[Study of immunological mechanisms of action of temperature and emotional stress factors in experimental flavivirus infections].
The influence of two stress factors, sharp changes in temperature and hypokinesia, on the course of experimental tick-borne encephalitis and Langat virus infections in mice has been studied. The data obtained in this study indicate that both factors produce defects in T- and B-cell-mediated immunity, accompanied by the activation of asymptomatic infection and the decrease of the mean survival time in acute infection. These two stress factors, differing in their intensity and nature (physical and emotional), have been shown to produce the same effect on the course of acute and asymptomatic flavivirus infections. In the former case the mean survival time of the animals decreases, and in the latter case clinically manifest infection develops. Under the conditions of hypokinesia (or changes in temperature), the death rate among the animals infected with langat virus has been found to increase 3- to 4-fold in comparison with the controls, the mortality level in the groups subjected to different stress factors being the same.


Psychedelics and the human receptorome.
We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT(2A) (and possibly 5-HT(2C)) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (K(i)) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.


Sensitization of imatinib-resistant CML cells to TRAIL-induced apoptosis is mediated through down-regulation of Bcr-Abl as well as c-FLIP.
Resistance to imatinib is commonly associated with reactivation of Bcr-Abl signalling. However, Bcr-Abl-independent signalling pathways may be activated and contributed to imatinib resistance in some CML (chronic myelogenous leukaemia) patients. We had isolated three imatinib-resistant K562/R1, R2 and R3 variants with gradual loss of Bcr-Abl from K562 cells to develop effective therapeutic strategies for imatinib-resistant CML. Interestingly, we found that these cells became highly sensitive to TRAIL (tumour necrosis factor-related apoptosis-inducing factor) in comparison with K562 cells showing high resistance to TRAIL. Treatment of K562/R3 cells with TRAIL resulted in activation of TRAIL receptor pathway by including caspase 8 activation, Bid cleavage, cytochrome c release and caspase 3 activation. These results were accompanied by down-regulation of c-FLIP {cellular FLICE [FADD (Fas-associated death domain)-like interleukin 1beta-converting enzyme]-inhibitory protein} in imatinib-resistant K562 variants compared with K562 cells. Overexpression of c-FLIP in K562/R3 cells acquired TRAIL resistance and conversely, c-FLIP-silenced K562 cells became sensitive to TRAIL. Moreover, Bcr-Abl-silenced K562 cells showed down-regulation of c-FLIP and the subsequent overcome of TRAIL resistance. Taken together, our results demonstrated for the first time that the loss of Bcr-Abl in imatinib-resistant cells led to the down-regulation of c-FLIP and subsequent increase of TRAIL sensitivity, suggesting that TRAIL could be an effective strategy for the treatment of imatinib-resistant CML with loss of Bcr-Abl.


[Obesity, arterial hypertension, metabolic disorders, and polycystic ovary syndrome].
To determine the prevalence of central and general obesity, arterial hypertension, and alterations in cholesterol, triglycerids, glycaemia and uric acid levels in patients with PCOS and to compare them with women who do not present this syndrome. To establish the possible association of this with the PCOS. This is a transversal analytic study. It includes fifty-five cases of PCOS and fifty-five healthy controls from gynecologic and familiar medicine consultation during the period from May 2nd to November 30th, 1999. It excludes patients with the Cushing disease, congenital suprarenal hyperplasia, pregnant women or women under hormonal treatments until three months prior the beginning of the study. The diagnostic of PCOS was established when the patient presents three of the following characteristics: menstrual disturbances, hirsutism, a LH/FSH relation > or = than 1.5 and ultrasound with polycystic ovaries. Their weight and height was taken in order to calculate the body mass index (BMI) and the waist/hip index (WHI) Blood samples in fasting where obtained to determine the FSH, LH, cholesterol, triglycerids, glycaemia and uric acid levels. Descriptive statistics where applied as well as the SPSS software along with the Saphiro-Francia test, the Mann Whitney test and logistic regression. The age of the patients with PCOS varied between 18 and 39 years old, average 26.6 years old and that of the controls from 19 to 39 years old, average 28.2 years old, (p = 0.165). The prevalence of general obesity (BMI > or = 30) was of 50.9% in the group of PCOS and of 18.2% in the group of controls. The systolic hypertension (BP > or = 140 mm Hg) was of 9% against 7.3%. A diastolic hypertension (BP > or = 90 mm Hg) of 25.5% against 7.3%. A hypercholesterolemia (> or = 220 mg/dL) of 30.9% against 10.9%. A hypertriglyceridemia (> or = 160 mg/dL) of 30.9% against 16.4%. A hyperglycaemia(> or = 115 mg/dL) of 5.5% against 3.6% and a hyperuricemia(> or = 6.5 mg/L) of 23.6% against 3.6%. The OR calculated through cross products showed that patients with PCOS have the possibility of presenting obesity, hypercholesterolemia, hypertriglyceridemia, hyperuricemia and diastolic hypertension, 4.6, 3.7, 2.3, 8.2 and 4.4 times more than the controls. The comparison of the average of the variables of both groups showed significant differences (p < 0.5) for the BMI, WHI, systolic BP, cholesterol and uric acid. The multiple logistic regression showed a consistent association between PCOS and hyperuricemia (MR = 5.23, = 1.4-26.26), obesity (MR = 3.26, CI = 1.33-8.01) and hypercholesterolemia (RM = 3.04, CI = 1.02-9.08). The study showed a higher prevalence of obesity, hypercholesterolemia, hypertriglyceridemia, hyperuricemia and diastolic hypertension in patients with PCOS than in the controls. No such thing for hyperglycaemia and systolic hypertension. Nevertheless, there are significant differences between both groups related to the BMI, WHI, systolic hypertension, hypercholesterolemia and hyperuricemia. A consistent association among the PCOS and hypercholesterolemia, obesity and hyperuricemia was found.


Bibliometric analysis of human monkeypox research from 1975 to 2022 and novel prevention and control strategies.
Since human monkeypox was reported, many related literatures have been published. This study aimed to evaluate the research hotspots and future development trends of human monkeypox by a bibliometric analysis, to analyze the preventive and control measures of various countries in response to human monkeypox outbreaks. The Web of Science Core Collection database was searched for all monkeypox related literature published from 1975 to 2022, and the search strategy was "TS = monkeypox." Bibliometric analysis was performed using VOSviewer software based on retrieval data. Contribution metric methods and visualization were used to analyze the top issues in the field of human monkeypox. From 1975 to 2022, a total of 1,068 monkeypox research papers were included, of which American researchers published 663 papers, and it was also the country that participated in the most international cooperation. Centers for Disease Control Prevention USA is the most prolific institution and a leader in research collaborations. The Journal of Virology has the largest number of published papers on monkeypox. In addition, Damon Inger K has made significant contributions to monkeypox research, with both the most published and the most citation. A total of 2,847 keywords were identified, four top topics were obtained through cluster analysis: (1) human monkeypox epidemiology and species research. (2) human monkeypox virus vaccine and experimental research. (3) human monkeypox disease diagnosis and treatment studies. (4) human monkeypox disease prevention and immunization studies. To curb the spread, regions or countries have developed and implemented detailed managements. The prevention and control measures focus on the isolation of suspected or confirmed patients, the investigation and tracking of the source of the disease, the disposal of pollutants, vaccination and the protection of health workers. The number of human monkeypox literature has grown since 2003. Infection, vaccine and efficacy were the top topic over the past 47 years while the contact tracing, testing, surveillance and vaccination have been the major concerns since the human monkeypox outbreak in May 2022. The treatment and management of human monkeypox deserves further attention.


Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109 trial, step 2).
The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter · h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/10⁶ cells (interquartile range [IQR], 53 to 430 fmol/10⁶ cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/10⁶ cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.


Thrombin-induced phosphoinositide hydrolysis in platelets. Receptor occupancy and desensitization.
The relationship between occupancy of thrombin receptors on platelets and enhanced phosphoinositide hydrolysis was analysed by examination of the dose-response relationship, the effects of thrombin inhibitors and the contribution of secondary effects. Washed human platelets were labelled with [3H]inositol, and agonist-induced accumulation of labelled inositol phosphates was measured. The dose-response curves and the time courses for alpha-thrombin- or gamma-thrombin-induced accumulation of inositol phosphates were similar to those for dense-granule secretion. Addition of the thrombin inhibitor hirudin to thrombin-activated platelets revealed that the continuous presence of active thrombin was required to maintain the accumulation of labelled inositol phosphates; the total production of inositol phosphates increased with longer periods of exposure to thrombin, reaching a maximum between 5 and 10 min. After activation with thrombin, the ability of a second, greater, addition of thrombin to induce additional phosphoinositide hydrolysis decreased with time; it was absent within 10 min after the first addition. The failure to sustain accumulation of labelled inositol phosphates or to respond to a second addition of thrombin beyond 10 min was not due to depletion of the pool of labelled precursors, because the platelets retained their ability to respond to collagen. Addition of ADP-consuming enzymes decreased sensitivity to thrombin, but inhibition of cyclo-oxygenase with indomethacin did not impair the thrombin-induced hydrolysis of phosphoinositides. It was concluded that thrombin-induced hydrolysis of phosphoinositides has characteristics consistent with mediation by a receptor that is similar to that that triggers dense-granule secretion, requires continuous presence of active thrombin to be maintained, is mediated by a receptor that displays thrombin-induced desensitization, and is only partially enhanced by secondary agents.


Awareness and use of folic acid, and blood folate concentrations among pregnant women in northern China--an area with a high prevalence of neural tube defects.
The prevalence of neural tube defects (NTDs) in northern China remains high after 10 years since periconceptional supplementation with folic acid has been known to be effective in reducing the risk of NTDs. The objectives of this study were to characterize folic acid awareness and use and to examine the association between folic acid supplementation with blood folate concentrations among early pregnant women in an area with a high prevalence of NTDs in northern China. From December 2002 to February 2004, 693 early pregnant women were recruited and interviewed about folic acid awareness, knowledge and use. Four millilitres of venous blood was drawn and blood folate concentrations were measured. About 36% of women reported having ever heard of folic acid. Of these, 82.7% knew that folic acid can prevent NTDs, and 64.5% knew the best time to take it. Overall, 15% of women reported having ever taken folic acid. However, only 34.3% had begun to take it before the last menstrual period. Women with less education (21.1%), farmers (19.6%), rural dwellers (23.5%), and women who had a previous child (23.0%) were less likely to be aware of folic acid, and were less likely to take folic acid. Among women who had ever heard of folic acid, 37.5% took it during current pregnancy, compared with only 2.0% among those who had not. Women who were aware of folic acid were 25 times more likely to take it than women who were not. Overall, 44% of women had plasma folate deficiency, and 35% had red cell folate deficiency. Those who reported having ever taken folic acid had a lower rate of plasma folate deficiency (13.7%), compared with those who reported not taking folic acid (49.4%). The former group's mean plasma concentrations were twice as high as those of the latter group. The levels of folic acid awareness, knowledge and use among Chinese women living in a high NTD prevalence area during early pregnancy were very low and folate deficiency was quite prevalent. Campaigns aimed at increasing the awareness, knowledge, and periconceptional use of folic acid should target to less educated, parous women and women living in rural areas.


Spdeadringer, a sea urchin embryo gene required separately in skeletogenic and oral ectoderm gene regulatory networks.
The Spdeadringer (Spdri) gene encodes an ARID-class transcription factor not previously known in sea urchin embryos. We show that Spdri is a key player in two separate developmental gene regulatory networks (GRNs). Spdri is expressed in a biphasic manner, first, after 12 h and until ingression in the skeletogenic descendants of the large micromeres; second, after about 20 h in the oral ectoderm, where its transcripts remain present at 30-50 mRNA molecules/cell far into development. In both territories, the periods of Spdri expression follow prior territorial specification events. The functional significance of each phase of expression was assessed by determining the effect of an alphaSpdri morpholino antisense oligonucleotide (MASO) on expression of 17 different mesodermal genes, 8 different oral ectoderm genes, and 18 other genes expressed specifically during endomesoderm specification. These effects were measured by quantitative PCR, supplemented by whole-mount in situ hybridization and morphological observations. Spdri is shown to act in the micromere descendants in the pathways that result in the expression of batteries of terminal skeletogenic genes. But, in the oral ectoderm, the same gene participates in the central GRN controlling oral ectoderm identity. Spdri is linked in the oral ectoderm GRN with several other genes encoding transcriptional regulators that are expressed specifically in various regions of the oral ectoderm. If its expression is blocked by treatment with alphaSpdri MASO, oral-specific features disappear and expression of the aboral ectoderm marker spec1 encompasses the whole of the ectoderm. In addition to disappearance of the oral ectoderm, morphological consequences of alphaSpdri MASO treatment include failure of spiculogenesis and of correct primary mesenchyme cell (pmc) patterning in the postgastrular embryo, and also failure of gastrulation. To further analyze these phenotypes, chimeric embryos were constructed consisting of two labeled micromeres combined with micromereless 4th cleavage host embryos; either the micromeres or the hosts contained alphaSpdri MASO. These experiments showed that, while Spdri expression is required autonomously for expression of skeletogenic genes prior to ingression, complete skeletogenesis also requires the expression of oral ectoderm patterning information. Presentation of this information on the oral side of the blastocoel in turn depends on Spdri expression in the oral ectoderm. Failure of gastrulation is not due to indirect interference with endomesodermal specification per se, since all endomesodermal genes tested function normally in alphaSpdri MASO embryos. Part of its cause is interference by alphaSpdri MASO with a late signaling function on the part of the micromere descendants that is needed to complete clearance of the Soxb1 repressor of gastrulation from the prospective endoderm, but in addition there is a nonautonomous oral ectoderm effect.


G(i)-coupled GPCR signaling controls the formation and organization of human pluripotent colonies.
Reprogramming adult human somatic cells to create human induced pluripotent stem (hiPS) cell colonies involves a dramatic morphological and organizational transition. These colonies are morphologically indistinguishable from those of pluripotent human embryonic stem (hES) cells. G protein-coupled receptors (GPCRs) are required in diverse developmental processes, but their role in pluripotent colony morphology and organization is unknown. We tested the hypothesis that G(i)-coupled GPCR signaling contributes to the characteristic morphology and organization of human pluripotent colonies. Specific and irreversible inhibition of G(i)-coupled GPCR signaling by pertussis toxin markedly altered pluripotent colony morphology. Wild-type hES and hiPS cells formed monolayer colonies, but colonies treated with pertussis toxin retracted inward, adopting a dense, multi-layered conformation. The treated colonies were unable to reform after a scratch wound insult, whereas control colonies healed completely within 48 h. In contrast, activation of an alternative GPCR pathway, G(s)-coupled signaling, with cholera toxin did not affect colony morphology or the healing response. Pertussis toxin did not alter the proliferation, apoptosis or pluripotency of pluripotent stem cells. Experiments with pertussis toxin suggest that G(i) signaling plays a critical role in the morphology and organization of pluripotent colonies. These results may be explained by a G(i)-mediated density-sensing mechanism that propels the cells radially outward. GPCRs are a promising target for modulating the formation and organization of hiPS and hES cell colonies and may be important for understanding somatic cell reprogramming and for engineering pluripotent stem cells for therapeutic applications.


Expression of cyclin d1 and its association with disease characteristics in bladder cancer.
Invasive urothelial carcinoma of the bladder (UCB) is characterized by alterations in cell-cycle regulatory pathways. Defects in the expression of cyclin D1, a key cell-cycle regulator, have been implicated in progression of various types of cancer. In the present study, we investigated whether cyclin D1 expression is associated with clinicopathological parameters and whether it has any potential prognostic value in determining risk of UCB recurrence. Tissue microarrays containing bladder cancer specimens (n=212) and adjacent normal bladder tissues (n=131) were immunostained using an antibody against cyclin D1. The association between cyclin D1 and clinicopathological parameters including stage, lymph node metastasis, and disease-free survival, were evaluated. Cyclin D1 mRNA expression data from human normal bladder (n=14) and cancer specimens (n=28) were extracted from the public Oncomine database. Cyclin D1 mRNA and protein expression were significantly higher in UCB compared to adjacent non-malignant bladder tissue (for mRNA p=0.003, for protein p=0.001). Cyclin D1 protein expression was significantly higher in non-invasive tumors than in muscle-invasive UCB (p=0.016). Among patients with muscle-invasive UCB, increased cyclin D1 expression in tumor cells significantly correlated with lymph node metastasis (p<0.001), and there was a trend of cyclin D1 together with lymph node positivity to be associated with disease recurrence (p=0.678). Loss of nuclear cyclin D1 expression in tumor cells was likewise significantly associated with the presence of lymph node metastasis (p<0.001). Altered expression of cyclin D1 is associated with lymph node metastasis and risk of UCB recurrence. Cyclin D1 expression may therefore have clinical value as a prognostic marker and potential therapeutic target.


Proteoglycans of human articular cartilage. Identification of several populations of large and small proteoglycans and of hyaluronic acid-binding proteins in successive cartilage extracts.
Two specimens of human articulage were successively extracted with solutions of phosphate-buffered saline (PBS), 7 M-urea and 4 M-guanidine hydrochloride (Gdn-HCl). Proteoglycans from individual extracts were fractionated by DEAE-Sephacel chromatography and gel chromatography on Sephacryl S-400. The presence of three populations of large proteoglycans was demonstrated in all three extracts by composite agarose/polyacrylamide-gel electrophoresis (CAPAGE). The population corresponding to the fastest CAPAGE band of aggregating proteoglycans was shown to be extremely polydisperse, having Mr (as estimated by SDS/PAGE) decreasing continuously from more than 300,000 to the size corresponding to 'free' hyaluronic acid-binding region (HABR) (about 70,000). A rather polydisperse set of HABR-containing fragments which spanned a broad range of sizes, and also differed in their keratan sulphate contents, was isolated from both 7 M-urea and 4 M-Gdn-HCl extracts. PBS and 7 M-urea extracts, but not the Gdn-HCl extract, further contained small proteoglycans, identified as fast-migrating bands on CAPAGE electrophoretograms. One of those small species was recognized with an antibody against the small proteoglycan PG II; the other two remain to be positively identified. However, the glycosaminoglycan of the small species which was present exclusively in the PBS extract was identified as keratan sulphate; this species may thus belong to the family of small keratan sulphate-containing proteolygans.


Dizziness in the Outpatient Care Setting.
This article summarizes an approach to evaluating dizziness for the general neurologist and reviews common and important causes of dizziness and vertigo. Improved methods of diagnosing patients with vertigo and dizziness have been evolving, including additional diagnostic criteria and characterization of some common conditions that cause dizziness (eg, vestibular migraine, benign paroxysmal positional vertigo, chronic subjective dizziness). Other uncommon causes of dizziness (eg, superior canal dehiscence syndrome, episodic ataxia type 2) have also been better clarified. Distinguishing between central and peripheral causes of vertigo can be accomplished reliably through history and examination, but imaging techniques have further added to accuracy. What has not changed is the necessity of obtaining a basic history of the patient's symptoms to narrow the list of possible causes. Dizziness and vertigo are extremely common symptoms that also affect function at home and at work. Improvements in the diagnosis and management of the syndromes that cause dizziness and vertigo will enhance patient care and cost efficiencies in a health care system with limited resources. Clinicians who evaluate patients with dizziness will serve their patient population well by continuing to manage patients with well-focused workup and attentive care.


Declining disease burden of HCC in the United States, 1992-2017: A population-based analysis.
The incidence of HCC has recently been consistently reported to decline in the United States. However, decreased overall mortality of HCC has just been suggested and needs further examination. Using data from the Surveillance, Epidemiology, and End Results databases, we assessed HCC incidence, incidence-based mortality (IBM), and 1-year survival rates from 1992 through 2017 in the United States. These secular trends were analyzed using the National Cancer Institute's Joinpoint Regression Program. Age-period-cohort analyses were performed to address underlying reasons for the observed temporal trends. The incidence and mortality of liver cancer in the United States by different etiologies were acquired from the Global Burden of Disease study (1990-2019) as a likely validation set. Joinpoint and age-period-cohort analyses were performed by etiologies. The incidence rates of HCC increased during 1992-2011 and sharply decreased thereafter by -2.3% annually (95% CI: -3.5% to -1.1%). IBM peaked in 2013 (age-standardized mortality rate: 6.98 per 100,000 person-years) in the US population. IBM started to decrease significantly in 2013 by -3.2%/year (95% CI: -5.4% to -1.1% per year) after a continuous increase of 3.5% annually during 1993-2013. Overall, the 1-year survival of HCC improved from 21.4% to 56.6% over the study period. However, the highest HCC incidence and mortality risk for patients aged 60-69 and born between 1952-1957 were found. We found significantly decreased overall HCC-specific mortality since 2013 in the US population, along with decreased incidence and continuously improved survival. The changing etiologies, advances in screening and diagnosis, and improved treatment modality and allocation might all contribute to the downward trends of the disease burden of HCC in the United States.


A novel RP-HPLC method for simultaneous determination of potassium sorbate and sodium benzoate in soft drinks using C18-bonded monolithic silica column.
Potassium sorbate and sodium benzoate are food additives that are generally employed for prevention of food spoilage originating from bacteria, molds or yeasts. Although these compounds were generally recognized as safe due to their low risk of acute and chronic toxicity, they have limitations of usage to protect human health. Development and validation of a novel RP-HPLC method, in which a C18-bonded monolithic silica column was used as stationary phase to assay these compounds, is described for the first time. Aliquots of 10 μL of samples were injected into chromatograph and eluted using phosphate buffer (0.025 M, pH 2.0)-water-acetonitrile (50:45:5, v/v/v) solution, which was pumped at the rate of 3.0 mL/min. To sharpen the peaks, 10 mM octylamine was added to the mobile phase. Potassium sorbate and sodium benzoate were detected at about 12(th) and 14(th) min, respectively, and quantified at 230 nm using photodiode array detector. A total of 41 samples were prepared by simply filtering through 0.45 μm filters after sonication, and injected into the system without any pre-treatment steps. Applicability of the method was demonstrated by performing total procedure on samples of different brands and types, and their compliance to official regulations was assessed.


Oral health in the elderly patient and its impact on general well-being: a nonsystematic review.
Data on the oral health of the elderly depict a worrying situation, with an elevated prevalence of caries and moderate periodontal disease, frequent edentulism, and numerous cases of dry mouth and oral cancer. There is wide evidence that periodontitis is a risk factor for certain systemic diseases, and impaired oral health has been associated with mastication and nutritional problems, especially among the elderly, with highly negative effects on their quality of life. In this nonsystematic review, the authors discuss the importance of evaluating the oral health of the geriatric population in a comprehensive manner, beyond simple clinical assessments.


Healthcare in the age of open innovation - A literature review.
In spite of an increased interest in open innovation and strategies that call for an increased collaboration between different healthcare actors, there is a lack of open innovation research in public contexts. This article presents the results of a review regarding the healthcare sector's engagement in open innovation as well as constraining factors and positive outcomes of open innovation in healthcare. The literature search focused on papers published in English between 2003 and 2014. Based on specified inclusion criteria, 18 articles were included. Results reveal that most studies focus on inbound open innovation where external knowledge is integrated with the internal knowledge base at an initial phase of the innovation process. Innovation primarily results in products and services through innovation networks. We also identified constraining factors for open innovation in healthcare, including the complex organizations of healthcare, the need to establish routines for capturing knowledge from patients and clinicians, regulations and healthcare data laws as well as the positive outcome patient empowerment. The healthcare sector's engagement in open innovation is limited, and it is necessary to perform further research with a focus on how open innovation can be managed in healthcare.


Anti-NF-κB peptide derived from nuclear acidic protein attenuates ovariectomy-induced osteoporosis in mice.
NF-κB is a transcription factor that is activated with aging. It plays a key role in the development of osteoporosis by promoting osteoclast differentiation and inhibiting osteoblast differentiation. In this study, we developed a small anti-NF-κB peptide called 6A-8R from a nuclear acidic protein (also known as macromolecular translocation inhibitor II, Zn2+-binding protein, or parathymosin) that inhibits transcriptional activity of NF-κB without altering its nuclear translocation and binding to DNA. Intraperitoneal injection of 6A-8R attenuated ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation, promoting osteoblast differentiation, and inhibiting sclerostin production by osteocytes in vivo with no apparent side effects. Conversely, in vitro, 6A-8R inhibited osteoclast differentiation by inhibiting NF-κB transcriptional activity, promoted osteoblast differentiation by promoting Smad1 phosphorylation, and inhibited sclerostin expression in osteocytes by inhibiting myocyte enhancer factors 2C and 2D. These findings suggest that 6A-8R has the potential to be an antiosteoporotic therapeutic agent with uncoupling properties.


Evaluation of natural antimicrobials on typical meat spoilage bacteria in vitro and in vacuum-packed pork meat.
The aim of this study was to investigate the inhibitory effect of natural antimicrobials on the growth of typical spoilage bacteria from marinated pork. Minimum inhibitory concentrations (MIC) of thymol, cinnamaldehyde, allyl isothiocyanate, citric acid, ascorbic acid, a rosemary extract, and a grapefruit seed extract against Lactobacillus algidus, Leuconostoc mesenteroides, Leuconostoc carnosum, Carnobacterium maltaromaticum, Carnobacterium divergens, Brochothrix thermosphacta, and Serratia proteamaculans were determined in a microplate assay. Combinations of antimicrobials were tested and several combinations showed synergistic effects in inhibiting bacterial growth. Single and combined antimicrobials were added to vacuum-packed pork meat to evaluate preserving effects. Antimicrobial concentrations of up to 10 times the MIC values showed no effect on total bacterial growth in vacuum packed pork meaning that although most antimicrobials inhibited the growth of spoilage bacteria in vitro, results from the microplate assay could not be transferred to the meat system. Most natural antimicrobials possess strong odor and flavor that limit their use as a food preservative. In conclusion, this study showed that the use of natural antimicrobials in meat products is limited and that bacterial quality and shelf life was not enhanced under the chosen conditions.


Analysis of synchrony demonstrates 'pain networks' defined by rapidly switching, task-specific, functional connectivity between pain-related cortical structures.
Imaging studies indicate that experimental pain is processed in multiple cortical areas which are often characterized as a network. However, the functional connectivity within the network and the other properties of the network is poorly understood. Substantial evidence demonstrates that synchronous oscillations between two cortical areas may indicate functional connectivity between those areas. We test the hypothesis that cortical areas with pain-related activity are functionally connected during attention to a painful stimulus. We stimulated with a painful, cutaneous, laser stimulus and recorded the response directly from the cortical surface (electrocorticography--ECoG) over primary somatosensory (SI), parasylvian (PS), and medial frontal (MF) cortex through subdural electrodes implanted for treatment of epilepsy. The results demonstrate synchrony of ECoGs between cortical structures receiving input from nociceptors, as indicated by the occurrence of laser-evoked potentials (LEPs) and/or event-related desynchronization (ERD). Prior to the stimulus, directed attention to the painful stimulus consistently increased the degree of synchrony between SI and PS regions, as the subject anticipated the stimulus. After the laser stimulus, directed attention to the painful stimulus consistently increased the degree of synchrony between SI and MF cortex, as the subject responded by counting the stimulus. Therefore, attention to painful stimuli always enhanced synchrony between cortical pain-related structures. The pattern of this synchrony changed as the patient switched tasks from anticipation of the stimulus to counting the stimulus. These results are the first compelling evidence of pain networks characterized by rapidly switching, task-specific functional connectivity.


[Experimental investigations of 211Am accumulation by macrophytes of the Yenisei River].
Experiments were carried out in which 241Am was added to water samples containing macrophytes of the Yenisei River, and the radionuclide absorption rates and concentration factors were determined for the plants. It has been shown that the water moss (Fontinalis antipyretica) has a higher capacity to accumulate 241Am than the Canadian pondweed (Elodea canadensis) does. The laboratory experiments revealed that the capacity of dead biomass of the Canadian pondweed to accumulate 241Am is twice higher than that of living biomass. In contrast, no significant increase in 241Am accumulation by dead biomass of the water moss has been recorded. The transuranic element 241Am was firmly fixed by the plant biomass and was not released into water in the course of long-duration experiments.


Celiac disease.
Celiac disease is more prevalent than it was previously thought to be, and screening of selected population groups may reveal many new cases. Tissue transglutaminase appears to have a significant role in the degradation of gliadin and antigen production. Specific gliadin epitopes have been defined using T-cell responses. Bone disease is a significant problem for patients with celiac disease but management guidelines are being developed. Refractory sprue (nonresponsive celiac disease) appears to be a manifestation of enteropathy-associated T-cell lymphoma in most cases.


Is cytochrome P-450 transported from the endoplasmic reticulum to the Golgi apparatus in rat hepatocytes?
The Golgi apparatus mediates intracellular transport of not only secretory and lysosomal proteins but also membrane proteins. As a typical marker membrane protein for endoplasmic reticulum (ER) of rat hepatocytes, we have selected phenobarbital (PB)-inducible cytochrome P-450 (P-450[PB]) and investigated whether P-450(PB) is transported to the Golgi apparatus or not by combining biochemical and quantitative ferritin immunoelectron microscopic techniques. We found that P-450(PB) was not detectable on the membrane of Golgi cisternae either when P-450 was maximally induced by phenobarbital treatment or when P-450 content in the microsomes rapidly decreased after cessation of the treatment. The P-450 detected biochemically in the Golgi subcellular fraction can be explained by the contamination of the microsomal vesicles derived from fragmented ER membranes to the Golgi fraction. We conclude that when the transfer vesicles are formed by budding on the transitional elements of ER, P-450 is completely excluded from such regions and is not transported to the Golgi apparatus, and only the membrane proteins destined for the Golgi apparatus, plasma membranes, or lysosomes are selectively collected and transported.


Cardiac remodeling by fibrous tissue after infarction in rats.
After transmural myocardial infarction (MI), extensive myocardial remodeling by fibrous tissue appears in both infarcted and noninfarcted myocardium, which contributes to ventricular diastolic dysfunction. In the present study we sought to assess the time course of collagen remodeling in the infarcted rat hearts by detecting spatial and time-dependent cellular events related to collagen synthesis and degradation 2 to 28 days after left coronary artery ligation. In infarcted hearts, and compared with findings in sham-operated and unoperated rat hearts, we found the following: (1) macrophages infiltrated into sites of MI and visceral pericardium on day 2 and gradually disappeared after day 14; (2) myofibroblasts (MyoFb) first appeared at these sites of repair on day 3 and remained abundant thereafter at all time points examined; (3) transforming growth factor-beta1 (TGF-beta1) mRNA was enhanced in infarcted and noninfarcted myocardium on day 2 and remained throughout 28 days; (4) type I and III collagen mRNAs began to increase at and remote to MI on day 3 and remained elevated thereafter; (5) matrix metalloproteinase-1 mRNA was significantly increased at and remote to MI on day 3, declined to the control level on day 7, and remained low thereafter; (6) tissue inhibitor of matrix metalloproteinase (TIMP)-I, -II, and -III mRNAs were markedly elevated at sites of repair on day 3 and sustained throughout 28 days; (7) fibrillar collagen accumulation that was evident at and remote to MI on day 7 continued to accumulate thereafter at each site over 4 weeks. When compared with findings in unoperated rat heart, pericardial fibrosis was evident in both infarcted and noninfarcted heart, and the temporal response of collagen generation/ degradation in pericardium was similar to that in infarcted myocardium. Thus collagen synthesis is activated in both infarcted and noninfarcted rat myocardium after transmural anterior infarction and is persistent throughout the 28-day period of study, whereas early collagen degradation is short lived and inactivated in the fibrogenic phase. Activated TGF-beta1 mRNA expression is accompanied by the appearance of MyoFb and the expression of fibrillar collagens and TIMPs, suggesting that this fibrogenic cytokine may contribute to collagen remodeling in the rat heart after MI.


Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin/beta-catenin.
Ezrin, radixin, moesin and merlin form a subfamily of conserved proteins in the band 4.1 superfamily. The function of these proteins is to link the plasma membrane to the actin cytoskeleton. Merlin is defective or absent in schwannomas and meningiomas and has been suggested to function as a tumour suppressor. In this study, we have examined the role of ezrin as a potential regulator of the adhesive and invasive behaviour of tumour cells. We have shown that following inhibition of ezrin expression in colo-rectal cancer cells using antisense oligonucleotides, these cells displayed a reduced cell-cell adhesiveness together with a gain in their motile and invasive behaviour. These cells also displayed increased spreading over matrix-coated surfaces. Immunofluorescence studies revealed that antisense-treated cells also displayed an increased staining of paxillin in areas representing focal adhesions. Furthermore, coprecipitation studies revealed an association of ezrin with E-cadherin and beta-catenin. Induction of the phosphorylation of ezrin by orthovanadate and hepatocyte growth factor/scatter factor resulted in changes similar to those seen with antisense treatment, together with a marked decrease in the association of ezrin with both beta-catenin and E-cadherin. It is concluded that ezrin regulates cell-cell and cell-matrix adhesion, by interacting with cell adhesion molecules E-cadherin and beta-catenin, and may thus play an important role in the control of adhesion and invasiveness of cancer cells.


An epitope on VLA-6 (alpha6beta1) integrin involved in migration but not adhesion is required for extravasation of murine melanoma B16F1 cells in liver.
VLA-6 (alpha6beta1) integrin represents the major receptor for interaction with laminin substrate. It has been proposed that VLA-6 mediates tumor cell adhesion to the endothelium during extravasation. We have further explored this possibility using mouse melanoma B16F1 cells, which express VLA-6 as the principal laminin receptor, and two VLA-6 monoclonal antibodies (mAbs), MA6 and GoH3. Adhesion is a prerequisite of cell movement on matrix proteins. Thus, GoH3, which inhibited VLA-6-mediated adhesion, blocked cell movement on laminin. The recently prepared alpha6 integrin-specific mAb MA6 bound to an epitope in close proximity to GoH3, but it had no effect on VLA-6-mediated cell adhesion. We report here that although MA6 did not affect adhesion, it blocked mouse melanoma B16F1 cell movement on laminin to the same extent as GoH3. Results therefore demonstrate an active role of VLA-6 in providing cell movement as well as the initial adhesive event on laminin. In addition, mAb MA6 had no effect on the induction of tyrosine phosphorylation of focal adhesion kinase upon adhesion of B16F1 cells to laminin. Therefore, inhibition of cell movement by MA6 involved mechanism(s) other than an interference of VLA-6 signaling events leading to phosphorylation of focal adhesion kinase. The epitopes of GoH3 and MA6 may represent spatially and temporally related sites on VLA-6 that are involved during cell movement, or, alternatively, MA6 may inhibit the interaction of VLA-6 with associated cell surface molecules required for cell movement. In vivo videomicroscopy experiments also revealed that an inhibition of VLA-6 migratory function by MA6 resulted in a reduction in the ability of B16F1 to extravasate during hematogenous metastasis in the liver.


Evaluation of the Effect of Hévíz Mud in Patients with Hand Osteoarthritis: A Randomized, Controlled, Single-Blind Follow-Up Study.
Heat therapy is one of the most popular non-pharmacological treatments for osteoarthritis of the hand. To investigate the therapeutic and chemical effects of Hévíz mud on patients with hand osteoarthritis. We randomly assigned 47 patients with mild-to-moderate hand osteoarthritis to two groups. Patients in group 1 (n=23) received Hévíz mud applied directly to both hands, whereas patients in group 2 (n=24) also received mud to both hands, but nylon gloves separated the skin from the mud. Patients in both groups underwent five 20 minute treatment sessions per week for 3 weeks. The temperature of the mud was 42°C. Outcome measures were Visual Analogue Scale (VAS) scores, hand grip strength, the number of swollen and tender joints of the hand, the duration of morning joint stiffness, Health Assessment Questionnaire score, and EuroQoL Group 5-Dimension Self-Report Questionnaire score. The study parameters were evaluated at baseline, immediately after treatment, and after 16 weeks. Both groups showed improvement in nearly all assessed parameters at the end of treatment and at 16 weeks from the start of treatment. At the week 16 follow-up visit, the patient group directly treated with mud showed significantly better improvement in VAS for II and IV parameters and in swollen joint count in both hands compared to the nylon glove-mud group. Hévíz mud therapy significantly improved objective and subjective parameters in patients with hand osteoarthritis and had a beneficial effect on the patients' quality of life. Further studies are required to evaluate the chemical effects of the mud.


Efficient inhibition of influenza A viral replication in cells by deoxyribozymes delivered by nanocomposites.
Nucleic-acid-based drugs are a promising class of novel therapeutics; however, their use in medicine is widely limited because of insufficient delivery into cells. This article proposes a new delivery strategy of nucleic acid fragments into cells as components of TiO2-based nanocomposites. For the first time, unmodified Dz molecules were non-covalently immobilized on TiO2 nanoparticles precovered with polylysine (TiO2•PL) with the formation of (TiO2•PL)•Dz nanocomposites. DNAzymes in the proposed nanocomposites were shown to retain their ability to cleave the RNA target in a cell-free system with the same selectivity as unbound Dz molecules. It was shown by confocal laser microscopy that the fluorescein-labelled (TiO2•PL)•DzFlu nanocomposites penetrate into eukaryotic cells, where DzFlu is internalized in the cytoplasm and predominantly in nuclei. Delivery of deoxyribozymes into cells in the proposed nanocomposites permits very efficient interactions with RNA targets inside cells. This was demonstrated by an example of inhibition of H5N1 influenza A virus replication (inhibition by a factor of ca. 3000). This effect was one order of magnitude higher than with using lipofectamine as the transfection agent. The proposed (TiO2•PL)•Dz nanocomposites demonstrated high antiviral activity and are thus potent as nucleic-acid-based drugs.


[Vestibular dizziness. Differential diagnosis and therapy].
Dizziness includes a wide variety of subjective sensations which are not conclusive as to their localization or pathogenesis. Even in the absence of other symptoms an analysis of dizziness, including consideration not only of its occurrence but also of its quality and course, can suggest several possibilities for differential diagnosis. We differentiate between positional vertigo, permanent vertigo and attacks of dizziness, which may be of long or only short (seconds to few minutes) duration. Based on this classification the differential diagnosis of vestibularly-induced dizziness, which ranges from distinct entities of peripheral disease (acute vestibulopathy, Ménière's disease) to symptomatic forms of peripheral or central pathogenesis, is discussed. The symptomatic medical treatment of vestibular dizziness is based on sedation of the central vestibular system. Translabyrinthine vestibular neurectomy is the treatment of choice for drug resistant Ménière's disease with a high frequency of attacks.


Development of an Internet-based system to guide and telemonitor hearing aid users.
To develop and verify the usability of an internet-based system for telemonitoring and guidance of the hearing aid user as well as monitoring the long-term performance in a pilot group. The system "I can hear, but I can't understand" was developed based on recommendations in the literature regarding layout, design, and content for guidance and advice. Three stages were followed: planning, design and content development, and pilot testing. The sample consisted of 43 adults and older adults with any type and degree of hearing loss, who had been regularly using a hearing aid for at least 30 days and at most 24 months, with reading skills and no evidence of cognitive impairments. The individuals were followed up for 8 to 12 months. The users' performance was monitored with the Speech, Spatial and Qualities of Hearing Scale. The usability of this material was assessed with the System Usability Scale. Improved performance and increased self-reported daily use of the hearing aid were observed after the period of guidance and telemonitoring via the system for all research participants. In all analyzes of the SUS scale, it was possible to observe a performance superior to 70 points, demonstrating good usability of the system. In the analysis of the performance of the SSQ, in the three moments of the research, a positive response was observed in all domains, thus showing progress in the use of hearing aids, with significant data for the domain of Hearing Speech. The system "I can hear, but I can't understand" proved to be an easy-to-use and effective tool to telemonitor hearing aid users.


Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining.
To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms. The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranking the drug families known to be true adverse drug reactions above those that are not. This was not the case without the inclusion of the candidate confounding interaction terms, where confounding leads to a non-adverse drug reaction being ranked highest. The methodology is efficient, can identify high-order confounding interactions and does not require expert input to specify outcome specific confounders, so it can be applied for any outcome of interest to quickly refine its signals. The proposed method shows excellent potential to overcome some forms of confounding and therefore reduce the false positive rate for signal analysis using longitudinal data.


On the Applicability of Quantum Machine Learning.
In this article, we investigate the applicability of quantum machine learning for classification tasks using two quantum classifiers from the Qiskit Python environment: the variational quantum circuit and the quantum kernel estimator (QKE). We provide a first evaluation on the performance of these classifiers when using a hyperparameter search on six widely known and publicly available benchmark datasets and analyze how their performance varies with the number of samples on two artificially generated test classification datasets. As quantum machine learning is based on unitary transformations, this paper explores data structures and application fields that could be particularly suitable for quantum advantages. Hereby, this paper introduces a novel dataset based on concepts from quantum mechanics using the exponential map of a Lie algebra. This dataset will be made publicly available and contributes a novel contribution to the empirical evaluation of quantum supremacy. We further compared the performance of VQC and QKE on six widely applicable datasets to contextualize our results. Our results demonstrate that the VQC and QKE perform better than basic machine learning algorithms, such as advanced linear regression models (Ridge and Lasso). They do not match the accuracy and runtime performance of sophisticated modern boosting classifiers such as XGBoost, LightGBM, or CatBoost. Therefore, we conclude that while quantum machine learning algorithms have the potential to surpass classical machine learning methods in the future, especially when physical quantum infrastructure becomes widely available, they currently lag behind classical approaches. Our investigations also show that classical machine learning approaches have superior performance classifying datasets based on group structures, compared to quantum approaches that particularly use unitary processes. Furthermore, our findings highlight the significant impact of different quantum simulators, feature maps, and quantum circuits on the performance of the employed quantum estimators. This observation emphasizes the need for researchers to provide detailed explanations of their hyperparameter choices for quantum machine learning algorithms, as this aspect is currently overlooked in many studies within the field. To facilitate further research in this area and ensure the transparency of our study, we have made the complete code available in a linked GitHub repository.


A filter-rectify-filter model of the tactile perception of 3D-printed, texture-defined form.
We show that a two-stage filter-rectify-filter (FRF) model, previously used to explain the visual perception of texture-defined form, can also account for the tactile perception of texture-defined form. This result is interesting because, first, relatively little is known about the neural mechanisms of tactile form perception, and second, the generalization of the model may reflect a canonical computation at work in both visual and somatosensory cortex. We 3D-printed test objects comprising a regular, rectangular array of raised, oriented bars measuring 0.75 × 0.75 × 3 mm (width × height × length) that were centre-to-centre spaced by 4 mm. Bars on the left-hand-side of a test object were horizontal, and those on the right were vertical, thus defining a texture boundary. We independently jittered the orientations of bars by drawing random numbers from a uniform distribution; across trials, we systematically increased jitter from 0° (i.e., no jitter) to ±90° (i.e., no boundary). Blindfolded participants (n = 25) used the preferred index finger pad to actively scan objects for 10 seconds before reporting the texture boundary's orientation (vertical or horizontal; randomised across trials). Results showed a threshold jitter of ±52.7° (i.e., the jitter at which the boundary orientation was only just discriminable). Computational modelling indicated that the first stage of the FRF model is a Gabor function tuned to spatial frequency = 0.23 cycles per mm with extent = 2.53 mm (full-width at half-maximum). We discuss this result with regard to neuronal receptive field structure in non-human primate somatosensory cortex.


FaTEMa: A Framework for Multi-Layer Fault Tolerance in IoT Systems.
Fault tolerance in IoT systems is challenging to overcome due to its complexity, dynamicity, and heterogeneity. IoT systems are typically designed and constructed in layers. Every layer has its requirements and fault tolerance strategies. However, errors in one layer can propagate and cause effects on others. Thus, it is impractical to consider a centralized fault tolerance approach for an entire system. Consequently, it is vital to consider multiple layers in order to enable collaboration and information exchange when addressing fault tolerance. The purpose of this study is to propose a multi-layer fault tolerance approach, granting interconnection among IoT system layers, allowing information exchange and collaboration in order to attain the property of dependability. Therefore, we define an event-driven framework called FaTEMa (Fault Tolerance Event Manager) that creates a dedicated fault-related communication channel in order to propagate events across the levels of the system. The implemented framework assist with error detection and continued service. Additionally, it offers extension points to support heterogeneous communication protocols and evolve new capabilities. Our empirical results show that introducing FaTEMa provided improvements to the error detection and error resolution time, consequently improving system availability. In addition, the use of Fatema provided a reliability improvement and a reduction in the number of failures produced.


Higher susceptibility of the ventral versus the dorsal hippocampus and the posteroventral versus anterodorsal amygdala to soman-induced neuropathology.
Nerve agents are acetylcholinesterase inhibitors, exposure to which causes brain damage, primarily by inducing intense seizure activity. Knowledge of the brain regions that are most vulnerable to nerve agent-induced brain damage can facilitate the development of drugs targeting the protection of these regions. Both the amygdala and the hippocampus have been shown to suffer significant damage after nerve agent exposure, but the amygdala appears to be the more severely affected structure. However, damage in the amygdala has generally been compared with damage in the dorsal hippocampus, whereas there is evidence that the ventral hippocampus is significantly more susceptible to seizures than the dorsal region and, therefore, it may also be more susceptible to nerve agent-induced neuropathology. Here, we report that after status epilepticus induced by soman administration to rats, neuronal degeneration as assessed by Fluoro-Jade C staining was more extensive in the ventral than the dorsal hippocampal subfields, 1 day after soman exposure. Seven days later, the difference between dorsal and ventral regions was not statistically significant. In the amygdala, soman-induced neurodegeneration was more severe in the posteroventral regions of the lateral, basolateral, and medial nuclei compared to the anterodorsal regions of these nuclei. In contrast, the basomedial nucleus was more severely affected in the anterodorsal region. The extent of neurodegeneration in the amygdala was not significantly different from that in the ventral hippocampus. However, when compared with the whole hippocampus, the amygdala displayed more severe neurodegeneration, on both day 1 and day 7 after soman exposure. Testing the protective efficacy of drugs against nerve agent-induced brain damage should include examination of the ventral hippocampus and the posteroventral regions of the amygdala, as these areas are most vulnerable to nerve agent-induced neurodegeneration.


Enhancing the sensitivity and stability of electrochemical aptamer-based sensors by AuNPs@MXene nanocomposite for continuous monitoring of biomarkers.
Electrochemical aptamer-based (E-AB) sensors offer exciting potential for real-time tracking of various biomarkers, such as proteins and small molecules, due to their exceptional selectivity and adaptability. However, most E-AB sensors rely on planar gold structures, which inherently limit their sensitivity and operational stability for continuous monitoring of biomarkers. Although gold nanostructures have recently enhanced E-AB sensor performance, no studies have explored the combination of gold nanostructure with other types of nanomaterials for continuous molecular monitoring. To fill this gap, we employed gold nanoparticles and MXene Ti3C2 (AuNPs@MXene), a versatile nanocomposite, in designing an E-AB sensor targeted at vascular endothelial growth factor (VEGF), a crucial human signaling protein. Remarkably, the AuNPs@MXene nanocomposite achieved over thirty-fold and half-fold increases in active surface area compared to bare and AuNPs-modified gold electrodes, respectively, significantly elevating the analytical capabilities of E-AB sensors during continuous operation. After a systematic optimization and characterization process, the newly developed E-AB sensor, powered by AuNPs@MXene nanocomposite, demonstrated both enhanced stability and heightened sensitivity. Overall, our findings open new avenues for the incorporation of nanocomposites in E-AB sensor design, enabling the creation of more sensitive and durable real-time monitoring systems.


Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry-sponsored clinical trials.
In this paper we set out what we consider to be a set of best practices for statisticians in the reporting of pharmaceutical industry-sponsored clinical trials. We make eight recommendations covering: author responsibilities and recognition; publication timing; conflicts of interest; freedom to act; full author access to data; trial registration and independent review. These recommendations are made in the context of the prominent role played by statisticians in the design, conduct, analysis and reporting of pharmaceutical sponsored trials and the perception of the reporting of these trials in the wider community.


Morphological appearance of epidermal cells cultured on fibroblast-reorganized collagen gels.
Human foreskin fibroblasts were used to reorganize hydrated collagen gels into a dermal-like matrix, after which freshly isolated keratinocytes isolated from rabbit ear skin were placed on the surfaces of the matrices and cultured for up to 12 days. Transmission electron microscopy revealed 8-12 cell layers of epidermal cells organized in three distinct strata. The basal stratum consisted of cuboidal to columnar cells with typical complement of organelles, oval nuclei, and prominent tonofilaments inserting into desmosomes. Mitotic cells often were found at this level. There was no well-defined basement membrane region; rather, many of the cells appeared to be in close contact with collagen fibrils. The intermediate stratum of suprabasal cells consisted of elongated cells that had reduced organelles, but still were connected to each other by desmosomes. Finally, the superficial stratum of suprabasal cells contained cells that were completely flattened and often appeared to be sloughing off the apical surfaces of the cultures. Indirect immunofluorescence studies carried out on frozen sections revealed bullous pemphigoid antigen associated with basal epidermal cells; pemphigus vulgaris antigen around the epidermal cells of all strata, and keratin present in the epidermal cells of all strata. Filaggrin was observed in punctate and fibrillar arrangements in suprabasal cells. Fibronectin was found in a linear deposit at the dermal-epidermal junction and around the fibroblasts in the reorganized collagen gels. Type-IV collagen and laminin, however, were not detected.


Intradermal Scalp Closure Using Barbed Suture in Cranial Tumor Surgeries: A Technical Note.
Traditional scalp closure technique following elective craniotomy involves placement of staples or a continuous running suture. Despite low complication rates, these techniques are often considered to be disfiguring by patients, contribute to the psychosocial trauma of brain surgery, and are associated with discomfort during postoperative staple or suture removal. Some authors have described scalp closure using intradermal absorbable suture, but this technique likely does not reach the tensile strength of closure using traditional methods, and requires knots at the apices of the incision, which can act as a nidus for infection. We employed a barbed intradermal closure method in supratentorial elective craniotomies for tumor resection. Complication rates were recorded, and cosmetic outcomes were informally assessed. Intradermal closure with barbed sutures was utilized in 76 patients. At the 2-wk postoperative clinic visit, cosmetic outcomes were excellent in all cases. There was 1 superficial wound infection that presented 6 wk after a pterional craniotomy for low-grade glioma. This resolved with superficial wound revision and oral antibiotic therapy. We present a novel scalp closure technique for craniotomies using intradermal barbed Monocryl suture. We have had excellent cosmetic outcomes, and the infection rate of 1.3% compares favorably to published rates. Further studies are required to quantify the improvement in patient satisfaction compared to conventional closure methods.


Modification of isoflavones in soybean seeds via expression of multiple phenolic biosynthetic genes.
To modify the level and composition of isoflavones, the important bioactive constituents of soybean seeds, soybean was transformed via co-bombardment of embryogenic cultures with three DNA cassettes containing the CHS6-chalcone synthase and IFS2-isoflavone synthase genes, and a fragment of PAL5-phenylalanine ammonia-lyase gene, all in sense orientation under the lectin promoter mixed with the selectable marker gene, HPT (hygromycin phosphotransferase) under the 35S promoter. Four of six fertile lines produced integrated all four genes. Isoflavone levels were lower in T1 mature seeds of 5 of the 6 lines compared to the control. Transgene segregation was found in one selected line, with formation of additional sublines with different transgene composition found also in the homozygous plants. Decreased isoflavone concentrations (by about 70%) were found in T4 homozygous seeds of the two lines studied in detail here. The embryo axes accumulated most of the glycitein and contained a higher isoflavone concentration than the cotyledons. Expression of transgenes driven by the lectin promoter reduced the isoflavone concentration only in the cotyledons and not in embryo axes, indicating that this promoter is preferably active in cotyledons.


Immunohistochemical expression of perforin in adult systemic lupus erythematosus associated macrophage activation syndrome: Clinicohematological correlation and literature review.
To study the bone marrow (BM) immunohistomorphological characteristics in adult systemic lupus erythematosus (SLE) associated macrophage activation syndrome (SLE-MAS). Immunohistochemical (IHC) expression of CD3, CD8, perforin (PFN), and CD163 was studied on BM trephine biopsies from 30 cytopenic adult SLE cases (male: female = 1:5, age; 24 years, range; 19-32) and compared them with ten age matched controls. Clinicopathological parameters were compared among the cases likely (L) or unlikely (U) to have MAS using probability scoring criteria. The best cut off laboratory parameters to discriminate between the two were obtained through receiver operator curve (ROC) analysis. MAS occurred in 12/30 (40%) cases and was more commonly associated with prior immunosuppressive therapy (p = .07), ≥ 3 system involvement (p = .09), lower fibrinogen (p < .01), increased triglyceride (p = .002), increased BM hemophagocytosis (p = .002), and higher MAS score [185 (176-203) vs. 105 (77-119), p < .01] than MAS-U subgroup. Although PFN+CD8+ T lymphocytes significantly decreased among cases than controls (p < .05), it was comparable between MAS-L and MAS-U subgroups. Fibrinogen (< 2.4 g/L, AUC; 0.93, p < .01), hemophagocytosis score (> 1.5, AUC; 0.71, p = .03), and an MAS probability score of ≥ 164 (AUC; 1, p < .01) discriminated MAS from those without MAS. We noted a decrease in perforin mediated CD8 + T cell cytotoxicity in SLE. Immunohistochemical demonstration of the same along with histiocytic hemophagocytosis on BM biopsy may be useful adjunct in early diagnosis and management of MAS in SLE.


Modular 'click' sensors for zinc and their application in vivo.
Although the central role that zinc plays in many biological processes and important disease states is now well-established, there remains a pressing need to develop an absolute understanding of the underlying biology of zinc trafficking in terms of its dynamic and quantitative processing in specific organelles. Here we describe the modular synthesis of zinc sensors using a 'click' approach and demonstrate the applicability of our new sensors in vivo using a zebrafish model.


How to educate prescribers in antimicrobial stewardship practices.
Widespread antimicrobial use has compromised its value, leading to a crisis of antimicrobial resistance. A major cause of misuse is insufficient knowledge of prescribing of antimicrobials in many categories of professionals. An important principle of antimicrobial stewardship is avoiding selection pressure in the patient, both on pathogen and commensal by avoiding unnecessary use, choosing the least broad-spectrum antibiotic, adequate doses, a good timing and the shortest possible duration. Up to now, most educational efforts have been targeted at professionals (mostly medical doctors) after their training and at the adult public. In the past few years, progress has been made in educating children. It is now crucial that academia and ministries of Health and Education jointly focus on an adapted undergraduate medical/professional curriculum that teaches all necessary principles of microbiology, infectious diseases and clinical pharmacology, with emphasis on the principles of prudent prescribing.


Manipulating and Monitoring On-Surface Biological Reactions by Light-Triggered Local pH Alterations.
Significant research efforts have been dedicated to the integration of biological species with electronic elements to yield smart bioelectronic devices. The integration of DNA, proteins, and whole living cells and tissues with electronic devices has been developed into numerous intriguing applications. In particular, the quantitative detection of biological species and monitoring of biological processes are both critical to numerous areas of medical and life sciences. Nevertheless, most current approaches merely focus on the "monitoring" of chemical processes taking place on the sensing surfaces, and little efforts have been invested in the conception of sensitive devices that can simultaneously "control" and "monitor" chemical and biological reactions by the application of on-surface reversible stimuli. Here, we demonstrate the light-controlled fine modulation of surface pH by the use of photoactive molecularly modified nanomaterials. Through the use of nanowire-based FET devices, we showed the capability of modulating the on-surface pH, by intensity-controlled light stimulus. This allowed us simultaneously and locally to control and monitor pH-sensitive biological reactions on the nanodevices surfaces, such as the local activation and inhibition of proteolytic enzymatic processes, as well as dissociation of antigen-antibody binding interactions. The demonstrated capability of locally modulating the on-surface effective pH, by a light stimuli, may be further applied in the local control of on-surface DNA hybridization/dehybridization processes, activation or inhibition of living cells processes, local switching of cellular function, local photoactivation of neuronal networks with single cell resolution and so forth.


Damage control resuscitation for vascular surgery in a combat support hospital.
Hemorrhage from extremity wounds is a leading cause of potentially preventable death during modern combat operations. Optimal management involves rapid hemostasis and reversal of metabolic derangements utilizing damage control principles. The traditional practice of damage control surgery favors a life over limb approach and discourages elaborate, prolonged vascular reconstructions. We hypothesized that limb preservation could be successful when the damage control approach combines advanced resuscitative strategies and modern vascular techniques. Trauma Registry records at a Combat Support Hospital from April to June 2006 were retrospectively reviewed. Patients with life-threatening hemorrhage (defined as >4 units of packed red blood cells) who underwent simultaneous revascularization for a pulseless extremity were included. Data collection included the initial physiologic parameters in the emergency department (ED), total and 24-hour blood product requirements, and admission physiology and laboratory values in the intensive care unit (ICU). Outcome measures were survival, graft patency, and amputation rate at 7 days. Sixteen patients underwent 20 vascular reconstructions for upper (3) or lower extremity (17) wounds. Patients were hypotensive (blood pressure 105/60 +/- 29/18), acidotic (pH 7.27 +/- 0.1; BD -7.50 +/- 5.5), and coagulopathic (international normalized ratio 1.3 +/- 0.4) on arrival to the ED and essentially normal upon admission to the ICU, 4 hours later. Vein grafts (19/20, 95%) were used preferentially. Prosthetic grafts (1), shunting and delayed repair (4) or amputation (1) were infrequent. Heparin was not used or limited to a half dose (5/20, 25%). Tourniquets (12/16, 75%) and fasciotomies (13/16, 81%) were routine. Most (75%) received recombinant factor VIIa in the ED and in the operating room. All survived with normalized physiology on arrival in the ICU. Twenty-four-hour crystalloid use averaged 7.1 +/- 3.2 L, whereas packed red blood cells averaged 23 +/- 18 units, and 88% were massively transfused. Median operative time was 4.5 hours (range, 1.7-8.4 hours). Aggressive damage control resuscitation maneuvers in critically injured casualties successfully permitted prolonged, complex extremity revascularization with excellent early limb salvage and graft patency. Recombinant VIIa and liberal resuscitation with fresh whole blood, plasma, platelets and cryoprecipitate, while minimizing crystalloid, allowed limb salvage and did not result in early graft failures.


Coculture of peripheral blood-derived mesenchymal stem cells and endothelial progenitor cells on strontium-doped calcium polyphosphate scaffolds to generate vascularized engineered bone.
Vascularization of engineered bone tissue is critical for ensuring its survival after implantation and it is the primary factor limiting its clinical use. A promising approach is to prevascularize bone grafts in vitro using endothelial progenitor cells (EPC) derived from peripheral blood. Typically, EPC are added together with mesenchymal stem cells (MSC) that differentiate into osteoblasts. One problem with this approach is how to promote traditional tissue engineering bone survival with a minimally invasive method. In this study, we examined the effectiveness of administering to stimulate the release of peripheral blood stem cells and their co-culturing system for generating prevascularized engineered bone. Cells were isolated by Ficoll density gradient centrifugation and identified as EPC and MSC based on morphology, surface markers, and functional analysis. EPC and MSC were cocultured in several different ratios, and cell morphology and tube formation were assessed by microscopy. Expression of osteogenesis and vascularization markers was quantified by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction, and histochemical and immunofluorescence staining. Increasing the proportion of EPC in the coculture system led to greater tube formation and greater expression of the endothelial cell marker CD31. An EPC:MSC ratio of 75:25 gave the highest expression of osteogenesis and angiogenesis markers. Cocultures adhered to a three-dimensional scaffold of strontium-doped calcium polyphosphate and proliferated well. Our findings show that coculturing peripheral blood-derived EPC and MSC may prove useful for generating prevascularized bone tissue for clinical use.


Observed trends in the magnitude and persistence of monthly temperature variability.
Climate variability is critically important for nature and society, especially if it increases in amplitude and/or fluctuations become more persistent. However, the issues of whether climate variability is changing, and if so, whether this is due to anthropogenic forcing, are subjects of ongoing debate. Increases in the amplitude and persistence of temperature fluctuations have been detected in some regions, e.g. the North Pacific, but there is no agreed global signal. Here we systematically scan monthly surface temperature indices and spatial datasets to look for trends in variance and autocorrelation (persistence). We show that monthly temperature variability and autocorrelation increased over 1957-2002 across large parts of the North Pacific, North Atlantic, North America and the Mediterranean. Furthermore, (multi)decadal internal climate variability appears to influence trends in monthly temperature variability and autocorrelation. Historically-forced climate models do not reproduce the observed trends in temperature variance and autocorrelation, consistent with the models poorly capturing (multi)decadal internal climate variability. Based on a review of established spatial correlations and corresponding mechanistic 'teleconnections' we hypothesise that observed slowing down of sea surface temperature variability contributed to observed increases in land temperature variability and autocorrelation, which in turn contributed to persistent droughts in North America and the Mediterranean.


Single-molecule fluorescence-based approach reveals novel mechanistic insights into human small heat shock protein chaperone function.
Small heat shock proteins (sHsps) are a family of ubiquitous intracellular molecular chaperones; some sHsp family members are upregulated under stress conditions and play a vital role in protein homeostasis (proteostasis). It is commonly accepted that these chaperones work by trapping misfolded proteins to prevent their aggregation; however, fundamental questions regarding the molecular mechanism by which sHsps interact with misfolded proteins remain unanswered. The dynamic and polydisperse nature of sHsp oligomers has made studying them challenging using traditional biochemical approaches. Therefore, we have utilized a single-molecule fluorescence-based approach to observe the chaperone action of human alphaB-crystallin (αBc, HSPB5). Using this approach we have, for the first time, determined the stoichiometries of complexes formed between αBc and a model client protein, chloride intracellular channel 1. By examining the dispersity and stoichiometries of these complexes over time, and in response to different concentrations of αBc, we have uncovered unique and important insights into a two-step mechanism by which αBc interacts with misfolded client proteins to prevent their aggregation.


[Treatment of dissecting aneurysms of renal artery. Report of four cases (author's transl)].
The localized dissection of visceral arteries, renal arteries in particular, is less frequent than the extension forward the visceral arteries of aneurysms of the abdominal aorta which are well known. Reporting on four cases within their own personal experience, the authors present their commentaries and insist upon the necessity of early diagnosis which, thanks to an adapted surgical treatment, permits protection of these patients from the complications inherent in this reno-vascular pathology.


Longitudinal Analysis of Mental Disorder Burden Among Elderly Patients With Gastrointestinal Malignancies.
Patients with cancer are at high risk for having mental disorders, resulting in widespread psychosocial screening efforts. However, there is a need for population-based and longitudinal studies of mental disorders among patients who have gastrointestinal cancer and particular among elderly patients. We used the SEER-Medicare database to identify patients aged ≥65 years with colorectal, pancreatic, gastric, hepatic/biliary, esophageal, or anal cancer. Earlier (12 months before or up to 6 months after cancer diagnosis) and subsequent mental disorder diagnoses were identified. Of 112,283 patients, prevalence of an earlier mental disorder was 21%, 23%, 20%, 20%, 19%, and 26% for colorectal, pancreatic, gastric, hepatic/biliary, esophageal, and anal cancer, respectively. An increased odds of an earlier mental disorder was associated with pancreatic cancer (odds ratio [OR], 1.17; 95% CI, 1.11-1.23), esophageal cancer (OR, 1.10; 95% CI, 1.02-1.18), and anal cancer (OR, 1.17; 95% CI, 1.05-1.30) compared with colorectal cancer and with having regional versus local disease (OR, 1.09; 95% CI, 1.06-1.13). The cumulative incidence of a subsequent mental disorder at 5 years was 19%, 16%, 14%, 13%, 12%, and 10% for patients with anal, colorectal, esophageal, gastric, hepatic/biliary, and pancreatic cancer, respectively. There was an association with having regional disease (hazard ratio [HR], 1.08; 95% CI, 1.04-1.12) or distant disease (HR, 1.36; 95% CI, 1.28-1.45) compared with local disease and the development of a mental disorder. Although the development of a subsequent mental disorder was more common among patients with advanced cancers, there continued to be a significant number of patients with earlier-stage disease at risk. This study suggests a larger role for incorporating psychiatric symptom screening and management throughout oncologic care.


Altered circadian rhythms in a mouse model of neurodevelopmental disorders based on prenatal maternal immune activation.
Individuals with neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder, exhibit various sleep and circadian rhythm disturbances that often persist and worsen throughout the lifespan. To study the interaction between circadian rhythm disruption and neurodevelopmental disorders, we utilized a mouse model based on prenatal maternal immune activation (MIA). We hypothesized that MIA exposure would lead to impaired circadian locomotor activity rhythms in adult mouse offspring. We induced MIA by injecting pregnant dams with polyinosinic:polycytidylic acid (poly IC) at embryonic day 9.5, then aged resulting offspring to adulthood. We first confirmed that poly IC injection in pregnant dams elevated plasma levels of pro- and anti-inflammatory cytokines and chemokines. We then placed adult offspring in running wheels and subjected them to various lighting conditions. Overall, poly IC-exposed male offspring exhibited altered locomotor activity rhythms, reminiscent of individuals with neurodevelopmental disorders. In particular, we report increased (subjective) day activity across 3 different lighting conditions: 12 h of light, 12 h of dark (12:12LD), constant darkness (DD) and constant light. Further data analysis indicated that this was driven by increased activity in the beginning of the (subjective) day in 12:12LD and DD, and at the end of the day in 12:12LD. This effect was sex-dependent, as in utero poly IC exposure led overall to much milder alterations in locomotor activity rhythms in female offspring than in male offspring. We also confirmed that the observed behavioral impairments in adult poly IC-exposed offspring were not due to differences in maternal behavior. These data further our understanding of the link between circadian rhythm disruption and neurodevelopmental disorders and may have implications for mitigating risk to the disorders and/or informing the development of circadian-based therapies.


[Pulmonary varicosity, a rare reason of solitary nodule].
Pulmonary varicosity is a very rare entity. Beside congenital varices, most combined with other malformations of the pulmonary vessels, varicosities are described above all in connection with mitral insufficiency. Most cases with pulmonary varicosity are diagnosed by chance, because of absence of any symptoms or only slight symptoms respectively. We demonstrate our own case with respect to the diagnostic requirements (computerized tomography, multi-slice CT) and the differential diagnostic aspects.


Simultaneous creatine and phosphocreatine mapping of skeletal muscle by CEST MRI at 3T.
To confirm that CrCEST in muscle exhibits a slow-exchanging process, and to obtain high-resolution amide, creatine (Cr), and phosphocreatine (PCr) maps of skeletal muscle using a POlynomial and Lorentzian Line-shape Fitting (PLOF) CEST at 3T. We used dynamic changes in PCr/CrCEST of mouse hindlimb before and after euthanasia to assign the Cr and PCr CEST peaks in the Z-spectrum at 3T and to obtain the optimum saturation parameters. Segmented 3D EPI was employed to obtain multi-slice amide, PCr, and Cr CEST maps of human skeletal muscle. Subsequently, the PCrCEST maps were calibrated using the PCr concentrations determined by 31 P MRS. A comparison of the Z-spectra in mouse hindlimb before and after euthanasia indicated that CrCEST is a slow-exchanging process in muscle (<150.7 s-1 ). This allowed us to simultaneously extract PCr/CrCEST signals at 3T using the PLOF method. We determined optimal B1 values ranging from 0.3 to 0.6 μT for CrCEST in muscle and 0.3-1.2 μT for PCrCEST. For the study on human calf muscle, we determined an optimum saturation time of 2 s for both PCr/CrCEST (B1 = 0.6 μT). The PCr/CrCEST using 3D EPI were found to be comparable to those obtained using turbo spin echo (TSE). (3D EPI/TSE PCr: (2.6 ± 0.3) %/(2.3 ± 0.1) %; Cr: (1.3 ± 0.1) %/(1.4 ± 0.07) %). Our study showed that in vivo CrCEST is a slow-exchanging process. Hence, amide, Cr, and PCr CEST in the skeletal muscle can be mapped simultaneously at 3T by PLOF CEST.


Antigenic interrelationship between endoflagella of Treponema phagedenis biotype Reiter and Treponema pallidum (Nichols): molecular characterization of endoflagellar proteins.
Purified endoflagella from nonpathogenic Treponema phagedenis biotype Reiter were characterized biochemically and compared antigenically with the endoflagellar proteins of Treponema pallidum. T. phagedenis biotype Reiter endoflagella were dissociated into constituent polypeptides by incubation under conditions which disrupt noncovalent bonds. Chymotrypsin peptide maps of T. phagedenis biotype Reiter endoflagellar proteins revealed that the 37- and 33-kilodalton (kDa) major components shared significant homology with the 27- and 30-kDa minor components, respectively. The peptide maps also suggested that the major components shared a lesser degree of structural similarity with each other. These relationships were confirmed by Western blots of T. phagedenis biotype Reiter endoflagellar proteins employing antibodies that were purified against the individual endoflagellar polypeptides. Western blots of T. pallidum with the purified antibodies also demonstrated strong cross-reactivity between the T. phagedenis biotype Reiter endoflagellar proteins and T. pallidum proteins of identical or similar molecular weights. A unique Western blotting technique that we called epitope bridging was used to determine that the 37-kDa subunit contains most of the external epitopes on T. phagedenis biotype Reiter endoflagella. Immunoelectron microscopy with human syphilitic serum and rabbit T. phagedenis biotype Reiter endoflagellar antiserum confirmed the presence of cross-reactive epitopes on the surface of intact T. phagedenis and T. pallidum endoflagella.


[Immunological changes in patients with pulmonary tuberculosis during glutoxim therapy].
The paper deals with the effect of glutoxim included into a preoperative preparation regimen on immunological parameters in patients with fibrocavernous pulmonary tuberculosis. On admission, all the patients had inadequate cellular immunity and activated humoral immunity. After termination of a course of glutoxim therapy, there was an increase in the baseline low values of lymphocytic proliferative activity, in the count of mature T lymphocytes, and in the production of IL-2 induced by phytohemagglutinin. At the same time the similar parameters remained unchanged in the control group. The drug exerted the most noticeable stimulating effect on cellular immunity in patients with a limited process. Glutoxim produced no noticeable effect on humoral immunity. The immunomodulating effect of glutoxim was followed by improvement of the clinical and X-ray pictures of the disease. In glutoxim-treated patients with baseline immunological disorders, progression was found to occur 1.5-2 times more infrequently than in the control group. Indications for the use of glutoxim in the treatment of tuberculosis are specified on the basis of the baseline immunological parameters of each patient.


[Informing psychiatric patients about medication - results of a query].
Physicians are obliged to inform all patients about the purpose and risks of therapeutic procedures, also drug treatment. However, although there may be some severe difficulties in informing psychiatric patients only very few data concerning this topic are available as yet. Thus, the aim of this query was to evaluate the patients' opinion of the information about medication. In this investigation 255 psychiatric inpatients were asked to complete a questionnaire. 42 % of the patients complained about no or insufficient information of the expected effects of the prescribed medication and 62 % about no or insufficient information of side-effects. An association was found between the willingness to take the medication for a long time and insight in their psychic condition, but not with satisfying informing. This query showed the need of a more precise and satisfying information on medication and the need to develop strategies for a better information about side-effects.


[Present state of female urology].
This chapter critically reviews the literature on surgery for stress urinary incontinence (SUI) and pelvic organ prolapse (POP), and medical treatment for overactive bladder in women. The midurethral polypropylene sling was reported to provide a durable option with significant improvement. The tension-free vaginal tape (TVT) procedure is based on a theory of pathophysiology of stress incontinence presented by Petros and Ulmsten. In their "integral theory" impairment of the pubourethral ligament is one of the primary cause of SUI. The transobturator sling was found to be effective in SUI patients with less incidence of perioperative complications and voiding difficulties. Prolapse of the uterus/vaginal apex and posterior vaginal wall may also be found in women with stress incontinence. There are many procedures for the correction of POP. Transvaginal repair of anterior and posterior compartment prolapse with polypropylene mesh has been developed in recent years. It is necessary to assess and compare the current quality of outcomes.


Professional experiences of international medical graduates practicing primary care in the United States.
International medical graduates (IMGs) comprise approximately 25% of the US physician workforce, with significant representation in primary care and care of vulnerable populations. Despite the central role of IMGs in the US healthcare system, understanding of their professional experiences is limited. To characterize the professional experiences of non-US born IMGs from limited-resource nations practicing primary care in the US. Qualitative study based on in-depth in-person interviews. Purposeful sample of IMGs (n = 25) diverse in country of origin, length of practice in the US, specialty (internal medicine, family medicine and pediatrics), age and gender. Participants were currently practicing primary care physicians in New York, New Jersey or Connecticut. A standardized interview guide was used to explore professional experiences of IMGs. Four recurrent and unifying themes characterize these experiences: 1) IMGs experience both overt and subtle forms of workplace bias and discrimination; 2) IMGs recognize professional limitations as part of "the deal"; 3) IMGs describe challenges in the transition to the culture and practice of medicine in the US; 4) IMGs bring unique skills and advantages to the workplace. Our data reveal that IMGs face workplace challenges throughout their careers. Despite diversity in professional background and demographic characteristics, IMGs in our study reported common experiences in the transition to and practice of medicine in the US. Findings suggest that both workforce and workplace interventions are needed to enable IMG physicians to sustain their essential and growing role in the US healthcare system. Finally, commonalities with experiences of other minority groups within the US healthcare system suggest that optimizing IMGs' experiences may also improve the experiences of an increasingly diverse healthcare workforce.


ORIS Criteria of Success for the Zygoma-Related Rehabilitation: The (Revisited) Zygoma Success Code.
Zygomatic-related implant rehabilitation differs from traditional implant treatment in biomechanics, clinical procedures, outcomes, and eventual complications such as soft tissue incompetence or recession that may lead to recurrent sinus/soft tissue complications. The extreme maxillary atrophy that indicates the use of zygomatic implants prevents use of conventional criteria to describe implant success/failure. Currently, results and complications of zygomatic implants reported in the literature are inconsistent and lack a standardized systematic review. Moreover, protocols for the rehabilitation of the atrophic maxilla using zygomatic implants have been in continuous evolution. The current zygomatic approach is relatively new, especially if the head of the zygomatic implant is located in an extramaxillary area with interrupted alveolar bone around its perimeter. Specific criteria to describe success/survival of zygomatic implants are necessary, both to write and to read scientific literature related to zygomatic implant-based oral rehabilitations. The aim of this article was to review the criteria of success used for traditional and zygomatic implants and to propose a revisited Zygomatic Success Code describing specific criteria to score the outcome of a rehabilitation anchored on zygomatic implants. The ORIS acronym is used to name four specific criteria to systematically describe the outcome of zygomatic implant rehabilitation: offset measurement as evaluation of prosthetic positioning; rhino-sinus status report based on a comparison of presurgical and postsurgical cone beam computed tomography in addition to a clinical questionnaire; infection permanence as evaluation of soft tissue status; and stability report, accepting as success some mobility until dis-osseointegration signs appear. Based on these criteria, the assessment of five possible conditions when evaluating zygomatic implants is possible.


The role and pathway of VQ family in plant growth, immunity, and stress response.
This review provides a detailed description of the function and mechanism of VQ family gene, which is helpful for further research and application of VQ gene resources to improve crops. Valine-glutamine (VQ) motif-containing proteins are a large class of transcriptional regulatory cofactors. VQ proteins have their own unique molecular characteristics. Amino acids are highly conserved only in the VQ domain, while other positions vary greatly. Most VQ genes do not contain introns and the length of their proteins is less than 300 amino acids. A majority of VQ proteins are predicted to be localized in the nucleus. The promoter of many VQ genes contains stress or growth related elements. Segment duplication and tandem duplication are the main amplification mechanisms of the VQ gene family in angiosperms and gymnosperms, respectively. Purification selection plays a crucial role in the evolution of many VQ genes. By interacting with WRKY, MAPK, and other proteins, VQ proteins participate in the multiple signaling pathways to regulate plant growth and development, as well as defense responses to biotic and abiotic stresses. Although there have been some reports on the VQ gene family in plants, most of them only identify family members, with little functional verification, and there is also a lack of complete, detailed, and up-to-date review of research progress. Here, we comprehensively summarized the research progress of VQ genes that have been published so far, mainly including their molecular characteristics, biological functions, importance of VQ motif, and working mechanisms. Finally, the regulatory network and model of VQ genes were drawn, a precise molecular breeding strategy based on VQ genes was proposed, and the current problems and future prospects were pointed out, providing a powerful reference for further research and utilization of VQ genes in plant improvement.


Expansion of the cytochrome C oxidase subunit I database and description of four new lobose testate amoebae species (Amoebozoa; Arcellinida).
Arcellinida is ascending in importance in protistology, but description of their diversity still presents multiple challenges. Furthermore, applicable tools for surveillance of these organisms are still in developing stages. Importantly, a good database that sets a correspondence between molecular barcodes and species morphology is lacking. Cytochrome oxidase (COI) has been suggested as the most relevant marker for species discrimination in Arcellinida. However, some major groups of Arcellinida are still lacking a COI sequence. Here we expand the database of COI marker sequences for Arcellinids, using single-cell PCR, transcriptomics, and database scavenging. In the present work, we added 24 new Arcellinida COI sequences to the database, covering all unsampled infra- and suborders. Additionally, we added six new SSUrRNA sequences and described four new species using morphological, morphometrical, and molecular evidence: Heleopera steppica, Centropyxis blatta, Arcella uspiensis, and Cylindrifflugia periurbana. This new database will provide a new starting point to address new research questions from shell evolution, biogeography, and systematics of arcellinids.