Hypoparathyroidism following total laryngopharyngectomy and gastric pull-up.
We have used the gastric pull-up technique for closure of large pharyngoesophageal defects after radical oncological surgery since 1979. The management of severe hypocalcemia and hypovitaminosis D seemed more difficult in patients undergoing pull-up reconstruction than in patients undergoing the same extirpative surgery, but reconstructed with more traditional methods. To determine if hypocalcemia and hypovitaminosis D were more common in gastric pull-up patients, and if postoperative management of these conditions is more problematic in this group, we retrospectively compared three groups of head and neck surgery patients. Group 1 consisted of 17 patients undergoing total laryngectomy with thyroid complex preservation. Group 2 consisted of 7 patients undergoing mediastinal dissection with total laryngectomy-thyroidectomy previously or concurrently. Group 3 consisted of 30 patients undergoing total laryngopharyngoesophagectomy-thyroidectomy and gastric pull-up reconstruction. The incidences of hypocalcemia requiring therapy were 12%, 50%, and 73%, respectively, with an overall incidence of 51%. The average amounts of supplemental calcium and vitamin D in the three groups were compared. A significant between the three groups was noted. Finally, the dietary calcium and vitamin D requirements for one problematic patient were prospectively recorded and summarized graphically. We conclude that any patient should be carefully monitored for the signs and symptoms of hypocalcemia after major head and neck surgery. In the special instance of the gastric pull-up patient, calcium requirements and the range of serum calcium fluctuation are greatly increased compared to patients undergoing more traditional methods of reconstruction.


A cleavable signal peptide enhances cell surface delivery and heterodimerization of Cerulean-tagged angiotensin II AT1 and bradykinin B2 receptor.
Heterodimerization of the angiotensin II AT1 receptor with the receptor for the vasodepressor bradykinin, B2R, is known to sensitize the AT1-stimulated response of hypertensive individuals in vivo. To analyze features of that prototypic receptor heterodimer in vitro, we established a new method that uses fluorescence resonance energy transfer (FRET) and applies for the first time AT1-Cerulean as a FRET donor. The Cerulean variant of the green fluorescent protein as donor fluorophore was fused to the C-terminus of AT1, and the enhanced yellow fluorescent protein (EYFP) as acceptor fluorophore was fused to B2R. In contrast to AT1-EGFP, the AT1-Cerulean fusion protein was retained intracellularly. To facilitate cell surface delivery of AT1-Cerulean, a cleavable signal sequence was fused to the receptor's amino terminus. The plasma membrane-localized AT1-Cerulean resembled the native AT1 receptor regarding ligand binding and receptor activation. A high FRET efficiency of 24.7% between membrane-localized AT1-Cerulean and B2R-EYFP was observed with intact, non-stimulated cells. Confocal FRET microscopy further revealed that the AT1/B2 receptor heterodimer was functionally coupled to receptor desensitization mechanisms because activation of the AT1-Cerulean/B2R-EYFP heterodimer with a single agonist triggered the co-internalization of AT1/B2R. Receptor co-internalization was sensitive to inhibition of G protein-coupled receptor kinases, GRKs, as evidenced by a GRK-specific peptide inhibitor. In agreement with efficient AT1/B2R heterodimerization, confocal FRET imaging of co-enriched receptor proteins immobilized on agarose beads also detected a high FRET efficiency of 24.0%. Taken together confocal FRET imaging revealed efficient heterodimerization of co-enriched and cellular AT1/B2R, and GRK-dependent co-internalization of the AT1/B2R heterodimer.


Abandoning the dead donor rule? A national survey of public views on death and organ donation.
Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the 'dead donor rule', which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma.


Response of microtubules to the addition of colchicine and tubulin-colchicine: evaluation of models for the interaction of drugs with microtubules.
The effects of free drug and tubulin-drug complexes on steady-state GTP/GDP-associated microtubules and on equilibrium guanosine 5'[beta,gamma-imido]triphosphate-associated microtubules are compared. The addition of colchicine or the tubulin-colchicine complex (TuCol) to steady-state microtubules induces microtubule disassembly. Only limited disassembly of equilibrium microtubules is observed under similar conditions. Addition of colchicine or the bifunctional colchicine analogue 2-methoxy-5-(2'3',4'-trimethoxyphenyl)tropone to preassembled steady-state or equilibrium microtubules does induce disassembly, but establishment of the new steady state or equilibrium is very slow. These observations are related to the fact that TuCol readily adds to the microtubule end, but is only incorporated into the lattice with difficulty. As a result, microtubule growth is effectively inhibited and the critical concentration is significantly increased. Nevertheless, drug-induced disassembly can be extremely slow, because the frequency of addition reactions increases as the concentration of soluble dimers increases. The efficiency of incorporation of TuCol decreases as it concentration increases. The work further confirms the existence of colchicine-binding sites with low affinity (association constant KMT approximately 3 x 10(2) M-1) along the microtubule lattice. This value suggests that part of the colchicine-binding site on tubulin remains available in the polymer. The interaction of colchicine with these sites has no appreciable effect on microtubule dynamics. These observations are reproduced and rationalized by the model described elsewhere [Vandecandelaere, Martin, Bayley and Schilstra (1994) Biochemistry 33, 2792-2801], and the possibility that there are co-operative effects in the inhibition is considered.


Concept recognition as a machine translation problem.
Automated assignment of specific ontology concepts to mentions in text is a critical task in biomedical natural language processing, and the subject of many open shared tasks. Although the current state of the art involves the use of neural network language models as a post-processing step, the very large number of ontology classes to be recognized and the limited amount of gold-standard training data has impeded the creation of end-to-end systems based entirely on machine learning. Recently, Hailu et al. recast the concept recognition problem as a type of machine translation and demonstrated that sequence-to-sequence machine learning models have the potential to outperform multi-class classification approaches. We systematically characterize the factors that contribute to the accuracy and efficiency of several approaches to sequence-to-sequence machine learning through extensive studies of alternative methods and hyperparameter selections. We not only identify the best-performing systems and parameters across a wide variety of ontologies but also provide insights into the widely varying resource requirements and hyperparameter robustness of alternative approaches. Analysis of the strengths and weaknesses of such systems suggest promising avenues for future improvements as well as design choices that can increase computational efficiency with small costs in performance. Bidirectional encoder representations from transformers for biomedical text mining (BioBERT) for span detection along with the open-source toolkit for neural machine translation (OpenNMT) for concept normalization achieve state-of-the-art performance for most ontologies annotated in the CRAFT Corpus. This approach uses substantially fewer computational resources, including hardware, memory, and time than several alternative approaches. Machine translation is a promising avenue for fully machine-learning-based concept recognition that achieves state-of-the-art results on the CRAFT Corpus, evaluated via a direct comparison to previous results from the 2019 CRAFT shared task. Experiments illuminating the reasons for the surprisingly good performance of sequence-to-sequence methods targeting ontology identifiers suggest that further progress may be possible by mapping to alternative target concept representations. All code and models can be found at: https://github.com/UCDenver-ccp/Concept-Recognition-as-Translation .


The role of brain gaseous neurotransmitters in anxiety.
Although anxiety is perhaps one of the most significant current medical and social problems, the neurochemical mechanistic background of this common condition remains to be fully understood. Multifunctional regulatory gasotransmitters are novel, atypical inorganic factors of the brain that are involved in the mechanisms of anxiety responses. Nitric oxide (NO) signaling shows ambiguous action in animal models of anxiety, while NO donors exert anxiogenic or anxiolytic effect depending on their chemical structure, dose, treatment schedule and gas release rapidity. The majority of NO synthase inhibitors act as a relatively potent axiolytic agents, while hydrogen sulfide (H2S) and carbon monoxide (CO) delivered experimentally in the form of "slow" or "fast" releasing donors have recently been considered as anxiolytic neurotransmitters. In this comprehensive review we critically summarize the literature regarding the intriguing roles of NO, H2S and CO in the neuromolecular mechanisms of anxiety in the context of their putative, yet promising therapeutic application. A possible mechanism of gasotransmitter action at the level of anxiety-related synaptic transmission is also presented. Brain gasesous neuromediators urgently require further wide ranging studies to clarify their potential value for the current neuropharmacology of anxiety disorders.


Transactional analysis of the reciprocal links between peer experiences and academic achievement from middle childhood to early adolescence.
This study tested a transactional model of reciprocal influences regarding students' peer experiences (peer acceptance, peer rejection, and friends' academic achievement) and students' academic achievement from middle childhood to early adolescence. This longitudinal model was tested on 452 students (198 girls), mostly Caucasian and French speaking, who were assessed yearly from Grades 2 through 7. Structural equation models revealed that, for boys and for girls, higher academic achievement predicted (a) increases in peer acceptance from Grades 2 through 6, (b) decreases in peer rejection from Grades 2 through 4 (through Grade 5 for girls), and (c) increases in friends' achievement from Grades 4 through 7. Also, rejection predicted decreases in academic achievement from Grades 3 through 5. These results suggest that academic achievement is a good predictor of peer group status in middle childhood and that high-achieving students start selecting each other as friends as they enter early adolescence. These data also suggest that peer rejection in childhood may disrupt future academic achievement. Possible mediating mechanisms, as well as peer selection and influences in the context of social development, are discussed.


Measuring and improving the quality of postoperative epidural analgesia for major abdominal surgery using statistical process control charts.
To explore and improve the quality of continuous epidural analgesia for pain relief using Statistical Process Control tools. Measuring the quality of pain management interventions is complex. Intermittent audits do not accurately capture the results of quality improvement initiatives. The failure rate for one intervention, epidural analgesia, is approximately 30% in everyday practice, so it is an important area for improvement. Continuous measurement and analysis are required to understand the multiple factors involved in providing effective pain relief. Process control and quality improvement Routine prospectively acquired data collection started in 2006. Patients were asked about their pain and side effects of treatment. Statistical Process Control methods were applied for continuous data analysis. A multidisciplinary group worked together to identify reasons for variation in the data and instigated ideas for improvement. The key measure for improvement was a reduction in the percentage of patients with an epidural in severe pain. The baseline control charts illustrated the recorded variation in the rate of several processes and outcomes for 293 surgical patients. The mean visual analogue pain score (VNRS) was four. There was no special cause variation when data were stratified by surgeons, clinical area or patients who had experienced pain before surgery. Fifty-seven per cent of patients were hypotensive on the first day after surgery. We were able to demonstrate a significant improvement in the failure rate of epidurals as the project continued with quality improvement interventions. Statistical Process Control is a useful tool for measuring and improving the quality of pain management. The applications of Statistical Process Control methods offer the potential to learn more about the process of change and outcomes in an Acute Pain Service both locally and nationally. We have been able to develop measures for improvement and benchmarking in routine care that has led to the establishment of a national pain registry.


Center of Excellence to build nursing scholarship and improve health care in Italy.
This article profiles the establishment and initial phase (2010-2014) of a Center of Excellence (CoE) as an instrument to strengthen nursing scholarship and improve health care in Italy. This CoE is unique as a non-university-based center. The National Regulatory Board of Registered Nurses, Health Visitors, and Pediatric Nurses (IPASVI) designated substantial administrative and funding support to the CoE for advancing nursing education, clinical practice, research development, and research training. Boyer's Model of Scholarship underpinned the CoE's conceptual framework, and its operational infrastructure was adapted from the U.S. National Institutes of Health P20 program award mechanism. Diverse methods included sponsoring research studies by nurse-led teams, research training courses, nursing education longitudinal studies, evidence-based practice training, and related pilot studies. Multiple collaborative projects were conducted via the CoE in conjunction with the successful launch of an expansive digital library and communication system accessible to nurses. The introduction of English proficiency courses was also a unique contribution. The CoE concept is a potential instrument to strengthen nursing scholarship in Italy with potential scalability considerations to other global settings. An overlapping focus on research, education, and practice under the umbrella of nursing scholarship within a CoE while engaging all levels of nursing is important to impact healthcare changes.


Safety of oral terbinafine: results of a postmarketing surveillance study in 25,884 patients.
To broaden the safety database for oral terbinafine by determining the incidence of adverse events, particularly rare risks, that accompany its uncontrolled use in actual clinical practice. Four open, prospective, uncontrolled, postmarketing surveillance studies were conducted in unselected patients in 4 countries. No exclusion criteria were applied. The only treatment instructions participating physicians received were the manufacturer's product information. Physicians monitored patients for adverse events at baseline, during treatment, and at the end of treatment. Serious events were identified according to study protocol, which was consistent for all 4 studies, allowing data to be pooled and analyzed collectively. Patients were recruited from dermatology, general, and family practices in the United Kingdom, the Netherlands, Germany, and Austria. Of the 25884 patients who entered the study, 38.6% had concomitant diseases, 42.8% were taking other medications, and 22.7% were older than 60 years. The predominant indication for terbinafine treatment was onychomycosis (72.2%). Data on treatment duration was available for 25091 patients. Median duration of treatment was 12 weeks (mean, 13.2 weeks). Treatment extended beyond 6 weeks in 76.0% of patients and for at least 12 weeks in 59.3%. The incidence of adverse events as reported by physicians, with their opinions regarding relationship to terbinafine therapy. The incidence of adverse events was 10.5%; the majority involved the gastrointestinal system (4.9%) or skin (2.3%). These tended to be mild, transient, and reversible. Terbinafine was considered a possible or probable cause of 11 (0.04%) serious adverse events. No drug interactions were reported, even in patients taking oral antidiabetic agents, astemizole, terfenadine, or cimetidine hydrochloride. The positive safety profile established during controlled clinical trials of oral terbinafine extends to its uncontrolled use in clinical practice. No previously unrecognized risks were identified.


Characterization of (R)- and (S)-[18F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors.
The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [18F]OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[18F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.


The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions.
The aim of the present study was to investigate whether selective antagonism of the cysteine-X-cysteine chemokine receptor-2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens. In a double-blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte-colony stimulating factor (G-CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli. AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of -1.67 (0.67) ×10(9) l(-1) vs. 0.19 (0.78) ×10(9) l(-1) for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10-min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G-CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo- and AZD5069-treated subjects. Superoxide anion production in E. coli-stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated. CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.


Novel acyl alpha-pyronoids, dictyopyrone A, B, and C, from Dictyostelium cellular slime molds.
For the elucidation of the diversity of secondary metabolites of Dictyostelium cellular slime molds, we investigate the constituent of three species of slime molds. From the methanol extract of their fruit bodies, we obtained three novel compounds, dictyopyrone A (1) and B (2) from D. discoideum and D. rhizoposium and dictyopyrone C (3) from D. longosporum. They possess a unique alpha-pyrone moiety with a side chain at the C-3 position. Their relative structures were elucidated by spectral means, and the absolute configuration was confirmed by asymmetric synthesis of 1. Since these compounds were obtained from different species of Dictyostelium slime molds, they may be a type of compound common to this genus.


Platelet-rich plasma in the management of Asherman's syndrome: An RCT.
Asherman's syndrome (AS) is a rare reproductive abnormality, resulting in endometrial collapse due to aggressive or recurrent endometritis and/or curettage. We aimed to assess the effectiveness of using platelet-rich plasma (PRP) to lower the recurrence rate of intrauterine adhesions (IUAs) following hysteroscopy. In this non-randomized clinical trial, women aged 20-45 years with AS diagnosed by sonohysterography, 3D sonography, hysteroscopy, or uterosalpingography between May 2018 and September 2018 were included. Participants (n = 30) were divided into case and control groups. Following hysteroscopic adhesiolysis, a Foley catheter was placed into the uterine cavity in all women. After two days, the catheter was removed, and 1-mL PRP was injected into the uterine cavity of women in the PRP (case) group, while the control received no PRP. All controls and subjects underwent diagnostic hysteroscopy 8-10 weeks following the intervention to assess the IUAs according to the American Society for Reproductive Medicine scoring system. Our results did not reveal any significant difference in the menstrual pattern of either the control or test groups before or after treatment (p = 0.2). Moreover, the IUA stage in both studied groups before and after treatment was similar (p = 0.2). The duration of menstrual bleeding in both studied groups before and after treatment was also similar. PRP cannot change the menstrual pattern or development of postsurgical AS, as evaluated by follow-up hysteroscopy.


Hospital accreditation, reimbursement and case mix: links and insights for contractual systems.
Resource consumption is a widely used proxy for severity of illness, and is often measured through a case-mix index (CMI) based on Diagnosis Related Groups (DRGs), which is commonly linked to payment. For countries that do not have DRGs it has been suggested to use CMIs derived from International Classification of Diseases (ICD). Our research objective was to use ICD-derived case-mix to evaluate whether or not the current accreditation-based hospital reimbursement system in Lebanon is appropriate. Our study population included medical admissions to 122 hospitals contracted with the Lebanese Ministry of Public Health (MoPH) between June 2011 and May 2012. Applying ICD-derived CMI on principal diagnosis cost (CMI-ICDC) using weighing similar to that used in Medicare DRG CMI, analyses were made by hospital accreditation, ownership and size. We examined two measures of 30-day re-admission rate. Further analysis was done to examine correlation between principal diagnosis CMI and surgical procedure cost CMI (CMI-CPTC), and three proxy measures on surgical complexity, case complexity and surgical proportion. Hospitals belonging to the highest accreditation category had a higher CMI than others, but no difference was found in CMI among the three other categories. Private hospitals had a higher CMI than public hospitals, and those more than 100 beds had a higher CMI than smaller hospitals. Re-admissions rates were higher in accreditation category C hospitals than category D hospitals. CMI-ICDC was fairly correlated with CMI-CPTC, and somehow correlated with the proposed proxies. Our results indicate that the current link between accreditation and reimbursement rate is not appropriate, and leads to unfairness and inefficiency in the system. Some proxy measures are correlated with case-mix but are not good substitutes for it. Policy implications of our findings propose the necessity for changing the current reimbursement system by including case mix and outcome indicators in addition to accreditation in hospital contracting. Proxies developed may be used to detect miss-use and provider adverse behavior. Research using ICD-derived case mix is limited and our findings may be useful to inform similar initiatives and other limited-setting countries in the region.


Food or medicine? A European regulatory perspective on nutritional therapy products to treat inborn errors of metabolism.
Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs.


A comparison of the cardiovascular effects of simulated and spontaneous laughter.
Laughter has long been regarded as beneficial for health, but the mechanisms are not clearly understood. The current study aimed to compare the acute cardiovascular effects of spontaneous and simulated laughter. A mixed factorial experiment was performed to examine changes in cardiovascular variables in response to experimental tasks across conditions. A sample of 72 participants were randomised to one of three 6 min interventions. Participants in the simulated laughter condition were asked to generate fake laughter, the spontaneous laughter condition viewed a humorous video, and the control condition watched a non-humorous documentary. This was followed by a laboratory stress task. Heart rate and heart rate variability (as indexed by rMSSD) were monitored continuously throughout the experiment using ECG. The simulated laughter condition had a significantly higher heart rate (p < .001, ηp2 = .26) and lower rMSSD (p < .001, ηp2 = .13) during the laughter task compared to the other two conditions. Follow-up hierarchical regressions indicated that the difference in heart rate was due to the fact that the simulated condition produced more laughter. The difference in rMSSD, however, was unique to the simulated condition even when controlling for the amount of laughter. The simulated laughter condition had a significantly lower mean HR during the stress task but this was not significant after controlling amount of laughter produced. Laughter leads to increased heart rate and reduced heart rate variability, which is similar to the effects of exercise. This finding is more pronounced in simulated laughter.


Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development.
The homeobox transcription factor hepatocyte nuclear factor 1beta (HNF1beta) is a tissue-specific regulator that plays an essential role in early vertebrate development. In humans, heterozygous mutations in the HNF1beta gene are associated with young-onset diabetes as well as a variety of disorders of renal development with cysts as the most consistent feature. This report compares and classifies nine different HNF1beta mutations that lead in humans to distinct renal diseases, including solitary functioning kidney, renal dysplasia, glomerulocystic kidney disease, and oligomeganephronia. Analysis of these mutants in vitro identifies mutants that either retain or lack DNA binding. Investigation of the transactivation potential in transfected cell lines reveals a strict correlation between DNA binding and transactivation. Introduction of these mutants into developing Xenopus embryos shows that these mutants interfere with pronephros development, the first kidney form in amphibian. Whereas three mutants lead in Xenopus to a reduction or agenesis of the pronephric tubules and the anterior part of the duct, six mutants generate an enlargement of the pronephric structures. The differential morphogenetic potential in the developing embryo does not strictly correlate with the properties observed in vitro or in transfected cell lines. This suggests that the functional test in the developing embryo defines features of the HNF1beta protein that cannot be assessed in cell cultures. The distinct properties observed in the various HNF1beta mutants may guide the classification of the phenotypes observed in patients with a mutated HNF1beta gene.


Anti-Müllerian hormone is an independent marker for oocyte survival after vitrification.
This study explored the relationship between anti-Müllerian hormone (AMH) and oocyte survival after vitrification. The association between AMH and blastocyst formation after oocyte vitrification was also assessed. A retrospective observational analysis was performed in a private IVF centre. A total of 4507 metaphase-II warmed oocytes were included from 450 couples, predominantly of Arab ethnicity. Between August 2015 and August 2018, couples underwent 484 intracytoplasmic sperm injection (ICSI) treatments using vitrified-warmed oocytes. Patients' median age ± SD was 36.2 ± 6.1 years, AMH concentration 2.6 ± 3.4 ng/ml and body mass index (BMI) 26.5 ± 4.6 kg/m2. The oocyte survival rate after vitrification was 87.37 ± 20.42%. AMH concentration showed a significant correlation (Kendall's tau 0.087, P = 0.0079) with oocyte survival rate independent of oocyte yield. Correlation was significant (odds ratio 1.041, 95% confidence interval 1.007-1.077, P = 0.018) when a multivariant model was applied that included AMH, age and BMI. The receiver operating characteristic curve showed an AMH cut-off value of 1.09 ng/ml that could obtain at least a 70% survival rate, with an area under the curve of 0.669. Regarding embryo development in ICSI cycles including fresh and warmed oocytes for the same patient, blastocyst formation rate was higher in fresh compared with warmed oocytes (P < 0.001). In this subgroup no significant correlation was seen between fertilization or blastocyst rate and AMH concentration. AMH concentration showed a significant correlation with oocyte survival. Blastocyst formation was significantly lower after oocyte vitrification, but no correlation was found with AMH. Clinicians should carefully evaluate oocyte vitrification for patients with AMH below 1.09 ng/ml and consider embryo accumulation for these patients in preference to oocyte accumulation.


Administration of human umbilical cord blood cells produces interleukin-10 (IL-10) in IL-10 deficient mice without immunosuppression.
Recent studies from our laboratory have shown that intravenous administration of human umbilical cord blood (HUCB) mononuclear cells to mice improved blood glucose levels, survival, atherosclerosis and prostate cancer. In this study, we examined the effect of HUCB cells on the production of IL-10 levels in IL-10 knockout mice. It has been proposed that administration of IL-10 may be beneficial in the treatment of inflammatory bowl disease. The results show that mice treated with HUCB cells (100 x 10(6)) produce IL-10, as demonstrated by both qualitative and quantitative analyses, and that the levels of this cytokine persisted until the mice were sacrificed (5.5 months after administration). Immunohistochemical staining of the intestine using HuNu antibody cocktail demonstrated the presence of HUCB cells in the knockout mouse. Although the mice did not receive any immunosuppression, there was no evidence of graft-versus-host disease. Our data suggest that HUCB cells are capable of producing IL-10, and the use of these cells or HUCB may be indicated in the treatment of certain human diseases.


[Intravascular lymphomatosis. A report of three cases].
Intravascular lymphomatosis (IVL) is a rare malignancy characterized by a proliferation of atypical lymphoid cells occluding small blood vessels (venules, capillaries and small arteries). The symptoms are caused by embolisms due to massive proliferation. Nervous system and skin are the most common sites of involvement but all organs may be involved, although it is typified by the absence of malignant cells in lymphoid tissues. We describe three cases of IVL: first patient was a 57 years old man with rapidly progressive dementia and neurological involvements and second case of a 69 years old man hospitalised with predominant symptoms in the lung (cough, dyspnea and fever), and a woman presenting as fever of unknown origin (FUO) with systemic inflammatory response syndrome. In all cases that we reported have been diagnosed post-mortem because of rapid progression of a multisystem disease and the absence of pathognomonic clinical manifestations. Diagnosis can be made using biopsy of one of the involved organs. In conclusion, we propose that IVL should be included in the differential diagnosis of acute confusional state, dementia or other unexplained neurological manifestations, fever of unknown origin, vasculitis, occult neoplasia or infections with signs of a systemic disease and marked elevation of serum lactate dehydrogenase (LDH).


A study to compare the performance of anganwadi workers in owned and rented anganwadi centers in a district of the western part of India.
The Integrated Child Development Services (ICDS) scheme is one of the flagship programs, and under this, various activities like non-formal education on one hand and breaking the vicious cycle of malnutrition, morbidity, and mortality on the other hand are carried out by anganwadi worker (AWW). The aim of this study is to assess the AWWs performance and beneficiary participation in respect to the ICDS scheme. This is a community-based, cross-sectional study done in two stages using a simple random sampling technique. Ahmedabad Municipal Corporation (AMC) area is divided into 10 parts called ghatak, and out of these 10 ghataks, 6 were chosen in the first stage, and in the second stage, 12 anganwadi centers were selected from these 6 selected ghataks using simple random sampling. In this study, 58.3% of anganwadi workers were graduates. While talking about work related to "Home Visit" and "Immunization Sessions," there was no statistically significant difference between owned and rented anganwadi center noted. While in "Nutrition & health education"-related work, there was a statistically significant difference between owned and rented anganwadi centers observed. Accuracy of weighing, plotting, and interpretation skill was more than 90% found in both the rented and owned anganwadi center. An almost similar level of nutritional status was observed in both owned and rented centers. In terms of performance and participation, there was not much difference between corporation own and rented anganwadi centers, although there were shared concerns related to frequent changes of place of rented anganwadi centers affecting the participation of beneficiaries.


Hypertension and obesity in African-American patients undergoing surgery.
This study was designed to determine the prevalence of hypertension and obesity in a population of African-American patients scheduled to undergo surgery. Weight and blood pressure were measured in 431 randomly selected patients. This included 282 women (65%) and 149 men (35%). Hypertension was present in 27% of the women and 32% of the men. Obesity was present in 58% of the women and 23% of the men. Fifteen percent of all patients met the criteria for having both hypertension and obesity. This study confirms the high incidence of hypertension and obesity in the African-American population. The high morbidity and mortality associated with these conditions suggest that a renewed community-wide effort and public education program on the part of health-care providers is needed to inform this patient population of these dangers.


New Logic-In-Memory Paradigms: An Architectural and Technological Perspective.
Processing systems are in continuous evolution thanks to the constant technological advancement and architectural progress. Over the years, computing systems have become more and more powerful, providing support for applications, such as Machine Learning, that require high computational power. However, the growing complexity of modern computing units and applications has had a strong impact on power consumption. In addition, the memory plays a key role on the overall power consumption of the system, especially when considering data-intensive applications. These applications, in fact, require a lot of data movement between the memory and the computing unit. The consequence is twofold: Memory accesses are expensive in terms of energy and a lot of time is wasted in accessing the memory, rather than processing, because of the performance gap that exists between memories and processing units. This gap is known as the memory wall or the von Neumann bottleneck and is due to the different rate of progress between complementary metal-oxide semiconductor (CMOS) technology and memories. However, CMOS scaling is also reaching a limit where it would not be possible to make further progress. This work addresses all these problems from an architectural and technological point of view by: (1) Proposing a novel Configurable Logic-in-Memory Architecture that exploits the in-memory computing paradigm to reduce the memory wall problem while also providing high performance thanks to its flexibility and parallelism; (2) exploring a non-CMOS technology as possible candidate technology for the Logic-in-Memory paradigm.


N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection.
Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment.


A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex.
Rad9, Rad1, and Hus1 are members of the Rad family of checkpoint proteins that are required for both DNA replication and DNA damage checkpoints and are thought to function as sensors in the DNA integrity checkpoint control. These proteins can interact with each other and form a stable proliferating cell nuclear antigen-related Rad9.Rad1.Hus1 heterotrimeric complex that might encircle DNA at or near the damaged sites. In this study, we demonstrate that the human Rad9 (hRad9) protein contains a predicted nuclear localization sequence (NLS) near its C terminus, which plays an essential role in the hRad9-mediated G(2) checkpoint. Deletion experiments indicate that the NLS-containing region of hRad9 is critical for the nuclear transport of not only hRad9 but also human Rad1 (hRad1) and human Hus1 (hHus1), although this region is not required for hRad9.hRad1.hHus1 complex formation. In support of the role that hRad9 NLS plays in the nuclear targeting of the hRad9.hRad1.hHus1 complex, overexpression of a deletion mutant of hRad9 lacking the NLS-containing C-terminal region can bypass the G(2) checkpoint and result in cell death after ionizing radiation or hydroxyurea treatment. Moreover, knockdown of hRad9 expression by small interfering RNA (siRNA) results in hRad1 accumulation in the cytoplasm and significantly abrogates the G(2) checkpoint in the presence of damaged DNA or incomplete DNA replication. Thus, the C-terminal region of human Rad9 protein is important for G(2) checkpoint control by operating the transport of the hRad9.hRad1.hHus1 checkpoint complex into the nucleus.


Neutrality tests using DNA polymorphism from multiple samples.
The polymorphism of a gene or a locus is studied with increasing frequency by multiple laboratories or the same group at different times. Such practice results in polymorphism being revealed by different samples at different regions of the locus. Tests of neutrality have been widely conducted for polymorphism data but commonly used statistical tests cannot be applied directly to such data. This article provides a procedure to conduct a neutrality test and details are given for two commonly used tests. Applying the two new tests to the chemokine-receptor gene (CCR5) in humans, we found that the hypothesis that all mutations are selectively neutral cannot explain the observed pattern of DNA polymorphism.


Analysis of aneuploid lines of bread wheat to map chromosomal locations of genes controlling root hair length.
Long root hairs enable the efficient uptake of poorly mobile nutrients such as phosphorus. Mapping the chromosomal locations of genes that control root hair length can help exploit the natural variation within crops to develop improved cultivars. Genetic stocks of the wheat cultivar 'Chinese Spring' were used to map genes that control root hair length. Aneuploid stocks of 'Chinese Spring' were screened using a rapid method based on rhizosheath size and then selected lines were assayed for root hair length to identify chromosomes harbouring genes controlling root hair length. A series of lines with various fractional deletions of candidate chromosomes were then screened to map the root hair loci more accurately. A line with a deletion in chromosome 5A was analysed with a 90 000 single nucleotide polymorphism (SNP) array. The phosphorus acquisition efficiency (PAE) of one deletion line was compared with that of euploid 'Chinese Spring' by growing the seedlings in pots at low and luxury phosphorus supplies. Chromosomes 1A, 1D and 5A were found to harbour genes controlling root hair length. The 90 000 SNP array identified two candidate genes controlling root hair length located on chromosome 5A. The line with a deletion in chromosome 5A had root hairs that were approx. 20 % shorter than euploid 'Chinese Spring', but this was insufficient to reduce its PAE. A rapid screen for rhizosheath size enabled chromosomal regions controlling root hair length to be mapped in the wheat cultivar 'Chinese Spring' and subsequent analysis with an SNP array identified candidate genes controlling root hair length. The difference in root hair length between euploid 'Chinese Spring' and a deletion line identified in the rapid screen was still apparent, albeit attenuated, when the seedlings were grown on a fully fertilized soil.


Prediction of recidivism in extrafamilial child molesters based on court-related assessments.
One hundred ninety-two convicted extrafamilial child molesters were followed for an average of 7.8 years after their conviction. The percentage of men who had committed a sexual, a violent, or any criminal offense by the 12th year was 15.1, 20.3, and 41.6, respectively. The sexual recidivists, compared with the nonrecidivists; demonstrated more problems with alcohol and showed greater sexual arousal to assaultive stimuli involving children than to mutually consenting stimuli with children. The violent recidivists, compared with the nonrecidivists, were more likely to have a history of violence in the families in which they were raised and were rated significantly more psychopathic on the Psychopathy Checklist--Revised (PCL-R). They also showed more sexual arousal to stimuli depicting mutually consenting sexual interactions with children than to adult stimuli. In terms of any criminal recidivism, recidivists were younger, had completed fewer years of school, and were raised in psychologically more harmful family environments compared with nonrecidivists. They also reported that, before 16 years of age, they were more likely to have been physically abused and were more likely to have been removed from their homes compared to those that did not recidivate. In addition, recidivists demonstrated more general hostility on the Buss-Durkee Hostility Inventory and were rated significantly more psychopathic on the PCL-R. The phallometric assessments revealed, that the criminal recidivists, compared to the nonrecidivists, showed more sexual arousal to stimuli depicting coercive sexual activity with children than consenting sexual activities with children. In addition, they showed more sexual arousal to scenes depicting adult rape then adult mutually consenting sex. Finally, the recidivists also had more charges or convictions for violence and any criminal acts. The small number of significant differences between recidivists and nonrecidivists in the sexual and violent categories precluded an attempt to determine which combination of factors meaningfully predicted reoffending. However, for criminal recidivism, a stepwise discriminant function analysis to assess the combination of factors that most successfully distinguished between groups in terms of criminal recidivism was significant, with subjects' age, total number of criminal convictions, and pedophile assault index being retained for optimal prediction. The procedure correctly classified 70.6% of the original group, 82.8% of the nonrecidivists, and 52.6% of the recidivists. PCL-R Total Score alone was equally successful in a similar discriminant function.


A middle fidelity model is effective in teaching and retaining skill set needed to perform a laparoscopic pyloromyotomy.
An inanimate technical skills trainer for laparoscopic pyloromyotomy (LP) has not been described. A middle fidelity model, reproducing the three consistent steps in LP, was developed as a component of a teaching module for surgical residents, and tested on medical students, residents, and pediatric surgeons. In the first phase of the study, a cohort of 29 pediatric surgeons used the LP model and completed questionnaires about the model's realism and accuracy. Descriptive statistics were used to analyze questionnaire responses. Chi-square tests were performed to determine if level of experience influenced responses. For the second phase of the study, medical students and surgical residents individually participated in the training of cognitive knowledge about hypertrophic pyloric stenosis and skills acquisition for LP. Subject testing consisted of simulator task performance and multiple-choice quiz administration immediately after training and repeated at 8 weeks after training. Data were analyzed by using paired sample t-tests and one-way analyses of variance (ANOVA). The pediatric surgeons agreed that the model accurately simulated essential components of the pyloromyotomy, and that the model would be an excellent tool to introduce surgeons to LP. A total of 26 students and early surgical residents completed the training and testing. Knowledge-based test performance improved from pre- to postinstruction by 17.45 [standard error of the mean (SEM) + 3.5] (P < 0.001) and from preinstruction to 8 weeks by 4.54 (SEM = 3.2) (P = 0.17). Mean improvement in time of simulator task performance was 85.2 +/- 75.4 seconds. Based on a one-way ANOVA, higher level of training was associated with decreased mean times (P = 0.04). Face and content validities of the simulation were demonstrated by the pediatric surgeons. An effective training experience was demonstrated with medical students and residents. At 2 months, simulator task-completion rates and task-performance times showed technical skills were retained, whereas, based on test scores, cognitive knowledge was not as well retained.


To tell or not to tell? Examining the role of discrimination in the pregnancy disclosure process at work.
Despite the rapid entrance of women into the workforce over the past several decades, many workplace experiences unique to women remain poorly understood. One critical, yet understudied, area is the intersection of work and pregnancy. Because pregnancy remains concealable for a substantial amount of time, expectant employees must navigate decisions regarding to whom, when, and how to disclose their pregnant identities at work. In light of evidence that has suggested pregnancy is often stigmatized within the workplace, I employed a retrospective longitudinal design to explore the extent to which women's expectations about discrimination-anticipated discrimination-shape their pregnancy disclosure behaviors, and the extent to which these different behavioral strategies are associated with higher or lower experienced discrimination. I also examined the link between pregnancy disclosure strategies and psychological distress. Taken together, findings suggest that pregnant employees' expectations about pregnancy discrimination play a role in shaping disclosure behaviors at work. Furthermore, certain behavioral strategies for pregnancy disclosure were linked with average reports of experienced discrimination and momentary reports of psychological distress. I also discuss theoretical and practical implications. (PsycINFO Database Record


Short-term bioassays of nitro derivatives of benzo[a]pyrene and perylene.
Several nitroarenes derived from benzo[a]pyrene and perylene and the parent hydrocarbons have been assayed for mutagenicity in the Salmonella microsome test and for affinity for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-receptor protein in rat liver cytosol. 1- and 3-nitrobenzo[a]pyrene are mutagenic in the absence of S9 and have a response pattern in several Salmonella strains resembling that shown by 1-nitropyrene. 6-Nitrobenzo[a]pyrene, 3-nitroperylene as well as the parent unsubstituted hydrocarbons require S9 for activation. The 3,6- and 3,7-dinitroperylenes and a mixture of 3,9-/3,10-dinitroperylene are all mutagenic in the absence of S9. The response pattern of 3,9-/3,10-dinitroperylene resembles that shown by 1,6- and 1,8-dinitropyrenes. The nitro derivatives which are active in the absence of S9 are all inactivated by the addition of an incomplete S9 lacking NADP but activity is regained in the presence of the complete S9 for 1-and 3-nitrobenzo[a]pyrene and 3,6-dinitroperylene, showing that these compounds are also activated by S9 enzymes. Benzo[a]pyrene, 1- and 3-nitrobenzo[a]pyrene, 3-nitroperylene and the mixture of 3,9-/3,10-dinitroperylene have a high affinity for the TCDD-receptor protein whereas the affinity is low or below the detection level for the other compounds. These results are in good agreement with known structural requirements for receptor binding.


Resolution of cell-mediated airways diseases.
"Inflammation resolution" has of late become a topical research area. Activation of resolution phase mechanisms, involving select post-transcriptional regulons, transcription factors, 'autacoids', and cell phenotypes, is now considered to resolve inflammatory diseases. Critical to this discourse on resolution is the elimination of inflammatory cells through apoptosis and phagocytosis. For major inflammatory diseases such as asthma and COPD we propose an alternative path to apoptosis for cell elimination. We argue that transepithelial migration of airway wall leukocytes, followed by mucociliary clearance, efficiently and non-injuriously eliminates pro-inflammatory cells from diseased airway tissues. First, it seems clear that numerous infiltrated granulocytes and lymphocytes can be speedily transmitted into the airway lumen without harming the epithelial barrier. Then there are a wide range of 'unexpected' findings demonstrating that clinical improvement of asthma and COPD is not only associated with decreasing numbers of airway wall inflammatory cells but also with increasing numbers of these cells in the airway lumen. Finally, effects of inhibition of transepithelial migration support the present hypothesis. Airway inflammatory processes have thus been much aggravated when transepithelial exit of leukocytes has been inhibited. In conclusion, the present hypothesis highlights risks involved in drug-induced inhibition of transepithelial migration of airway wall leukocytes. It helps interpretation of common airway lumen data, and suggests approaches to treat cell-mediated airway inflammation.


STACKED - Solvation Theory of Aromatic Complexes as Key for Estimating Drug Binding.
The use of fragments to biophysically characterize a protein binding pocket and determine the strengths of certain interactions is a computationally and experimentally commonly applied approach. Almost all drug like molecules contain at least one aromatic moiety forming stacking interactions in the binding pocket. In computational drug design, the strength of stacking and the resulting optimization of the aromatic core or moiety is usually calculated using high level quantum mechanical approaches. However, as these calculations are performed in a vacuum, solvation properties are neglected. We close this gap by using Grid Inhomogeneous Solvation Theory (GIST) to describe the properties of individual heteroaromatics and complexes and thereby estimate the desolvation penalty. In our study, we investigated the solvation free energies of heteroaromatics frequently occurring in drug design projects in complex with truncated side chains of phenylalanine, tyrosine, and tryptophan. Furthermore, we investigated the properties of drug-fragments crystallized in a fragment-based lead optimization approach investigating PDE-10-A. We do not only find good correlation for the estimated desolvation penalty and the experimental binding free energy, but our calculations also allow us to predict prominent interaction sites. We highlight the importance of including the desolvation penalty of the respective heteroaromatics in stacked complexes to explain the gain or loss in affinity of potential lead compounds.


Pulsed Electromagnetic Fields Induce Skeletal Muscle Cell Repair by Sustaining the Expression of Proteins Involved in the Response to Cellular Damage and Oxidative Stress.
Pulsed electromagnetic fields (PEMF) are employed as a non-invasive medicinal therapy, especially in the orthopedic field to stimulate bone regeneration. However, the effect of PEMF on skeletal muscle cells (SkMC) has been understudied. Here, we studied the potentiality of 1.5 mT PEMF to stimulate early regeneration of human SkMC. We showed that human SkMC stimulated with 1.5 mT PEMF for four hours repeated for two days can stimulate cell proliferation without inducing cell apoptosis or significant impairment of the metabolic activity. Interestingly, when we simulated physical damage of the muscle tissue by a scratch, we found that the same PEMF treatment can speed up the regenerative process, inducing a more complete cell migration to close the scratch and wound healing. Moreover, we investigated the molecular pattern induced by PEMF among 26 stress-related cell proteins. We found that the expression of 10 proteins increased after two consecutive days of PEMF stimulation for 4 h, and most of them were involved in response processes to oxidative stress. Among these proteins, we found that heat shock protein 70 (HSP70), which can promote muscle recovery, inhibits apoptosis and decreases inflammation in skeletal muscle, together with thioredoxin, paraoxonase, and superoxide dismutase (SOD2), which can also promote skeletal muscle regeneration following injury. Altogether, these data support the possibility of using PEMF to increase SkMC regeneration and, for the first time, suggest a possible molecular mechanism, which consists of sustaining the expression of antioxidant enzymes to control the important inflammatory and oxidative process occurring following muscle damage.


Heart failure in patients with preserved and deteriorated left ventricular ejection fraction.
To determine clinical and prognostic differences between preserved and deteriorated systolic function (defined as left ventricular (LV) ejection fractions > or = 50% and < 50%, respectively) in patients with heart failure satisfying modified Framingham criteria. Records were studied of 1252 patients with congestive heart failure (CHF) (mean (SD) age 69.4 (11.7) years; 485 women, 767 men) who had been admitted to a cardiology service for CHF in the period 1991-2002 and whose LV systolic function had been echocardiographically evaluated within two weeks of admission. Data were collected on the main clinical findings, supplementary examinations, treatment, and duration of hospitalisation. Whether the patient was alive in the spring of 2003 was evaluated by searching the general archives of the hospital and by telephone survey. LV systolic function was preserved in 39.8% of patients. Age, female to male sex ratio, and prevalence of atrial fibrillation, valve disease, and other non-ischaemic, non-dilated cardiopathies were all significantly greater in the group with preserved systolic function. New York Heart Association functional class IV, third heart sound, jugular vein congestion, cardiomegaly, radiological signs of lung oedema, pathological Q waves, left bundle branch block, sinus rhythm, ischaemic cardiopathy, and dilated cardiomyopathy were all significantly more prevalent in the group with deteriorated systolic function, as was treatment with angiotensin converting enzyme inhibitors and most other antihypertensive drugs on discharge from hospital. There was no significant difference in survival between the groups with preserved and deteriorated systolic function (either survival regardless of age at admission or in subgroups aged < 75 and > or = 75 years at admission). In the whole group, survival rates after one, three, and five years were 84.0%, 66.7%, and 50.9%, respectively. In view of the poor prognosis of patients with CHF with preserved LV systolic function, who are currently treated empirically, it is to be hoped that relevant controlled clinical trials under way will afford information allowing optimisation of their treatment.


Formation of exoplanetary satellites by pull-down capture.
The large size and wide orbit of the recently announced exomoon candidate Kepler-1625b-i are hard to explain within traditional theories of satellite formation. We show that these properties can be reproduced if the satellite began as a circumstellar co-orbital body with the original core of the giant planet Kepler-1625b. This body was then drawn down into a circumplanetary orbit during the rapid accretion of the giant planet gaseous envelope, a process termed "pull-down capture." Our numerical integrations demonstrate the stability of the original configuration and the capture process. In this model, the exomoon Kepler-1625b-i is the protocore of a giant planet that never accreted a substantial gas envelope. Different initial conditions can give rise to capture into other co-orbital configurations, motivating the search for Trojan-like companions to this and other giant planets.


Beverage consumption is not associated with changes in weight and body mass index among low-income preschool children in North Dakota.
To examine prospectively the association between beverage consumption (fruit juice, fruit drinks, milk, soda, and diet soda) and changes in weight and body mass index among preschool children. A prospective cohort study that collected dietary, anthropometric, and sociodemographic data.Subjects/Setting The study population included 1,345 children age 2 to 5 years participating in the North Dakota Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) on two visits between 6 to 12 months apart. Statistical analyses We performed linear regression analyses to examine whether beverage consumption was associated with annual change in weight and body mass index. Intakes were measured as continuous (oz/day) and we also dichotomized fruit juice, fruit drinks, and milk at high intakes. In multivariate regression analyses adjusted for age, sex, energy intake, change in height, and additional sociodemographic variables, weight change was not significantly related to intakes (per ounce) of fruit juice (beta=0.01 lb/year, 95% CI: -0.01 to 0.20, P=.28), fruit drinks (beta=-0.03 lb/year, 95% CI: -0.07 to 0.01, P=.28), milk (beta=0.00 lb/year, 95% CI: -0.02 to 0.02, P=.86), soda (beta=-0.00 lb/year, 95% CI: -0.08 to 0.08, P=.95), or diet soda (beta=0.01 lb/year, 95% CI: -0.11 to 0.13, P=.82). Findings remained null when we examined associations with body mass index and when fruit juice, fruit drinks, and milk were dichotomized at high intake levels in both analyses. Our study does not show an association between beverage consumption and changes in weight or body mass index in this population of low-income preschool children in North Dakota.


[Isolation, degradation and phylogenetic analysis of methylparathion degradative strain X4].
The strain X4 was isolated from polluted wastes of Shandong Huayang Pesticide Chemical Industry Group Co., Ltd. It was cultured with methylparathion and p-nitrophenol, a kind of intermediate during methylparathion degrading process, and used them as the sole carbon source and decomposed them into carbon dioxide and wastes. It is identified as Arthrobacter sp. by means of a series of tests, and it has visible sphere-pole variable cycle. It is bacilliform when it is cultured in nutrient broth medium within 36h, then it become short gradually, and ultimately become uniform sphericity. Bacilliform strains array in "V" or "Y" shape. It has flagellum, moveable, no sporangium, oxidates glucose: The degradative ability to pesticides of X4 was determined by gas chromatography (GC) and spectrophotometer, and the degradative rate for methylparathion at 50mg/L and rho - nitrophenol at 50mg/L is above 99% within 7h. Moreover, X4 also can degrade other organophosphate pesticides quickly. The degradative rate for methamidophos, chlorpyrifos and carbofuran is 64%, 54% and 68%, respectively. The maximal tolerant concentration of X4 to MP, PNP, methamidophos, chlorpyrifos and carbofuran is 1700mg/L, 500mg/L, 500mg/L, 300mg/L and 300mg/L, respectively. All of the above tests were determined at 30 degrees C , pH7, with an inoculum of 30% . At the same time, 16S rRNA sequence of X4 is obtained, and the similar sequences to X4 were selected from GenBank by BLAST program and the phylogenetic tree with these sequences was constructed, the relationship between X4 and referenced strains was worked out. At present, methylparathion and p-nitrophenol degradative strains reported are mostly Pseudomonas sp., Flavobacterium, Alcaligenes sp. and so on. Furthermore, those strains can only degrade MP and PNP partially. It is reported firstly here that Arthrobacter sp. can degrade both MP and PNP to small molecule synchronously and effectively. Finally, the strain X4 shows a huge potential to be used in a bioremediation application for the treatment of methlparation residues, and further research may lead to an alternative route of disposal for use in agriculture or industry.


Influence of Extracellular Vesicles on Lung Stromal Cells during Breast Cancer Metastasis.
Breast cancer is a prominent cause of cancer diagnosis and death in women globally, with over 90% of deaths being attributed to complications that arise from metastasis. One of the common locations for breast cancer metastasis is the lung, which is associated with significant morbidity and mortality. Curative treatments for metastatic breast cancer patients are not available and the molecular mechanisms that underlie lung metastasis are not fully understood. In order to better treat these patients, identifying events that occur both prior to and during metastatic spread to the lung is essential. Several studies have demonstrated that breast cancer-derived extracellular vesicles secreted from the primary breast tumor play a key role in establishing the lung pre-metastatic niche to support colonization of metastatic tumor cells. In this review, we summarize recent work supporting the influence of extracellular vesicles on stromal components of the lung to construct the pre-metastatic niche and support metastasis. Furthermore, we discuss the potential clinical applications of utilizing extracellular vesicles for diagnosis and treatment. Together, this review highlights the dynamic nature of extracellular vesicles, their roles in breast cancer metastasis to the lung, and their value as potential biomarkers and therapeutics for cancer prevention.


A Pilot E-Cigarette Voucher Scheme in a Rural County of the United Kingdom.
E-Cigarette voucher schemes have been piloted across the UK to support populations to quit smoking. This short report evaluates a scheme that targets vulnerable and disadvantaged smokers who had failed to quit smoking by other means. Descriptive summary evaluation of service data on smoking outcomes and qualitative data from selected participants, as "key-informants" (n = 4) and key stakeholders (stop smoking staff, vape shop staff, and general practitioners [GPs]). In total, 668 participants were referred to the scheme, and 340 participants redeemed a voucher. By intention to treat analysis (ITT) 143/668 (21%) were recorded as quit smoking at 4 weeks. At 12 weeks, 7.5% of participants had quit, by ITT. Overall, the pilot project was well received by clients as it offered an affordable route into vaping for smoking cessation. GPs supported the scheme and appreciated being able to offer an alternative to entrenched smokers. The scheme shows promise in supporting entrenched smokers to quit smoking. The offer of similar voucher schemes across the UK suggests the potential to reduce overall smoking prevalence and associated morbidity and mortality. Working with GPs in a deprived area, it was possible to set-up a vape shop voucher scheme for smoking cessation. Patients with comorbidities who had tried and failed to quit smoking previously were referred to receive a vape shop voucher to be redeemed for an initial starter kit, alongside support from the stop smoking service. This innovative scheme enabled 42% of entrenched smokers who redeemed a voucher to successfully quit smoking within 4 weeks.


Exosomes are endogenous nanoparticles that can deliver biological information between cells.
Exosomal particular size of 30-100 nm matches the size criterion for nanoparticles, and opens up the possibility of using exosomes as a nanoparticle drug carrier. More importantly, exosomes released from different types of host cells have different biological effects and targeting specificities. Therefore, depending on the therapeutic goal, different types of exosomes can be combined with specific drugs and serve as carriers so that personalized medicine needs are met. In addition, exosomes do not appear to have cytotoxicity. Based on the perceived advantages of exosomes, they may well serve as a next generation drug delivery mechanism that combines nanoparticle size with a non-cytotoxic effect, target specificity, and a high drug carrying capacity, to make them useful in the treatment of a variety of diseases. This review will focus on exosomes as a biological nanoparticle drug carrier with emphasis on their immune-regulatory activities.


Evaluation of systemic estrogen for preventing urinary tract infections in postmenopausal women.
Current guidelines for postmenopausal recurrent urinary tract infection (rUTI) prevention recommend the use of vaginal topical estrogen products but not systemic estrogens. Studies show that vaginal estrogen decreases the risk of rUTI, but evidence against use of systemic estrogen is less convincing. We performed a comprehensive literature review to evaluate the effect of systemic estrogen on UTI occurrence among postmenopausal women. MEDLINE (PubMed), EMBASE, and CINAHL were searched for manuscripts published in English between January 1990 and July 2020. The search terms were "urinary tract infection" and "estrogen." Inclusion criteria were studies of postmenopausal women who received systemic estrogen therapy (any regimen) that reported UTI frequency during any follow-up period. Case studies, commentaries, and reviews were excluded. A priori specifications of seven study criteria were set representing the ideal study for assessing efficacy of systemic estrogen for rUTI prevention and were used to evaluate each included study. Searches identified 281 results, and after deduplication and review, 8 studies met inclusion criteria: 4 randomized controlled trials, 1 secondary analysis of a randomized controlled trial, 1 prospective cohort study, 1 case-control study, and 1 cross-sectional study. Of the eight included studies, only two enrolled postmenopausal women with a rUTI diagnosis, four had sufficient sample size to detect a clinically meaningful difference between systemic estrogen versus placebo, two used dosage regimens anticipated to achieve a therapeutic effect, and three assessed UTI rates for an adequate duration of 6 months or more (the standard minimum duration of time needed to make a diagnosis of rUTI). Overall, none of the studies met all predefined criteria for the ideal study to assess the efficacy of systemic estrogen for rUTI prevention. UTIs will continue to be a significant cause of morbidity and hospitalizations in postmenopausal women unless more research is done to better understand the role of estrogen on UTI rates. The evidence arguing use (or abandonment) of systemic estrogen for the prevention of rUTI is based on few studies with substantial methodologic limitations; there is significant room for improvement.


Mouse model of experimental pulmonary hypertension: Lung angiogram and right heart catheterization.
Pulmonary arterial hypertension is a progressive and fatal disease and rodents with experimental pulmonary hypertension (PH) are often used to study pathogenic mechanisms, identify therapeutic targets, and develop novel drugs for treatment. Here we describe a hands-on set of experimental approaches including ex vivo lung angiography and histology and in vivo right heart catheterization (RHC) to phenotypically characterize pulmonary hemodynamics and lung vascular structure in normal mice and mice with experimental PH. We utilized Microfil polymer as contrast in our ex vivo lung angiogram to quantitatively examine pulmonary vascular remodeling in mice with experimental PH, and lung histology to estimate pulmonary artery wall thickness. The peripheral lung vascular images were selected to determine the total length of lung vascular branches, the number of branches and the number of junctions in a given area (mm-2). We found that the three parameters determined by angiogram were not significantly different among the apical, middle, and basal regions of the mouse lung from normal mice, and were not influenced by gender (no significant difference between female and male mice). We conducted RHC in mice to measure right ventricular systolic pressure, a surrogate measure for pulmonary artery systolic pressure and right ventricle (RV) contractility (RV ± dP/dtmax) to estimate RV function. RHC, a short time (4-6 min) procedure, did not alter the lung angiography measurements. In summary, utilizing ex vivo angiogram to determine peripheral vascular structure and density in the mouse lung and utilizing in vivo RHC to measure pulmonary hemodynamics are reliable readouts to phenotype normal mice and mice with experimental PH. Lung angiogram and RHC are also reliable approaches to examine pharmacological effects of new drugs on pulmonary vascular remodeling and hemodynamics.


AIR12, a b-type cytochrome of the plasma membrane of Arabidopsis thaliana is a negative regulator of resistance against Botrytis cinerea.
AIR12 (Auxin Induced in Root culture) is a single gene of Arabidopsis that codes for a mono-heme cytochrome b. Recombinant AIR12 from Arabidopsis accepted electrons from ascorbate or superoxide, and donated electrons to either monodehydroascorbate or oxygen. AIR12 was found associated in vivo to the plasma membrane. Though linked to the membrane by a glycophosphatidylinositol anchor, AIR12 is a hydrophilic and glycosylated protein predicted to be fully exposed to the apoplast. The expression pattern of AIR12 in Arabidopsis is developmentally regulated and correlated to sites of controlled cell separation (e.g. micropilar endosperm during germination, epidermal cells surrounding the emerging lateral root) and cells around wounds. Arabidopsis (Landsberg erecta-0) mutants with altered levels of AIR12 did not show any obvious phenotype. However, AIR12-overexpressing plants accumulated ROS (superoxide, hydrogen peroxide) and lipid peroxides in leaves, indicating that AIR12 may alter the redox state of the apoplast under particular conditions. On the other hand, AIR12-knock out plants displayed a strongly decreased susceptibility to Botrytis cinerea infection, which in turn induced AIR12 expression in susceptible wild type plants. Altogether, the results suggest that AIR12 plays a role in the regulation of the apoplastic redox state and in the response to necrotrophic pathogens. Possible relationships between these functions are discussed.


Prevalence of dental agenesis in a sample of Italian orthodontic patients: an epidemiological study.
The congenital absence of one or more teeth is a dental anomaly that frequently occurs in the world's population with a wide variability of distribution. The aim of this study is to assess the current prevalence of dental agenesis in the permanent dentition (excluding third molars) using a sample of Italian orthodontic patients. Panoramic radiographs of 4006 Caucasian children between 9 and 16 years of age (1865 males and 2141 females) performed over a 5-year period (from 2010 to 2015) were carefully examined to identify congenital missing teeth. A chi-square test was used to determine the difference in the prevalence of hypodontia between genders and between arches. The prevalence of dental agenesis was 9% (9.1% for females and 8.7% for males). The most common congenitally missing teeth were the mandibular second premolars (20.3 and 18.1%) followed by the upper lateral incisors (17.8 and 17.7%) and the maxillary second premolars (7.4 and 6.3%). The absence of one tooth to five teeth was observed in 344 patients (8.6%), while 15 patients showed from six to nine missing teeth (0.4%). The analysis showed 363 cases of agenesis in the upper arch (0.64%) and 339 in the lower arch (0.60%). Unilateral (4.6%) and bilateral (4.4%) agenesis demonstrated a similar frequency. The most common bilateral missing teeth were the mandibular second premolars (1.9%) and the maxillary lateral incisors (1.6%). The results of this study observed a higher prevalence of hypodontia compared to previous studies conducted on the Italian population. Thus, a detailed and careful radiographic examination was important in diagnosing one or more missing teeth. This could help plan the best possible treatments, both esthetically and functionally, for these patients.


Comparing the Discussion of Telehealth in Two Social Media Platforms: Social Listening Analysis.
Social media is used as a source of information and platform to discuss health care; however, there is little research on discussion of telehealth in social media. Past research has looked at individual platforms, but a comparison of discussion on two platforms (Reddit and Twitter) has not been performed. Understanding telehealth-related social media discourse and the differences between platforms may provide insights into how telehealth is characterized online and which platforms provide patient perspectives. The COVID-19 pandemic provides a unique case study to examine how social media users approached both Reddit and Twitter during an international health crisis. This study used natural language processing tools and two social media platforms to (1) characterize and contrast each platform's telehealth-related posts according to themes and (2) assess the frequency of telehealth and telehealth-related terms posts before and during the onset of the COVID-19 pandemic. We collected 6 years (2016 through 2021) of social media posts from Twitter and Reddit. The themes of the corpus were extracted using hashtags, subreddits, and Latent Dirichlet Allocation (LDA) and were analyzed using descriptive statistics. Both Twitter and Reddit showed exponential growth in the use of the term "telehealth" and telehealth-related terms in early 2020. The use of telehealth-related terms and discussion of COVID-19 coincided in both social media sites; however, other themes were discussed, including how to use telehealth. Reddit LDA clusters showed greatest usage of "telehealth" when associated with using or suggesting telehealth for receiving therapy, counseling, or psychoanalysis while Twitter focused on sharing telehealth news, products, and services. Twitter and Reddit had extensive growth in the use of telehealth-related terms after the COVID-19 pandemic. Twitter and Reddit showed themes connecting COVID-19 to telehealth, especially in reference to services, therapy, and counseling, however, Reddit had more discussion suggesting use of telehealth services or requesting peer insights into how to use telehealth as compared with Twitter, which appeared more focused on telehealth as a business or product.


Recombinant unpurified rETXH106P/ CTB-rETXY196E protects rabbits against Clostridium perfringens epsilon toxin.
Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, has been touted as a potential biological weapon and is known to induce fatal enterotoxemia in a variety of livestock animals. For the efficient production of recombinant proteins with the objective of investigating the effects of different recombinant vaccines against ETX, a bicistronic design (BCD) expression system including the ETX coding sequence with mutation of amino acid 106 from Histidine to Proline (ETXH106P) in the first cistron, followed by Cholera Toxin B (CTB) linked with the ETX coding sequence with mutation of amino acid 196 from Tyrosine to Glutamic acid (ETXY196E) in the second cistron, was generated under the control of a single promoter. Rabbits were immunized twice with five inactivated recombinant Escherichia coli (E. coli) vaccines containing 100 µg/ml of the recombinant mutant rETXH106P/CTB-rETXY196E proteins mixed with different adjuvants. Apart from rETXH106P/CTB-rETXY196E-IMS1313-vaccinated rabbits, the neutralizing antibody titers of rETXH106P/CTB-rETXY196E-vaccinated rabbits were higher after the initial immunization than those administered the ETX toxoid or current commercial vaccines. rETXH106P/CTB-rETXY196E mixed with ISA201 induced the highest neutralizing antibody titer of 120 after the first immunization, suggesting that 0.1 ml of pooled sera could neutralize 120× mouse LD100 (100% lethal dose) of ETX. Following the second vaccination, rETXH106P/CTB-rETXY196E mixed with ISA201 or GR208 produced the highest neutralizing titer of 800. Rabbits from all vaccinated groups were completely protected from a 2× rabbit LD100 of ETX challenge. These results show that these novel recombinant proteins can induce a strong immune response and represent potential targets for the development of a commercial vaccine against the C. perfringens epsilon toxin.


A new endstation at the Swiss Light Source for ultraviolet photoelectron spectroscopy, X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy measurements of liquid solutions.
A new liquid microjet endstation designed for ultraviolet (UPS) and X-ray (XPS) photoelectron, and partial electron yield X-ray absorption (XAS) spectroscopies at the Swiss Light Source is presented. The new endstation, which is based on a Scienta HiPP-2 R4000 electron spectrometer, is the first liquid microjet endstation capable of operating in vacuum and in ambient pressures up to the equilibrium vapor pressure of liquid water at room temperature. In addition, the Scienta HiPP-2 R4000 energy analyzer of this new endstation allows for XPS measurements up to 7000 eV electron kinetic energy that will enable electronic structure measurements of bulk solutions and buried interfaces from liquid microjet samples. The endstation is designed to operate at the soft X-ray SIM beamline and at the tender X-ray Phoenix beamline. The endstation can also be operated using a Scienta 5 K ultraviolet helium lamp for dedicated UPS measurements at the vapor-liquid interface using either He I or He II α lines. The design concept, first results from UPS, soft X-ray XPS, and partial electron yield XAS measurements, and an outlook to the potential of this endstation are presented.


Cervical spine instability following axial compression injury: a biomechanical study.
Axial compression injuries of the cervical spine occur during contact sports, automobile collisions, and falls. The objective of this study was to use flexibility tests to determine biomechanical instability of the cervical spine due to simulated axial compression injuries. We hypothesized that the axial compression injuries cause severe biomechanical instability throughout the cervical spine. The injuries were simulated using 2.4m/s head-first impacts of a cadaveric cervical spine model (n=10) mounted horizontally to a torso-equivalent mass on a sled and carrying a surrogate head in protruded posture. Intact and post-impact flexibility tests were performed up to 1.5, 3, and 1.5 Nm in flexion-extension, axial torque, and lateral bending, respectively. Instability parameters of range of motion (RoM) and neutral zone (NZ) were determined for injured spinal levels and statistically compared (P<0.05) between intact and post-impact. The sagittal instability parameters indicated extension-compression injuries at the upper and middle cervical spine and flexion-compression injuries at the lower cervical spine. Increases in extension RoM were 14.9° at the upper cervical spine and 24.9° (P<0.05) at the middle cervical spine and in flexion RoM at C7/T1 were 25.6°. RoM and NZ increases in axial rotation and lateral bending were nearly symmetric among left and right. Multidirectional instability of the upper cervical spine caused by atlas and dens fractures was evidenced by increases between 36% and 53% in RoM and NZ due to the impacts. The sagittal RoM of injured spinal levels of the middle and lower cervical spine exceeded a proposed threshold for clinical instability by between 67% and 114%. The instability documented throughout the cervical spine was consistent with clinical observations of cord injuries and paralysis in patients. Level IV, controlled laboratory investigation.


Does Antigen Glycosylation Impact the HIV-Specific T Cell Immunity?
It is largely unknown how post-translational protein modifications, including glycosylation, impacts recognition of self and non-self T cell epitopes presented by HLA molecules. Data in the literature indicate that O- and N-linked glycosylation can survive epitope processing and influence antigen presentation and T cell recognition. In this perspective, we hypothesize that glycosylation of viral proteins and processed epitopes contribute to the T cell response to HIV. Although there is some evidence for T cell responses to glycosylated epitopes (glyco-epitopes) during viral infections in the literature, this aspect has been largely neglected for HIV. To explore the role of glyco-epitope specific T cell responses in HIV infection we conducted in silico and ex vivo immune studies in individuals with chronic HIV infection. We found that in silico viral protein segments with potentially glycosylable epitopes were less frequently targeted by T cells. Ex vivo synthetically added glycosylation moieties generally masked T cell recognition of HIV derived peptides. Nonetheless, in some cases, addition of simple glycosylation moieties produced neo-epitopes that were recognized by T cells from HIV infected individuals. Herein, we discuss the potential importance of these observations and compare limitations of the employed technology with new methodologies that may have the potential to provide a more accurate assessment of glyco-epitope specific T cell immunity. Overall, this perspective is aimed to support future research on T cells recognizing glycosylated epitopes in order to expand our understanding on how glycosylation of viral proteins could alter host T cell immunity against viral infections.


First principle computational study on the full conformational space of L-proline diamides.
Ab initio molecular orbital computations were carried out at three levels of theory: RHF/3-21G, RHF/6-31G(d), and B3LYP/6-31G(d), on four model systems of the amino acid proline, HCO-Pro-NH2 [I], HCO-Pro-NH-Me [II], MeCO-Pro-NH2 [III], and MeCO-Pro-NH-Me [IV], representing a systematic variation in the protecting N- and C-terminal groups. Three previously located backbone conformations, gammaL, epsilonL, and alphaL, were characterized together with two ring-puckered forms syn (gauche+ = g+) or "DOWN" and anti (gauche- = g-) or "UP", as well as trans-trans, trans-cis, cis-trans, and cis-cis peptide bond isomers. The topologies of the conformational potential energy cross-sections (PECS) of the potential energy hypersurfaces (PEHS) for compounds [I]-[IV] were explored and analyzed in terms of potential energy curves (PEC), and HCO-Pro-NH2 [I] was also analyzed in terms of potential energy surfaces (PESs). Thermodynamic functions were also calculated for HCO-Pro-NH2 [I] at the CBS-4M and G3MP2 levels of theory. The study confirms that the use of the simplest model, compound [I] with P(N) = P(C) = H, along with the RHF/3-21G level of theory, is an acceptable practice for the analysis of peptide models because only minor differences in geometry and stability are observed.


Peptide-conjugated antimiRs improve myotonic dystrophy type 1 phenotypes by promoting endogenous MBNL1 expression.
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by a CTG repeat expansion in the DMPK gene that generates toxic RNA with a myriad of downstream alterations in RNA metabolism. A key consequence is the sequestration of alternative splicing regulatory proteins MBNL1/2 by expanded transcripts in the affected tissues. MBNL1/2 depletion interferes with a developmental alternative splicing switch that causes the expression of fetal isoforms in adults. Boosting the endogenous expression of MBNL proteins by inhibiting the natural translational repressors miR-23b and miR-218 has previously been shown to be a promising therapeutic approach. We designed antimiRs against both miRNAs with a phosphorodiamidate morpholino oligonucleotide (PMO) chemistry conjugated to cell-penetrating peptides (CPPs) to improve delivery to affected tissues. In DM1 cells, CPP-PMOs significantly increased MBNL1 levels. In some candidates, this was achieved using concentrations less than two orders of magnitude below the median toxic concentration, with up to 5.38-fold better therapeutic window than previous antagomiRs. In HSALR mice, intravenous injections of CPP-PMOs improve molecular, histopathological, and functional phenotypes, without signs of toxicity. Our findings place CPP-PMOs as promising antimiR candidates to overcome the treatment delivery challenge in DM1 therapy.


Mild cognitive impairment is associated with poorer decision-making in community-based older persons.
To test the hypothesis that mild cognitive impairment (MCI) is associated with poorer financial and healthcare decision-making. Community-based epidemiological cohort study. Communities throughout northeastern Illinois. Older persons without dementia from the Rush Memory and Aging Project (N = 730). All participants underwent a detailed clinical evaluation and decision-making assessment using a measure that closely approximates materials used in real-world financial and healthcare settings. This allowed for measurement of total decision-making and financial and healthcare decision-making. Regression models were used to examine whether MCI was associated with a lower level of decision-making. In subsequent analyses, the relationship between specific cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, visuospatial ability) and decision-making was explored in participants with MCI. MCI was associated with lower total, financial, and healthcare decision-making scores after accounting for the effects of age, education, and sex. The effect of MCI on total decision-making was equivalent to the effect of more than 10 additional years of age. Additional models showed that, when considering multiple cognitive systems, perceptual speed accounted for the most variance in decision-making in participants with MCI. Persons with MCI may have poorer financial and healthcare decision-making in real-world situations, and perceptual speed may be an important contributor to poorer decision-making in persons with MCI.


Expression of FCepsilonII/CD23 on human neutrophils isolated from rheumatoid arthritis patients.
CD23, the low affinity receptor for IgE, is a 45 kilodalton molecule belonging to the C-type lectin family, some members of which have been identified as adhesion molecules. Since it has been described upregulated in different cells in chronic inflammatory diseases and in rheumatoid arthritis in particular, where neutrophils are directly involved in tissue damage, our interest, in this work, has been focused on the expression and regulation of this antigen on neutrophil membrane. We studied 22 patients suffering from rheumatoid arthritis and 22 healthy control subjects. CD23 expression on neutrophil membrane was analyzed by immunofluorescence. Neutrophils of 9 out of 22 patients expressed CD23 molecules, neutrophils of 11 out of 22 patients expressed CD23 only after 24 h of incubation in RPMI; only 2 out of 22 patients did not express the CD23 antigen on neutrophil membrane either after isolation or after a 24 h incubation. On the contrary neutrophils isolated from healthy subjects did not express CD23 molecules upon isolation. Only in 7/22 control subjects neutrophils resulted positive after 24 h of incubation in RPMI. Moreover, we found that in our experimental conditions the presence of IFN-g or GM-CSF alone or in combination with IL-4 inhibited CD23 expression during the 24 h incubation. Our results show that there is a strong association between neutrophil ability to express CD23 and rheumatoid arthritis, and that such expression may be regulated by GM-CSF, IFN-gamma and IL-4.


Endocrine regulation of circadian physiology.
Endogenous circadian clocks regulate 24-h rhythms of behavior and physiology to align with external time. The endocrine system serves as a major clock output to regulate various biological processes. Recent findings suggest that some of the rhythmic hormones can also provide feedback to the circadian system at various levels, thus contributing to maintaining the robustness of endogenous rhythmicity. This delicate balance of clock-hormone interaction is vulnerable to modern lifestyle factors such as shiftwork or high-calorie diets, altering physiological set points. In this review, we summarize the current knowledge on the communication between the circadian timing and endocrine systems, with a focus on adrenal glucocorticoids and metabolic peptide hormones. We explore the potential role of hormones as systemic feedback signals to adjust clock function and their relevance for the maintenance of physiological and metabolic circadian homeostasis.


Emotion-related regulation: sharpening the definition.
Cole, Martin, and Dennis (this issue) considered many important conceptual and methodological issues in their discussion of emotion regulation. Although it may be necessary to develop an integrated definition of the construct of emotion regulation, the definition provided in the Cole et al. article is too encompassing. It is important to differentiate emotion regulation from the effects of emotions on others and to differentiate among (a) regulation that stems from individuals external to the child versus behavior that is accomplished by the child, (b) behavior that is goal oriented versus unintentional, and (c) regulation that is voluntary versus behavior that is less voluntarily controlled. An alternate definition of emotion-related self-regulation is provided.


Comparative treatment of Helicobacter pylori-positive duodenal ulcer using pantoprazole at low and high doses versus omeprazole in triple therapy.
Helicobacter pylori eradication has become the standard treatment for peptic ulcer disease. H. pylori-eradicating triple therapy with omeprazole plus two antibiotics has been used until recently; however, the efficacy of pantoprazole and antibiotics for H. pylori eradication has not been researched thoroughly until now. The aim of this randomized clinical trial was to verify the efficacy of triple oral therapy comparing the effects of pantoprazole using two different doses versus omeprazole twice daily in H. pylori eradication, in ulcer healing and relapses, and in gastritis improvement. We enrolled 243 patients with H. pylori-positive duodenal ulcer and randomized them into three treatment groups: 84 patients (group Ome40) were assigned to receive omeprazole, 20 mg twice daily, plus amoxicillin, 1 gm twice daily, and clarithromycin, 500 mg twice daily for 10 days; 79 patients (group Pan40) were treated with pantoprazole, 40 mg daily, plus amoxicillin and clarithromycin at the same doses as those of group Ome40; and 80 patients (group Pan80) were treated with pantoprazole, 40 mg twice daily, plus amoxicillin and clarithromycin at the same doses as those of group Ome40. Ulcer healing was observed in 81 of 84 patients (96.4%) in group Ome40; in 66 of 79 patients (83.5%) in group Pan40; and in 77 of 80 patients (96.2%) in group Pan80. H. pylori was eradicated in 79 of 84 patients (94%) in group Ome40; in 63 of 79 patients (79.7%) in group Pan40; and in 75 of 80 patients (93.7%) in group Pan80. We found that 10-day triple therapy with amoxicillin, clarithromycin, and either pantoprazole, 80 mg daily, or omeprazole, 40 mg daily, is highly effective in ulcer healing and is very well tolerated, achieving the 90% cure recommended for an ideal first-line anti-H. pylori positive duodenal ulcer treatment regimen.