures) can wait to be started without a change in the patient's risk. The scheduled surgical procedure itself provides sufficient information to assess safe waiting times to start add-on cases (e.g., appendectomy). In contrast, MRI provides no context as to how potential findings will influence treatment. Our results show that the assumption cannot reasonably be made when sequencing cases that all imaging studies can or cannot wait longer than pending surgical procedures. Our results show that, for evidence-based OR management decision-making, information to decide appropriate waiting should be obtained electronically or verbally for each imaging study.


Multigene phylogenetic analysis detects cryptic species of Tryblidiopsis in China.
Tryblidiopsis pinastri (Rhytismatales) has been recognized as being distributed throughout northern temperate regions. In the present study, comparative studies showed that species of Tryblidiopsis from China were distinct from the European type species. They are shown to belong to two new Tryblidiopsis species, T sichuanensis and T. sinensis, with a third known to be present in China but not described because the reference material is immature. Combined LSU rDNA, ITS rDNA and mtSSU rDNA sequences analyses revealed that Chinese species and European species formed a monophyletic clade. Collections of Tryblidiopsis from North America need to be re-examined and sequenced; they are probably not conspecific with T. pinastri. Tryblidiopsis species appear to be highly host specific and are probably restricted to the host genus Picea.


Ddi1, a eukaryotic protein with the retroviral protease fold.
Retroviral aspartyl proteases are homodimeric, whereas eukaryotic aspartyl proteases tend to be large, monomeric enzymes with 2-fold internal symmetry. It has been proposed that contemporary monomeric aspartyl proteases evolved by gene duplication and fusion from a primordial homodimeric enzyme. Recent sequence analyses have suggested that such "fossil" dimeric aspartyl proteases are still encoded in the eukaryotic genome. We present evidence for retention of a dimeric aspartyl protease in eukaryotes. The X-ray crystal structure of a domain of the Saccharomyces cerevisiae protein Ddi1 shows that it is a dimer with a fold similar to that of the retroviral proteases. Furthermore, the double Asp-Thr-Gly-Ala amino acid sequence motif at the active site of HIV protease is found with identical geometry in the Ddi1 structure. However, the putative substrate binding groove is wider in Ddi1 than in the retroviral proteases, suggesting that Ddi1 accommodates bulkier substrates. Ddi1 belongs to a family of proteins known as the ubiquitin receptors, which have in common the ability to bind ubiquitinated substrates and the proteasome. Ubiquitin receptors contain an amino-terminal ubiquitin-like (UBL) domain and a carboxy-terminal ubiquitin-associated (UBA) domain, but Ddi1 is the only representative in which the UBL and UBA domains flank an aspartyl protease-like domain. The remarkable structural similarity between the central domain of Ddi1 and the retroviral proteases, in the global fold and in active-site detail, suggests that Ddi1 functions proteolytically during regulated protein turnover in the cell.


Evaluation of the MS-2 urine screening method for detection of bacteriuria.
A collaborative evaluation of the MS-2 urine screening system indicated that the automated method could successfully identify at least 84% of urine specimens that contained greater than or equal to 10(5) colony-forming units per ml. Most specimens not detected as positive by the system contained primarily diphtheroids and yeasts. Excluding those specimens which contained diphtheroids and yeasts, the MS-2 system correctly identified as positive 94.8% of specimens that contained greater than or equal to 10(5) colony-forming units per ml and as negative 96.1% of specimens that contained less than 10(4) colony-forming units per ml. The automated system is an attractive method for the screening of urine specimens for significant bacteriuria.


Altered FoxO1 and PPARγ interaction in age-related ER stress-induced hepatic steatosis.
Decreased forkhead box O1 (FoxO1) activity induces hyperlipidemia and increased PPARγ, leading to hyperlipidemia in association with endoplasmic reticulum (ER) stress. In the liver, aging and comorbidities such as hyperlipidemia and diabetes significantly influence a wide variety of steatosis, but the underlying mechanisms are complex and remain elusive.To establish the modulatory role of FoxO1 and the functional consequences of its altered interaction with PPARγ in the present study, we utilized a cell culture system, aged rats and diabetic db/db mice.We found that, under ER stress, FoxO1 induces PPARγ-mediated lipid accumulation in aged rat livers. Our data showed that the FoxO1-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPARγ, a key lipogenesis transcription factor, was increased in aged liver, resulting in lipid accumulation via hepatic ER stress under hyperglycemic conditions. We further demonstrated that loss of FoxO1 causes a decline in PPARγ expression and reduces lipid accumulation. In addition, the interaction between FoxO1 and PPARγ was shown to induce hepatic steatosis in aging and db/db mice.We provide evidence that, in aged rats, FoxO1 interaction with PPARγ promotes hepatic steatosis, due to hyperglycemia-induced ER stress, which causes an impairment in Akt signaling, such in aging-related diabetes.


Attitudes of school teachers toward influenza and COVID-19 vaccine in Greece during the COVID-19 pandemic.
Our study aims to assess the attitudes, knowledge, and influenza vaccine uptake of school teachers, the intention to uptake influenza vaccine as well as the COVID-19 vaccine and to identify factors associated with vaccine acceptance during the COVID-19 pandemic in Greece. A cross-sectional online survey was conducted among elementary and kindergarten school teachers in the area of Western Greece from June 2020 to August 2020. A self-administered questionnaire was distributed via an internet-based link along with an invitation e-mail. Responses from 399 participants were retrieved. 139 (34.8%) had received the annual influenza vaccine in the season 2019-2020, whereas 215 (53.9%) stated that they would get it in the forthcoming season 2020-2021 (p < .001). 152 (38.1%) intent to get the COVID-19 vaccine when available. For COVID-19 vaccine factors that were independently associated with the intention to uptake included more than 15 years at work (p = .001), prior influenza vaccine uptake (p = .003), believing that COVID-19 vaccine should be mandatory (p = .04) and that school teachers are a high-risk group for COVID-19 (p = .001). In conclusion, COVID-19 pandemic appeared to have an impact on the intention of school teachers to get vaccinated for influenza. The low level of COVID-19 vaccine acceptance intention among the teachers in our cohort warrants further attention. Public health interventions should aim to increase knowledge on both influenza and COVID-19 and prevention of them via immunization in this particular at-risk population.


[A scientific dialogue between Freud and Fliess. The research project on neurasthenia (1893)].
This study, following upon the publication of the letters written by Freud to Fliess, deals with the objective content of the relationship between Freud and Fliess as it appears in a joint research project drawn up in 1893 and that was never carried out. This project had been elaborated with an extensive use of practician's notes in mind, this practice being in accordance with Fliess's habits but contrary to Freud's: this is to be linked with the rivalry existing between practitioners with scientific ambitions and university doctors. One of the principal goals of the project was to establish a nosography of the diffuse clinical picture of "neurasthenia". It was with this aim in mind that Fliess had already published a book on "nasal reflex neurosis" which fully reveals his tendency to establish descriptive classifications; on the contrary, Freud endeavoured--following the principle that form is to be found in typical cases (the "initial cases")--to arrive at an etiological and theoretical understanding of phenomena, an ambition that he also opposed to Fliess. Even if an interest for sexuality could be detected in Fliess's work, it was only under Freud's influence that it became an explicit theme. His role consisted--and this remained valid throughout their relationship--in supplying an organic basis to Freud's theses, the corner-stone of which was a theory of sexuality. He thus aided Freud in ridding himself of his scientific scruples and facilitated the construction of the psychoanalytic theory under its psychological form.


Role of calcium antagonists in progression of arteriosclerosis. Evidence from animal experiments and clinical experience. Part I. Preventive effects of calcium antagonists in animal experiments.
The quantitative predominance of free and total cholesterol over the amount of mural calcium is a most significant criterion of healthy human coronary arteries during the whole life span (0-90 years). However, this normal ratio increasingly changes as soon as arteriosclerotic alterations of the coronary walls set in. Accordingly, the mural calcium content steadily rises from fatty streaks over severe arteriosclerosis and, lastly, seems to reach a climax in plaques which caused lethal coronary infarction. Furthermore, the severe arteriosclerosis of human art. dorsalis pedis with gangrene (and amputation) is characterized by a tremendous calcium incorporation and absence of any mural cholesterol changes. Only in rare cases of human basilary plaques was a dangerous cholesterol incorporation in brain arterial wall found without significant elevation of serum cholesterol levels. The presented data indicate the existence of two different types of arteriosclerosis in one and the same patient and two basically different types of experimental coronary plaques according to their chemical composition, microscopic aspect and responsiveness to calcium antagonists: 1) the calcium type, developing in vitamin-D3-treated rats, and 2) the cholesterol type, represented by fatty coronary atheromata of cholesterol-fed rabbits. Coronary atheromata of cholesterol-fed New Zealand rabbits may be suitable models for coronary heart disease in rare cases of human familiar hypercholesterolemia. The formation of conventional human coronary artery plaques, however, essentially requires a progressive uptake of calcium, thereby representing a calcium dominated type of arteriosclerosis. Calcium antagonists specifically inhibit progredient mural calcium uptake in all experimental models of arteriosclerosis tested so far. However, neither in atheromatous arteries nor in afflicted organs (myocardium, liver, kidneys) of cholesterol-fed rabbits were we able to find any significant prevention of cholesterol accumulation by calcium antagonist.


Multiple Whole Chromosomal Gains Define Angiomatous Meningiomas and Are Absent From the Tumor Vasculature.
Angiomatous meningioma is a variant with prominent vascularity that can mimic other highly vascularized tumors and present diagnostic challenges. Unlike most meningioma variants, where NF2 gene loss on chromosome 22 is the most common genetic abnormality, angiomatous meningiomas are unique in having multiple whole chromosome gains (polysomies). We analyzed 38 meningiomas, 9 angiomatous (including 2 atypical and 1 anaplastic), and 29 nonangiomatous meningiomas, using array comparative genomic hybridization (aCGH). Angiomatous meningiomas showed multiple chromosomal alterations including polysomies and copy neutral loss of heterozygosity in comparison to nonangiomatous variants. The most frequent gains were of chromosomes 5 and 20 (100% and 89% of cases, respectively); none showed chromosome 22 loss. Furthermore, using fluorescence in situ hybridization we show that the vasculature lacked chromosomal polysomy. While generally benign, we present 2 grade II and the first cytogenetically confirmed grade III angiomatous meningioma, demonstrating their potentially aggressive behavior. Thus, multiple polysomies define angiomatous meningioma and aCGH can distinguish this variant from nonangiomatous meningiomas and other histological mimics in diagnostically challenging cases. Furthermore, the prominent vasculature is not neoplastic and likely induced by angiogenic factors. Together, these findings suggest a distinct tumorigenic pathway in angiomatous meningiomas.


Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients.
Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen-reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(-) B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.


Type II DNA topoisomerase from Saccharomyces cerevisiae is a stable dimer.
Type II DNA topoisomerases function as homodimeric enzymes in transiently cleaving double-stranded DNA to catalyze unlinking and unknotting reactions. The dimeric enzyme creates a DNA double-strand break by forming a covalent attachment between an active site tyrosine from each monomer and a 5'-phosphate from each strand of DNA. The dimer must be very stable to dissociation or subunit exchange when covalently attached to DNA to prevent directly or indirectly catalyzed rearrangements of the genome. Past studies have indicated conflicting results for the monomer-dimer stability of topoisomerase II in solution. Here, we report results from sedimentation equilibrium studies and two different subunit exchange assays indicating that purified Saccharomyces cerevisiae DNA topoisomerase II exists as a stable dimer in solution, with a Kd estimated to be < or = 10(-11) M. This high dimer stability is not detectably altered by a change of ionic strength or by the presence of ATP, ADP, or DNA.


Apparent mediation of the stimulus properties of a low dose of quinpirole by dopaminergic autoreceptors.
This study examined the hypothesis that, if the stimulus properties of the D2 agonist quinpirole (QUIN) were mediated by autoreceptors, then pharmacological treatments engendering a decline in dopamine (DA) release and consequent decrease in postsynaptic DA receptor stimulation should result in QUIN-appropriate responding; those that activate postsynaptic receptors should result in saline-appropriate responding. In rats trained to discriminate 0.05 mg/kg of QUIN from saline using standard operant drug discrimination procedures, QUIN (up to the training dose), two other putative D2 autoreceptor agonists (low-dose apomorphine and N-propylnorapomorphine), the DA depeleter alpha-methyl-p-tyrosine (AMPT) and the D1 antagonist SCH 23390 all produced primarily QUIN-lever responding. Moreover, coadministration of alpha-methyl-p-tyrosine with QUIN potentiated QUIN-stimulus properties. Higher doses of apomorphine, known to stimulate postsynaptic D1 and D2 receptors and pretreatment with the D2 antagonist haloperidol decreased QUIN-lever responding. Neither the D1 agonist SKF38393, the indirect D1/D2 agonist d-amphetamine, the D2 antagonist haloperidol or coadministration of SCH 23390 and d-amphetamine substituted for QUIN. Coadministration of either SKF 38393 or d-amphetamine with QUIN decreased levels of QUIN responding. Taken together, the data are consistent with the contention that the stimulus properties of 0.05 mg/kg of QUIN are primarily mediated by D2-type presynaptic autoreceptors and that these stimulus properties involve a decline in DA release and consequent decreased postsynaptic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)


Resource utilisation and costs of depressive patients in Germany: results from the primary care monitoring for depressive patients trial.
Background. Depression is the most common type of mental disorder in Germany. It is associated with a high level of suffering for individuals and imposes a significant burden on society. The aim of this study was to estimate the depression related costs in Germany taking a societal perspective. Materials and Methods. Data were collected from the primary care monitoring for depressive patients trial (PRoMPT) of patients with major depressive disorder who were treated in a primary care setting. Resource utilisation and days of sick leave were observed and analysed over a 1-year period. Results. Average depression related costs of €3813 were calculated. Significant differences in total costs due to sex were demonstrated. Male patients had considerable higher total costs than female patients, whereas single cost categories did not differ significantly. Further, differences in costs according to severity of disease and age were observed. The economic burden to society was estimated at €15.6 billion per year. Conclusion. The study results show that depression poses a significant economic burden to society. There is a high potential for prevention, treatment, and patient management innovations to identify and treat patients at an early stage.