Zerumbone ameliorates high-fat diet-induced adiposity by restoring AMPK-regulated lipogenesis and microRNA-146b/SIRT1-mediated adipogenesis.
Obesity is characterized by increased fat mass, as adipose tissue serves as a storage site for excess energy from food consumption. In obesity, altered lipid metabolism of adipose tissue, characterized by fatty acid uptake, de novo lipogenesis, and lipolysis, are induced. In this study, we examined the effect of zerumbone, a major sesquiterpene from wild ginger, on high-fat diet (HF)-induced obesity and dysregulated lipid metabolism in the white adipose tissues (WAT) of C57BL/6N mice. Dietary supplementation with zerumbone ameliorated HF-induced obesity and improved impaired lipid metabolism in WAT. Zerumbone additionally induced AMPK activation and phosphorylation of acetyl-CoA carboxylase, and effectively decreased adipogenic differentiation, in a concentration-dependent manner in the 3T3-L1 cells. Dysregulated microRNAs in obese WAT and adipocytes were examined, and zerumbone treatment was found to effectively reverse the robust upregulation of microRNA-146b. An increase in the levels of SIRT1, the direct target of microRNA-146b, was observed in zerumbone-treated differentiated adipocytes. This increase was additionally observed in WAT of zerumbone-supplemented mice. The antiadipogenic effect of zerumbone was found to be abolished in SIRT1-silenced 3T3-L1 cells. The increase in SIRT1 levels induced by zerumbone led to deacetylation of FOXO1 and PGC1α in WAT and differentiated 3T3-L1 cells. These findings indicate that zerumbone ameliorated diet-induced obesity and inhibited adipogenesis, and that the underlying mechanisms involved AMPK and the microRNA-146b/SIRT1 pathway. Zerumbone may represent a potential therapeutic candidate for the prevention and treatment of metabolic diseases, particularly obesity.


HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy.
Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. Blood mononuclear cells obtained during 7-12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. Thirty participants were studied. HIV-1 DNA decreased significantly from years 0-1 and 1-4 of ART with median decay slopes of -0.86 (interquartile range, -1.05, -0.59) and -0.11 (-0.17, -0.06) log10(copies/10(6) CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4-7 (-0.02 [-0.06, 0.02]; P = .09) or after year 7 of ART (-0.006 [-0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10(6) CD4+ T-cells; range: 7-2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1-4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1-4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.


Marker-Based Estimates Reveal Significant Nonadditive Effects in Clonally Propagated Cassava (Manihot esculenta): Implications for the Prediction of Total Genetic Value and the Selection of Varieties.
In clonally propagated crops, nonadditive genetic effects can be effectively exploited by the identification of superior genetic individuals as varieties. Cassava (Manihot esculenta Crantz) is a clonally propagated staple food crop that feeds hundreds of millions. We quantified the amount and nature of nonadditive genetic variation for three key traits in a breeding population of cassava from sub-Saharan Africa using additive and nonadditive genome-wide marker-based relationship matrices. We then assessed the accuracy of genomic prediction for total (additive plus nonadditive) genetic value. We confirmed previous findings based on diallel crosses that nonadditive genetic variation is significant for key cassava traits. Specifically, we found that dominance is particularly important for root yield and epistasis contributes strongly to variation in cassava mosaic disease (CMD) resistance. Further, we showed that total genetic value predicted observed phenotypes more accurately than additive only models for root yield but not for dry matter content, which is mostly additive or for CMD resistance, which has high narrow-sense heritability. We address the implication of these results for cassava breeding and put our work in the context of previous results in cassava, and other plant and animal species.


New animal-free concepts and test methods for developmental toxicity and peripheral neurotoxicity.
The complex toxicological fields of repeat dose organ toxicity (RDT) and developmental and reproductive toxicity (DART) still require new concepts and approaches to achieve a fully animal-free safety assessment of chemicals. One novel approach is the generation of relevant human cell types from pluripotent stem cells, and the use of such cells for the establishment of phenotypic test methods. Due to their broad endpoints, such tests capture multiple types of toxicants, i.e. they are a readout for the activation of many adverse outcome pathways (AOPs). The 2016 Lush Science Prize was awarded for the development of one such assay, the PeriTox test, which uses human peripheral neurons generated from stem cells. The assay endpoints measure various cell functions, and these give information on the potential neurotoxicity and developmental neurotoxicity hazard of test compounds. The PeriTox test method has a high predictivity and sensitivity for peripheral neurotoxicants, and thus addresses the inherent challenges in pesticide testing and drug development. Data from the test can be obtained quickly and at a relatively high-throughput, and thus, the assay has the potential to replace animal-based safety assessment during early product development or for screening potential environmental toxicants.


Anaesthesia, pain and recovery profiles in children following dental extractions.
The aim of this prospective cohort study was to describe the anaesthetic practices, rates of postoperative pain and the recovery trajectory of children having urgent dental extractions at our institution. Demographic, anaesthetic and surgical details of children undergoing dental extractions were obtained by case note review. Parent-proxy pain scores were collected via telephone on the day of surgery and on postoperative days, as well as details of analgesia given, behavioural disturbance, and nausea and vomiting. Follow-up was continued until each child no longer had pain. Datasets were analysed for 143 patients. Fasting times were prolonged, with 81 children (56.6%) fasted for over four hours from fluids. Moderate or severe pain was recorded in 14 children (9.8%) postoperatively on the day of surgery, with higher rates in children who had a greater number of teeth extracted. Low rates of moderate to severe pain were observed during follow-up, affecting six children (4.2%) on postoperative day 1 and three children (2.1%) on postoperative day 2 with primarily simple analgesia administered at home. Only eight children (5.6%) had nausea and/or vomiting on the day of surgery. Rates of reported behavioural disturbance at home were low, extending beyond the second postoperative day in only two children (1.4%), and only four children (2.8%) attended a dentist during the follow-up period. In conclusion, the low rates of pain and nausea and vomiting reported in the days following surgery for urgent dental procedures suggest that children can be cared for at home with simple analgesia.


[Regional assessment of treatment in lung cancer using lung perfusion and ventilation images].
In 30 patients with lung cancer undergoing non-surgical treatment, we performed perfusion lung imaging using 99mTc-MAA and inhalation lung studies using Technegas before and after treatment and evaluated regional perfusion and ventilation status in the lung regions where bronchogenic carcinoma was located. Regional ventilation status was preserved rather than perfusion counterpart (V > P) in 18 patients (18/30 = 60.0%) before treatment, while the former was better than the latter in 27 patients (27/30 = 90.0%) after treatment, indicating that regional ventilation status improved more significantly than regional perfusion counterpart after treatment (p = 0.005). We also classified the therapeutic effect for regional perfusion and ventilation status as improved, unchanged, or worsened, respectively; improvement in regional perfusion status was observed in 17 patients (56.7%) and that in regional ventilation status in 24 patients (80.0%). There was a statistically significant correlation between improved regional perfusion and ventilation status (p = 0.0018) when therapeutic effect was recognized. The patients who showed improvement in regional perfusion status after treatment always showed improved regional ventilation status, but 7 patients showed either unchanged or worsened regional perfusion status after treatment, although regional ventilation status was improved. In conclusion the pulmonary vascular beds seem more vulnerable to bronchogenic carcinoma and improvement in regional perfusion status was revealed to be more difficult than that in regional ventilation status after treatment.


Influence of food intake on the bioavailability of zuclopenthixol.
The single-dose kinetics of the neuroleptic thioxanthene zuclopenthixol was assessed in 12 healthy volunteers who ingested 10 mg of the drug orally, both on an empty stomach and together with a standardized breakfast of 1840 kj (440 kcal). The serum concentrations of zuclopenthixol were measured by HPLC. Concomitant food intake did not influence the peak concentration nor the time to reach the peak concentration or the elimination half-life of zuclopenthixol, but the AUC values were significantly increased. Hence it seems likely that concomitant food intake enhances the bioavailability of zuclopenthixol, without influencing its absorption rate. The most likely mechanism is that food reduces the presystemic clearance of the drug. As the increase in AUC was only 26%, it is doubtful whether zuclopenthixol has to be administered in a standardized relation to meals.


Relationship Between Working Memory and Speech-in-Noise Recognition in Young and Older Adult Listeners With Age-Appropriate Hearing.
Purpose The purpose of this study was to investigate the relationship between working memory (WM) capacity and speech recognition in noise in both a group of young adults and a group of older adults. Method Thirty-three older adults with a mean age of 71.0 (range: 60.4-82.7) years and 27 young adults with a mean age of 21.7 (range: 19.1-25.0) years participated in the study. All participants had age-appropriate hearing and no history of central nervous system dysfunction. WM capacity was measured using the van den Noort version of the Reading Span Test, and recognition of sentences in the presence of a stationary speech-shaped noise was measured as the speech reception threshold for 50% correct identification by using the Leuven Intelligibility Sentence Test. Results The older adults had significantly worse WM capacity scores, t(58) = 8.266, p < .001, and significantly more difficulty understanding sentences in noise than the younger adults, t(58) = -6.068, p < .001. In the group of older adults, a correlation was found (r = -.488, n = 33, p = .004) between the results of the WM capacity test (Reading Span Test) and the results of the speech-recognition-in-noise test (Leuven Intelligibility Sentence Test), meaning that the higher the WM performance was, the better was the speech recognition in noise. This correlation cannot be found in young normal-hearing listeners. Conclusions This study shows deleterious effects of age on both WM capacity and speech recognition in noise. Interestingly, only in the group of older adults was a significant relation found between WM capacity and speech recognition in noise. The current results caution against the assumption that WM necessarily supports speech-in-noise identification independently of the age and hearing status of the listener.


Tumorigenicity and its suppression in cybrids of mouse and Chinese hamster cell lines.
The effect of cytoplasm upon the expression of tumorigenicity was examined with a pair of mouse and a pair of Chinese hamster cell lines, in intraspecies cybrids formed by reciprocal fusions between either tumorigenic or nontumorigenic cells and cytoplasms derived from them. With the mouse cells, 3T3 and the simian virus 40-transformed line SVT2, the cybrid clones were tumorigenic when SVT2 cells were fused with 3T3 cytoplasts, but not in the reciprocal fusion. With the hamster cells, CHEF/18 and the spontaneous transformant CHEF/16, however, tumorigenicity was partially suppressed in cybrid clones formed by fusion of tumorigenic CHEF/16 cells with CHEF/18 cytoplasts; cybrids were nontumorigenic in the reciprocal fusion. Thus, cybrid analysis has shown that tumorigenicity is not cytoplasmically transmitted in these two cell pairs, but suppression of tumor-forming ability may be cytoplasmically transmitted in the hamster cybrids.


Determination of urinary concentrations of pseudoephedrine and cathine after therapeutic administration of pseudoephedrine-containing medications to healthy subjects: implications for doping control analysis of these stimulants banned in sport.
Due to its stimulatory effects on the central nervous system, and its structural similarity to banned stimulants such as ephedrine and methamphetamine, pseudoephedrine (PSE) at high doses is considered as an ergogenic aid for boosting athletic performance. However, the status of PSE in the International Standard of the Prohibited List as established under the World Anti-Doping Code has changed over the years, being prohibited until 2003 at a urinary cut-off value of 25 µg/ml, and then subsequently removed from the Prohibited List during the period 2004-2009. The re-consideration of this position by the World Anti-Doping Agency (WADA) List Expert Group has led to the reintroduction of PSE in the Prohibited List in 2010. In this manuscript, we present the results of two WADA-sponsored clinical studies on the urinary excretion of PSE and its metabolite cathine (CATH) following the oral administration of different PSE formulations to healthy individuals at therapeutic regimes. On this basis, the current analytical urinary threshold for the detection of PSE as a doping agent in sport has been conservatively established at 150 µg/ml


Accelerated treatment with rtPA for pulmonary embolism induced circulatory arrest.
Patients with circulatory arrest due to pulmonary embolism (PE) should be treated with fibrinolytics. Current guidelines do not specify which regimen to apply, and it has been suggested that the regimen of 100 mg rtPA/2 h should be used, because this is recommended for hemodynamic instable PE in the ESC/ERS Guideline. This two hour regimen, however, is incompatible with key principles of cardiopulmonary resuscitation (CPR), such as employment of interventions that allow fast evaluation of effectiveness, and limitation of the total duration of CPR to avoid poor neurological outcomes. Additionally, the low flow-state during CPR has important consequences for the pharmacokinetic properties of rtPA. Arguably, the volume of distribution is lower, the metabolism reduced and the half life time longer. Therefore, these changes largely discard the rationale to use high dosages of rtPA over a prolonged period of time. More importantly, these changes highlight that the guideline recommendations, based on studies in patients without circulatory arrest, cannot be easily translated to the situation of circulatory arrest. An accelerated regimen of rtPA (0.6 mg/kg/15 min., max 50 mg) is mentioned by the 2019 ESC/ERS Guideline. However, empirical support or a rationale is not provided. Due to the rarity of the situation and ethical difficulties associated with randomizing unconscious patients, a randomized head-to-head comparison between the two regimens is unlikely to ever be performed. With this comprehensive overview of the pharmacokinetics of rtPA and current literature, a strong rationale is provided that the accelerated protocol is the regimen of choice for patients with PE-induced circulatory arrest.


Protein volumes and hydration effects. The calculations of partial specific volumes, neutron scattering matchpoints and 280-nm absorption coefficients for proteins and glycoproteins from amino acid sequences.
Amino acid sequences, carbohydrate compositions and residue volumes are used to compare critically calculations of partial specific volumes v, neutron scattering matchpoints and 280-nm absorption coefficients with experimental v values for proteins and glycoproteins. The v values that are obtained from amino acid densitometry underestimate experimental v values by 0.01-0.02 ml/g while the v values from crystallographic volumes overestimate the experimental v values by 0.04-0.05 ml/g. An intermediate consensus volume set of amino-acid-residue volumes is proposed in order to predict experimental v values using sequence information. The method is extended to carbohydrates and glycoproteins. Neutron scattering matchpoints can be calculated from crystallographic residue volumes on the basis of the non-exchange of 10% of the main-chain NH protons. Crystallographic results on protein-bound water are used to account for the experimental values of v and matchpoints. Finally, 280-nm absorption coefficients, A1%, 1 cm 280, of 5-27 are found to be well predicted by the Wetlaufer procedure based on the totals of Trp, Tyr and Cys residues. Average errors are +/- 0.7, and the experimental A(1%,1cm)280 values can be larger than the predicted values by 3%.


[Nephroblastoma with primary metastasis to the right thigh].
A clinical case of Wilms' tumor with primary metastasis to right thigh without pulmonary metastasis that would explain the dissemination to soft tissues is presented. Considerations on the mechanism of metastasis dissemination are made in regard to the question in this particular location. We have not found a similar case in medical literature.


[Anemia--prevalence and etiology among acutely admitted geriatric patients].
The purpose of this study was to determine the prevalence of anemia among acutely admitted geriatric patients, and among these patients to ascertain how often anemia is listed as a diagnosis, the distribution of these diagnoses and to compare the diagnostic approach to anemia with that suggested in the literature. Age, sex and hemoglobin concentrations (hgb) were registered for patients referred to the acute geriatric ward of Odense University Hospital between 6/1/04 and 8/31/04. The prevalence of anemia was determined on the basis of the local laboratory's sex-specific lower reference limits for hgb. Diagnoses of discharge, laboratory data and, if performed, results of bone marrow and endoscopic investigations were also registered for anemic patients. 110 of 289 patients (38%) were anemic. The prevalence was significantly higher among men (61%, 95% confidence interval 51-71%) than among women (27%, 95% confidence interval 21-34%). 30 of the anemic patients (27%) had anemia listed as a diagnosis, including 14 with the diagnosis anemia without specification. A minority of anemic patients had measurements of serum ferritin (37%), serum iron (10%), plasma cobalamin (35%) and erythrocyte folate (35%), and a blood smear was likewise performed on a minority of anemic patients (26%). Anemia often remains undiagnosed or ignored. Clinicians should be aware of the high prevalence of anemia among geriatric patients and should appreciate the importance of a correct diagnostic approach to anemia in the elderly.


Assessment of pulmonary/systemic blood flow ratio after first-stage palliation for hypoplastic left heart syndrome: development of a new index with the use of doppler echocardiography.
Circulatory maldistribution is believed to be a major cause of early death after first-stage palliation for hypoplastic left heart syndrome. Flow reversal in the reconstructed aorta may reflect the pulmonary/systemic blood flow ratio. The purpose of our study was to investigate the utility of arterial PO (2), arterial oxygen saturation, and a newly developed Doppler-derived flow index in predicting the pulmonary/systemic flow ratio after first-stage palliation for hypoplastic left heart syndrome. Twenty-four infants who underwent first-stage palliation for hypoplastic left heart syndrome or a variant were studied. Superior vena cava blood samples were drawn to estimate the mixed venous saturation and permit calculation of the pulmonary/systemic blood flow ratio. Fifty-four samples were evaluated within the first 24 hours after surgery. Simultaneous blood draw and Doppler echocardiography were performed with interrogation in the distal aspect of the arch reconstruction. The ratio of the Doppler velocity-time integral of retrograde flow to the velocity-time integral of forward flow was calculated and compared with the pulmonary/systemic blood flow ratio The median mixed venous saturation for the 54 samples was low (38.5%; range, 18%-64%). The median calculated pulmonary/systemic blood flow ratio was 1.4:1 (range, 0.3:1 to 4. 2:1). Pulse pressure, mixed venous saturation, and arterial PO (2) were not statistically significant predictors of the measured pulmonary/systemic blood flow ratio. Although both aortic oxygen saturation (R (2) = 0.84, P <.01) and Doppler flow reversal ratio (R (2) = 0.94, P <.001) were significantly associated with the measured pulmonary/systemic blood flow ratio, the model coefficient of determination was greatest for Doppler flow reversal ratio. Measures of arterial oxygen saturation and arterial PO (2) may be misleading in assessing the circulatory status of infants after first-stage palliation for hypoplastic left heart syndrome. Doppler echocardiography, through use of the Doppler flow reversal ratio, provides a more useful measure of pulmonary/systemic blood flow ratio. Low mixed venous saturation after surgery may be due to factors other than pulmonary overcirculation, such as ventricular dysfunction and low cardiac output.


Understanding the Metastability of Theophylline FIII by Means of Low-Frequency Vibrational Spectroscopy.
While theophylline has been extensively studied with multiple polymorphs discovered, there is still currently no conclusive structure for the metastable theophylline form III. In this present work, by combining more widely used techniques such as X-ray diffraction and thermogravimetric analysis with more emerging techniques like low-frequency Raman and terahertz time-domain spectroscopy, to analyze the structure and dynamics of a crystalline system, it was possible to provide further evidence that the form III structure has a theophylline monohydrate structure with the water molecules removed. Solid-state density functional theory simulations were paramount in proving that this proposed structure is correct and explain how vibrational modes within the crystal structures feature and govern polymorphic transitions and the metastable form III. Through the insight provided by both simulated and experimental results, it was possible to decisively conclude the elusive crystal structure of theophylline form III. It was also shown that the correct space group for theophylline monohydrate is not P21/n but, in fact, Pc.


Antithrombotic and anticoagulant properties of synthetic polyanions: sulfated bis-aldonic acid amides.
Fifteen polyanionic bis-aldonic acid amides were synthesized by condensation of the corresponding aldonic acids and alpha,omega-diamines and by subsequent sulfation of the intermediates. The compounds were completely sulfated and exhibited molecular weights between 1450 and 2600 daltons. The antithrombotic activity of these synthetic heparin analogs was evaluated in a rat jugular vein clamping induced thrombosis model. Several compounds pounds were potent antithrombotic substances comparable in potency to the low molecular weight heparin Fraxiparin. Some structure activity relationships on their pharmacologic action could be deduced. The antithrombotic activity of a representative agent was confirmed using the Wessler stasis model in rabbits. In the in vitro tests the bis-aldonic acid amides exhibited moderate to low anticoagulant effects depending on the assay used. In the activated partial thromboplastin time assay, the anticoagulant potency of these compounds was between 2- and 30-fold lower than that of heparin. The anti-factor Xa activity of the experimental substances was at least 50 times lower than that of heparin, whereas the compounds were devoid of anti-factor IIa activity when measured in an amidolytic assay. The anticoagulant effects of these agents were dependent on the length of the spacing and on the type of aldonic acid moieties. These bisaldonic acid amides represent a novel class of potent antithrombotic substances without any anti-factor IIa activities and only very low anti-factor Xa activities, suggesting that these antiprotease actions are not a prerequisite for the antithrombotic action of polyanionic substances.


Concept of a Neck Protective Device (CNPD).
During impact or sudden acceleration, the cervical and thoracic region of the spine of operators of Habitable Mobile Vehicles (HMV) may be exposed to extensive trauma since "whiplash"-type motion typically leads to impairment of a cervical joint. Furthermore, the frequent necessity of supporting added mass above the shoulders (e.g., crash helmet, displays, oxygen mask) can magnify the moment of inertia of the head. This additional mass affects the biomechanics of a Helmet-Head-Neck System and determination of the tolerable magnitudes of acceleration which it can undergo. Even if the body of the operator is restrained by seat belts, such acceleration can arise in all three vectors (Gx, Gy, and Gz). The population at risk for injury due to such forces are individuals exposed to forces generated in racing cars, involved in automobile impacts or emergency landing of aircraft, in normal landing on carriers or in piloting of 5th generation fighter planes, and in other aspects of operator activity in HMV. Various methods of fixation of the head to prevent cervical injury are described in the literature: cervical collars, inflated thoracic defensive members, airbags, cervical supports, etc. However, all of these have some deficiencies related either to one-time availability or the restricted range of head motion which they produce. Widely used automatic retaining systems composed of belts with forced pull and airbags, while successful in other regards, do not adequately protect the head and neck of the operators who are chronically exposed to iterated percussion, and other acceleration forces under diverse extreme conditions.


A biometrical study of the relationship between sodium-lithium countertransport and triglycerides.
We addressed the question: Is there evidence that allelic variation in a single unmeasured gene that has a large effect on maximal activity of erythrocyte sodium-lithium countertransport (Na-Li CNT) also has pleiotropic effects on variation in plasma triglyceride levels? Complex segregation analysis models that included plasma triglyceride levels as a covariate were considered as explanations for interindividual variation in Na-Li CNT. A sample of 711 healthy adults from 254 pedigrees enrolled in the Rochester Family Heart Study was selected for this study. The majority of the pedigrees supported the hypothesis that variations in a single unmeasured non-transmitted environmental factor have large effects on the Na-Li CNT distribution. Only gender-specific first-order covariate parameters were necessary in the complex segregation models suggesting that the form of the relationship between Na-Li CNT and plasma triglyceride level was not influenced by variation in the inferred environmental factor with large effects. Stratification of the sample by this inferred environmental factor resulted in three classes of individuals with significant differences in the distributions of coronary heart disease risk factor traits, as well as interindividual variation in both Na-Li CNT and plasma triglyceride levels. These results, along with other observations from the Rochester Family Heart Study sample, emphasize the complex and multifactorial nature of the causes of interindividual variation in Na-Li CNT. Our study further suggests that new research strategies are needed for studying the relationships between genetic and environmental variation and variation in quantitative traits such as Na-Li CNT that have been identified as risk factors for hypertension.


Value of soluble TREM-1, procalcitonin, and C-reactive protein serum levels as biomarkers for detecting bacteremia among sepsis patients with new fever in intensive care units: a prospective cohort study.
The purpose of this study was to explore the diagnostic value of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for differentiating sepsis from SIRS, identifying new fever caused by bacteremia, and assessing prognosis when new fever occurred. We enrolled 144 intensive care unit (ICU) patients: 60 with systemic inflammatory response syndrome (SIRS) and 84 with sepsis complicated by new fever at more than 48 h after ICU admission. Serum sTREM-1, PCT, and CRP levels were measured on the day of admission and at the occurrence of new fever (>38.3°C) during hospitalization. Based on the blood culture results, the patients were divided into a blood culture-positive bacteremia group (33 patients) and blood culture-negative group (51 patients). Based on 28-day survival, all patients, both blood culture-positive and -negative, were further divided into survivor and nonsurvivor groups. On ICU day 1, the sepsis group had higher serum sTREM-1, PCT, and CRP levels compared with the SIRS group (P <0.05). The areas under the curve (AUC) for these indicators were 0.868 (95% CI, 0.798-0.938), 0.729 (95% CI, 0.637-0.821), and 0.679 (95% CI, 0.578-0.771), respectively. With 108.9 pg/ml as the cut-off point for serum sTREM-1, sensitivity was 0.83 and specificity was 0.81. There was no statistically significant difference in serum sTREM-1 or PCT levels between the blood culture-positive and -negative bacteremia groups with ICU-acquired new fever. However, the nonsurvivors in the blood culture-positive bacteremia group had higher levels of serum sTREM-1 and PCT (P <0.05), with a prognostic AUC for serum sTREM-1 of 0.868 (95% CI, 0.740-0.997). Serum sTREM-1, PCT, and CRP levels each have a role in the early diagnosis of sepsis. Serum sTREM-1, with the highest sensitivity and specificity of all indicators studied, is especially notable. sTREM-1, PCT, and CRP levels are of no use in determining new fever caused by bacteremia in ICU patients, but sTREM-1 levels reflect the prognosis of bacteremia. ClinicalTrial.gov identifier NCT01410578.


[Possibility of occurrence of mild spinal forms of poliomyelitis in subjects immunized repeatedly with live poliomyelitis vaccine].
The results of clinical, epidemiological, serological and virological examinations of patients with mild spinal forms of poliomyelitis occurring under conditions of mass immunization with oral live poliomyelitis vaccine are presented. The etiological role of poliomyelitis virus types I and III in these diseases has been established. It has been shown that multiple vaccination does not always prevent diseases but in these cases they are milder. Serological examination of patients and normal subjects suggests inadequacy of seroconversion to poliomyelitis viruses under conditions of mass vaccination of the population against poliomyelitis.


Pre-rehabilitation interventions for patients with head and neck cancers: A systematic review and meta-analysis.
To investigate the effect of pre-rehabilitation interventions such as nutrition and exercise for patients with head and neck cancer (HNC). Web of Science, PubMed, Scopus, Google Scholar, and Cochrane databases were searched up to December 2022. Quality of life, length of hospital stay, postoperative complications, change in body mass index or muscle mass, and functional assessments were the primary outcomes. PRISMA guidelines were adhered to, and the study was registered on PROSPERO. The Cochrane Collaboration tool and Newcastle Ottawa scale assessed the quality of included studies. Pooled data are presented as odds ratios (OR) and 95% confidence intervals (CI). Analysis was conducted using RevMan5.4. A total of 31 articles were included for quantitative analysis and 15 for qualitative synthesis. Nutrition alone resulted in significant weight retention (2.60; 2.32, 2.88, p < 0.00001), length of stay (-4.00; -6.87, -1.13), p = 0.0006) and complications (0.64; 0.49, 0.83, p = 0.0009). Nutrition and psychoeducation resulted in a significant reduction in mortality rate (0.70; 0.49, 1.00, p = 0.05 and 0.60; 0.48, 0.74, p < 0.00001), and exercise resulted in a significant reduction in dysphagia (0.55; 0.35, 0.87, p = 0.01). Exercise with nutrition resulted in significant improvements in weight loss, length of stay, complications, and dysphagia. Randomized controlled trials (RCTs) had a moderate risk of bias and cohort studies were of fair to good quality. Prehabilitation programs based on exercise, nutrition, or psychoeducation demonstrated improved post-interventional outcomes in HNC, such as quality of life, and mortality and morbidity. Studies with longer follow-ups and larger sample sizes, and investigations comparing nutritional supplements with exercise programs are needed.


Integrin-driven actin polymerization consolidates long-term potentiation.
Long-term potentiation (LTP), like memory, becomes progressively more resistant to disruption with time after its formation. Here we show that threshold conditions for inducing LTP cause a rapid, long-lasting increase in polymerized filamentous actin in dendritic spines of adult hippocampus. Two independent manipulations that reverse LTP disrupted this effect when applied shortly after induction but not 30 min later. Function-blocking antibodies to beta1 family integrins selectively eliminated both actin polymerization and stabilization of LTP. We propose that the initial stages of consolidation involve integrin-driven events common to cells engaged in activities that require rapid morphological changes.


Sarcolemmal Ca influx through L-type Ca channels in ventricular myocytes of a teleost fish.
The whole cell patch clamp method was used to measure Ca current through L-type Ca channels in enzymatically isolated ventricular myocytes of crucian carp (Carassius carassius L.) heart. Fish were acclimated to 22 degrees C for more than 4 wk, and properties of Ca current were measured at room temperature (21 +/- 1 degrees C). Depolarizing voltage steps from -50 mV evoked rapidly activating Ca currents, which exhibited a bell-shaped voltage dependence with peak amplitude at 0 mV. The currents were suppressed by nifedipine (5 microM), verapamil (2.5 microM), and Cd2+ (175 microM). The current amplitude was increased by 67.5 +/- 17.2% (n = 5) in the presence of 1 microM isoproterenol. Steady-state inactivation and activation curves showed half-maximal inactivation at -31.3 +/- 0.95 mV, with a slope factor of 5.88 +/- 0.51, and half-maximal activation at -10.6 +/- 1.65 mV, with a slope factor of 7.84 +/- 0.54 (n = 9). The overlap of inactivation and activation curves suggests the presence of a small window current, which is maximally 4% of the peak current at -27 mV. The density of L-type Ca current was 6.95 +/- 0.79 pA/pF at 0 mV (n = 35). A total increment in cellular Ca contributed by L-type Ca current during a 500-ms voltage clamp pulse was calculated from the integral of Ca current and cell volume. The charge transfer through L-type Ca current was 0.325 +/- 0.023 pC/pF, and the mean cell volume was 1,377 +/- 44 microns3. The increment in total cellular Ca by Ca influx through L-type Ca channels was calculated to be 39.3 +/- 2.8 microM. These findings imply that Ca influx through L-type Ca channels can contribute significantly to the activation of contraction in the ventricular myocytes of fish heart.


In-situ hybridization using digoxigenin-labelled probes in human skin.
This study demonstrated that in-situ hybridization using digoxigenin-labelled oligonucleotide poly-T probes and digoxigenin-labelled riboprobes for keratin 14 is possible on routinely fixed paraffin-embedded sections. The resolution and time course of the detection system compared favourably with isotopically labelled probes. Major differences were shown in keratinocyte messenger RNA content with differentiating cells expressing high levels when compared with the basal layers. Previous work on the distribution of keratin 14 messenger RNA was confirmed and we were able to show that using non-isotopic in-situ hybridization, sensitive and accurate cellular localization was feasible in skin sections.


Intimate-partner violence and reproductive decision-making by women attending Victorian Maternal- and Child-Health services: a cross-sectional study.
The reproductive years are a critical period where women experience greater risk of intimate-partner violence (IPV). Most studies investigating the association between IPV and reproductive health have been completed in low- and middle-income countries. This study aimed to examine the relationship between IPV and women's reproductive decision-making in Victoria, Australia. We analysed secondary data from a cluster-randomised trial of IPV screening that surveyed new mothers attending Maternal- and Child-Health centres in Melbourne. Survey measures included the experience of partner abuse in the past 12 months using the Composite Abuse Scale and four reproductive decision-making indicators. Results showed that IPV affects reproductive decision-making among postpartum women. Women who reported abuse were less likely to plan for a baby (adjusted Odds Ratio 0.48, 95% CI: 0.31-0.75) than were non-abused women, significantly more likely to have partners make decisions for them about contraception (Risk ratio (RR) 4.09, 95% CI: 1.31-12.75), and whether and when to have a baby (RR 12.35, 95% CI: 4.46-34.16), than they were to make decisions jointly. Pregnant and postpartum women need to be screened for partner violence that compromises women's decision-making power regarding their reproductive rights.


Registration-based segmentation with articulated model from multipostural magnetic resonance images for hand bone motion animation.
The quantitative measurements of hand bones, including volume, surface, orientation, and position are essential in investigating hand kinematics. Moreover, within the measurement stage, bone segmentation is the most important step due to its certain influences on measuring accuracy. Since hand bones are small and tubular in shape, magnetic resonance (MR) imaging is prone to artifacts such as nonuniform intensity and fuzzy boundaries. Thus, greater detail is required for improving segmentation accuracy. The authors then propose using a novel registration-based method on an articulated hand model to segment hand bones from multipostural MR images. The proposed method consists of the model construction and registration-based segmentation stages. Given a reference postural image, the first stage requires construction of a drivable reference model characterized by hand bone shapes, intensity patterns, and articulated joint mechanism. By applying the reference model to the second stage, the authors initially design a model-based registration pursuant to intensity distribution similarity, MR bone intensity properties, and constraints of model geometry to align the reference model to target bone regions of the given postural image. The authors then refine the resulting surface to improve the superimposition between the registered reference model and target bone boundaries. For each subject, given a reference postural image, the proposed method can automatically segment all hand bones from all other postural images. Compared to the ground truth from two experts, the resulting surface image had an average margin of error within 1 mm (mm) only. In addition, the proposed method showed good agreement on the overlap of bone segmentations by dice similarity coefficient and also demonstrated better segmentation results than conventional methods. The proposed registration-based segmentation method can successfully overcome drawbacks caused by inherent artifacts in MR images and obtain more accurate segmentation results automatically. Moreover, realistic hand motion animations can be generated based on the bone segmentation results. The proposed method is found helpful for understanding hand bone geometries in dynamic postures that can be used in simulating 3D hand motion through multipostural MR images.


Surgical outcomes of newly categorized peripheral T3 non-small cell lung cancers: comparisons between chest wall invasion and large tumors (>7 cm).
The prognosis for non-small cell lung cancer (NSCLC) with chest wall invasion can vary due to the heterogeneous nature of the cell population. Because NSCLC with large tumors (>7 cm) have been reclassified as T3, the applicability of the new designation must be evaluated. We reviewed 140 patients with chest wall T3 and 28 patients with T3 NSCLC with large tumors, but no chest wall invasion who underwent resection at our institution. Among chest wall T3 patients, elderly T3 patients (≥80 years old) who died within 42 months, patients with either lymph node or pulmonary metastasis, or patients with a large tumor (>7 cm) had poorer prognoses than those who had not. The survival rates for cases with chest wall T3 and cases with a large tumor without chest wall invasion were not significantly different. NSCLC patients with chest wall T3 with lymph node, or pulmonary metastasis, or with a large tumor should be considered for further multimodal treatment with or without resection to enhance their survival time. Elderly patients with chest wall invasion may not be good candidates for resection. A large tumor is so aggressive that re-classification of large tumor cases as T3 is suitable.


Normal Developmental Globe Morphology on Fetal MR Imaging.
Age-dependent structural changes of the globes occur during gestation. The posterolateral globe margins bulge outward, and the eyes are conical in early gestation. Later, the globes are ellipsoid. The purpose of this study was to establish normal developmental fetal globe morphology. The fetal MR imaging data base at an academic children's hospital was queried for all brain MRIs performed during 8 years. Motion artifacts, brain/craniofacial/globe malformations, and chromosomal defects were exclusion criteria. Two board-certified neuroradiologists evaluated each examination for globe shape (elliptic/nonelliptic) and hyaloid visibility. Logistic regression was used to evaluate correlations among variables. Age-specific cut-points for globe shape and hyaloid visibility were chosen to optimize specificity. We identified 1243 examinations from 1177 patients. Six hundred eighty-two examinations met the inclusion criteria (17-39 weeks). Receiver operating characteristic analysis showed that age was highly predictive of globe shape (area under the curve = 0.99) and fetal vasculature visibility (area under the curve = 0.94). Nonelliptic globes were universal up to 22 weeks. Thereafter, globes gradually assumed an elliptic shape, present in nearly all patients 29 weeks and older (sensitivity, 81%; 95% CI, 76%-85%; specificity, 99%; 95% CI, 98%-100%). The hyaloid vasculature was visible in most patients up to 19 weeks and occasionally in those at 20-24 weeks, but never in those 25 weeks and older (sensitivity, 69%; 95% CI, 65%-72%; specificity, 100%; 95% CI, 95%-100%). Physiologic nonspheric globe shapes are normal up to 29 weeks' gestation and should not be misinterpreted as pathologic. Thereafter, globes are generally elliptic. The timing of this process coincides with the resolution of the primary vitreous and may be related.


Multiple-Step Injection Molding for Fibrin-Based Tissue-Engineered Heart Valves.
Heart valves are elaborate and highly heterogeneous structures of the circulatory system. Despite the well accepted relationship between the structural and mechanical anisotropy and the optimal function of the valves, most approaches to create tissue-engineered heart valves (TEHVs) do not try to mimic this complexity and rely on one homogenous combination of cells and materials for the whole construct. The aim of this study was to establish an easy and versatile method to introduce spatial diversity into a heart valve fibrin scaffold. We developed a multiple-step injection molding process that enables the fabrication of TEHVs with heterogeneous composition (cell/scaffold material) of wall and leaflets without the need of gluing or suturing components together, with the leaflets firmly connected to the wall. The integrity of the valves and their functionality was proved by either opening/closing cycles in a bioreactor (proof of principle without cells) or with continuous stimulation over 2 weeks. We demonstrated the potential of the method by the two-step molding of the wall and the leaflets containing different cell lines. Immunohistology after stimulation confirmed tissue formation and demonstrated the localization of the different cell types. Furthermore, we showed the proof of principle fabrication of valves using different materials for wall (fibrin) and leaflets (hybrid gel of fibrin/elastin-like recombinamer) and with layered leaflets. The method is easy to implement, does not require special facilities, and can be reproduced in any tissue-engineering lab. While it has been demonstrated here with fibrin, it can easily be extended to other hydrogels.


The Use of Gallamycin for Controlling Infectious Atrophic Rhinitis in Bacon Pigs.
The use of Gallamycin to control nasal deterioration and permit increased growth rates in bacon type pigs was studied. Litters were randomly divided according to sex into treatment and control groups. Animals were treated by injection with 2.5 mgm of Gallamycin per pound liveweight at weekly intervals commencing during the first through the fifth week of age. Treatments ceased during the eighth week of age. Gallamycin treatment did not reduce significantly the percentage of nasal turbinate degeneration nor increase the rate of gain per day of treatment compared with control animals within litters. Possible explanations of results obtained are hypothesized.


DNA sequence of a human Sm autoimmune antigen. The multigene family contains a processed pseudogene.
The sequence of a complementary DNA clone coding for a human autoimmune antigen has been determined. This DNA sequence predicts the amino acid sequence of a small protein ("E") which is associated with small nuclear RNA in human cells. Analysis of the predicted protein sequence suggests that the E protein is not closely related to other nucleic acid binding proteins. Screening of a human genomic DNA library has led to the isolation of several members of the E protein multigene family. Sequence analysis of one member of this family reveals that it is flanked by direct repeats and contains several mutations. One of these mutations, an insertion, terminates the long open reading frame. These features are compatible with the designation of this sequence as a processed pseudogene.


Naturally Acquired Human Antibodies Against Reticulocyte-Binding Domains of Plasmodium vivax Proteins, PvRBP2c and PvRBP1a, Exhibit Binding-Inhibitory Activity.
Crucial gaps in our understanding of Plasmodium vivax reticulocyte invasion and protective immunity have hampered development of vivax vaccines. P. vivax exclusively invades reticulocytes that is mediated by the P. vivax reticulocyte-binding proteins (PvRBPs) specifically PvRBP2c and PvRBP1a. Vivax infections in Duffy-null individuals have suggested the evolution of alternate invasion pathways that may be mediated by the PvRBPs. Thus, PvRBPs appear as potential targets for efficacious P. vivax neutralization. However, there are limited data validating their vaccine efficacy. In the absence of vivax invasion assays, binding-inhibitory activity of antibodies has been reported to be associated with protection and a measure of vaccine potential. -based analysis was performed of the PvRBP reticulocyte-binding properties and binding-inhibitory activity of specific anti-PvRBP2c/PvRBP1a human antibodies. PvRBP2c and PvRBP1a displayed a distinct reticulocyte-binding specificity, and their specific reticulocyte-binding domains were mapped within their N-terminal regions. Importantly, naturally acquired antibodies against the reticulocyte-binding domains efficaciously blocked reticulocyte binding of native PvRBPs, suggesting that the human immune system produced functional binding-inhibitory antibodies through exposure to vivax malaria. Reticulocyte-binding domains of PvRBP2c/PvRBP1a are targets of naturally acquired binding-inhibitory antibodies, substantiating their promise as candidate antigens against which vaccine-inducible immunity could potentially be boosted through natural infections.


[Slowly progressive schizophrenia with signs of chronic hypomania during its course].
A total of 44 patients suffering from slow-progressive schizophrenia with affective disorders prevalence were examined. A long latent stage was defined as Bonn's "masked mania", two variants of the development were singled out in the active period of the disease. The first variant was characterized by depressive disorders and "mixed states" type of a clinical picture. The patients were optimistic, demonstrating high self-estimation in spite of depressive complaints, flaccidity, suppression, weakness, apathy and pseudoneurotic disorders. Accelerated development of associations was retained and motor retardation was absent Personality changes were limited by emotional and psychopathic ones. The second variant represented affective paranoia, delusional disorders formed on the basis of chronic hypomania. Its expressivity correlated with the intensity of hypomanic effect. Personality changes included thought disturbances, autization, mild decrease of the energy potential.


Persistence and resistance as complementary bacterial adaptations to antibiotics.
Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics. Here, we investigate the co-evolution of resistance and persistence across the genus Pseudomonas using comparative methods that correct for phylogenetic nonindependence. We find that strains of Pseudomonas vary extensively in both their intrinsic resistance to antibiotics (ciprofloxacin and rifampicin) and persistence following exposure to these antibiotics. Crucially, we find that persistence correlates positively to antibiotic resistance across strains. However, we find that different genes control resistance and persistence implying that they are independent traits. Specifically, we find that the number of type II toxin-antitoxin systems (TAs) in the genome of a strain is correlated to persistence, but not resistance. Our study shows that persistence and antibiotic resistance are complementary, but independent, evolutionary adaptations to stress and it highlights the key role played by TAs in the evolution of persistence.


Increasing the low lipid phosphate phosphatase 1 activity in breast cancer cells decreases transcription by AP-1 and expressions of matrix metalloproteinases and cyclin D1/D3.
Metastasis is the leading cause of mortality in breast cancer patients and lysophosphatidate (LPA) signaling promotes this process. LPA signaling is attenuated by lipid phosphate phosphatase-1 (LPP1) whose activity is decreased in cancers. Consequently, increasing LPP1 levels suppresses breast tumor growth and metastasis. This study shows that increasing LPP1 in breast cancer cells decreases transcription through cFos and cJun. This decreases production of cyclin D1/D3 and matrix metalloproteinases (MMPs), which provides new insights into the role of LPP1 in controlling tumor growth and metastasis. Methods: Invasiveness was determined by a Matrigel invasion assay. MMP expression was measured by qPCR, multiplex LASER bead technology and gelatin zymography. Levels of cJUN, cFOS, FRA1, cyclin D1, and cyclin D3 were determined by qPCR and western blotting. Collagen was determined by Picro-Sirius Red staining. Results: Increasing LPP1 expression inhibited invasion of MDA-MB-231 breast cancer cells through Matrigel. This was accompanied by decreases in expression of MMP-1, -3, -7, -9, -10, -12 and -13, which are transcriptionally regulated by the AP-1 complex. Increasing LPP1 attenuated the induction of mRNA of MMP-1, -3, cFOS, and cJUN by EGF or TNFα, but increased FRA1. LPP1 expression also decreased the induction of protein levels for cFOS and cJUN in nuclei and cytoplasmic fractions by EGF and TNFα. Protein levels of cyclin D1 and D3 were also decreased by LPP1. Although FRA1 in total cell lysates or cytoplasm was increased by LPP1, nuclear FRA1 was not affected. LPP1-induced decreases in MMPs in mouse tumors created with MDA-MB-231 cells were accompanied by increased collagen in the tumors and fewer lung metastases. Knockdown of LPP1 in MDA-MB-231 cells increased the protein levels of MMP-1 and -3. Human breast tumors also have lower levels of LPP1 and higher levels of cJUN, cFOS, MMP-1, -7, -8, -9, -12, -13, cyclin D1, and cyclin D3 relative to normal breast tissue. Conclusion: This study demonstrated that the low LPP1 expression in breast cancer cells is associated with high levels of cyclin D1/D3 and MMPs as a result of increased transcription by cFOS and cJUN. Increasing LPP1 expression provides a novel approach for decreasing transcription through AP-1, which could provide a strategy for decreasing tumor growth and metastasis.


Th1 immune responses can be modulated by varying dimethyldioctadecylammonium and distearoyl-sn-glycero-3-phosphocholine content in liposomal adjuvants.
Cationic liposomes of dimethyldioctadecylammonium bromide (DDA) combined with trehalose 6,6'-dibehenate (TDB) elicit strong cell-mediated and antibody immune responses; DDA facilitates antigen adsorption and presentation while TDB potentiates the immune response. To further investigate the role of DDA, DDA was replaced with the neutral lipid of distearoyl-sn-glycero-3-phosphocholine (DSPC) over a series of concentrations and these systems investigated as adjuvants for the delivery of Ag85B-ESAT-6-Rv2660c, a multistage tuberculosis vaccine. Liposomal were prepared at a 5 : 1 DDA-TDB weight ratio and DDA content incrementally replaced with DSPC. The physicochemical characteristics were assessed (vesicle size, zeta potential and antigen loading), and the ability of these systems to act as adjuvants was considered. As DDA was replaced with DSPC within the liposomal formulation, the cationic nature of the vesicles decreases as does electrostatically binding of the anionic H56 antigen (Hybrid56; Ag85B-ESAT6-Rv2660c); however, only when DDA was completed replaced with DSPC did vesicle size increase significantly. T-helper 1 (Th1)-type cell-mediated immune responses reduced. This reduction in responses was attributed to the replacement of DDA with DSPC rather than the reduction in DDA dose concentration within the formulation. These results suggest Th1 responses can be controlled by tailoring the DDA/DSPC ratio within the liposomal adjuvant system.


A Robust Ensemble of Convolutional Neural Networks for the Detection of Monkeypox Disease from Skin Images.
Monkeypox is a smallpox-like disease that was declared a global health emergency in July 2022. Because of this resemblance, it is not easy to distinguish a monkeypox rash from other similar diseases; however, due to the novelty of this disease, there are no widely used databases for this purpose with which to develop image-based classification algorithms. Therefore, three significant contributions are proposed in this work: first, the development of a publicly available dataset of monkeypox images; second, the development of a classification system based on convolutional neural networks in order to automatically distinguish monkeypox marks from those produced by other diseases; and, finally, the use of explainable AI tools for ensemble networks. For point 1, free images of monkeypox cases and other diseases have been searched in government databases and processed until we are left with only a section of the skin of the patients in each case. For point 2, various pre-trained models were used as classifiers and, in the second instance, combinations of these were used to form ensembles. And, for point 3, this is the first documented time that an explainable AI technique (like GradCAM) is applied to the results of ensemble networks. Among all the tests, the accuracy reaches 93% in the case of single pre-trained networks, and up to 98% using an ensemble of three networks (ResNet50, EfficientNetB0, and MobileNetV2). Comparing these results with previous work, a substantial improvement in classification accuracy is observed.


The evolution of spacers and valved holding chambers.
Spacers and valved holding chambers (VHCs) are pressurized metered dose inhaler (pMDI) accessory devices, designed to overcome problems that patients commonly experience when administering aerosol via a pMDI. Spacers were developed in direct response to patient-related issues with pMDI technique, particularly, poor coordination between actuation and inhalation, and local side-effects arising from oropharyngeal deposition. Current clinical guidelines indicate the need for widespread prescription and use of spacers, but, despite their apparent ubiquity, the devices themselves are, unfortunately, all too commonly "disused" by patients. An understanding of the background from which spacers developed, and the key factors influencing the optimization of the spacer and the later VHC, is crucial to developing an appreciation of the potential of these devices, both contemporary and future, for improving the delivery of pressurized aerosols to patients. This review, informed by a full patent search and an extensive scientific literature review, takes into account the clinical and laboratory evidence, commercial developments, and the sometimes serendipitous details of scientific anecdotes to form a comprehensive perspective on the evolution of spacers, from their origins, in the early days of the pMDI, up to the present day.


Mechanistic investigation of the selective reduction of Meldrum's acids to β-hydroxy acids using SmI2 and H2O.
The mechanism of a recently reported first mono-reduction of cyclic 1,3-diesters (Meldrum's acids) to β-hydroxy acids with SmI2-H2O has been studied using a combination of reactivity, deuteration, kinetic isotope and radical clock experiments. Most crucially, the data indicate that the reaction proceeds via reversible electron transfer and that water, as a ligand for SmI2, stabilizes the radical anion intermediate rather than only promoting the first electron transfer as originally proposed.


The risk of type 2 oral polio vaccine use in post-cessation outbreak response.
Wild type 2 poliovirus was last observed in 1999. The Sabin-strain oral polio vaccine type 2 (OPV2) was critical to eradication, but it is known to revert to a neurovirulent phenotype, causing vaccine-associated paralytic poliomyelitis. OPV2 is also transmissible and can establish circulating lineages, called circulating vaccine-derived polioviruses (cVDPVs), which can also cause paralytic outbreaks. Thus, in April 2016, OPV2 was removed from immunization activities worldwide. Interrupting transmission of cVDPV2 lineages that survive cessation will require OPV2 in outbreak response, which risks seeding new cVDPVs. This potential cascade of outbreak responses seeding VDPVs, necessitating further outbreak responses, presents a critical risk to the OPV2 cessation effort. The EMOD individual-based disease transmission model was used to investigate OPV2 use in outbreak response post-cessation in West African populations. A hypothetical outbreak response in northwest Nigeria is modeled, and a cVDPV2 lineage is considered established if the Sabin strain escapes the response region and continues circulating 9 months post-response. The probability of this event was investigated in a variety of possible scenarios. Under a broad range of scenarios, the probability that widespread OPV2 use in outbreak response (~2 million doses) establishes new cVDPV2 lineages in this model may exceed 50% as soon as 18 months or as late as 4 years post-cessation. The risk of a cycle in which outbreak responses seed new cVDPV2 lineages suggests that OPV2 use should be managed carefully as time from cessation increases. It is unclear whether this risk can be mitigated in the long term, as mucosal immunity against type 2 poliovirus declines globally. Therefore, current programmatic strategies should aim to minimize the possibility that continued OPV2 use will be necessary in future years: conducting rapid and aggressive outbreak responses where cVDPV2 lineages are discovered, maintaining high-quality surveillance in all high-risk settings, strengthening the use of the inactivated polio vaccine as a booster in the OPV2-exposed and in routine immunization, and gaining access to currently inaccessible areas of the world to conduct surveillance.


Phase noise characterization of sub-hertz linewidth lasers via digital cross correlation.
Phase noise or frequency noise is a key metric to evaluate the short-term stability of a laser. This property is of great interest for the applications but delicate to characterize, especially for narrow linewidth lasers. In this Letter, we demonstrate a digital cross-correlation scheme to characterize the absolute phase noise of sub-hertz linewidth lasers. Three 1542 nm ultra-stable lasers are used in this approach. For each measurement, two lasers act as references to characterize a third one. Phase noise power spectral density from 0.5 Hz to 0.8 MHz Fourier frequencies can be derived for each laser by a mere change in the configuration of the lasers. To the best of our knowledge, this is the first time showing the phase noise of sub-hertz linewidth lasers with no reference limitation. We also present an analysis of the laser phase noise performance.


Estimation of Lumbar Spine Loading of Low Back Pain Participant During Lifting Using an Open Source Musculoskeletal Model.
Biomechanical modeling of spinal load during lifting in OpenSim has the potential for rehabilitation and clinical assessment. In the literature, several spinal models have been developed and validated with movement data from healthy individuals. Although these models are valid for predicting spinal load in healthy individuals, it is unknown whether these models are applicable for people with chronic low back pain (CLBP). This study aims to compare the application of the lifting full body (LFB) model between a healthy participant and a participant with CLBP. The participants performed the lifting activity, and the motion capture data was used to analyze how an open-source model predicts the loading of the lumbar spine. Peak spinal loading at L5/S1 joint was estimated as 3.9 kN for the healthy participant and 3.1 kN for the CLBP participant. The results suggest that a longer duration of lift and lower lumbar range of motion reduces lumbar spinal loading.


HOLMESv2: A CRISPR-Cas12b-Assisted Platform for Nucleic Acid Detection and DNA Methylation Quantitation.
The next-generation CRISPR-based molecular diagnostics has the merits of rapidness, accuracy, and portability. We discovered the Cas12a trans-cleavage activity against collateral single-stranded DNA (ssDNA) and employed the activity to develop a rapid nucleic acid detection system, namely HOLMES (one-hour low-cost multipurpose highly efficient system). Here, with the employment of thermophilic CRISPR-Cas12b, we create HOLMESv2 for four different applications: (1) specifically discriminating single nucleotide polymorphism (SNP); (2) simply detecting virus RNA, human cell mRNA and circular RNA; (3) conveniently quantitating target nucleic acids with a one-step system combined with LAMP amplification in a constant temperature, thus avoiding cross-contamination; (4) accurately quantitating target DNA methylation degree with the combination of Cas12b detection and bisulfite treatment. These results highlight the potential of HOLMESv2 as a promising platform for both molecular diagnostics and epigenetics applications.


Epithelioid trophoblastic tumor: clinicopathologic and immunohistochemical analysis of three cases.
Epithelioid trophoblastic tumor is an unusual type of trophoblastic tumor. Here we report on the clinicopathologic and immunohistochemical features of three cases of epithelioid trophoblastic tumor. All three patients were of reproductive age and presented with vaginal bleeding and mild elevation of human chorionic gonadotropin (hCG). All patients underwent a hysterectomy. The tumors consisted of epithelioid intermediate trophoblastic cells that were mononucleated and eosinophilic, or showed clear cytoplasm on microscopic examination. One case presented with a focal choriocarcinoma component. Immunohistochemically, the tumors displayed diffuse positivity for cytokeratin 18, E-cadherin, epidermal growth factor receptor, and p53 and focal positivity for p63 and hCG. However, expression of α-inhibin and placental alkaline phosphatase was almost negative. Tests for human placental lactogen and epithelial membrane antigen were also negative in all cases.


[Course of wound process in chemical burns of the stomach (results of morphological and endoscopic studies)].
The dynamics of the wound process in chemical burns of the stomach were studied on the basis of histological and endoscopic examinations. The patients who were studied were given nonoperative treatment, in all cases for corrosive gastric ulcers. The most frequent complications were cicatricial stenoses (86.6%) in involvement of the antral part of the stomach. Regeneration of the damaged tissues of the gastric wall was disturbed, the specific features of these disorders were studied.


[The role of cytokine gene polymorphisms in the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march in the children].
Interleukin 1-beta (IL-1b), its endogenous receptor antagonist (IL-1 Ra), and interleukin IL-4 have been shown to play a role in immunopathological processes, such as the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march. However, the influence of Il-1 and IL-4 gene polymorphisms as etiological factors of this pathology remains obscure. The objective of the present work was to study characteristics of gene polymorphisms of proinflammatory and proallergic cytokines depending on the degree of hypertrophy of the tonsils of the lymphoid pharyngeal ring (LPR) and atopic march to selected species of the opportunistic pathogenic biota. Polymorphisms of the following genes were investigated in the children, residents of the Kemerovo region, presenting with hypertrophic tonsils of LPR: IL-1b+3953 (C->T), IL4 (70 bp VNTR), and IL-1Ra (86 bp VNTR). IL-1b, IL-1Ra, and IL-4 genotypes were determined by PCR of autosomal DNAs obtained from 129 children presenting with hypertrophic tonsils and 41 healthy children with the use of conventional genetic-statistical methods. Odds ratios (ORs) were estimated by the logistic regression models for each locus and after adjusting polymorphisms for the neighbouring loci. The 2R, 2R, Il-1Ra and T, T IL-1b genotypes occurred more frequently in the patients with isolated adenoid vegetations (20.93% and 25.58% respectively) than in the healthy children (4.95%) (OR=3.78, p=0.049; OR=3.25, p=0.047). The results of this study indicate that IL-1b and IL-1Ra gene polymorphisms play a role in the development of clinically significant features in the lymphoid pharyngeal ring.


Diagnostic pitfalls of Hashimoto's/lymphocytic thyroiditis on fine-needle aspirations and strategies to avoid overdiagnosis.
The importance of identifying papillary carcinoma or lymphoma amidst background Hashimoto's/lymphocytic thyroiditis (H/LT) is well documented. However, avoidance of overdiagnosing neoplasms on thyroid fine-needle aspiration (FNA) with only H/LT has not been adequately addressed. This study aimed to identify cytomorphologic features leading to overdiagnosing neoplasms within background H/LT. Nine thyroid FNAs classified as suspicious or positive for neoplasm with subsequent thyroidectomy specimens having only H/LT were identified. Cytologic features of these cases were compared to 8 control cases from the same time period and FNAs from both groups were reevaluated for features from the cytology literature. Features leading to overdiagnosing papillary carcinoma were: powdery chromatin, occasional nuclear grooves or holes, and paucity of background lymphocytes. One feature differentiating H/LT from neoplasm noted in most cases was lymphocytes infiltrating follicular groups. In contrast, true papillary carcinomas displayed characteristic features in multiple cell clusters. These clusters were devoid of infiltrating lymphocytes or displayed only rare lymphocytes at their periphery. A microfollicular pattern with paucity of background lymphocytes was the major pitfall in overdiagnosing follicular neoplasm. Features suspicious for neoplasm are often seen in FNA of H/LT, leading to unnecessary surgery. Recognizing this pitfall and its differentiating features should avert overdiagnosis.


Quantification of Compactness and Local Order in the Ensemble of the Intrinsically Disordered Protein FCP1.
Intrinsically disordered protein regions (IDRs) partially or completely lack a cooperatively folded structure under native conditions, preventing their equilibrium state from being adequately described by a single structural model. As a direct consequence of their disorder, remarkably few experimental studies have quantified the ensembles IDRs adopt in solution. Here, we conduct unbiased computer simulations of the RAP74 interaction motif from the human phosphatase FCP1 in the unbound state, which provides an ensemble in quantitative agreement with both experimental NMR chemical shift information and small-angle X-ray scattering data. The partially α-helical short linear motif found in the C-terminus of FCP1 has been the subject of extensive biophysical characterization aimed at developing a molecular description for the mechanism of coupled folding and binding and establishing the functional relevance of partial order in the unbound state. The analysis presented here yields a remarkably consistent molecular picture enumerating the diversity of structures present in a "partially formed" helix. Specific interactions, including anticorrelations in backbone dihedral angle fluctuations as well as the transient formation of a helix-stabilizing salt bridge, stabilize the preformed structure in the unbound state. The general consequences of these findings for mechanistic analysis of protein-protein interactions are discussed.


Anticoagulation Management of Atrial Fibrillation: The Relationship of Prevailing Adherence to a Dose Protocol and Recall Schedule on TTR in Primary Care.
To investigate the prevailing level of adherence to a dosing algorithm and a recall schedule and its relationship with the time in therapeutic range (TTR) among patients with atrial fibrillation. The study was carried out at a regional primary care clinic in Malaysia. Patients on anticoagulation therapy aged older than 18 years were included in the study. The participants have received continuation of their anticoagulation therapy at the primary care clinic for at least 6 months to 1 year after being discharged from a tertiary center. Correlation and multiple regression studies were performed to determine the significance of the predictors of TTR. A majority (217) of patients with atrial fibrillation received anticoagulation therapy at the clinic followed by patients with mitral valve replacement and aortic valve replacement. The mean TTR for patients with atrial fibrillation was 57.6%. General practitioners (GPs) adhered to 75.5% of the dose protocol but fared poorly in adhering to the recall schedule (36.2%). The concordance to the dose algorithm and recall schedule were significantly related to TTR. Multiple regression analysis proved that the concordance to the dose algorithm and recall schedule were important predictors of the level of TTR in patients with atrial fibrillation. The study provides preliminary evidence on the relationship between a validated dose algorithm that is integrated with a recall schedule in the control of TTR in patients with atrial fibrillation on anticoagulation treatment. A larger multicenter study is needed to confirm the results of this finding.


Impact of a Genetic Risk Score on Myocardial Infarction Risk Across Different Ethnic Populations.
Myocardial infarction (MI) risk varies by ethnicity, although the influence of genetic factors remains unclear. Using a genetic risk score (GRS), we examined the association between 25 coronary artery disease (CAD)-related single nucleotide polymorphisms and MI across 6 ethnic groups. We studied 8556 participants in the INTERHEART case-control study from 6 ethnic groups: Europeans, South Asians, Southeast Asians, Arabs, Latin Americans, and Africans. Associations between the GRS and MI were tested in each group by logistic regression and overall by meta-analysis. Overall, the GRS increased the odds of MI by 1.07 (95% confidence interval [CI], 1.04-1.09) per risk allele in the unadjusted model, with little change (odds ratio, 1.06; 95% CI, 1.04-1.09) after adjusting for demographic and modifiable factors. In Europeans, South Asians, Southeast Asians, and Arabs, the GRS was significantly associated with MI, with minimal heterogeneity observed. In these groups, a score > 23 risk alleles (highest 4 quintiles) was associated with only a 5% difference in population attributable risk (PAR) (36% to 41%) for MI. The GRS was not significant in Latin Americans or Africans. In the overall cohort, modest changes, beyond clinical factors, in PAR (88% to 91%), concordance statistic (0.73 to 0.74), and continuous net reclassification improvement (12%) were observed with the GRS. A CAD GRS is associated with MI across a multiethnic cohort, with significant and consistent effects across 4 distinct ethnicities. However, it only modestly improves MI risk prediction beyond clinical factors.


Laboratory confirmation of C60(+) as the carrier of two diffuse interstellar bands.
The diffuse interstellar bands are absorption lines seen towards reddened stars. None of the molecules responsible for these bands have been conclusively identified. Two bands at 9,632 ångströms and 9,577 ångströms were reported in 1994, and were suggested to arise from C60(+) molecules (ref. 3), on the basis of the proximity of these wavelengths to the absorption bands of C60(+) measured in a neon matrix. Confirmation of this assignment requires the gas-phase spectrum of C60(+). Here we report laboratory spectroscopy of C60(+) in the gas phase, cooled to 5.8 kelvin. The absorption spectrum has maxima at 9,632.7 ± 0.1 ångströms and 9,577.5 ± 0.1 ångströms, and the full widths at half-maximum of these bands are 2.2 ± 0.2 ångströms and 2.5 ± 0.2 ångströms, respectively. We conclude that we have positively identified the diffuse interstellar bands at 9,632 ångströms and 9,577 ångströms as arising from C60(+) in the interstellar medium.


A joint inter- and intrascale statistical model for Bayesian wavelet based image denoising.
This paper presents a new wavelet-based image denoising method, which extends a "geometrical" Bayesian framework. The new method combines three criteria for distinguishing supposedly useful coefficients from noise: coefficient magnitudes, their evolution across scales and spatial clustering of large coefficients near image edges. These three criteria are combined in a Bayesian framework. The spatial clustering properties are expressed in a prior model. The statistical properties concerning coefficient magnitudes and their evolution across scales are expressed in a joint conditional model. The three main novelties with respect to related approaches are (1) the interscale-ratios of wavelet coefficients are statistically characterized and different local criteria for distinguishing useful coefficients from noise are evaluated, (2) a joint conditional model is introduced, and (3) a novel anisotropic Markov random field prior model is proposed. The results demonstrate an improved denoising performance over related earlier techniques.


Small iron-carbonyl clusters bearing imidazolium-2-trithioperoxycarboxylate ligands.
The reaction of [Fe2(CO)9] with two representative imidazolium-2-dithiocarboxylate zwitterions derived from common N-heterocyclic carbenes (NHCs) bearing mesityl (IMes) or 2,6-diisopropylphenyl substituents on their nitrogen atoms (IDip) unexpectedly afforded two small bimetallic iron-carbonyl clusters with the generic formula [Fe2(CO)6(μ-κ2-S,S'-κ2-S,S'-S3C·NHC)]. After a brief optimization of the reaction conditions, these two "sulfur-enriched" products were isolated in low yields. They were fully characterized by IR, NMR, UV/Visible, and ESI-MS techniques, and their molecular structures were determined by single crystal X-ray diffraction analysis. The two compounds adopted a butterfly-type disposition in the solid state, with an [Fe2(CO)6] core bridged by the trithioperoxycarboxylate moiety of the in situ generated NHC·CS3 ligands. Bond lengths recorded for the CS3- unit revealed that its negative charge was mostly located on the remote sulfur atom.


Substance P modulates electroacupuncture analgesia in humanized mice with sickle cell disease.
Purpose: Chronic pain is a major comorbidity of sickle cell disease (SCD). Acupuncture, a non-opioid and non-addictive therapy to treat pain, was found to reduce pain in the majority (80%) of SCD patients in an earlier retrospective review. We observed that electroacupuncture (EA) decreased hyperalgesia in transgenic mice with SCD with varied analgesia from high to moderate to no response. Interestingly, poor responders exhibited high levels of substance P (SP), a mediator of chronic pain, as well as active p38 MAPK in spinal cords. The present study aimed to investigate the roles of inhibition of SP and SP-activated p38 MAPK in chronic pain in sickle mice that are poorly responsive to EA intervention (moderate/non-responders). Materials and methods: Humanized mouse model with SCD defined as moderate- and non-responders to EA were intraperitoneally administered with antagonist of SP receptor NK1R (netupitant, 10 mg/kg/day, i.p.) or p38 MAPK inhibitor (SB203580, 10 mg/kg/day, i.p.) alone or in combination with EA (acupoint GB30, every 3rd day until day 12). Hyperalgesia to mechanical, thermal and cold stimuli, as well as deep tissue were measured. Phosphorylated p38 MAPK (phospho-p38 MAPK) in the lumbar spinal cord was quantified using western blotting. Phospho-p38 MAPK nuclear translocation in spinal dorsal horn was examined using immunohistochemical staining and confocal microscopy. Results: In EA poor-responders, combined treatment with EA and netupitant significantly enhanced the analgesic effects of EA in poor-responders on mechanical, heat, cold, and deep tissue pain, and decreased phosphorylation of p38 MAPK in lumbar spinal cords and its nuclear translocation in the spinal dorsal horn. Furthermore, combined treatment with EA and SB203580 significantly improved analgesic effects of EA on mechanical and heat hyperalgesia, but not cold or deep tissue hyperalgesia. However, additional EA treatment only, or administration of either netupitant or SB203580 alone did not lead to analgesic effects. Conclusions: These results suggest a pivotal role of SP in maintaining the chronic pain in SCD via spinal phospho-p38 MAPK signaling, which may hinder the effect of EA in poor responders. Inhibition of SP signaling pathway or activity of p38 MAPK significantly improved the EA analgesia In EA poor-responders with SCD, which provides a promising way to treat the chronic pain in patients with SCD.


Mary Poppins was right: Adding small amounts of sugar or salt reduces the bitterness of vegetables.
Only a quarter of adults and 7% of children consume recommended amounts of vegetables each day. Often vegetables are not initially palatable due to bitterness, which may lead children and adults to refuse to taste or eat them. The objective of this research was to determine if very small amounts of sugar or salt (common household ingredients) could lead to significant reductions in bitterness intensity and increased hedonic ratings of green vegetable purees. For Experiment 1, three different green vegetable purees (broccoli, spinach, and kale) were prepared with different levels of sugar (0%, 0.6%, 1.2%, and 1.8%) or salt (0 and 0.2%). Samples were evaluated using standard descriptive analysis techniques with nine adults who completed more than 20 h of green vegetable specific training as a group. For Experiment 2, each vegetable puree was prepared with either 0% or 2% sugar, and bitterness was assessed via a forced choice task with 84 adults. For Experiment 3, each vegetable puree was prepared with 0%, 1%, or 2% sugar and rated for liking on standard 9 point hedonic scales by 99 adults. Experiments 1 and 2 showed that addition of small amounts of sugar and salt each reduced the bitterness (and increased sweetness and saltiness) from all three vegetables without altering other sensory properties (e.g. texture or aroma). Experiment 3 showed that adding sugar to vegetable purees increased hedonic ratings for adult consumers. We also found parents had mixed attitudes about the idea of adding sugar to foods intended for infants and toddlers. Further research on the effects of bitterness masking especially for specific populations (e.g., infants and young children or adults who have higher sensitivity to bitter taste) is warranted.


Thyroid disease and autoimmunity in obese patients: a narrative review.
The high prevalence of obesity and thyroid diseases worldwide justifies di per se their simultaneous coexistence. In recent decades, there has been a parallel and significant rise in obesity and thyroid diseases in industrialised countries, although the underlying mechanisms are complex and not well known. The authors accomplished a comprehensive literature search of original articles concerning obesity and thyroid status. Original papers exploring the association between these two morbidities in children and adults were included. A total of 79 articles were included in the present analysis. A total of 12% of obese children (mean age 10.9 ± 1.4 years) showed a thyroid disease, and they were younger than healthy obese children (10.9 ± 1.2 vs. 11.0 ± 0.4 years, p < 0.001). Isolated hyperthyrotropinaemia was the most frequent finding in children (10.1%). Autoimmune thyroid disease was more frequent in puberal age. Thyroid antibodies and subclinical hypothyroidism were more frequent in obese that in non-obese patients (7% vs. 3%, p < 0.001; 10% vs. 6%, p < 0.001). Among obese adults, 62.2% displayed a thyroid disease; those affected were younger (35.3 ± 6.8 vs. 41.0 ± 1.9 years, p < 0.001), heavier [body mass index (BMI): 39.4 ± 6.3 vs. 36.1 ± 2.3 kg/m², p < 0.001], and more frequently female (13% vs. 8%, p < 0.001). The most frequent disease was overt hypothyroidism (29.9%). BMI appears to be correlated with TSH levels in obese adults. Overt hypothyroidism was significantly more frequent in obese patients (7% vs. 3%, p < 0.005), but no difference was found in thyroid antibodies (15% vs. 14%, p = 0.178). An undeniable relationship between obesity and thyroid impairments exists. Isolated hyperthyrotropinaemia is frequently seen in obese children, often followed by spontaneous resolution. Subclinical hypothyroidism should never be treated in children or adults with the aim of reducing body weight.


Repeated echocardiographic examinations of patients with suspected infective endocarditis.
To study the diagnostic contribution of repeated transthoracic (TTE) and transoesophageal echocardiography (TOE) among patients with suspected infective endocarditis. 262 patients with 266 episodes of suspected infective endocarditis were referred for TTE and TOE over three years in a 423 bed university cardiology hospital. Patients were a mean (SD) of 47.6 (17.9) years old. 139 (52.3%) episodes occurred in men and 127 (47.7%) in women. The diagnostic information obtained from repeated TTE and TOE examinations was evaluated relative to the diagnosis of endocarditis. TTE examinations were repeated in 192 (72.2%) and TOE examinations were repeated in 49 (18.4%) of 266 episodes. A mean of 2.4 TTE and 1.2 TOE examinations were performed for each episode of suspected endocarditis. The second and third TTEs added diagnostic information in 34 (26.7%) and the second and third TOEs added diagnostic information in 25 (19.7%) of 127 episodes with definite endocarditis. After the third TTE or TOE no additional diagnostic information was obtained. The diagnostic contribution of repeated TTE or TOE for the diagnosis of endocarditis decreased as the number of repetitions increased. In this setting, the data do not substantiate more than three TTE or TOE examinations as an efficient strategy to increase the diagnostic yield for all but selected patients with suspected endocarditis.


Minimally Invasive Myomectomy.
Uterine fibroids can significantly impact a woman's health, fertility, and quality of life. When medical therapy fails, surgery is recommended; the gold standard in uterine-sparing surgery is myomectomy. The evidence-based benefits of minimally invasive myomectomy are detailed in this manuscript. Minimally invasive myomectomy techniques are reviewed, including laparoscopic, robotic-assisted, and laparoscopic or robotic-assisted with mini-laparotomy. Criteria for minimally invasive myomectomy are outlined and preoperative planning is discussed. Both institutional data and data from systematic reviews are included to compare outcomes. Each myomectomy case should take into account clinical characteristics of the myomas, patient preference, and surgeon skill and experience.


[Influence of smoking on pregnency course and fetal development].
Smoking is a significant factor which affects not only reproduction and the process of pregnancy but also the offspring. Endangering for tobacco smoke and nicotine either passive or active has an important influence for shortening the time of pregnancy, the weight of the newborn and the Placenta. The occurrence of complications connected with smoking is probably correlated with the amount of cigarettes smoked per day. The aim of the paper was to analyse the influence of passive and active smoking on the course of pregnancy. The study involved a group of 113 women who gave birth in Gynaecological and Obstetrics Clinical Hospital of the Karol's Marcinkowski University of Medical Sciences in Poznan during the period from January to June 2011. Based on data gained from documentation and mothers three groups were separated: 22 women who were active smokers, 32 passive smokers and 59 women from control group who have never been smoking. There were analyzed selected obstetric data and term of pregnancy, condition and weight of newborn, blood pH and alkaline balance from umbilical vessels. In research there were no correlation between groups and/or results of researches of blood Ph, alkaline balance from umbilical vessels and the assessment of the newborn in Apgar score at 1, 3, 5 minute. In fact passive smoking women were younger (the average 27.84) than actively smoking woman (30.23) and non-smokers (30.25) (p = 0.03). The most of small as for their gestational age infants were in the group of active smoking women (14%). Non-smokers more often did have a miscarriage (84%) in the past than other groups (active smokers 60%, passive 33%) (p = 0.04). Smoking women usually come from countryside or small towns, they were not marriage and they had preterm delivery. In this group there was found the biggest percent of too small newborns for their gestational age--14%.


The Emergency Medicine-Focused Review of Cholangitis.
Cholangitis is a life-threatening infection of the biliary tract. Historically, the mortality secondary to cholangitis approached 100%. However, with early recognition, antibiotics, resuscitation, and surgical or endoscopic intervention, patient outcomes have significantly improved, although there is still progress to be made. The objective of this review is to provide an emergency medicine-centered approach to the risk factors, presentations, and various diagnostic and treatment modalities in cholangitis. Early recognition and treatment of cholangitis in the emergency department is instrumental in ensuring a favorable outcome for patients. Recognition of acute cholangitis can be challenging, as many patients do not present with the classic symptoms of Charcot's triad. This article reviews the risk factors in cholangitis, as well as the typical presentations and necessary diagnostic studies. Furthermore, once diagnosis is made, distinguishing those requiring emergent biliary decompression from those who may tolerate a delayed procedure can also be difficult. Scoring systems that attempt to identify patients who may tolerate a delayed approach have yet to be validated. This review discusses the appropriate antibiotic therapy based on most common pathogens, as well as the options for achieving biliary decompression. Cholangitis is a life-threatening infection that carries a high likelihood of poor outcomes if not treated early and aggressively in the emergency department. Appropriate recognition, early broad-spectrum antibiotics, and fluid resuscitation are paramount, and in patients with severe disease, early biliary decompression will significantly reduce mortality.


Effects of a slow-release urea product on performance, carcass characteristics, and nitrogen balance of steers fed steam-flaked corn.
Two experiments were conducted to examine the impact of source, urea (U) or Optigen II (OP), and level of dietary NPN on performance (Exp.1) and N balance (Exp. 2) of growing cattle. Sixty Angus crossbred steers (initial BW = 353 ± 13.9 kg) were used to evaluate performance, and fed 1 of 3 steam-flaked corn based diets: U (U(1.2), 1.2% NPN), OP (OP(1.3), 1.3% NPN), or OP without cottonseed meal (OP(3.1), 3.1% NPN). U(1.2)and OP(1.3) contained cottonseed meal and NPN as CP sources, whereas OP(3.1) contained only NPN. For Exp. 1, steers were blocked by postweaning BW and assigned to treatment (TRT) and pen within block. Body weight was collected every 14 d during the 105-d trial. Six steers from each TRT were selected based on residual feed intake (RFI) and harvested. Carcass and organ measurements were obtained. Cumulative animal performance was evaluated in 3 periods (0 to 35, 0 to 70, and 0 to 105 d) using a mixed coefficient model with initial BW as a covariate. For Exp. 2, 5 ruminally cannulated Holstein steers in a 5 × 5 Latin square design were used to evaluate N balance. Steers were fed a steam-flaked corn based diet with either no NPN, 0.75% U or N equivalent OP, or 1.5% U or N equivalent OP. Intake was measured, and feed, orts, urine, and fecal samples were obtained and composited for each steer by period. Data were analyzed using a mixed coefficient model. Orthogonal contrasts were used to evaluate differences between OP and U, and high and low level of NPN. For Exp. 1, there were no differences (P > 0.10) in initial BW, final BW, ADG, or DMI among TRT for any of the periods. However, for period 1 steers on OP(3.1) had reduced F:G than U(1.2) (5.71 kg/kg vs. 7.39 kg/kg; P = 0.03), and steers fed OP(1.3) tended to have less F:G than those fed U(1.2) (6.07 kg/kg vs. 7.39 kg/kg; P = 0.07). In period 2, OP(3.1) had reduced F:G than U(1.2) (5.58 kg/kg vs. 6.56 kg/kg; P = 0.03), but did not differ from OP(1.3) (5.97). For Exp. 2, steers fed OP tended (P = 0.09) to have less apparent N absorption than those fed U. Apparent N absorption differed (P < 0.05) for level of NPN. There were no differences (P > 0.10) in intake or digestibility among source or level of NPN. No major differences (P > 0.10) on performance and carcass composition were observed between U and OP diets. Steers had better initial F:G (Period 1 and 2) when OP was used as the only source of feed N (OP(3.1)), suggesting that OP may replace true protein feeds in finishing cattle diets, minimizing feed use with no impact on carcass quality.


Flexibility of "polyunsaturated fatty acid chains" and peptide backbones: A comparative ab initio study.
The conformational properties of omega-3 type of polyunsaturated fatty acid (PUFA) chains and their fragments were studied using Hartree-Fock (RHF/3-21G) and DFT (B3LYP/6-31G(d)) methods. Comparisons between a unit (U) fragment of the PUFA chain and a mono N-Ac-glycine-NHMe residue show that both structures have the same sequence of sp2-sp3-sp2 atoms. The flexibility of PUFA originates in the internal rotation about the above pairs of sigma bonds. Therefore, potential energy surfaces (PESs) were generated by a scan around the terminal dihedral angles (phi t1 and phi t2) as well as the phi 1 and psi 1 dihedrals of both 1U congeners (Me-CHCH-CH2-CHCHMe and MeCONH-CH2-CONHMe) at the RHF/3-21G level of theory. An interesting similarity was found in the flexibility between the cis allylic structure and the trans peptide models. A flat landscape can be seen in the cis 1U (hepta-2,5-diene) surface, implying that several conformations are expected to be found in this (PES). An exhaustive search carried out on the 1U and 2U models revealed that straight chain structures such as trans and cis beta (phi 1 approximately psi 1 approximately 120 degrees; phi 2 approximately psi 2 approximately -120 degrees) or trans and cis extended (phi 1 approximately psi 1 approximately phi 2 approximately psi 2 approximately 120 degrees) can be formed at the lowest energy of both isomers. However, forming helical structures, such as trans helix (phi 1 approximately -120 degrees, psi 1 approximately 12 degrees; phi 2 approximately -120 degrees, psi 2 approximately 12 degrees) or cis helix (phi 1 approximately -130 degrees, psi 1 approximately 90 degrees; phi 2 approximately -145 degrees, psi 2 approximately 90 degrees) will require more energy. These six conformations, found in 2U, were selected to construct longer chains such as 3U, 4U, 5U, and 6U to obtain the thermochemistry of secondary structures. The variation in the extension or compression of the chain length turned out to be a factor of 2 between the helical and nonhelical structures. The inside diameter of the "tube" of cis helix turned out to be 3.5 A after discounting the internal H atoms. Thermodynamic functions were computed at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d). The cis-trans isomerization energy of 1.7 +/- 0.2 kcal mol(-1) unit(-1) for all structure pairs indicates that the conformer selection was consistent. A folding energy of 0.5 +/- 0.1 kcal mol(-1) unit(-1) has been extracted from the energy comparison of the helices and most extended nonhelical structures. The entropy change associated with the folding (Delta S(folding)) is decreases faster with the degree of polymerization (n) for the cis than for the trans isomer. As a consequence, the linear relationships between (Delta G(folding)) and n for the cis and trans isomer crossed at about n = 3. This suggested that the naturally occurring cis isomer less ready to fold than the trans isomer since a greater degree of organization is exhibited by the cis isomer during the folding process. The result of this work leads to the question within the group additivity rule: could the method applied in our study of the folding of polyallylic hydrocarbons be useful in investigating the thermochemistry of protein folding?


Radioactivity of the lunar surface.
Diffusion of radon and thoron from the Ilunar surface provides a mechanism for production of a radioactive surface layer on the moon. If the radon and thoron flux from the lunar surface is equal to that measured at the earth's surface, the equilibrium activity of this surface layet is estimated as approximately 1 microcurie per square meter, due to radon and its decay products. This activity consists of alpha particles and gamnmna rays at well-defined energies and of beta rays.