The relationship between right-wing ideological attitudes and psychological well-being.
The relationship between right-wing ideological attitudes and psychological well-being has been intensively studied. Although some studies supported the hypothesis that right-wing attitudes are negatively related with well-being, other research yielded positive or nonsignificant relationships. We conducted a meta-analysis (total samples = 97, total N = 69,221) of measures of well-being, including positive and negative affect, life satisfaction, self-esteem, and intrinsic goal pursuit. The obtained effect sizes were generally weak and nonsignificant, except for a moderate relationship between intrinsic goal pursuit and social dominance orientation. Our results thus do not support previous theories that claim that right-wing attitudes yield substantial relationships with psychological well-being.


[A preliminary study on the surgical timing of spinal tuberculosis].
To observe the changes of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and nerve function in patients with spinal tuberculosis before and after surgery, explore the timing of surgical intervention, and evaluate its influence on surgical safety. A retrospective analysis was conducted on 387 patients with spinal tuberculosis who received surgical treatment from March 2012 to March 2017, including 278 males and 109 females, aged 12 to 86 years old with an average of (49.9±19.1) years. There were 64 cases of cervical tuberculosis, 86 cases of thoracic tuberculosis, 76 cases of thoracolumbar tuberculosis and 161 cases of lumbar tuberculosis. There were 297 patients with single segmental involvementand 90 patients with multiple segmental involvement. Among them, 62 cases presented neurological damage, and preoperative spinal cord neurological function depended on ASIA grade, 5 cases of grade A, 8 cases of grade B, 39 cases of grade C, and 10 cases of grade D. According to the duration of preoperative antituberculosis treatment, the patients were divided into group A (256 cases, receiving conventional quadruple antituberculosis treatment for 2-4 weeks before surgery) and group B (131 cases, receiving conventional quadruple antituberculosis treatment for more than 4 weeks before surgery). The two groups were compared in terms of gender, age, preoperative complicated pulmonary tuberculosis, lesion site, lesion scope, surgical approach, drug resistance and other general clinical characteristics. ESR, CRP, visual analogue scale(VAS), Oswestry Disability Index (ODI), Frankel grade and postoperative complications were observed. All 387 patients were followed up for 12 to 36 (18.3±4.5) months. There were no significant differences in gender, age, preoperative pulmonary tuberculosis, lesion site, lesion range, surgical approach, preoperative drug resistance and other characteristics between two groups. A total of 32 patients in two groups did not heal after surgery, with an incidence rate of 8.27%. The VAS and spinal cord dysfunction index of the two groups were significantly improved after surgery (P<0.05), but there was no significant difference between two groups at the same time point (P>0.05) . From 1 to 14 days after operation, the neurological function began to gradually recover, and the neurological function grade was increased by 1 to 3 grades. From 3 months after operation to the final follow up, 52 cases recovered completely, 8 cases partially recovered, and 2 cases did not improve. There was no significant difference in ESR and CRP between two groups before admission, 1 month after surgery, and final follow-up (P>0.05). After 2-4 weeks of anti tuberculosis treatment before operation, patients with spinal tuberculosis could be operated upon with ESR and CRP in a descending or stable period. In principle, patients with spinal tuberculosis and paraplegia should be treated as soon as possible after active preoperative management of the complication without emergency surgery.


Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases.
Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.


Photocatalytic degradation of two selected textile dye derivatives, eosine yellowish and p-rosaniline, in aqueous suspensions of titanium dioxide.
Thephotocatalytic degradation of two selected textile dye derivatives, eosine yellowish (1) and p-rosaniline (2) has been investigated in aqueous suspensions of titanium dioxide under a variety of conditions. The degradation was studied by monitoring the change in substrate concentration employing UV spectroscopic technique and decrease in Total Organic Carbon (TOC) content as a function of irradiation time under a variety of conditions. The degradation of the dye was studied under different conditions such as pH, catalyst concentration, substrate concentration, different types of TiO2 and in the presence of electron acceptor such as hydrogen peroxide (H2O2), potassium bromate (KBrO3), and ammonium persulphate (NH4)2S2O8) besides molecular oxygen. The degradation rates were found to be strongly influenced by all the above parameters. The photocatalyst Degussa P25 was found to be more efficient as compared with other photocatalyst in the case of p-rosaniline, whereas UV100 was found to be better for the degradation of eosine yellowish. The xanthene dye (1) was found to degrade faster as compared to the triphenylmethane dye (2). The degradation products were analyzed by GC/MS technique and plausible mechanism for the formation of products have been proposed.


Hypoxia triggers high-altitude headache with migraine features: A prospective trial.
Given the high prevalence and clinical impact of high-altitude headache (HAH), a better understanding of risk factors and headache characteristics may give new insights into the understanding of hypoxia being a trigger for HAH or even migraine attacks. In this prospective trial, we simulated high altitude (4500 m) by controlled normobaric hypoxia (FiO2 = 12.6%) to investigate acute mountain sickness (AMS) and headache characteristics. Clinical symptoms of AMS according to the Lake Louise Scoring system (LLS) were recorded before and after six and 12 hours in hypoxia. O2 saturation was measured using pulse oximetry at the respective time points. History of primary headache, especially episodic or chronic migraine, was a strict exclusion criterion. In total 77 volunteers (43 (55.8%) males, 34 (44.2%) females) were enrolled in this study. Sixty-three (81.18%) and 40 (71.4%) participants developed headache at six or 12 hours, respectively, with height and SpO2 being significantly different between headache groups at six hours (p < 0.05). Binary logistic regression model revealed a significant association of SpO2 and headache development (p < 0.05, OR 1.123, 95% CI 1.001-1.259). In a subgroup of participants, with history of migraine being a strict exclusion criterion, hypoxia triggered migraine-like headache according to the International Classification of Headache Disorders (ICHD-3 beta) in n = 5 (8%) or n = 6 (15%), at six and 12 hours, respectively. Normobaric hypoxia is a trigger for HAH and migraine-like headache attacks even in healthy volunteers without any history of migraine. Our study confirms the pivotal role of hypoxia in the development of AMS and beyond that suggests hypoxia may be involved in migraine pathophysiology.


Are Pathogenic Germline Variants in Metastatic Melanoma Associated with Resistance to Combined Immunotherapy?
Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11-15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01-4.64; p = 0.048 and HR = 3.21; 95% CI: 1.31-7.87; p = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (p = 0.036; p = 0.044 and p = 0.001, respectively). The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.


Flow-mediated interactions between two self-propelled flapping filaments in tandem configuration.
The mechanism by which aggregates of active swimmers are formed is an intriguing problem. In this Letter we show that, for two tandem self-propelled filaments driven by harmonic plunging motions of identical frequency and amplitude, stable configurations can be spontaneously formed by locking the trajectories onto the vortex centers. Further analysis indicates that the grouping energetics is also dictated by the wake vortex structure. The rationale behind the energetic advantage of the follower is found to be the interplay among actuation, self-propulsion, and the vortical fluid environment.


Singlino resonant dark matter and 125 GeV Higgs boson in high-scale supersymmetry.
We consider a singlino dark matter (DM) scenario in a singlet extension model of the minimal supersymmetric standard model, which is the so-called the nearly minimal supersymmetric standard model. We find that with high-scale supersymmetry breaking the singlino can obtain a sizable radiative correction to the mass, which opens a window for the DM scenario with resonant annihilation via the exchange of the Higgs boson. We show that the current DM relic abundance and the Higgs boson mass can be explained simultaneously. This scenario can be fully probed by XENON1T.


Red human hair pheomelanin is a potent pro-oxidant mediating UV-independent contributory mechanisms of melanomagenesis.
The highest incidence of melanoma in red haired individuals is attributed to the synthesis and phototoxic properties of pheomelanin pigments. Recently, pheomelanin has also been implicated in UV-independent pathways of oxidative stress; however, the underlying mechanisms have remained uncharted. Herein, we disclose the unprecedented property of purified red human hair pheomelanin (RHP) to promote (i) the oxygen-dependent depletion of major cell antioxidants, for example glutathione and NADH; (ii) the autoxidative formation of melanin pigments from their precursors. RHP would thus behave as a unique 'living' polymer and biocatalyst that may grow by simple exposure to monomer building blocks and may trigger autoxidative processes. These results yield new clues as to the origin of the pro-oxidant state in the red hair phenotype, uncover non-enzymatic pathways of melanogenesis, and pave the way to innovative strategies for melanoma prevention.


Single-cell Microinjection for Cell Communication Analysis.
Gap junctions are intercellular channels that allow the communication of neighboring cells. This communication depends on the contribution of a hemichannel by each neighboring cell to form the gap junction. In mammalian cells, the hemichannel is formed by six connexins, monomers with four transmembrane domains and a C and N terminal within the cytoplasm. Gap junctions permit the exchange of ions, second messengers, and small metabolites. In addition, they have important roles in many forms of cellular communication within physiological processes such as synaptic transmission, heart contraction, cell growth and differentiation. We detail how to perform a single-cell microinjection of Lucifer Yellow to visualize cellular communication via gap-junctions in living cells. It is expected that in functional gap junctions, the dye will diffuse from the loaded cell to the connected cells. It is a very useful technique to study gap junctions since you can evaluate the diffusion of the fluorescence in real time. We discuss how to prepare the cells and the micropipette, how to use a micromanipulator and inject a low molecular weight fluorescent dye in an epithelial cell line.


Withdrawal symptoms after long-term treatment with low-potency neuroleptics.
Twenty-six chronic schizophrenic outpatients receiving low-potency anticholinergic neuroleptics were switched over periods of up to 2 years to an equivalent dose of high-potency neuroleptics. Of these patients, 85% experienced withdrawal symptoms, mainly insomnia, anxiety, and tensional restlessness. Complete withdrawal of low-potency medication was achieved during the study period in 9 patients only. The mean duration of treatment with low-potency neuroleptics was 15 years and the mean dose was 147 mg chlorpromazine equivalents/day. It is suggested that new symptoms associated with withdrawal of low-potency neuroleptics may lead to overcompliance by patients and difficulty in achieving the minimum therapeutic dosage. Thus, low-potency neuroleptics would not appear suitable for the long-term treatment of most schizophrenic patients.


Identification of Potentially Functional Circular RNA/Long Noncoding RNA-MicroRNA-mRNA Regulatory Networks Associated with Vascular Injury in Type 2 Diabetes Mellitus by Integrated Microarray Analysis.
This research is aimed at figuring out the potential circular RNA (circRNA)/long noncoding RNA- (lncRNA-) microRNA- (miRNA-) mRNA regulatory networks associated with a vascular injury in type 2 diabetes mellitus (T2DM). Differentially expressed genes (DEGs) screened in T2DM-related expression datasets were intersected with genes associated with vascular injury in T2DM to obtain candidate DEGs, followed by the construction of an interaction network of DEGs. The upstream miRNAs of candidate genes were predicted by mirDIP, miRWalk, and DIANA TOOLS databases, and the upstream lncRNAs/circRNAs of miRNAs by DIANA-LncBase/circBank database, followed by the construction of circRNA/lncRNA-miRNA-mRNA regulatory networks. Peripheral blood was attained from T2DM patients with macroangiopathy for clinical validation of expression and correlation of key factors. Differential analysis screened 37 candidate DEGs correlated with vascular injury in T2DM. Besides, MAPK3 was a core gene associated with vascular injury in T2DM. Among the predicted upstream miRNAs of MAPK3, miR-4270, miR-92a-2-5p, miR-423-5p, and miR-613 ranked at the top according to binding scores. The upstream lncRNAs and circRNAs of the 4 miRNAs were further predicted, obtaining 11 candidate lncRNAs and 3 candidate circRNAs. Moreover, KCNQ1OT1, circ_0020316, and MAPK3 were upregulated, but miR-92a-2-5p was downregulated in the peripheral blood of T2DM patients with macroangiopathy. Mechanistically, KCNQ1OT1 and circ_0020316 bound to miR-92a-2-5p that inversely targeted MAPK3. Collectively, KCNQ1OT1/circ_0020316-miR-92a-2-5p-MAPK3 coexpression regulatory networks might promote vascular injury in T2DM.


Localization of metal-induced gap states at the metal-insulator interface: origin of flux noise in SQUIDs and superconducting qubits.
The origin of magnetic flux noise in superconducting quantum interference devices with a power spectrum scaling as 1/f (f is frequency) has been a puzzle for over 20 years. This noise limits the decoherence time of superconducting qubits. A consensus has emerged that the noise arises from fluctuating spins of localized electrons with an areal density of 5x10(17) m(-2). We show that, in the presence of potential disorder at the metal-insulator interface, some of the metal-induced gap states become localized and produce local moments. A modest level of disorder yields the observed areal density.


Stanozolol-induced changes in fibrinolysis and coagulation in healthy adults.
The effect of orally-administered stanozolol, 5 mg b.d. on fibrinolysis, coagulation and on various haematological and biochemical parameters have been studied in 16 healthy adults, 8 males and 8 females. Statistically significant enhancement of extrinsic (tissue-type) plasminogen activator activity was detected in all subjects studied. This was associated with significant increases in plasma plasminogen and a concomitant reduction in histidine-rich glycoprotein. There were no changes in plasma urokinase activity. Changes in the coagulation system included significant reduction in plasma fibrinogen and elevation of protein C and antithrombin III. Changes in plasma lipids included significant reduction of HDL cholesterol associated with an increase in LDL triglycerides. No change occurred in total cholesterol. There were no major differences between the sexes, nor were there serious side effects. The effects of stanozolol on extrinsic (tissue-type) plasminogen activator activity, "free" plasminogen, protein C and antithrombin III, argue strongly in favour of its therapeutic potential.


Effect of depression on the speed of recall of pleasant and unpleasant experiences.
An experiment is described in which depressed patients were asked to recall pleasant or unpleasant experiences from their past life in response to a standard series of stimulus words. The ratio between the time for recall of pleasant and unpleasant experiences was found to fall progressively with increasing severity of depression or of "neuroticism" and to be significantly related to each. Among patients who scored relatively low on depression or neuroticism pleasant memories were recalled more speedily than unpleasant; among those who scored high this relationship was reversed. Possible mechanisms to account for these findings are discussed.


Triplet-triplet annihilation upconversion based nanocapsules for bioimaging under excitation by red and deep-red light.
Non-toxic and biocompatible triplet-triplet annihilation upconversion based nanocapsules (size less than 225 nm) were successfully fabricated by the combination of miniemulsion and solvent evaporation techniques. A first type of nanocapsules displays an upconversion spectrum characterized by the maximum of emission at λmax = 550 nm under illumination by red light, λexc = 633 nm. The second type of nanocapsules fluoresces at λmax = 555 nm when excited with deep-red light, λexc = 708 nm. Conventional confocal laser scanning microscopy (CLSM) and flow cytometry were applied to determine uptake and toxicity of the nanocapsules for various (mesenchymal stem and HeLa) cells. Red light (λexc = 633 nm) with extremely low optical power (less than 0.3 μW) or deep-red light (λexc = 708 nm) was used in CLSM experiments to generate green upconversion fluorescence. The cell images obtained with upconversion excitation demonstrate order of magnitude better signal to background ratio than the cell images obtained with direct excitation of the same fluorescence marker.


[Recent advances in miR-200c and fibrosis in organs].
In the fibrosis and pterygium of lung, liver, kidney, peritoneum or skin, miR-200c was aberrantly expressed. It has been shown that the regulatory effect of miR-200c on fibrosis in organ was involved in TGF-β-mediated epithelial-mesenchymal transition. The abnormal level of miR-200c in serum may be a basis for early diagnosis of lung fibrosis. Furthermore, miRNA mimics, miRNA agomir, and miRNA inhibitor are potential therapeutic tools for fibrosis. In present review, we summarize the recent progress in relevant studies on the expression and regulatory function of miR-200c and focus on its role in diagnosis, treatment, and prognosis of fibrosis in organ.


Lianhua Qingwen Capsules Reduced the Rate of Severity in Patients with COVID-19: A System Review and Meta-Analysis of Randomized Controlled Trials.
The rate of severity is a critical factor affecting the prognosis and mortality in coronavirus disease 2019 (COVID-19). Lianhua Qingwen capsules or granules (LQ) have been a promising Chinese patent medicine in treating infectious diseases and recommended for treating COVID-19. This meta-analysis aims to demonstrate the association between LQ treatment and the rate of severity in patients with mild or moderate COVID-19. 7 electronic databases were systematically searched from the inception dates to March 27, 2021, using the search terms to identify randomized controlled trials (RCTs). Two reviewers independently identified studies, extracted the data, and assessed study quality. All analyses were conducted on RevMan 5.3 software. A total of 5 RCTs involving 830 patients with mild or moderate COVID-19 were identified according to the inclusion and exclusion criteria. The quality of included studies is moderate. Compared with conventional therapy, there was a significant association of LQ treatment with a higher clinical efficacy (RR = 1.24, 95% CI (1.13, 1.36), P < 0.00001), rate of CT improvement (RR = 1.22, 95% CI (1.10, 1.34), P=0.0001), and a lower rate of conversion to severe cases (RR = 0.47, 95%CI (0.31, 0.71), P=0.0003). LQ combined with conventional therapy had great effects in reducing the rate of severity, and these findings supported the routine treatment of LQ in patients with mild or moderate COVID-19.


[Energy metabolism during intensive care of children in the early postoperative period].
Energy metabolism have been investigated using indirect calorimetry technique combined with determination of daily nitrogen excretion with urine, in the early postoperative period in children, aged 4 to 14 years after thoracic surgery. No significant increase in total energy expenditure in the earliest postoperative period have been observed. The changes were associated predominantly with the structure of energy expenditure and were most vividly manifested in younger children aged 4 to 8 years.


A review on comparing two commonly used rabbit anti-thymocyte globulins as induction therapy in solid organ transplantation.
Two rabbit anti-thymocyte globulins (ATGs) (Thymoglobulin™ and ATG-Fresenius (ATG-F)™) have been used commonly for induction immunosuppression and treatment of acute rejection in solid organ transplantation. Therefore, literature review on comparative efficacy and side-effect profile of them would be of clinical interest. This review evaluated all comparative studies in English language, focusing on the solid organ transplant patients who received Thymoglobulin or ATG-F as induction therapy. This review concluded that compared to ATG-F, Thymoglobulin possibly provides better protection against acute rejection and improves patient and graft survival but may result in more cytomegalovirus infection and post-transplant malignancy. Thymoglobulin produced more leukocyte depletion with a greater delay to recover, while ATG-F had more reduction effects on platelet and erythrocyte counts with an increased need to erythropoiesis-stimulating agent. The benefits of induction therapy with ATGs must be weighed against the costs and post-transplant complications. It is suggest that there is no substantial clinical difference between these two rabbit ATGs and each may be considered as induction therapy for solid organ transplantation based on availability and drug cost. Of special importance is adding antiviral therapy to the treatment regimen of patients who receive ATGs as induction therapy.


Targeting of under-75 years for the optimization of medication reconciliation with an approach based on medication risks: An observational study.
To date, how medication reconciliation (MR) could be prioritized in younger patients remains poorly evaluated. This study aimed at assessing whether a MR prioritization strategy based on the identification of high-risk medication at patients' admission treatment could be of interest in non-elderly patients. This prospective study was conducted between July and September 2017 in an internal medicine unit at Bordeaux teaching hospital. All patients aged 16 to 74 years and receiving at least two long-term treatments at admission were considered eligible. High-risk medications were defined on the basis of a pharmacovigilance study, which identified the drugs most involved in serious adverse effects reported in the Nouvelle-Aquitaine region in non-elderly adults. They included antithrombotics, analgesics, antipsychotics and cardiac therapies. MR-induced treatment changes were compared according to the existence of high-risk medications at admission in study participants. Among the 92 study participants, 46 presented with high-risk medications at admission (median age 66 years, IQR 58-70) and 46 without such (median age 54 years, IQR 47-64). High risk-medications (HRM) existing at admission were antithrombotics (52.2%) and antipsychotics (22.4%). MR resulted in treatment changes in 37% of patients admitted with at-risk medications vs. 8.7% of those admitted without such (P=0.001). Overall, the mean number of treatment changes performed after MR was of 1 (95%CI 0.4-1.6) in patients with high-risk medication at admission and of 0.2 (95%CI 0-0.4) in patients without such. MR-induced treatment changes assessed as clinically major at least once by pharmacists or clinicians was greater in HRM group (43.5%) than in non-HRM group (31.6%). However, the consistency was low between clinicians and pharmacists, especially to distinguish the clinical importance of significant and minor interventions. Targeting high-risk medications at admission appeared efficient for the prioritization of MR in non-elderly patients hospitalised in internal medicine.


Study of electron transfer across the liquid/ice-like matrix interface by scanning electrochemical microscopy.
In this work, we report the findings of a study on scanning electrochemical microscopy (SECM) to investigate the interfacial electron-transfer (ET) reaction between the 7,7,8,8-tetracyanoquinodimethane radical anion (TCNQ*-) in 1,2-dichloroethane and ferricyanide in an ice-like matrix (a mixture of insulting ice and conductive liquid) under low temperatures. Experimental results indicate that the formed liquid/ice-like matrix interface is superficially similar in electrochemical characteristics to a liquid/liquid interface at temperatures above -20 degrees C. Furthermore, imaging data show that the surface of the ice-like matrix is microscopically flat and physically stable and can be applied as either a conductive or an insulting substrate for SECM studies. Perchlorate ion was selected as the common ion in both phases, the concentrations of which controlled the interfacial potential difference. The effect of perchlorate concentration in the DCE phase on interfacial reactions has been studied in detail. The apparent heterogeneous rate constants for TCNQ*- oxidation by Fe(CN)6(3-) in another phase under different temperatures have been calculated by a best-fit analysis, where the experimental approach curves are compared with the theoretically derived relationships. Reaction rate data obey Butler-Volmer formulation before and after the freezing point, which is similar to most other known cases of ET reactions at liquid/liquid interfaces. However, there is a sharp change observed for heterogeneous rate constants around the freezing point of the aqueous phase, which reflects the phase transition. At temperatures below -20 degrees C, surface-confined voltammograms for the reduction of ferricyanide were obtained, and the ice-like matrix became an insulating one, which indicates that the aqueous phase is really a frozen phase.


Molecular and morphological changes in placenta and embryo development associated with the inhibition of polyamine synthesis during midpregnancy in mice.
Polyamines play an essential role in murine development, as demonstrated by both gene ablation in ornithine decarboxylase (ODC)-deficient embryos and pharmacological treatments of pregnant mice. However, the molecular and cellular mechanisms by which ODC inhibition affects embryonic development during critical periods of pregnancy are mostly unknown. Our present results demonstrate that the contragestational effect of alpha-difluoromethylornithine (DFMO), a suicide inhibitor of ODC, when given at d 7-9 of pregnancy, is associated with embryo growth arrest and marked alterations in the development of yolk sac and placenta. Blood island formation as well as the transcript levels of embryonary globins alpha-like x chain and beta-like y-chain was markedly decreased in the yolk sac. At the placental level, abnormal chorioallantoic attachment, absence of the spongiotrophoblast layer and a deficient development of the labyrinthine zone were evident. Real-time RT-PCR analysis showed that transcript levels of the steroidogenic genes steroidogenic acute regulatory protein, 3beta-hydroxysteroid dehydrogenase VI, and 17alpha-hydroxylase were markedly decreased by DFMO treatment in the developing placenta at d 9 and 10 of pregnancy. Plasma values of progesterone and androstenedione were also decreased by DFMO treatment. Transcriptomic analysis also detected changes in the expression of several genes involved in placentation and the differentiation of trophoblastic lineages. In conclusion, our results indicate that ODC inhibition at d 8 of pregnancy is related to alterations in yolk sac formation and trophoblast differentiation, affecting processes such as vasculogenesis and steroidogenesis.


[Ultrasound enhances microbubble-mediated gene transfection without affecting the cytoskeletons of endothelial cells].
To investigate the effect of therapeutic ultrasound on enhancing albumin microbubble-mediated gene delivery and evaluate the cytoskeletal damages in endothelial cells (ECs). The ECs cultured in 6-well plates were transfected with the plasmid eGFP in the presence or absence of the microbubbles at different concentrations, followed by ultrasound exposure for 30 to 180 s at 2 MHz, with the mechanical index (MI) of 0.5-1.8. The gene transfection efficiency was evaluated by observing the green fluorescence of the cells, and the cytoskeletal damage was assessed using immunofluorescence staining 24 to 48 h after ultrasound exposure. Within the MI range of ultrasound exposure between 0.50 and 1.00, the gene transfection efficiency was positively correlated to MI (P<0.001), and further increment of the MI failed to further increase the transfection efficiency. The duration of ultrasound exposure, within the range of 30-90 s, was also positively correlated to the gene transfection efficiency and microtubule fluorescence intensity(P<0.001), and prolonged exposure did not further enhance the effects. Variation of the MI and ultrasound exposure time within the above ranges did not cause significant changes in the florescence intensity of the microfilaments (P>0.05). Albumin microbubbles in the presence of ultrasound exposure can substantially enhance the gene transfection efficiency due to therapeutic ultrasound-mediated microbubble destruction without causing obvious damage of the cytoskeletons, and allows safe and efficient nonviral gene delivery in gene therapy.


Risk Prediction Using Polygenic Risk Scores for Prevention of Stroke and Other Cardiovascular Diseases.
Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.


Modifications of lectin binding on human leukemic cells after neuraminidase treatment.
Cell surface modifications after vibrio cholerae neuraminidase treatment were investigated using three different tritiated lectins: Concanavalin A, Ricinus sanguineus agglutinin (R.S.A.) and Robinia pseudoacacia lectin. Lectin binding measurements were performed on untreated and enzyme treated cells. The cells used were from chronic and acute leukemic donors. After neuraminidase treatment, a significant increase in the number of receptor sites, from 1 to 3 times, was found in all cases tested and for all three lectins utilized with only one exception. The affinity constant was generally decreased after neuraminidase treatment. The increase in number lectin binding sites, indicating extensive modification of the cell surface, is completely consistant with the known importance of sialic acid in determining immunogenicity.


An Internet-Based Intervention (Mamma Mia) for Postpartum Depression: Mapping the Development from Theory to Practice.
As much as 10-15% of new mothers experience depression postpartum. An Internet-based intervention (Mamma Mia) was developed with the primary aims of preventing depressive symptoms and enhancing subjective well-being among pregnant and postpartum women. A secondary aim of Mamma Mia was to ease the transition of becoming a mother by providing knowledge, techniques, and support during pregnancy and after birth. The aim of the paper is to provide a systematic and comprehensive description of the intervention rationale and the development of Mamma Mia. For this purpose, we used the intervention mapping (IM) protocol as descriptive tool, which consists of the following 6 steps: (1) a needs assessment, (2) definition of change objectives, (3) selection of theoretical methods and practical strategies, (4) development of program components, (5) planning adoption and implementation, and (6) planning evaluation. Mamma Mia is a fully automated Internet intervention available for computers, tablets, and smartphones, intended for individual use by the mother. It starts in gestational week 18-24 and lasts up to when the baby becomes 6 months old. This intervention applies a tunneled design to guide the woman through the program in a step-by-step fashion in accordance with the psychological preparations of becoming a mother. The intervention is delivered by email and interactive websites, combining text, pictures, prerecorded audio files, and user input. It targets risk and protective factors for postpartum depression such as prepartum and postpartum attachment, couple satisfaction, social support, and subjective well-being, as identified in the needs assessment. The plan is to implement Mamma Mia directly to users and as part of ordinary services at well-baby clinics, and to evaluate the effectiveness of Mamma Mia in a randomized controlled trial and assess users' experiences with the program. The IM of Mamma Mia has made clear the rationale for the intervention, and linked theories and empirical evidence to the contents and materials of the program. This meets the recent calls for intervention descriptions and may inform future studies, development of interventions, and systematic reviews.


Antimicrobial efficacy and compatibility of solid copper alloys with chemical disinfectants.
Chemical disinfection is state of the art in preventing spread of infectious agents in the healthcare setting. Additionally, the antimicrobial properties of solid copper alloy surfaces against various microorganisms have recently been substantiated. Thus, antimicrobially active copper surfaces may serve as an additional barrier against distribution of pathogenic microorganisms and be combined with chemical disinfection measures in the hospital. The aim of this study was therefore to investigate on a quantitative basis whether the combination of chemical disinfectants with copper alloy surfaces results in an overall compromised, combined or even synergistic antimicrobial efficacy. Experiments were carried out using the quantitative carrier test devised by the German Society for Hygiene and Microbiology (DGHM) to study antimicrobial efficacy of chemical disinfectants. Requirements for microbicidal efficacy as defined by prEN 14885 were applied. The chemical disinfectants tested in our study contained alcohols (ethanol, 1-propanol), quaternary ammonium compounds (benzalkonium chloride) and glutaraldehyde as actives. Quantitative carrier tests were carried out on different carriers (tiles, copper alloy discs, stainless steel discs) using Pseudomonas aeruginosa, Staphylococcus aureus, Kocuria rhizophila and Candida albicans as test organisms. For the alcohol-based disinfectant no difference in antimicrobial efficacy was observed when applied to antimicrobial active copper alloy carriers, tiles or stainless steel discs. For all test organisms microbial contamination was reduced to the detection limit of < 1 log (CFU/ml) within a contact time of 2 min indicating a ≥ 5 log reduction for the tested bacteria and a ≥ 4 log reduction for the yeast, as being requested for chemical disinfectants by prEN 14885. In order to elucidate a potential synergism the chemical disinfectant based on quaternary ammonium compounds (benzalkonium chloride) and glutaraldehyde was used at a sub-effective concentration. Hence, no complete reduction of microbial contamination was achieved on stainless steel or tile carriers for Pseudomonas aeruginosa and Candida albicans. Interestingly, when using copper alloy carriers complete reduction indicating a ≥ 5 log reduction for P. aeruginosa and a ≥ 4 log reduction for C. albicans was detected. Thus, data of this study indicates that solid copper alloy surfaces and disinfectants synergize. According to this data, commercially available disinfectants based on alcohol, quaternary ammonium compounds and aldehyde can effectively be combined in a dual strategy with solid copper alloy surfaces to reduce microbial contamination.


The agglutination of Proteus vulgaris by cystic fibrosis serum: a re-examination.
The agglutination of the bacterium Proteus vulgaris by serum from cystic fibrosis patients and obligate heterozygotes was shown to be insufficiently specific or reproducible to be of diagnostic value by itself. Approximately 20% of health controls gave a substantial agglutination reaction, whereas the carrier frequency for cystic fibrosis is around 5%. The agglutination did not predominantly involve the bacterial flagella, but appeared to depend on components of the cell surface. The main serum proteins that bind to P. vulgaris cells were shown to be albumin, immunoglobulin G, and complement component C3. In addition, an unidentified protein(s) of low molecular weight was found to bind to the cells. However, no systematic differences were found in the proteins that bind to P. vulgaris cells between cystic fibrosis and normal sera.


Doctor's Knowledge and Practices of Traumatic Brain Injury Management in Chinese Prehospital Settings.
The incidence and mortality of traumatic brain injury (TBI) has increased rapidly in the last decade in China. Appropriate ambulance service can reduce case-fatality rates of TBI significantly. This study aimed to explore the factors (age, gender, education level, clinical experience, professional title, organization, specialty before prehospital care, and training frequency) that could influence prehospital doctors' knowledge level and practices in TBI management in China, Hubei Province. A cross-sectional questionnaire survey was conducted in two cities in Hubei Province. The self-administered questionnaire consisted of demographic information and questions about prehospital TBI management. Independent samples t-test and one-way ANOVA were used to analyze group differences in the average scores in terms of demographic character. General linear regression was used to explore associated factors in prehospital TBI management. A total of 56 questionnaires were handed out and 52 (93%) were returned. Participants received the lowest scores in TBI treatment (0.64; SD=0.08) and the highest scores in TBI assessment (0.80; SD=0.14). According to the regression model, the education level was associated positively with the score of TBI identification (P=.019); participants who worked in the emergency department (ED; P=.011) or formerly practiced internal medicine (P=.009) tended to get lower scores in TBI assessment; participants' scores in TBI treatment were associated positively with the training frequency (P=.011); and no statistically significant associated factor was found in the overall TBI management. This study described the current situation of prehospital TBI management. The prehospital doctors' knowledge level and practices in TBI management were quantified and the influential factors hidden underneath were explored. The results indicated that an appropriate continuing medical education (CME) program enables improvement of the quality of ambulance service in China.


The molecular basis for disease phenotype in chronic Chlamydia-induced arthritis.
Genital Chlamydia trachomatis infections can elicit an inflammatory arthritis in some individuals, and recent surprising studies have demonstrated that only ocular (trachoma) strains, not genital strains, of the organism are present in the synovial tissues of patients with the disease. This observation suggests an explanation for the small proportion of genitally-infected patients who develop Chlamydia-induced arthritis. Other recent studies have begun to identify the specific chlamydial gene products that elicit the synovial inflammatory response during both active and quiescent disease, although much more study will be required to complete the understanding of that complex process of host-pathogen interaction. Several newly developed experimental methods and approaches for study of the process will enable identification of new therapeutic targets, and possibly strategies for prevention of the disease altogether.


Liver transplantation for refractory hepatic hydrothorax is associated with a greater survival benefit compared to other complications of cirrhosis.
Hepatic hydrothorax (HH) is a significant complication of cirrhosis associated with increased mortality. Liver transplantation (LT) remains the best treatment modality. We aim to assess predictors of mortality and the survival benefit of LT in patients with HH. A prospectively maintained cohort of adult patients with cirrhosis, being evaluated for LT at our institution, was retrospectively reviewed from 2015 to 2020. The primary outcome was death or LT. Cox proportional hazard regression identified associations between covariates and death. We calculated the years saved due to LT by comparing patients who were on the waiting list with patients who received an LT. This was done by calculating the area under the Kaplan-Meier curve. Censoring occurred at the time of the last follow-up or death. Patients with refractory HH had the lowest median survival of only 0.26 years. Within the HH group, having a refractory HH group was significantly associated with an increased risk of mortality (HR 1.73; 95% CI 1.06-2.81; p -value 0.03). Refractory HH was also significantly associated with mortality when evaluated in the entire cohort and after adjusting for other covariates (HR 1.48, 95% CI 1.03-2.11; p -value 0.03). Patients with refractory HH had the highest 1-year survival benefit with LT (0.48 y), followed by patients with non-refractory HH (0.28 y), then patients with other complications of cirrhosis (0.19 y). In this large study evaluating the prognostic impact of HH on patients with cirrhosis, refractory HH was an independent predictor of mortality. LT provides an additional survival benefit to patients with HH compared with those without HH.


Effects of glycerol and mannitol on the interstitial fluid pressure of the facial nerve.
The pressure lowering effect of glycerol and mannitol on the interstitial fluid pressure of the facial nerve was studied in normal guinea pigs. The effect of low-molecular dextran on the interstitial fluid pressure of the facial nerve was also studied. Both peroral administration of glycerol and intravenous administration of mannitol lowered the interstitial fluid pressure of the facial nerve as well as the cerebrospinal fluid pressure. The pressure decrease in the facial nerve may be the result of a decreased cerebrospinal fluid pressure, caused by the administration of glycerol or mannitol. Low-molecular dextran did not cause significant pressure changes in the facial nerve.


Factors Governing the Thermal Stability of Lasso Peptides.
Lasso peptides belong to the natural product superfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). They are defined by an N-terminal macrolactam ring that is threaded by the C-terminal tail. In class II lasso peptides, this fold is maintained only through steric hindrance. Nonetheless, this fold can often withstand prolonged incubation at highly elevated temperatures. However, some lasso peptides will irreversibly unthread into their branched-cyclic counterparts upon heating. In recent years, an increasing number of research studies have focused on studying the factors that govern the thermal stability (or the lack thereof) of lasso peptides by using in vitro stability assays, mutational analysis, and molecular dynamics simulations. In this review, the current state of understanding the physicochemical parameters deciding the fate of a lasso peptide at elevated temperatures is discussed, and an overview is given of the techniques developed to streamline the separation and discrimination of lasso peptides from their branched-cyclic topoisomers.


Frequency of medication errors in an emergency department of a large teaching hospital in southern Iran.
This study was conducted with the purpose of determining the frequency of medication errors (MEs) occurring in tertiary care emergency department (ED) of a large academic hospital in Iran. The incidence of MEs was determined through the disguised direct observation method conducted by a trained observer. A total of 1,031 medication doses administered to 202 patients admitted to the tertiary care ED were observed over a course of 54 6-hour shifts. Following collection of the data and analysis of the errors with the assistance of a clinical pharmacist, frequency of errors in the different stages was reported and analyzed in SPSS-21 software. For the 202 patients and the 1,031 medication doses evaluated in the present study, 707 (68.5%) MEs were recorded in total. In other words, 3.5 errors per patient and almost 0.69 errors per medication are reported to have occurred, with the highest frequency of errors pertaining to cardiovascular (27.2%) and antimicrobial (23.6%) medications. The highest rate of errors occurred during the administration phase of the medication use process with a share of 37.6%, followed by errors of prescription and transcription with a share of 21.1% and 10% of errors, respectively. Omission (7.6%) and wrong time error (4.4%) were the most frequent administration errors. The less-experienced nurses (P=0.04), higher patient-to-nurse ratio (P=0.017), and the morning shifts (P=0.035) were positively related to administration errors. Administration errors marked the highest share of MEs occurring in the different medication use processes. Increasing the number of nurses and employing the more experienced of them in EDs can help reduce nursing errors. Addressing the shortcomings with further research should result in reduction of MEs in EDs.


Solitary plasmacytoma of the rectum: report of a case treated by endoscopic polypectomy and radiotherapy.
Solitary extramedullary plasmacytoma (EMP) of the rectum is an exceedingly rare entity. We report the fourth case of solitary EMP of the rectum and the first one treated by endoscopic polypectomy and radiotherapy. The patient showed no signs of local recurrence or dissemination of the disease after a 12-month follow-up. This case report is presented along with a review of the literature dealing with solitary plasmacytomas of the rectum.


Short communication: Model for metritis severity predicts that disease misclassification underestimates projected milk production losses.
The objective of this research was to determine the effect of disease misclassification on the estimated effect of metritis on milk production. Misclassification introduces bias that usually results in an underestimation of the association between exposure (disease) and the outcome of interest (milk production). This distorted measure of association results from the comparison of an affected population (some of which may not truly be affected) to a nonaffected population (which often includes affected subjects that are unidentified). A convenience sample of DairyComp305 (Valley Agricultural Software, Tulare, CA) data representing 1 yr of calvings (n = 3,277) from 1 Midwestern Holstein herd was used. This herd was chosen because of its ongoing efforts to consistently and completely record all clinical diseases, including the incidence of both mild and severe metritis cases. Metritis was defined as the presence of a flaccid uterus containing fetid fluids or a foul watery discharge within 14 d of calving. Cows that appeared clinically normal other than the discharge were considered mild and those with systemic signs of disease were classified as severe. The original data set included metritis recorded as mild, severe, or not recorded (NR), where no metritis was observed, and was considered to contain the metritis true severity (TrS). First, to evaluate the effect of misclassification bias, we retrospectively randomized 45% of mild metritis to be classified as NR to simulate inconsistent disease recording (IR); then, in a separate model, all mild metritis cases were changed to NR to simulate a situation of very poor disease recording (PR), where only the most severe cases are recorded. The TrS, IR, and PR data sets were analyzed separately in JMP (SAS Institute Inc., Cary, NC). An ANOVA was conducted for second test 305-d mature-equivalent milk projection (2nd305ME), and nonsignificant variables were removed, but the variable metritis was forced into all models. Based upon the TrS model, adjusting for effects of lactation group, month of calving, dystocia, twins, retained placenta, early-lactation mastitis, displaced abomasum, and significant interactions, a case of mild metritis was associated with 384 kg less 2nd305ME and a case of severe metritis was associated with 847 kg less 2nd305ME compared with no metritis. For the IR model, a case of mild metritis was associated with 315 kg less 2nd305ME and a case of severe metritis was associated with 758 kg less 2nd305ME compared with no metritis. For the PR model, severe metritis was associated with 680 kg less 2nd305ME compared with NR. The IR and PR models underestimated 2nd305ME loss for severe metritis cases by 89 and 166 kg/cow, and resulted in 180,441 and 330,256 kg of total milk loss unaccounted for at the herd level, respectively, compared with TrS. Overall, misclassification of metritis cases results in greater bias and largely underestimates the true association between metritis and the consequence costs of the disease.


Fundamentals in expertise medicine.
Fundamentals in expertise medicine. The author describes how a medical expert appointed to assess damages to physical integrity must proceed. The individual is appointed an expert either directly by the Court of Justice, or appointed sapiteur by a colleague in order to give his opinion on a subject in which he is specialized.


Immunogenic epitopes of the p55 chain of the IL-2 receptor. Relationships to high-affinity IL-2 binding and modulation of the p55 chain.
Monoclonal antibodies were used to determine the relationships between epitopes on the p55 chain of the IL-2 receptor and high-affinity IL-2 binding. Five monoclonal antibodies to the human P55 chain of the IL-2 receptor were induced by immunizing mice with murine L cells that were transfected with human p55 cDNA. Since the p55 chain is the only human antigen expressed on these cells, all antihuman MABs thus generated were directed against this molecule. These antibodies were used to map epitopes on the p55 chain and determine their relationship to high-affinity IL-2 binding. Extensive flow cytometric studies with these MABs and a large panel of other anti-p55 MABs revealed three major patterns of competition. Type I MABs compete with anti-Tac extensively but not with antibodies of other groups. Type II MABs do not block anti-Tac but do block 7E11. Type III MABs do not block either type I or type II antibodies. 125I-IL2 competition studies under high-affinity conditions revealed that types I and II MABs inhibit IL-2 binding. Type III MABs can be resolved into two subgroups, one that inhibits IL-2 binding and one that does not. Together these data suggest that there are at least four distinct immunogenic epitopes on the human p55 chain, with three epitopes related to IL-2 binding. The competitive component evident by a change in Kd on the Scatchard plots suggests that all three epitopes are close to or part of the IL-2-binding site of the p55 chain. The noncompetitive component, as evidenced by the lower number of high-affinity IL-2 receptors induced by these antibodies, suggests that the same epitopes are also close to the site(s) of interaction between the p55 and p70 chains to form the high-affinity receptor. These studies indicated that the IL-2-binding site and site of interaction between the p55 and p70 chains are close together or identical. Modulation studies revealed that one type II antibody (7E11) modulates the p55 chain in the absence of IL2 and the p70 chain, thus revealing that modulation of the p55 chain can occur by an active process, and not merely passively comodulate by the p70 chain upon IL-2 binding. Modulation of the p55 chain alone has no proliferative effect on IL-2-responsive T lymphoblasts. Potentially this antibody-dependent modulation may be used to deliver toxin to activated lymphocytes.


A digital twin for simulating the vertebroplasty procedure and its impact on mechanical stability of vertebra in cancer patients.
We present the application of ReconGAN, introduced in a previous study, for simulating the vertebroplasty (VP) operation and its impact on the fracture response of a vertebral body. ReconGAN consists of a Deep Convolutional Generative Adversarial Network (DCGAN) and a finite element based shape optimization algorithm to virtually reconstruct the trabecular bone microstructure. The VP procedure involves injecting shear-thinning liquid bone cement through a needle in the trabecular region to reinforce a diseased or fractured vertebra. To simulate this treatment modality, computational fluid dynamics (CFD) is employed to predict the morphology of the injected cement within the bone microstructure. A power-law equation is utilized to characterize the non-Newtonian shear-thinning behavior of the polymethyl methacrylate (PMMA) bone cement during injection simulations. The CFD model is coupled with the level-set method to simulate the motion of the interface separating bone cement and bone marrow. After predicting the cement morphology, a data co-registration algorithm is employed to transform the CFD model to a high-fidelity continuum damage mechanics (CDM) finite element model of the augmented vertebra for predicting the fracture response. A feasibility study is presented to demonstrate the ability of this CFD-CDM framework to investigate the effect of VP on the mechanical integrity of the vertebral body in a cancer patient with a lytic metastatic tumor.


Oral immunotherapy for the treatment of food allergy.
Oral immunotherapy (OIT) is an emerging new therapy for food allergy. With multiple small exploratory trials and some large randomized-controlled phase 2 trials recently published and under way, there is a clear progress and interest toward making this a treatment option for patients suffering from food allergies. However, there are still many questions to be answered and parameters to fine-tune before OIT becomes an accepted option outside of the research setting. This review covers the main milestones in the development of OIT for food allergy and further discusses important specific issues that will have direct impact on its clinical application. More specifically, previous publications showing evidence for the induction of tolerance are specifically reviewed and varying safety, tolerability and efficacy parameters from previous reports are also discussed.


Dislocated and Dissociated Dual-Mobility Components Are Easily Missed and More Than Half Fail Closed Reduction: Six Tips to Aid Management.
Dual-mobility (DM) implants reduce the risk of dislocation in patients who have undergone total hip arthroplasty (THA); however, DM implants are at risk for large-head dislocation and intraprosthetic dissociation (IPD), where the inner femoral head dissociates from the outer polyethylene head. This study aimed to report the incidence of DM dislocation and IPD, evaluate the rate of recognition of IPD before and after reduction, investigate the outcomes of these complications, and provide treatment recommendations for their management. Between 2010 and 2021, 695 primary and 758 revision THAs were performed with DM constructs at a single institution. There were 44 large-head dislocations (3.0%) and 10 IPDs (0.7%). Four additional IPDs occurred during attempted closed reduction, increasing the IPD incidence to 0.96%. We reviewed prior instability history, dislocation management, success of reduction, recognition of IPD, and subsequent rates of revision and complications. The mean follow-up was 2.5 years. Nine of 10 IPDs were missed at presentation and thus not treated as such. Sixty-three percent of attempted closed reductions in the emergency department failed and led to 4 IPDs and 1 periprosthetic fracture. Reduction success was associated with the following factors: use of general anesthesia with paralysis (p = 0.02), having the reduction performed by an orthopaedist (p = 0.03), and undergoing only 1 reduction attempt (p = 0.015). Two-thirds of dislocations required revision. The rate of redislocation was 33%, and 5 hips required subsequent revision at a mean of 1.8 years after the initial dislocation. We present an evaluation of DM-implant dislocation and dissociation along with management recommendations based on these data. Given the low success and high complication rates of attempted closed reduction and the need for eventual revision, we recommend that all patients with dislocated DM implants be brought to the operating room for closed reduction as well as potential revision if the reduction fails. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells.
Several endothelin receptor antagonists (ERAs) have been developed for the treatment of pulmonary arterial hypertension (PAH). Some of them have been related to clinical cases of hepatocellular injury (sitaxentan [SIT]) and/or cholestasis (bosentan [BOS]). We aimed to determine if ambrisentan (AMB) and macitentan (MAC), in addition to BOS and SIT, could potentially cause liver damage in man by use of human HepaRG cells. Our results showed that like BOS, MAC-induced cytotoxicity and cholestatic disorders characterized by bile canaliculi dilatation and impairment of myosin light chain kinase signaling. Macitentan also strongly inhibited taurocholic acid and carboxy-2',7'-dichlorofluorescein efflux while it had a much lower inhibitory effect on influx activity compared to BOS and SIT. Moreover, these three drugs caused decreased intracellular accumulation and parallel increased levels of total bile acids (BAs) in serum-free culture media. In addition, all drugs except AMB variably deregulated gene expression of BA transporters. In contrast, SIT was hepatotoxic without causing cholestatic damage, likely via the formation of reactive metabolites and AMB was not hepatotoxic. Together, our results show that some ERAs can be hepatotoxic and that the recently marketed MAC, structurally similar to BOS, can also cause cholestatic alterations in HepaRG cells. The absence of currently known or suspected cases of cholestasis in patients suffering from PAH treated with MAC is rationalized by the lower therapeutic doses and Cmax, and longer receptor residence time compared to BOS.


Detection of typhoid fever by diatom-based optical biosensor.
Surface-modified diatom substrates are employed for the development of immunocomplex-based optical biosensor for diagnosis of typhoid. Biosensor has been prepared by covalent immobilization of Salmonella typhi antibody onto the crosslinked diatom substrates via glutaraldehyde. Photoluminescent (PL) studies revealed good specificity and ability of conjugated diatom substrates to distinguish complementary (S. typhi) and non-complementary (Escherichia coli) antigens. The immunocomplexed biosensor showed detection limit of 10 pg. The excellent performance of biosensor is associated to its large surface-to-volume ratio, good photoluminescent property, and biocompatibility of diatom frustules, which enhances the antibody immobilization and facilitates the nucleophilic electron transfer between antibody and conjugated diatom surface. Hence, immunocomplexed diatom substrates are considered to be a suitable platform for the environmental monitoring of water-borne pathogen S. typhi.


A review of human immunodeficiency virus infection in India.
By the turn of the century 20-50 million adults are projected to be HIV positive in Asia, and India will have the largest burden of newly infected patients in a single country. To determine the present status of the epidemic, a systematic review of available data in India has been carried out. Regional differences in reported HIV seroprevalence were found, with high levels in western, northeastern, and southern India and lower levels in northern, central, and eastern India. While differences in the temporal introduction of HIV may be partly responsible, the more likely explanation is incomplete data and reporting. In the past 4 years HIV has rapidly increased among commercial sex workers and patients coming to sexually transmitted diseases clinics in western (Bombay) and southern (Madras and Vellore) India. Assessing HIV seroprevalence in the general population is difficult because of limited data, especially from rural areas, where 60% of Indians reside. Heterosexual contact with commercial sex workers is the major reported risk factor, except in eastern India, where intravenous drug use is common. The impact of transfusions or contaminated needles is uncertain, but between 25 and 75% of blood donations are not screened for HIV, and 15% of infected patients had received transfusions. By October 1993, 494 cases of AIDS had been reported, but this number grossly underestimates the real situation since HIV is often unrecognized. Tuberculosis is the major HIV-associated infection. In its efforts to control HIV, India needs to institute a standardized surveillance system to provide data needed to design and implement appropriate interventions.


Sarcoidosis of the heart.
Patients who have bilateral hilar lymphadenopathy (BHL) alone need annual follow-up with chest X-ray, ECG, 24-h monitoring, exercise testing, lung function and possible thallium 201 scanning. Provided these tests are normal or negative, there is no evidence of other organ or parenchymal lung involvement and the extent of BHL is stable or regressing, then restriction to multicrew operation should be required until regression has occurred or a period of two years has elapsed. Although a patient with generalized or systemic sarcoidosis and no apparent cardiac involvement should be allowed to drive a car, certification to fly should be dependent on physical well being and restricted to multicrew operation. With our present inability to diagnose cardiac involvement in sarcoidosis with complete sensitivity, this restriction should be indefinite as cardiac involvement in sarcoidosis may only become apparent many years after the diagnosis of systemic sarcoidosis has been made. Patients with known cardiac involvement in sarcoidosis should also be refused a driving licence unless they are under regular and close supervision for possible arrhythmic complications. Permanent pacing may be needed. Patients with known cardiac sarcoid should be refused certification to fly.


Persistence is not always a virtue: tort reform, civil liability for health care, and the lack of empirical evidence.
The efficacy of reforms in the civil system, including professional liability in the health care arena, depends upon the accuracy with which problems are defined. A growing empirical literature argues that the description of the civil justice system underlying the movement for tort reform in the health care arena is not an accurate one. Regardless, that description continues to be used successfully as the basis for a variety of enacted reforms. The interesting question now posed by some researchers is why that description persists despite its lack of empirical verification. This article summarizes the reformers' description; provides an overview of relevant empirical findings; and then draws on a theoretical literature in political science dealing with agenda-setting in the public policy process to answer that interesting question. The article concludes that the image persists because it is successful in a political, not rational, process in which appeals to emotion overshadow reasoned argument.


Prognostic Assessment of Interim F18-Fluorodeoxyglucose Positron Emission Tomography in Esophageal Cancer Treated With Chemoradiation With or Without Surgery.
Purpose This study aimed to evaluate if the F18-fluorodeoxyglucose positron emission tomography (F18-FDG PET) response after two weeks of chemoradiation for locoregionally advanced esophageal cancer (staged Tumor (T) 3 and/or Nodes (N)+ Metastases (M) 0) was linked to the pathologic response for patients undergoing surgery, to disease-free survival (DFS) or overall survival (OS). Materials and Methods Between March 2006 and September 2017, 40 patients were prospectively enrolled in our study, gave written consent, and had PET scans performed before treatment and after two weeks of chemoradiation. One patient did not undergo his two-week PET without informing study coordinators and was excluded from analyses. Results The median age at diagnosis was 62 years. Seventy-two percent of patients had N+ disease. Median OS for the entire group was 24 months. Five-year overall survival was 17%. Survival curves for patients with no PET response, minor PET response, or good PET response overlapped and were not statistically different. For the 25 patients who underwent surgery, the positive predictive value (PPV) of the PET response relative to the pathologic response was 75% and the negative predictive value (NPV) was 62%. In study patients, the crude recurrence rate was 68% and there was no correlation between PET response and DFS. Conclusion In our study, interim PET response after two weeks of chemoradiation for locoregionally advanced esophageal cancer was not predictive of outcome or pathologic response. Based on our data and current literature, interim PET should not be used to alter treatment (whether to escalate neo-adjuvant treatment or omit surgery).


Liganded peroxisome proliferator-activated receptors (PPARs) preserve nuclear histone deacetylase 5 levels in endothelin-treated Sprague-Dawley rat cardiac myocytes.
Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGKζ) is critically involved. DGKζ is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGKζ suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGKζ signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1)-induced nuclear export of HDAC5 in a manner that is dependent on DGKζ. When DGKζ-mediated PKC inhibition was circumvented using a constitutively-active PKCε mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14-3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin, and cardiac muscle α-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGKζ in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5 as a mechanism by which liganded PPARs suppress the hypertrophic gene program.


Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany.
To investigate regional variations in the frequency of undiagnosed thyroid disorders among 25- to 88-year-old men and women in two communities in the northeast and the south of Germany. In addition, autoantibodies to thyroperoxidase (TPO-Abs) and urinary iodine excretion were determined. Two population-based surveys of men and women using a common standardized protocol, the Study of Health in Pomerania (SHIP) in the northeast of Germany (2505 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) in the south of Germany (2316 participants), were compared with regard to the frequency of undiagnosed thyroid disorders. Compared with the northeast of Germany, urinary iodine excretion and serum thyroid-stimulating hormone (TSH) levels were significantly higher in the south. The median urinary iodine concentration was 110 μg/l (64; 169 μg/l) in SHIP and 151 μg/l (97; 214 μg/l) in KORA, and the median TSH value was 0.81 mIU/l (0.56; 1.15 mIU/l) in SHIP and 1.22 mIU/l (0.84; 1.80 mIU/l) in KORA. The frequency of elevated TSH (TSH ≥ 2.12 mIU/l) was 4.3% in SHIP and 14.1% in KORA (P<0.001); the corresponding values for suppressed TSH (<0.25 mIU/l) were 3.5 and 1.7% (P<0.001). The proportion of ultrasonographic findings was 55.5% in SHIP and 68.0% in KORA. The frequency of serum TPO-Abs did not differ significantly between northeast and south Germany. There were considerable regional disparities in the frequency of thyroid disorders within Germany. These differences can be explained not only by different regional histories of natural iodine deficiency but also by current differences in the iodine supply under an identical nationwide iodine fortification program.


Diversity and Inclusion Training in Health Care: What the Evidence Suggests.
On September 22, 2020, then-President Donald Trump signed Executive Order 13950, titled "Combating Race and Sex Stereotyping." This order restricted the types of diversity and inclusion (DI) training that federal agencies and contractors could offer with federal funding. In this column, the author denounces that order, uses this critique to examine DI training sessions in their current forms, and suggests evidence-based solutions for organizations that are committed to dismantling racism. Mental health organizations must move beyond single, standalone DI training sessions that target individual providers and initiate institution-wide activities that embrace antiracism and structural competence.


[Genetic defects and disorders at the neuromuscular junction].
Genetic defects in molecules expressed at the neuromuscular junction (NMJ) cause congenital myasthenic syndromes (CMSs), which are characterized by muscle weakness, abnormal fatigability, amyotrophy, and minor facial anomalies. Muscle weakness mostly develops under 2 years but is also sometimes seen in adults. Mutations identified to date include (i) muscle nicotinic acetylcholine receptor (AChR) subunits, (ii) rapsyn that anchors and clusters AChRs at the neuromuscular junction, (iii) agrin that is released from the nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway, (iv) muscle-specific kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to rapsyn/AChR, (v) Dok-7 that transmits the AChR-clustering signal from agrin/LRP4/MuSK to rapsyn/AChR, (vi) skeletal muscle sodium channel type 1.4 (Nav1.4) that spreads the depolarization potential from the endplate throughout muscle fibers, (vii) collagen Q that anchors acetylcholinesterase to the synaptic basal lamina, and (viii) choline acetyltransferase that resynthesizes acetylcholine from recycled choline at the nerve terminal. In addition, mutations in the heparin sulfate proteoglycan perlecan, which binds to many molecules including collagen Q and dystroglycan, causes Schwartz-Jampel syndrome. Interestingly, mutations in LRP4 cause Cenani-Lenz syndactyly syndrome but not CMS. AChR, MuSK, and LRP4 are also targets of auto-antibodies in myasthenia gravis. In addition, molecules at the NMJ are targets of many other disease states AChRs are blocked by the snake toxin alpha-bungarotoxin and the plant poison curare. The presynaptic SNARE complex is attacked by botulinum toxin. Acetylcholinesterase is inhibited by the nerve gas sarin and by organophosphate pesticides. This review focuses on the molecular bases underlying defects of AChR, rapsyn, Nav1.4, collagen Q, and choline acetyltransferase.


Telemedicine in the Management of ADHD: Literature Review of Telemedicine in ADHD.
Objective: Telemedicine has been used successfully in several medical specialties with favorable patient outcomes, satisfaction, in a cost-effective manner. However, its use in the context of ADHD remains unclear. Our main aim was to investigate what is known about the use of telemedicine in ADHD. Method: We conducted a systematic search of the literature assessing telemedicine in ADHD in PubMed, PsycINFO, and Medline. Included were original articles published in English with the main aim to assess the use of telemedicine in ADHD. Results: Only 11 articles met our inclusion and exclusion criteria, coming from only three systematic trials of telemedicine in ADHD. The studies suggest that telemedicine is valued by its users, is well accepted, and is associated with improved outcomes. Conclusion: The limited research indicates that telemedicine has potential to expand the delivery of clinical services to patients with ADHD. More work is needed to further evaluate this finding.


Does selection on increased cold tolerance in the adult stage confer resistance throughout development?
Artificial selection is a powerful approach to unravel constraints on genetic adaptation. Although it has been frequently used to reveal genetic trade-offs among different fitness-related traits, only a few studies have targeted genetic correlations across developmental stages. Here, we test whether selection on increased cold tolerance in the adult stage increases cold resistance throughout ontogeny in the butterfly Bicyclus anynana. We used lines selected for decreased chill-coma recovery time and corresponding controls, which had originally been set up from three levels of inbreeding (outbred control, one or two full-sib matings). Four generations after having terminated selection, a response to selection was found in 1-day-old butterflies (the age at which selection took place). Older adults showed a very similar although weaker response. Nevertheless, cold resistance did not increase in either egg, larval or pupal stage in the selection lines but was even lower compared to control lines for eggs and young larvae. These findings suggest a cost of increased adult cold tolerance, presumably reducing resource availability for offspring provisioning and thereby stress tolerance during development, which may substantially affect evolutionary trajectories.


Importance of clinical assessment in diagnosis of acute appendicitis and its role in decreasing negative appendicectomy rate.
Appendicitis is a common diagnosis, but is by no means a simple one to establish. It is impractical to have a definitive preoperative diagnosis, which leads to an appreciable rate of negative appendicectomy as reported in world literature varying from 20-40% with its morbidity around 10%. This retrospective study investigated the value of clinical assessment and medical imaging (ultrasonography) for patients with suspected appendicitis. Negative appendicectomy rate and appendiceal perforation with or without medical imaging were used as end points for this investigation. This study reviewed all patients admitted in Sheikh Khalifa Bin Zaid Hospital with suspected acute appendicitis. The patient cohort was identified from the unit registry and review of medical records. The medical records were analysed, and the outcomes of patients were followed up. Between June 2010 to June 2012, 375 patients' medical records were audited. These included 56.3% males and 43.7% females. The negative appendicitis rate was 7.2% and appendiceal perforation rate was 5.3%. Ultrasound was done in 103 (27.4%) patients in whom diagnosis of appendicitis was doubtful. Medical imaging had a 50% prediction rate for acute appendicitis, 40% false-negative rate, and 10% false-positive rate. Overall, the prediction rate for appendicitis by clinical assessment supplemented by laboratory tests and medical imaging at clinician's discretion was 92.8%. Despite studies advocating routine use of medical imaging for patients with suspected acute appendicitis, this study showed that the clinical evaluation is still paramount to the management of patients with suspected acute appendicitis before considering medical imaging.


Immobilized Seed-Mediated Growth of Two-Dimensional Array of Metallic Nanocrystals with Asymmetric Shapes.
Bottom-up fabrication of such arrays with specific orientation of nanoparticles remains a challenge. In this paper, we report an immobilized seed-mediated growth strategy for the fabrication of two-dimensional (2D) arrays of mono- and bimetallic polyhedral nanocrystals with well-defined shapes and orientations on a substrate. This method relies on the controlled solution-phase deposition of metals (i.e., Au and Pd) on a selectively exposed surface of self-assembled seed nanoparticles that are immobilized on a substrate through collapsed polymer brushes. By using this approach, we demonstrated the preparation of various 2D arrays of shaped Au nanocrystals and Au core/Pd shell nanocrystals with asymmetric geometry of two halves and controlled orientations with respect to the substrate. The shape evolution of seeds to final nanocrystals was systematically monitored and evaluated by electron microscopic imaging. Our study suggests that the shape and orientation of nanocrystals within arrays is determined by the preferential orientation of assembled seed nanoparticles on the substrate and controllable deposition of metals on exposed crystal facets of immobilized seeds. The synthetic approach we developed presents an important addition to current tools for the fabrication of substrate-supported functional nanostructures.


Spin wave excitation patterns generated by spin torque oscillators.
Spin torque nano-oscillators (STNO) are nanoscale devices that can convert a direct current into short wavelength spin wave excitations in a ferromagnetic layer. We show that arrays of STNO can be used to create directional spin wave radiation similarly to electromagnetic antennas. Combining STNO excitations with planar spin waves also creates interference patterns. We show that these interference patterns are static and have information on the wavelength and phase of the spin waves emitted from the STNO. We describe a means of actively controlling spin wave radiation patterns with the direct current flowing through STNO, which is useful in on-chip communication and information processing and could be a promising technique for studying short wavelength spin waves in different materials.


CDX2/mir-145-5p/SENP1 Pathways Affect LNCaP Cells Invasion and Migration.
Background/Aims: Recently, rapidly accumulating evidence has shown that microRNAs (miRNAs) are involved in human tumorigenesis, and the dysregulation of miRNAs has been observed in many cancers, including prostate cancer. miR-145-5p, an miRNA with reduced expression in prostate cancer cells, has been shown to have a tumor suppressive role in a variety of tumors. However, its underlying mechanism requires further elucidation. Methods: A lentiviral expression vector for miR-145-5p was constructed and used to establish a stable cell line (LNCaP) expressing miR-145-5p. The cells were cultured normally and divided into the control group (control), negative control group (negative control), and test group (miR-145-5p). Inhibition of proliferation was measured by a WST-8 assay. The early apoptosis rate of cells was detected by flow cytometry. Clone formation ability was detected by a clone formation inhibition test. Cell invasion and migration capacity was detected by a Transwell assay. The relative expression levels of proteins were detected by western blotting. We constructed a nude mouse model of prostate cancer to observe the effect of miR-145-5p on the growth of transplanted tumors. TargetScan bioinformatics software was used to predict target genes regulated by miR-14-5p. ChIPBase was used to predict transcription factors with binding sites in the upstream promoter region of miR-145-5p. Quantitative reverse transcription PCR was used to detect the relative expression level of genes. A bifluorescence-reporter gene vector was constructed to confirm the regulation of target genes by miR-145-5p. We used 5' rapid amplification of cDNA ends to confirm the transcription start site of miR-145-5p.Chromatin immunoprecipitation technology was used to detect the effect of transcription factors binding to miR-145-5p. Results: The overexpression of miR-145-5p not only inhibited the proliferation, invasion, and migration of LNCaP cells but also promoted their early apoptosis. After overexpressing miR-145-5p, the expression of small ubiquitin-like modifier protein-specific protease 1 (SENP1), and caudal-related homeobox 2 (CDX2) protein was decreased in LNCaP cells. The transcription factor CDX2 bound to the miR-145-5p promoter region and inhibited its transcription. The transcription start site of miR-145-5p was located at a guanine residue 1,408 bp upstream of the stem-loop sequence. Upon overexpression, miR-145-5p could bind to the 3'-untranslated region of SENP1 to inhibit its translation. Conclusion: These results suggested that CDX2 inhibits the expression of miR-145-5p, thereby relieving the inhibitory effect of miR-145-5p on the translation of SENP1 and affecting the invasion and migration of prostate cancer cells.


Microperforated hymen: a case of delayed diagnosis.
Although the incidence of microperforated hymen (MH) is unclear, this hymenal subocclusive anomaly is considered a rare entity. Differently from imperforated hymen, MH may be asymptomatic until puberty when the women's quality of life is jeopardized. Depending on the size of the microperforation, MH's clinical features me be very similar to those found in imperforated hymen cases. However, MH may present infectious complications since the accumulated secretion retained in the vaginal canal has contact with the external environment and therefore represents a source of entry for infectious agents. The authors report a case of a 28-year-old woman who sought the gynecologist complaining of inability to have vaginal intercourse. She referred normal menses, but in fact, although regular, bleeding was filiform and was exteriorized only through the right side of the vagina. Physical examination and imaging disclosed a microperforation of the hymenal membrane at 10 o'clock position. Hymenotomy under general anesthesia was undertaken. Outcome was favorable and the patient could thenceforth have a normal life. We conclude that this anomaly may be overlooked, interfering on its incidence determination. The delayed onset of symptoms and psychological embarrassing aspects, which postpone gynecological consultation, may contribute for misdiagnoses. We call attention to a mandatory detailed anamnesis and thorough physical examination to diagnose this anomaly before the puberty, when complications are less frequent and treatment is advisable.


Effects of bile salt deconjugation by probiotic strains on the survival of antibiotic-resistant foodborne pathogens under simulated gastric conditions.
This study was designed to evaluate the effects of bile acid deconjugation by probiotic strains on the antibiotic susceptibility of antibiotic-sensitive and multiple antibiotic-resistant Salmonella Typhimurium and Staphylococcus aureus. Eight probiotic strains, Bifidobacterium longum B6, Lactobacillus acidophilus ADH, Lactobacillus brevis KACC 10553, Lactobacillus casei KACC 12413, Lactobacillus paracasei ATCC 25598, Lactobacillus rhamnosus GG, Leuconostoc mesenteroides KACC 12312, and Pediococcus acidilactici KACC 12307, were used to examine bile acid tolerance. The ability to deconjugate bile acids was evaluated using both thin-layer chromatography and high-performance liquid chromatography. The antibiotic susceptibility testing was carried out to determine the synergistic inhibitory activity of deconjugated bile acids. L. acidophilus, L. brevis, and P. acidilactici showed the most tolerance to the conjugated bile acids. P. acidilactici deconjugated glycocholic acid and glycodeoxycholate from 3.18 and 3.09 mM to the detection limits, respectively. The antibiotic susceptibility of selected foodborne pathogens was increased by increasing the concentration of deconjugated bile acids. The study results are useful for understanding the relationship between bile acid deconjugation by probiotic strains and antibiotic susceptibility in the presence of deconjugated bile acids, and they may be useful for designing new probiotic-antibiotic combination therapy based on bile acid deconjugation.


[Cerebral cognitive deficits in the aged. Diagnostic and therapeutic standards: organization of strategies for problem detection and solution].
This paper reports the results of a representative survey which was performed in cooperation with 145 family physicians and 14 primary care neuropsychiatrists (response rate 83.2%) in the area of Göttingen, Germany. With the use of a standardised interview referring to written sample case histories, we investigated the diagnostic and therapeutic management of memory disturbances in old age. The results showed, that dementia and depression are underdiagnosed in primary care, and that memory disturbances are mainly regarded as consequences of disturbed cerebrovascular perfusion. About 70% of all physicians would prescribe a cognition enhancer, however about a third of them would do it in spite of major doubts about their efficacy. The results underline the necessity of continuing education especially with regard to early diagnosis of dementive and affective disorders in later life. The development of therapeutic standards in this area should take "irrational" motives into account. Appropriate exemplary case histories seem to be a potentially useful tool for the measurement of physicians' competence and its changes.


A novel family of plant DNA-binding proteins containing both HMG-box and AT-rich interaction domains.
The A/T-rich interaction domain (ARID) and the HMG-box domain represent DNA-interaction modules that are found in sequence-specific as well as nonsequence-specific DNA-binding proteins. Both domains are found in a variety of DNA-interacting proteins in a wide range of eukaryotic organisms. Proteins that contain both an ARID and an HMG-box domain, here termed ARID-HMG proteins, appear to be specific for plants. This protein family is conserved in higher plants (both mono- and dicot plants) as well as lower plants such as the moss Physcomitrella. Since ARID-HMG proteins have not been studied experimentally, we have examined here two family members from Arabidopsis. The genes encoding ARID-HMG1 and ARID-HMG2 are widely expressed in Arabidopsis but at different levels. Subcellular localization experiments studying ARID-HMG1 and ARID-HMG2 fused to GFP by fluorescence microscopy show that both proteins localize primarily to cell nuclei. Analyses of the DNA-binding properties using electrophoretic mobility shift assays revealed that mediated by the HMG-box domain, ARID-HMG1 binds structure specifically to DNA minicircles. Mediated by the ARID, the protein binds preferentially to A/T-rich DNA, when compared with G/C-rich DNA. Therefore, both DNA-binding domains contribute to the DNA interactions of ARID-HMG1. Accordingly, the protein combines DNA-binding properties characteristic of ARID and HMG-box proteins.


A cyclic peptide-based PROTAC induces intracellular degradation of palmitoyltransferase and potently decreases PD-L1 expression in human cervical cancer cells.
Our previous research has found that degradation of palmitoyltransferase in tumor cells using a linear peptide PROTAC leads to a significant decrease in PD-L1 expression in tumors. However, this degradation is not a sustained and efficient process. Therefore, we designed a cyclic peptide PROTAC to achieve this efficient anti-PD-L1 effect. We designed and synthesized an improvement in linear peptide PROTAC targeting palmitoyltransferase DHHC3, and used disulfide bonds to stabilize the continuous N- and C-termini of the peptides to maintain their structure. Cellular and molecular biology techniques were used to test the effect of this cyclic peptide on PD-L1. In human cervical cancer cells, our cyclic peptide PROTAC can significantly downregulate palmitoyl transferase DHHC3 and PD-L1 expressions. This targeted degradation effect is enhanced with increasing doses and treatment duration, with a DC50 value much lower than that of linear peptides. Additionally, flow cytometry analysis of fluorescence intensity shows an increase in the amount of cyclic peptide entering the cell membrane with prolonged treatment time and higher concentrations. The Cellular Thermal Shift Assay (CETSA) method used in this study indicates effective binding between our novel cyclic peptide and DHHC3 protein, leading to a change in the thermal stability of the latter. The degradation of PD-L1 can be effectively blocked by the proteasome inhibitor MG132. Results from clone formation experiments illustrate that our cyclic peptide can enhance the proliferative inhibition effect of cisplatin on the C33A cell line. Furthermore, in the T cell-C33A co-culture system, cyclic peptides target the degradation of PD-L1, thereby blocking the interaction between PD-L1 and PD-1, and promoting the secretion of IFN-γ and TNF-α in the co-culture system supernatant. Our results demonstrate that a disulfide-bridged cyclic peptide PROTAC targeting palmitoyltransferase can provide a stable and improved anti-PD-L1 activity in human tumor cells.


Fragile X families in a northern Swedish county--a genealogical study demonstrating apparent paternal transmission from the 18th century.
Eleven families including 35 cases with fra(X) mental retardation (MR) were traced genealogically using the Research Archives at Umeå University. Seven of the cases were women with fra(X). All of the families originated partly or totally from the county of Västerbotten. It was possible to link 7 of the index families to common ancestors over an 8-11 generation span. The remaining 4 families were not traced to the same ancestors. However, they were linked together pair-wise over a 7-8 generation span. Transmission of the fra(X) mutation was studied in these families. In the pedigree analyses, priority was given to maternal transmission. In 2 families the fra(X) mutation was transmitted solely through females over 7 or 8 generations respectively. Within 9 families the mutation was transmitted by males in 2-5 generations in order to reach common ancestors.


Effects of oxymetazoline on the ventilation of paranasal sinuses in healthy subjects.
Impairment of sinus ostial function is considered an important factor in the pathophysiology of sinus disease. The use of the decongestants such as alpha2-agonists is thought to improve sinus ostial function. Previous studies have shown an effect of alpha2-agonists on maxillary sinus ostial function only when administered in nasal bellows, but not as a nasal spray or nasal drops. The effect of decongestants on ventilation of the frontal and posterior ethmoidal and sphenoidal sinuses has not been studied to date. In this study, the 133-xenon washout method was used to determine ventilation for all paranasal sinuses before and after administration of oxymetazoline as nasal drops in eight subjects and from nasal bellows in nine healthy subjects. No significant effect of oxymetazoline on sinus ventilation was seen in either group. The results indicate that alpha2-agonists do not have any effect on sinus ventilation in healthy subjects. However, one cannot exclude that decongestants improve sinus ventilation in patients suffering from sinus disease and this requires further studies.


Comparison of the relative effects of aspirin, mefenamic acid, dihydrocodeine, dextropropoxyphene and paracetamol on visceral pain, respiratory rate and prostaglandin biosynthesis.
A comparison was made between the relative effects of aspirin, mefenamic acid, dihydrocodeine , dextropropoxyphene and paracetamol on visceral pain (chemically-inducing writhing), respiratory rate and prostaglandin (PG) biosynthesis (cyclo-oxygenase activity). A close correlation was found to exist between inhibition of PG biosynthesis and inhibition of visceral pain for mefenamic acid, aspirin and paracetamol. Analysis of the complete activity profiles derived from evaluation of the test parameters yielded the following rank order of overall ratios of their beneficial anti-writhing/anti-cyclo-oxygenase to respiratory depressive activities: (1) mefenamic acid, (2) aspirin, (3) dihydrocodeine , (4) dextropropoxyphene and paracetamol.


Vocational interests of air traffic control personnel.
The interest patterns of air traffic controllers were surveyed for the purposes of a) determining the interests of journeyman controllers, b) determining the relationships of controller interests to those of other occupational groups, c) devising an interest scale for air traffic work, and d) developing a measure for guidance for selection of air traffic specialtites (Terminal, En Route, Flight Service). A total of 787 male controllers from Terminal, En Route, and FSS facilities completed the Strong Vocational Interest Blank, a measure of interest patterns. It was found that none of the existing occupational scales clearly reflected the interest patterns of controllers. An air traffic controller scale was devised which distinguished the air traffic controllers from men in general and from men in other occupations. There were no substantial differences between the interest patterns for the three options; however, it was found that dissatisfied controllers scored lower on the overall air traffic controller scale than did satisfied controllers.