Association Between Local Anesthetic Dosing, Postoperative Opioid Requirement, and Pain Scores After Lumpectomy and Sentinel Lymph Node Biopsy with Multimodal Analgesia.
Multimodal analgesia (MMA) during breast surgery reduces postoperative pain and opioid requirements, but the relative contribution of local anesthetic dosing as a component of MMA is not well defined among patients undergoing lumpectomy and sentinel lymph node biopsy (SLNB). We identified consecutive patients who underwent lumpectomy and SLNB with MMA from 1/2019 to 4/2020. Univariable and multivariable linear and logistic regression were used to examine associations between local anesthetics, opioid requirements in the post-anesthesia care unit (PACU), and pain scores in the PACU and on postoperative day (POD) 1. In total, 1603 patients [median tumor size, 14 mm (interquartile range 8-20 mm)] were included. The median PACU opioid requirement was 0 morphine milligram equivalents (interquartile range 0-5). PACU maximum pain was none or mild in 58% of patients and moderate to severe in 42%; among 420 survey respondents, 56% reported no or mild pain and 44% reported moderate to severe pain on POD 1. On multivariable analysis that adjusted for routine components of MMA, increasing doses of 0.5% bupivacaine were associated with reduced PACU opioid requirements (β -0.04, 95% confidence interval -0.07 to -0.01, p = 0.011) and lower odds of moderate to severe pain (odds ratio 0.98, 95% confidence interval 0.97-0.99, p < 0.001). Local anesthetics were not associated with pain scores on POD 1. Higher amounts of local anesthetics reduce acute postoperative pain and opioid requirement after lumpectomy and SLNB. Maximizing dosing within weight-based limits is a low-risk, cost-effective pain control strategy that can be used in diverse practice settings.


Wavelength-Selective Light-Induced Release from Plasmon Resonant Liposomes.
Biodegradable, spectrally tunable plasmon resonant nanocapsules are created via the deposition of gold onto the surface of 100 nm diameter thermosensitive liposomes. These nanocapsules demonstrate selective release of encapsulated contents upon illumination with light of a wavelength matching their distinct resonance bands, which correspond to 760 and 1210 nm in this study. Spectrally selective release is accomplished through the use of multiple, low intensity laser pulses delivered over a period of less than four minutes, ensuring that illumination affects only the gold-coated liposomes and avoids heating the surrounding media. The result of this illumination scheme for selective release using multiple wavelengths of light is a biologically safe mechanism for realizing drug delivery, microfluidic, and sensor applications.


Novel electrochemical biosensor based on Exo III-assisted digestion of dsDNA polymer from hybridization chain reaction in homogeneous solution for CYFRA 21-1 DNA assay.
A novel electrochemical biosensing strategy was proposed to detect cytokeratin fragment antigen 21-1 (CYFRA 21-1) DNA based on Exo III-assisted digestion of dsDNA polymer (EADDP) from hybridization chain reaction (HCR). Primarily, the presence of target can drive a catalytic hairpin assembly (CHA) reaction, which was aimed to achieve target recognition and circulation. Then the HCR can be triggered for further signal amplification and generate long dsDNA polymer with signal tags. Subsequently, the introduction of Exo III can digest the long dsDNA polymer to produce large amounts of double signal fragments (DSFs). The above experiments were all carried out in homogeneous solution. Finally, the released DSF can be captured onto the electrode directly by capture probe (CP) and a highly amplified electrochemical signal can be detected. The EADDP in homogeneous solution circumvented complex solid-liquid interface reaction and tedious operation steps on electrode. Besides, one target can be converted into abundant DSFs, which greatly improved the sensitivity. This biosensor exhibited a low detection limit (0.0348 fM) and wide linear range (5 fM ∼ 50 nM) for CYFRA 21-1 DNA biosensing with reliable specificity and stability.


Evidential requirements for the regulatory hazard and risk assessment of respiratory sensitisers: methyl methacrylate as an example.
This review addresses the need for a framework to increase the consistency, objectivity and transparency in the regulatory assessment of respiratory sensitisers and associated uncertainties. Principal issues are considered and illustrated through a case study (with methyl methacrylate). In the absence of test methods validated for regulatory use, formal documentation of the weight-of-evidence for hazard classification both at the level of integration of individual studies within lines of evidence and across a broad range of data streams was agreed to be critical for such a framework. An integrated approach is proposed to include not only occupational studies and clinical evidence for the regulatory assessment of respiratory sensitisers, but also information on structure and physical and chemical factors, predictive approaches such as structure activity analysis and in vitro and in vivo mechanistic and toxicokinetic findings. A weight-of-evidence protocol, incorporating integration of these sources of data based on predefined considerations, would contribute to transparency and consistency in the outcome of the assessment. In those cases where a decision may need to be taken on the basis of occupational findings alone, conclusions should be based on transparent weighting of relevant data on the observed prevalence of occupational asthma in various studies taking into account all relevant information including the range and nature of workplace exposures to the substance of interest, co-exposure to other chemicals and study quality.


Arsenic metabolism in high altitude modern stromatolites revealed by metagenomic analysis.
Modern stromatolites thrive only in selected locations in the world. Socompa Lake, located in the Andean plateau at 3570 masl, is one of the numerous extreme Andean microbial ecosystems described over recent years. Extreme environmental conditions include hypersalinity, high UV incidence, and high arsenic content, among others. After Socompa's stromatolite microbial communities were analysed by metagenomic DNA sequencing, taxonomic classification showed dominance of Proteobacteria, Bacteroidetes and Firmicutes, and a remarkably high number of unclassified sequences. A functional analysis indicated that carbon fixation might occur not only by the Calvin-Benson cycle, but also through alternative pathways such as the reverse TCA cycle, and the reductive acetyl-CoA pathway. Deltaproteobacteria were involved both in sulfate reduction and nitrogen fixation. Significant differences were found when comparing the Socompa stromatolite metagenome to the Shark Bay (Australia) smooth mat metagenome: namely, those involving stress related processes, particularly, arsenic resistance. An in-depth analysis revealed a surprisingly diverse metabolism comprising all known types of As resistance and energy generating pathways. While the ars operon was the main mechanism, an important abundance of arsM genes was observed in selected phyla. The data resulting from this work will prove a cornerstone for further studies on this rare microbial community.


The rising incidence of idiopathic pulmonary fibrosis in the U.K.
Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the U.K. and U.S.A. Death registrations and primary care data were used to determine the current trends in IPF incidence in the U.K. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100,000 in the 1968-1972 calendar periods to 5.10 per 100,000 in the 2006-2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100,000 person-years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. The incidence of IPF-CS in primary care and registered deaths from this cause in the U.K. continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the U.K.


[Exopolysaccharide production and peculiarities of C6-metabolism in Acinetobacter sp. grown on carbohydrate substrates].
An Acinetobacter sp. strain grown on carbohydrate substrates (mono- and disaccharides, molasses, starch) was shown to synthesize exopolysaccharides (EPS). Glucose catabolism proved to proceed via the Embden-Meyerhof-Parnas and Entner-Doudoroff pathways. Pyruvate entered the tricarboxylic acid cycle due to pyruvate dehydrogenase activity. Pyruvate carboxylation by pyruvate carboxylase was the anaplerotic reaction providing for the synthesis of intermediates for the constructive metabolism of Acinetobacter sp. grown on C6-substrates. The C6-metabolism in Acinetobacter sp. was limited by coenzyme A. Irrespective of the carbohydrate growth substrate (glucose, ethanol), the activities of the key enzymes of both C2- and C6-metabolism was high, except for the isocitrate lyase activity in glucose-grown bacteria. Isocitrate lyase activity was induced by C2-compounds (ethanol or acetate). After their addition to glucose-containing medium, both substrates were utilized simultaneously, and an increase was observed in the EPS synthesis, as well as in the EPS yield relative to biomass. The mechanisms responsible for enhancing the EPS synthesis in Acinetobacter sp. grown on a mixture of C2- and C6-substrates are discussed.


The neurosecretory staining in the pleural-pedal ganglion of the Japanese abalone (Ezoawabi), Haliotis discus hannai, and its relationship to reproduction; with a description of a newly observed neurohemal organ.
Neurosecretory staining in the pleural-pedal ganglion of the Japanese abalone (ezoawabi), Haliotis discus hannai, was studied during the reproductive cycle. The variation in stain affinity of the cells and amount of neurosecretory material contained in the neurosecretory cells were measured during the study. The pleural-pedal ganglion contained 7 different cell types. The quantity of different cell types in the pleural-pedal ganglion was unusual for a prosobranch gastropod. Cell Types, α- and β-cells, showed neurosecretory staining and the stain intensity varied during the reproductive cycle. α-cells were the most abundant cells in the pleural-pedal ganglion and the quantity of neurosecretory material inside the cell body clearly correlated with gametogenesis. Neurosecretory material in β-cells showed a strong correlation with the induction of spawning. A neurohemal organ (pleural organ) was found in close proximity to the β-cells in the statocyst tissue. The pleural organ is the first ectodermal neurohemal organ reported in a prosobranch gastropod. A nervous connection (stato-pleural nerve) with a possible sensory function was found between the statocyst and the pleural-pedal ganglion.


Transcriptomic signature of bacteria exposed to benzalkonium chloride.
The COVID-19 pandemic has highlighted our reliance on biocides, the increasing prevalence of resistance to biocides is a risk to public health. Bacterial exposure to the biocide, benzalkonium chloride (BAC), resulted in a unique transcriptomic profile, characterised by both a short and long-term response. Differential gene expression was observed in four main areas: motility, membrane composition, proteostasis, and the stress response. A metabolism shift to protect the proteome and the stress response were prioritised suggesting these are main resistance mechanisms. Whereas "well-established" mechanisms, such as biofilm formation, were not found to be differentially expressed after exposure to BAC.


Synthesis, structure, and reactivity of monofunctional platinum(II) and palladium(II) complexes containing the sterically hindered ligand 6-(methylpyridin-2-yl)acetate.
Three complexes containing the novel, sterically hindered ligand 6-(methylpyridin-2-yl)acetate (PICAC) have been synthesized and characterized: [Pt(NH3)2(PICAC-N,O)]NO3 (1), [Pt(en)(PICAC-N,O)]NO3 (2), and [Pd(en)(PICAC-N,O)]NO3 (3) (en = ethane-1,2-diamine). The crystal structures of 2 and 3 have been determined. The two complexes are isostructural and exhibit a mixed [N3O] coordination. In both cases, PICAC forms a sterically crowded six-membered chelate. Signal multiplicities in 1H NMR spectra of 1-3 indicate that the N,O chelates are conformationally rigid on the NMR timescale as a result of the steric bulk of the pyridine derivative. Complex 2 undergoes facile ring opening in 0.1M NaCl solution at neutral pH, resulting in a zwitterionic species in which carboxylate oxygen has been replaced with chloride. The complex was identified by X-ray crystallography as [PtCl(en)(PICAC-N)] x H2O (4), which contains a "dangling" carboxylate group. In 4, the pyridine moiety adopts an almost perpendicular orientation relative to the platinum coordination plane. Likewise, complex 2 reacts rapidly with 5'-guanosine monophosphate (5'-GMP) to form the monofunctional adduct [Pt(en)(PICAC)(5'-GMP)] (5) (NMR, 25 degrees C, t(1/2) approximately 24 min). 2-D nuclear Overhauser enhancement spectroscopy (NOESY) and double quantum-filtered correlated spectroscopy (dqf-COSY) experiments (500 MHz) and variable temperature NMR spectroscopy confirm that adduct 5 exists as a 1:1 mixture of rotamers in solution as a result of the mutual repulsion between the cis-oriented pyridine and guanine bases. While 2 readily reacts with DNA nitrogen, its monofunctional adducts show no significant effect on the conformation of native DNA. Circular dichroism (CD) spectra recorded of platinum-modified calf-thymus DNA suggest that the structural damage produced by complex 2 does not mimic that produced by the clinical agent. Both the unusual reactivity and the inability to induce cisplatin-like DNA conformational changes are proposed to be responsible for the marginal biological activity of the new complexes.


A method for the reconstruction of multifocal structured illumination microscopy data with high efficiency.
We present and demonstrate an efficient method for the reconstruction of profiles acquired by multifocal structured illumination microscopy (MSIM) utilizing few raw images. Firstly, we propose a method to produce nine raw multifocal images with enhanced modulation depth to accomplish the uniform illumination of the sample. Then, combing with the parameter of the arrays, we perform the standard construct reconstruction procedure of structured illumination microscopy (SIM) row by row and column by column. Finally, we combine these restored images together to obtain the final image with enhanced resolution and good contrast. Based on theoretical analysis and numerical simulations, this method shows great potential in the field of the image reconstruction of MSIM data.


Epididymal cyst in children.
The terms "epididymal cyst" and "spermatocele" are commonly used to describe the same entity, but, conversely, they are slightly different. Epididymal cyst is a benign mass, and it is more common than previously thought in prepubertal age. Pathogenic mechanisms for epididymal cyst have not been fully clarified yet, even if epididymal cysts have been reported in association with other malformations of the urinary tract or complex syndromes. Epididymal cyst is easily characterized and differentiated from spermatocele using ultrasound imaging. Conservative management constitutes the treatment of choice in the majority of cases, and surgery is recommended only in selected cases. Conclusion: To date, a review on epididymal cyst in childhood is lacking in the literature. Herein, an overview of knowledge about epididymal cyst in children has been carried out with particular attention to differential diagnosis, proper management, and practice guidelines for caregivers of children who may present with an epididymal cyst. What is Known: • Epididymal cyst is a benign sac in the testicles which is usually asymptomatic. • Epididymal cyst is easily diagnosed by ultrasound scans, and it is considered a self-limiting disease in the majority of cases. What is New: • Insight on differential diagnosis between epididymal cyst and spermatocele. • Valuable knowledge on the best management strategy for epididymal cyst and on practice guidelines for parents of children presenting with epididymal cyst.


Oligonucleotide therapeutics for human leukaemia.
The concept of antisense oligonucleotide 'therapeutics' has generated a great deal of controversy. Questions abound regarding the mechanism of action of these compounds, their reliability and their ultimate utility. These problems are compounded by the 'hype', which has attended their development, and the inability of workers in this area to meet the expectations raised by its most zealous proponents. Nevertheless, it is worth pointing out that there have been some notable gene disruption successes with this technique that have stood up to rigorous scrutiny. Our own work with c-myb as a target is perhaps a reasonable example. Though much remains to be accomplished before antisense drugs are commonly, and usefully, employed in the clinic, it is important to remember what motivates their development. Gene-targeted drugs have the promise of exquisite specificity and the potential to do much good with little toxicity. Accordingly, antisense oligonucleotides can serve as a paradigm of rational drug development. For all these reasons then, we believe that efforts should be increased to decipher the mechanism of action of antisense oligodeoxynucleotides, and to learn how they may be successfully employed in the clinic.


[Percutaneous correction of acquired aortic stenosis and mitral insufficiency in adults].
Aortic stenosis and mitral regurgitation are the most common valvular diseases in western countries. Surgical treatment, aortic valve replacement or mitral valve repair, is the treatment of choice. Innovative technologies could offer an alternative therapeutic option to the patients with increased operative risk. This article will report the early experience with these promising techniques as presented at the High-Tech 2004 meeting.


P wave abnormalities in the orthogonal electrocardiogram: Correlation with ventricular overload in pulmonic and aortic valvular heart disease.
The correlation between several P wave measurements form the orthogonal electrocardiogram (SVEC III lead system) extracted by computer analysis and simple hemodynamic parameters related to ventricular dysfunction was studied in two groups of patients. Group I consisted of 32 patients with pulmonic valvular stenosis and intact interventricular septum. There was a significant correlation between electrocardiographic criteria of right atrial overload and the two hemodynamic parameters studied: peak pulmonic systolic pressure gradient and right ventricular end diastolic pressure (r = 0.502, p smaller than 0.005 and r = 0.661, p smaller than 0.001 respectively). Group II consisted of 49 patients with aortic valve disease. In this group, a significant correlation between the electrocardiographic parameters of left atrial overload and the left ventricular end diastolic pressure could be demonstrated only be a multivariate regression analysis (r = 0.630, p smaller than 0.005). The P wave measurements that are well correlated with the ventricular end diastolic pressure can be considered as valuable criteria for atrial enlargement secondary to a decrease of ventricular compliance, such as seen in ventricular hypertrophy, failure or in ventricular constrictive or restrictive diseases. The pathophysiologic mechanisms of the influence of the ventricular overload (dysfunction) on the atrial function and the resulting P wave changes are discussed.


Crescentic glomerulonephritis without immune deposits: clinicopathologic features.
Of 46 patients with acute crescentic glomerulonephritis involving 20 to 90% of glomeruli, 16 had no definable systemic disease and no significant glomerular immune deposits by immunofluorescent or electron microscopy. Anti-GBM antibody and circulating immune complexes were further excluded by radioimmunoassay and Raji cell assay in all patients tested. Clinical features included a 10:6 male:female ratio, mean age of 58 years (range, 13-77), disease duration of less than 3 months, rapidly deteriorating renal function, and frequent pulmonary manifestations. Nine patients had oliguria, serum creatinine concentrations over 6 mg/100 ml, and required dialysis, but three of these patients subsequently recovered renal function. These three patients and seven patients with creatinine concentrations of less than 6 mg/100 ml have not progressed to chronic renal failure. In this series, idiopathic acute crescentic glomerulonephritis without immune deposits was more common than was immune complex or anti-GBM nephritis. The clinical, laboratory, and pathologic characteristics of these patients were similar to those reported in anti-GBM and immune-complex-induced glomerulonephritis. These observations expand the spectrum of rapidly progressive crescentic glomerulonephritis. They suggest that glomerular immune deposits may be less important than other factors in determining the extent of renal injury and subsequent clinical course in crescentic glomerulonephritis.


MMTV-associated transcription factor binding sites increase nm23-H1 metastasis suppressor gene expression in human breast carcinoma cell lines.
We hypothesize that elevation of nm23-HI metastasis suppressor gene expression in micrometastatic tumor cells may reduce their subsequent colonization and invasion, and induce differentiation, with a clinical benefit. This report presents the first analysis of the nm23-HI promoter to identify sites which can increase its transcription. Deletion mapping of a 2.1 kb nm23-H1 promoter fragment tethered to a reporter gene identified three regions involved in its differential expression levels among a panel of human breast carcinoma cell lines: a 195 bp NheI-XbaI fragment responsible for basal expression levels, a 248 bp AvrII-Nhel fragment which contributed to the elevated nm23-H1 expression observed in the high expressing cell lines, and a 544 bp AvrII fragment containing an inhibitory element. Examination of the 248 bp AvrII-NheI fragment revealed the unexpected presence of three transcription factor binding sites (MAF/Ets, CTF/NF1 half site and ACAAAG enhancer) previously identified in the MMTV-LTR, and in WAP and milk gene promoters, proposed to mediate mammary-specific gene expression. Mutation of the three sites, individually or together, resulted in two-fold reductions in reporter gene expression. As controls, the same panel of mutations caused a different pattern of reporter gene expression in a non-mammary cell line, and mutation of another nearby site was without effect on nm23-HI. Our data identify a complex regulatory pattern for nm23-H1 transcription, and suggest that a mammary-specific cassette of transcription factors contribute to its elevated expression


Surgical outcomes in esophageal cancer patients with tumor recurrence after curative esophagectomy.
This study aimed to identify predictive factors and to evaluate appropriate treatments for recurrence of esophageal cancer after curative esophagectomy. About 166 consecutive patients, who underwent curative esophagectomy, were enrolled between April 1994 and March 2003. Recurrence was classified as loco-regional or distant. Logistic regression analysis was used to identify predictive factors for recurrence. Prognostic factors were evaluated by Log-rank test and Cox proportional hazard regression analysis. The disease-specific 5-year survival was 56.8%. Recurrence was observed in 72 patients (43.4%), with 64 of these occurring within 3 years. The number of metastatic lymph nodes and lymphatic invasion independently predicted recurrence. There were significant differences in time to recurrence and survival time between loco-regional, distant recurrence, and combined recurrence. The 5-year survival time in patients with recurrence was 11.9%, and median survival time was 24 months. There was also a significant difference in survival after recurrence between treatment methods (no treatment vs chemo-radiotherapy, p=0.0063; chemotherapy, p=0.0247; and radiotherapy, p<0.0001). Meticulous, long-term follow-up is particularly necessary in patients with four or more metastatic lymph nodes to achieve early detection of recurrence. Randomized controlled trials should be used to develop effective modalities for each recurrence pattern to improve therapeutic outcomes.


Substantive theory on commitment to nurse teacherhood.
Nurse teacherhood is usually examined from the perspectives of nurse teachers' tasks, roles, skills and managing. The purpose of this study was to discuss how nurse teachers themselves describe their teacherhood. The purpose was also to generate a substantive theory of nurse teacherhood, its development, changes and manifestation. Nurse teachers from different polytechnics (today called universities of applied sciences) in Finland (N=34) were interviewed using a semi-structured interview. The data were analysed by employing the grounded theory method. Nurse teacherhood was found to be a dynamic process influenced by processes of change in the organisation, the operating culture of the health care working community, nurse teachers' professional self-esteem, the focus of nurse teachers' competence, their relationship with students, the future of their profession and requirements for staying in the profession. Commitment emerged as the core feature of nurse teacherhood. It was possible to distinguish eight types of commitment: (1) searching for new content in one's position, (2) being adapted to one's position, (3) trying to advance in one's position, (4) having found one's position, (5) searching for one's position, (6) withdrawing from one's position, (7) being satisfied with one's position and (8) being uncertain about one's position.


Zero-Inflated Binomial Model for Meta-Analysis and Safety-Signal Detection.
Meta-analysis of related trials can provide an overall measure of safety-signal accounting for variability across studies. In addition to an overall measure, researchers may often be interested in study-specific measures to assess safety of the product. Likelihood ratio tests (LRT) methods serve this purpose by identifying studies that appear to show a safety concern. In this paper, we present a Bayesian approach. Despite having good statistical properties, the LRT methods may not be suitable for the meta-analysis of randomized controlled trials (RCTs) when there are several studies with zero events in at least one arm. In this article, we describe a Bayesian framework using a Zero-inflated binomial model with spike-and-slab parameterization for the treatment effects. In addition to providing an overall meta-analytic estimate, this method provides posterior probability of a safety-signal for each study. We illustrate the approach using two published data sets comprising several randomized controlled trials (RCTs) each and compare the model performance for different choices of priors for treatment effect. The proposed Bayesian methodological framework is useful to identify potential signal for single adverse event and to determine overall meta-analytic estimate of the magnitude of the signal. Practitioners may consider this approach as an alternative to the frequentist's LRT approach discussed in Jung et al. (J Biopharm Stat 31:47-54, 2020) when there are zero events in either the treatment arm or the control arm. In the future, this approach can be further extended to accommodate multiple adverse events.


Childhood obesity prevention policies in Iran: a policy analysis of agenda-setting using Kingdon's multiple streams.
Pediatric obesity is one of the most important health challenges of the twenty-first century. Primary prevention of childhood obesity, can lessen its consequences. This study aims to assess childhood obesity prevention policies in Iran through a policy analysis of agenda-setting using Kingdon's multiple streams. A qualitative study was conducted using in-depth interviews with 39 key informants and document review from different stages of the policymaking process of childhood and adolescent obesity prevention programs in Iran. The analysis of documents and interviews were guided based on Kingdon's multiple streams (problem, policy and political streams). The important factors of the problem stream were the high prevalence of childhood and adolescent obesity and its risk factors in Iran. In the policy stream, a focus on preventing non-communicable diseases in the health system, increasing the workforce in health centers, promoting health school programs, and creating healthy eating buffets in schools was identified. Under the political stream, the impact of the WHO ECHO program in 2015 and the implementation of the health system transformation plan in Iran in the new government took place after 2013, caused the Iran ECHO program entered the agenda and implemented from 2016. Now that a window of opportunity for childhood and adolescent obesity prevention policymaking has been created, the problems such as the therapeutic approach in the health system, the existence of sanctions against Iran and outbreak of coronavirus disease-19 (COVID-19), have hindered the successful implementation of this policy and the opportunity window has not been well used. However, actors need political support from the high levels of government to keep this policy on the agenda.


Deucravacitinib for the Treatment of Psoriatic Disease.
Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.


Competitive inhibition of cellobiohydrolase I by manno-oligosaccharides.
In the hydrolysis of softwood, significant amounts of manno-oligosaccharides (MOS) are released from mannan, the major hemicelluloses in softwood. However, the impact of MOS on the performance of cellulases is not yet clear. In this work, the effect of mannan and MOS in cellulose hydrolysis by cellulases, especially cellobiohydrolase I (CBHI) from Thermoascus aurantiacus (Ta Cel7A), was studied. The glucose yield of Avicel decreased with an increasing amount of added mannan. Commercial cellulases contained mannan hydrolysing enzymes, and β-glucosidase played an important role in mannan hydrolysis. Addition of 10mg/ml mannan reduced the glucose yield of Avicel (at 20g/l) from 40.1 to 24.3%. No inhibition of β-glucosidase by mannan was observed. The negative effects of mannan and MOS on the hydrolytic action of cellulases indicated that the inhibitory effect was at least partly attributed to the inhibition of Ta Cel7A (CBHI), but not on β-glucosidase. Kinetic experiments showed that MOS were competitive inhibitors of the CBHI from T. aurantiacus, and mannobiose had a stronger inhibitory effect on CBHI than mannotriose or mannotetraose. For efficient hydrolysis of softwood, it was necessary to add supplementary enzymes to hydrolyze both mannan and MOS to less inhibitory product, mannose.


Large concealed paravaginal haematoma: A case report of an occult postpartum haemorrhage.
Paravaginal haematomas are common but rarely do they cause severe postpartum haemorrhage. While surgical evacuation is classically recommended for large haematomas, conservative management may be an appropriate strategy. We present the case of a 30-year-old primiparous woman with a large paravaginal haematoma causing a postpartum haemorrhage managed conservatively. The patient became hypotensive to 80/40 mmHg three and a half hours after forceps delivery, despite minimal vaginal bleeding. On examination she had a palpable mass at the right vaginal wall and uterine fundus deviated to the right, above the umbilicus. A computerised tomography examination of the pelvis demonstrated two paravaginal haematomas, the largest measuring 7 cm × 8 cm × 12 cm, extending superiorly into the supralevator and extraperitoneal space. The patient's haemoglobin fell from 13.2 g/dL to 7.1 g/dL. She was managed conservatively with analgesia, intravenous fluid resuscitation and one unit of packed red blood cells, and was discharged home three days postpartum. This case supports the conservative management of even large paravaginal haematomas, which may extend into the supralevator space, making surgical evacuation technically difficult.


Kallikrein-like activity in salivary glands using a new tripeptide substrate, including preliminary secretory studies and observations on mast cells.
The tripeptide substrate D-val-leu-arg-4-methoxy-2-naphthylamine gave a precise localization of reaction product in cryostat sections of aldehyde-fixed salivary glands from a number of species, with Fast Blue B as the capture reagent. In submandibular glands, there was strong staining of the granules in granular tubules of rats and hamsters and somewhat less in mice. Submandibular striated ducts showed variable periluminal staining in a finer granular form; it was abundant in guinea-pigs, strong in cats but somewhat less pronounced in dogs. Parotid glands contained less reactivity with none detectable in hamsters and guinea-pigs. In the rabbit, neither gland showed any reaction. Mast cells were densely stained in glands from cats and dogs; they were less reactive in rats and unstained in the other species. The closely related 7-amino-4-trifluoromethylcoumarin derivative of the tripeptide has been found highly satisfactory for assessing activity in submandibular saliva from cats. Preliminary functional studies indicate that an extensive rapid secretion of enzyme occurs into saliva on sympathetic stimulation, with a corresponding depletion of reactive material from the striated ducts in tissue sections. Far less mobilization of enzyme occurs into saliva on parasympathetic stimulation with no obvious change in the histochemical reaction of striated ducts. The possible significance of these findings in cats is discussed. Extensive qualitative and quantitative studies are required to evaluate enzyme and substrate specificities in each species. Nevertheless, derivatives of D-val-leu-arg offer great promise for the functional testing of kallikrein-like reactivity both by histochemical means on cells and biochemically in their secretions.


Effect of time windows in LSTM networks for EEG-based BCIs.
People with impaired motor function could be helped by an effective brain-computer interface (BCI) based on a real-time electroencephalogram (EEG) and artificial intelligence algorithms. However, current methodologies for interpreting patient instructions from an EEG are not accurate enough to be completely safe in a real-world situation , where a poor decision would place their physical integrity at risk, such as when traveling in an electric wheelchair in a city. For various reasons, such as the low signal-to-noise ratio of portable EEGs or the effects of signal contamination (disturbances due to user movement, temporal variation of the features of EEG signals, etc.), a long short-term memory network (LSTM) (a type of recurrent neural network) that is able to learn data flow patterns from EEG signals could improve the classification of the actions taken by the user. In this paper, the effectiveness of using an LSTM with a low-cost wireless EEG device in real time is tested, and the time window that maximizes its classification accuracy is studied. The goal is to be able to implement it in the BCI of a smart wheelchair with a simple coded command protocol, such as opening or closing the eyes, which could be executed by patients with reduced mobility. Results show a higher resolution of the LSTM with an accuracy range between 77.61 and 92.14% compared to traditional classifiers (59.71%), and an optimal time window of around 7 s for the task done by users in this work. In addition, tests in real-life contexts show that a trade-off between accuracy and response times is necessary to ensure detection.


Studies on resistance in snails. 7. Evidence of interference with the defense reaction in Biomphalaria glabrata by trematode larvae.
Echinostoma lindoense sporocysts that develop from irradiated miracidia normally are destroyed by amebocyte capsules in the ventricle of Biomphalaria glabrata within 10 days postexposure. The survival period of these ventricular sporocysts was considerably longer in snails that also harbored normal sporocysts of E. lindoense, Paryphostomum segregatum, or Schistosoma mansoni. Protection of irradiated E. lindoense sporocysts by the same of different trematode species is presumed to be the result of an active process by which normal sporocysts interfere with capsule formation and protect themselves and other trematode larvae from encapsulation. Homologous protection was stronger than heterologous.


Clinical trial design in the neurocritical care unit.
Clinical trials provide a robust mechanism to advance science and change clinical practice across the widest possible spectrum. Fundamental in the Neurocritical Care Society's mission is to promote Quality Patient Care by identifying and implementing best medical practices for acute neurological disorders that are consistent with the current scientific knowledge. The next logical step will be to foster rapid growth of our scientific body of evidence, to establish and disseminate these best practices. In this manuscript, five invited experts were impaneled to address questions, identified by the conference organizing committee as fundamental issues for the design of clinical trials in the neurological intensive care unit setting.


Aspects of carotid structure and function in health and different stages of chronic kidney disease.
Arterial remodelling and stiffening have been demonstrated in end-stage renal disease (ESRD). The presence of vascular alterations in earlier-stage chronic kidney disease (CKD) is less studied. We evaluated vascular structure and function in mild-to-moderate CKD (stages 2-3) compared with healthy subjects and advanced CKD (stages 4-5). Carotid ultrasound was performed in 103 non-dialysis CKD patients and 54 healthy controls. Carotid intima-media thickness (CIMT) and common carotid artery (CCA) diameter were measured. Strain, stiffness and the pressure-strain elastic modulus (Ep ) of the right CCA were calculated. There was no significant difference in CCA diameter between CKD 2-3 and controls. The CCA diameter was larger in CKD 4-5 compared with CKD 2-3 and controls (CKD 4-5, 6·50 ± 0·79 mm versus CKD 2-3, 6·08 ± 0·56 mm, P = 0·003; and versus controls 5·97 ± 0·53 mm, P<0·001). However, after adjustments, the difference in CCA diameter was valid only for older ages and also dependent on systolic blood pressure (SBP). There were no significant differences in CIMT, strain or stiffness between the groups, but Ep was higher in CKD 4-5 compared with controls (P = 0·006). In mild-to-moderate CKD, there were no significant differences in carotid artery structure or function compared with healthy subjects. Only patients with advanced CKD and older ages showed signs of arterial remodelling. Our study indicates that vascular alterations occur in advanced CKD, with SBP and age as important contributing factors.


Tip of nose: an unusual site for a neurilemmoma.
An extremely rare case of neurilemmoma of the nasal tip is presented. The need for careful preoperative assessment is emphasised.


Mediating effect of circadian rhythm between work stress and sleep quality in Chinese shift-working nurses: A cross-sectional survey.
This study examined the mediating effect of circadian rhythm amplitude (LV) and stability (FR) between work stress and sleep quality among Chinese shift-working nurses (SWNs). A cross-sectional study. Three-hundred and seventy-nine nurses working in shifts were investigated by convenient sampling from six hospitals in Shanghai, China. The mediating effect was analysed using the structural equation model with bootstrapping procedures. Work stress could directly affect shift nurses' sleep quality and indirectly affect sleep quality through circadian rhythm amplitude and stability. The total indirect effects of work stress on sleep quality accounted for 36.7% of the total effect. The study revealed that poor sleep quality is very common among SWNs, which deserves attention. The mediating effect of the circadian rhythm provides new insights to improve sleep quality, not only by lightening the work stress but also by improving circadian rhythm in SWNs.


Examining the potential applicability of the minority stress model for explaining suicidality in individuals with disabilities.
The purpose of this conceptual article is to discuss the minority stress model and its potential applicability as a model for examining the higher rates of suicidality in people with disabilities. This conceptual article is based in the empirical literature on the minority stress model and the literature exploring the experiences of both proximal (e.g., internalized stigma, self-concealment) and distal (e.g., harassment, violence, and discrimination) minority stress among people with disabilities. It also draws from the literature on suicidality and disability. After establishing the higher rates of suicidality among people with disabilities as evidenced in the existing literature and discussing our gaps in the knowledge about the factors that drive this phenomenon, I discuss the minority stress model, which posits that elevated rates of suicidality among individuals with disabilities can be explained by a combination of proximal and distal stressors related to one's marginalized status. I then discuss the ways in which this model could be applied to suicidality and psychological distress in individuals with disabilities, drawing on research that establishes that they experience these proximal and distal stressors at high rates. The minority stress model is potentially useful for conceptualizing the higher rates of suicidality among people with disabilities, both alone and in conjunction with other models of suicide, in a manner that addresses disability justice and the experiences and effects of chronic, pervasive marginalization. Recommendations for research, and policy, including strategies for addressing both internalized ableism and disability-related discrimination and harassment, are provided. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Serpin-Enzyme Receptors LDL Receptor-Related Protein 1.
Early studies suggested the existence of an hepatic receptor that is involved in the clearance of serpin:enzyme complexes. Subsequent work has identified this receptor as the LDL receptor-related protein 1 (LRP1). LRP1 is a multifunctional receptor that serves to transport numerous molecules into the cell via endocytosis and also serves as a signaling receptor. LRP1 plays diverse roles in biology, including roles in lipoprotein metabolism, regulation of protease activity, activation of lysosomal enzymes, and cellular entry of bacterial toxins and viruses. Deletion of the Lrp1 gene leads to lethality in mice, revealing a critical, but as of yet undefined, role in development. Its identification as a receptor for serpin:enzyme complexes confirms a major role for LRP1 in regulating protease activity.


Determination of aristolochic acid I and its metabolites in cell culture with a hyphenated high-performance liquid chromatographic technique for cell toxicology.
Aristolochic acid I (AA I), a major component of the carcinogenic plant extract aristolochic acid (AA), is known to be nephrotoxic, carcinogenic and mutagenic. A simple, rapid and sensitive high-performance liquid chromatography-diode array detection-fluorescence detection (HPLC-DAD-FLD) method was developed and validated for the analysis of AA I and its metabolites in cell culture medium for the first time. The samples were prepared with ethyl acetate liquid-liquid extraction (LLE). Good separation was obtained on an ODS C(18) analytical column with 0.2% HAc/methanol gradient solution. Linearities of about three orders of magnitude were gained with correlation coefficients exceeding 0.9990. The method appears to be a suitable tool for the cellular toxicokinetic study with acceptable precisions and recoveries. Cytotoxicity of AA I on human liver cells (L-02) was investigated with morphological observation and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, cytotoxicity increased in AA I concentration-dependent manner. AA I and its metabolites were monitored with the proposed chromatographic analysis, and some preliminary toxicokinetics were investigated.


Diagnostic value of FDG PET/CT imaging in patients with surgically managed infective endocarditis: results of a retrospective analysis at a tertiary center.
We assessed the diagnostic value of FDG PET/CT in a real-world cohort of patients with surgically managed infective endocarditis (IE). We performed a retrospective analysis of all patients hospitalized in a tertiary IE referral medical center from January 2014 to October 2018 fulfilling the following criteria: ICD-10 code for IE and OPS code for both, heart surgery and FDG PET/CT. Final analysis included 29 patients, whereof 28 patients had surgically proven IE. FDG PET/CT scan was true-positive in 15 patients (sensitivity (SEN) 56%) and false-negative in 12 patients. Combination of Duke criteria (DC) with FDG PET/CT scan resulted in gain of SEN for all patients with confirmed IE (SEN of DC 79% vs SEN of combination DC and FDG PET/CT 89%), driven by a relevant gain in PVE patients only (SEN of DC 78% vs SEN of combination DC and FDG PET/CT 94%). Interestingly, higher prosthesis age was observed in patients with false-negative scans. We found a SEN of 56% for FDG PET/CT in a real-world cohort of patients with surgically proven IE which was associated with a 16% gain of IE diagnosis in patients with PVE when combined with DC.


Synthesis of lactones using substituted benzoic anhydride as a coupling reagent.
This protocol describes a procedure for the synthesis of a 29-membered macrolactone. The facile mixed-anhydride method is very effective for the preparation of carboxylic esters and lactones using substituted benzoic anhydrides by the promotion of Lewis acid or basic catalysts under mild reaction conditions. Owing to the reaction rapidly proceeding to produce the monomeric compounds with high chemoselectivity, the protocol is quite powerful for the synthesis of not only the giant-sized lactones but also the highly strained cyclic compounds such as medium-sized lactones. The remarkable efficiency of the lactonizations promoted by the substituted benzoic anhydrides has been already shown in the synthesis of many natural complex molecules. It takes approximately 19 h to complete the protocol: 0.5 h to set up the reaction, 13.5 h for the reaction and 5 h for isolation and purification.


Metastatic melanoma to the lung cured with lobectomy: A case report.
We herein present the case of a 79-year-old female patient who presents with a single asymptomatic pulmonary nodule, melanocytic in nature, later identified as a remote secondary lesion of a primary cutaneous melanoma that was resected 22 years before presentation. Although quite atypical, the patient underwent resection of the affected pulmonary lobe; follow-up imaging did not reveal any local or distant recurrences.


Successful treatment of synchronous chemoresistant pulmonary metastasis from pleomorphic rhabdomyosarcoma with stereotaxic body radiation therapy: A case report and a review of the literature.
Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma (STS), usually of adults, displaying skeletal muscle differentiation. STS principally metastasize to the lungs with more than 50% of metastatic patients presenting with isolated pulmonary metastasis. Paradoxically, the majority of drugs prescribed to treat RMS are associated with multidrug resistance. We report the case of a 53 year-old patient who developed three synchronous chemoresistant lung metastasis from pleomorphic RMS. Considering the poor prognosis, the patient's preference and the chemoresistance of her lung metastasis, we decided to perform two consecutive stereotactic body radiotherapy (SBRT) on two of these three lesions. Initially, the patient was referred to our institute with a painful mass in the anterior part of the left thigh increasing in volume for 3 months. Biopsy revealed a high-grade pleomorphic RMS. The cancer being staged IB, she had neoadjuvant radiotherapy. After complete surgical excision, pathology examination revealed a 6 cm Grade II pleomorphic RMS, with clear margins. Six months later, she developed three synchronous lung metastases. She got 4 courses of doxorubicin-ifosfamide which were poorly supported. After two courses, a heterogeneous (morphological and metabolic) response was observed, hence SBRT was delivered with a Biologically Equivalent Dose (α/β10)> 100 Gray on the two more chemoresistant lesions. This SBRT was very well tolerated, no side effects were reported. The patient remained alive and achieved a complete response of these three metastases, which sustains after more than 3 years. Early recognition and proper management of these oligometastatic patients may lead to motivating results in a poor prognosis disease.


RPLP1 is highly expressed in hepatocellular carcinoma tissues and promotes proliferation, invasion and migration of human hepatocellular carcinoma Hep3b cells.
Hepatocellular carcinoma (HCC) is a common primary malignant tumor with a high mortality rate. Increasing evidence suggests that ribosomal protein LP1 (RPLP1) is involved in the progression of different types of cancer. Thus, the present study aimed to investigate the underlying molecular mechanism of RPLP1 in HCC progression. The cellular behaviors of Hep3b cells were assessed via Cell Counting Kit-8, colony formation, wound healing and Transwell assays. Western blot analysis was performed to detect protein expression levels, while reverse transcription-quantitative PCR analysis was performed to detect mRNA expression levels. The results demonstrated that RPLP1 was highly expressed in HCC tissues and cells, and the overexpression of RPLP1 was associated with a less favorable prognosis of patients with HCC. Notably, downregulation of RPLP1 significantly suppressed the proliferation, migration and invasion of Hep3b cells. Taken together, the results of the present study suggested that RPLP1 acts as an oncogene in HCC, and thus may be used to treat patients with HCC.


Evaluation of Mast Cell Density using CD117 antibody and Microvessel Density Using CD34 Antibody in Different Grades of Oral Squamous Cell Carcinoma.
To compare mast cell and microvessel densities among histologic grades of oral squamous cell carcinoma. Armed Forces Institute of Pathology. A total of 60 specimens of OSCC comprising 20 each of well, moderately and poorly differentiated were evaluated. Immunohistochemical analysis was performed to measure MCD and MVD by applying monoclonal CD117 antibody and monoclonal CD34 antibody, on formalin fixed and paraffin embedded sections. ANOVA and Post Hoc Tukey test was employed to assess the densities and to compare the differences between different grades of OSCC. A p-value.


Fresh-frozen allografts combined with bovine bone mineral enhance bone formation in sinus augmentation.
We evaluated histologically, histomorphometrically, and tomographically the effects of the association of fresh-frozen bone allograft (FFB) with bovine bone mineral (BBM) in maxillary sinus floor augmentation. In total, 34 maxillary sinuses from 29 patients, with a mean age of 51.32 (±6.44) years, underwent sinus augmentation. Patients were divided into control and test groups (17 sinuses each). The controls were grafted with allograft bone, and the test group received a combination of FFB and BBM at a 2:1 ratio. After 6 months, bone samples were collected for histological and histomorphometric examinations. The implant survival rates were 93.02% (control group) and 100% (test group) at 6 months after functional loading. Median volumetric reductions of 28.32% (17.05-44.05) and 12.62% (5.65-16.87) were observed for the control and test groups, respectively. Statistically significant histomorphometric differences were found between the control and test groups regarding newly formed bone 12.54% (10.50-13.33) vs. 24.42% (17.62-35.92), p < 0.001, total bone 48.34% (39.03-54.42) vs. 61.32% (50.61-64.96), p = 0.007, and connective tissue 51.66% (45.57-60.97) vs. 39.30% (35.03-49.37), p = 0.007. The addition of BBM to allograft bone in maxillary sinus augmentation resulted in higher percentages of new bone formation and total bone, and permitted implant placement with a low rate of osseointegration failure at the 6-month follow-up.


Regulatory Divergence as a Mechanism for X-Autosome Incompatibilities in Caenorhabditis Nematodes.
The world's astounding biodiversity results from speciation, the process of formation of distinct species. Hybrids between species often have reduced fitness due to negative epistatic interactions between divergent genetic factors, as each lineage accumulated substitutions independently in their evolutionary history. Such negative genetic interactions can manifest as gene misexpression due to divergence in gene regulatory controls from mutations in cis-regulatory elements and trans-acting factors. Gene misexpression due to differences in regulatory controls can ultimately contribute to incompatibility within hybrids through developmental defects such as sterility and inviability. We sought to quantify the contributions of regulatory divergence to postzygotic reproductive isolation using sterile interspecies hybrids of two Caenorhabditis nematodes: Caenorhabditis briggsae and Caenorhabditis nigoni. We analyzed previous transcriptome profiles for two introgression lines with distinct homozygous X-linked fragments from C. briggsae in a C. nigoni genomic background that confers male sterility, owing to defects in spermatogenesis (Li R, et al. 2016. Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-chromosome introgression. Genome Res. 26:1219-1232). Our analysis identified hundreds of genes that show distinct classes of nonadditive expression inheritance and regulatory divergence. We find that these nonoverlapping introgressions affect many of the same genes in the same way and demonstrate that the preponderance of transgressive gene expression is due to regulatory divergence involving compensatory and joint effects of cis- and trans-acting factors. The similar transcriptomic responses to nonoverlapping genetic perturbations of the X-chromosome implicate multiway incompatibilities as an important feature contributing to hybrid male sterility in this system.


Fungemia in the French department of Mayotte, Indian Ocean: A 10 years survey.
This study aimed at providing original data on fungemia in the Centre Hospitalier de Mayotte in terms of prevalence, epidemiological characteristics of infected patients, yeast species distribution and profile of in vitro antifungals susceptibility. A total of 223 positive blood cultures for yeasts were retrospectively reported during the period April 2010-April 2020. Ninety-five episodes were identified corresponding to an incidence rate of 3.7 cases/100,000 inhabitants. The average age of patients was 33.5 years, and 63.3% patients were hospitalized in intensive care unit. The main co-morbidities were surgery in the 30 days prior to fungemia (27.8%), neoplasia (22.8%), parenteral nutrition (17.7%), diabetes (16.5%) and immunosuppressive medications (31.6%). Candida spp accounted for the majority of isolates (92.4%) with a predominance of non-albicans species (55.8% vs 33.7%), including C. albicans (33.7%), C. tropicalis (30.5%) and C. parapsilosis (20%). The antifungal susceptibility profiles did not differ from expected results for each species and did not change significantly over time. Fungemia remain frequent hospital infections associated with high mortality in Mayotte. The vast majority of fungemia was due to Candida spp. Non-albicansCandida species reach half of the Candida isolates with a high percentage of C. tropicalis. Surprisingly, no case of candidemia due to C. glabrata were identified. The management of candidemia remains satisfactory and the treatment was adapted according to the international recommendations. However, the high susceptibility of Candida spp. isolates to fluconazole may invite to reconsider the use of this molecule as empirical and first-line treatment of candidemia in Mayotte.


Telomerase inhibition promotes an initial step of cell differentiation of primate embryonic stem cell.
Embryonic stem (ES) cell is well known as a totipotent cell, which is derived from a blastcyst and has potential to differentiate into every kind of somatic cell. ES cell bears self-renewal characteristic as well as differentiation potential. ES cell bears telomerase activity to avoid telomere shortening, which is a characteristic of differentiated somatic cells. As the differentiation of ES cells proceeds, their telomerase activity is losing. However, it has not been convinced whether suppression of the telomerase activity promotes progression of ES cell differentiation. The effect of telomerase inhibitor on the differentiation potential of marmoset ES cell was assessed, counting cells expressing embryonic markers (alkaline phosphatase and TPA-1-60) under existence of a telomerase inhibitor. Telomerase inhibitor showed a promotional effect for the marmoset ES cell differentiation. This result suggests that exogenous inhibition of telomerase activity leads to induction of an early differentiation of primate ES cell.


Silver(I)-catalyzed novel cascade cyclization reactions: incorporation of allenes into the isochromenes.
[reaction: see text] The silver(I)-catalyzed reaction of alkynones with alcohols represents a general tool for the synthesis of 1-allenyl isochromenes. The reaction most probably proceeds via the formation of benzopyrylium cation, which subsequently undergoes nucleophilic attack of an alcohol to give the annulation products.


Salivary mucous glycoprotein MG1 in Sjögren's syndrome.
The aim of the study was to develop and apply a rapid method for the simultaneous analysis of the concentration and molecular weight of the human high-molecular weight mucin MG1 in small volumes of unprocessed saliva from healthy controls and from patients with Sjögren's syndrome (SS). In high performance liquid chromatography (HPLC) with a TSK 5000 PW size exclusion column, MG1 eluted with a retention time 10.6 min corresponding to a M(r) of 2 to 2.5 x 10(6). Molecular weight changes under various experimental conditions are compatible with the suggestion that the MG1 complex is composed of four 660 x 10(3) glycosylated subunits connected by disulphide bridges and associated with a 25-35 x 10(3) Da link protein. In SS the molecular weight of MG1 was normal and its concentration was high in resting (190 vs. 70 micrograms/ml, P = 0.001) but not in stimulated (46 vs. 48 micrograms/ml, P > 0.05) saliva; MG1 concentration in resting SS saliva did not vary in parallel with protein and the interindividual differences were considerable. Size exclusion HPLC is a rapid and reproducible method suitable for isolation and analysis of salivary MG1 from small volumes of unprocessed samples. The molecular weight or subunit structure of MG1 were not altered in SS. The high concentration of MG1 in resting saliva in SS, may be explained by the concentration effect, or alternatively by the low water retaining capacity, which may play an important pathogenic role in xerostomia of SS.


Vegetative propagation of Quercus suber L. by somatic embryogenesis. I. Factors affecting the induction in leaves from mature cork oak trees.
Somatic embryogenesis was induced in expanding leaves from epicormic shoots forced to sprout from segments of branches collected from several hundred-year-old cork oak trees. Following a basic protocol previously defined for leaves taken from seedlings of this species, several factors were studied to improve the response. The induction frequency was significantly higher when the length of exposure to growth regulators was increased from 7 to 30 days. The combined application of NAA and BAP was essential for induction. Although both regulators had a very significant influence, their interaction was not significant, suggesting independent roles. Leaf size had a crucial effect, because beyond a certain threshold, embryogenesis could not be obtained. Embryogenic lines were maintained via repetitive embryogenesis on hormone-free medium for more than 2 years.


Neprilysin inhibitors: A new hope to halt the diabetic cardiovascular and renal complications?
Diabetes is an enormous and ever-growing calamity and a global public health threat of the 21st century. Besides insulin and oral hypoglycaemic drugs, blockage of the renin-angiotensin system (RAS) denotes a key pharmacotherapy for the management of cardiovascular (CVD) and chronic kidney diseases (CKD), which are the leading causes of disability and death among diabetic patients. Neprilysin (NEP) inhibition, auxiliary to RAS blockage increases the bioavailability of natriuretic peptides and benefits the cardio-renal system. Omapatrilat, a dual angiotensin-converting enzyme (ACE) and NEP inhibitor has been reported to show superior anti-hypertensive, anti-atherosclerotic, insulin-sensitizing, cardiovascular and renoprotective effects to ACE inhibitors in experimental animal models for diabetes. In clinical trials on hypertensive subjects Omapatrilat increased the risk of angioedema due to which its further development as anti-hypertensive drug was hampered. This event prompted the development of angiotensin receptor neprilysin inhibitors (ARNi). The first representative of ARNi, LCZ696 (Sacubitril/ Valsartan) halted cardiovascular and renal functional decline and hence protected against CKD and CVD. Recently, LCZ696 was approved by U.S. Food and Drug Administration for the treatment of heart failure. This concise review intends to summarise the currently available reports on NEPi as a therapeutic intervention to treat CVD and CKD associated with diabetes.


The immunohistochemical analysis of antigens such as RCAS1 and B7H4 in the cervical cancer nest and within the fibroblasts and macrophages infiltrating the cancer microenvironment.
The presence of the aggressive phenotype of the tumor seems to be indicated by the local infiltration of cancer cells and by the development of metastases in the lymph nodes. This phenotype is related to the intensity of the suppressive profile of the tumor microenvironment. The aim of our study has been to gather information about the expression of both RCAS1 and B7H4 proteins in the macrophages and fibroblasts present within both the microenvironment of cervical cancer tumors and the cancer cells present on the front of the cancer nest. We analyzed the immunoreactivity levels of such antigens as B7H4 and RCAS1 in the macrophages and fibroblasts of the cancer microenvironment and within the cancer nest in the tissue samples derived from patients on whom both a radical hysterectomy and a lymphadenectomy had been performed following a diagnosis of uterine cervical carcinoma. These patients were then divided into two subgroups according to the extent of the local and distant advancement of the cancer - that is, according to the FIGO stage and the presence or absence of lymph node metastases. RCAS1 immunoreactivity levels on the front of the cancer nest statistically significantly increase according to the FIGO stage or the extent of the local spread of the disease while B7H4 immunoreactivity levels on the tumor front increase in relation to the extent of the distant spread of the disease or the presence of lymph nodes metastases. The intensity of the suppressive profile of the cervical cancer microenvironment indicated by the presence of both RCAS1 and B7H4 on the front of the tumor and in the macrophages and fibroblasts infiltrating the cancer stroma seems to correlate with the extent of both the local and distant advancement of the disease.


Graphene Oxide Papers in Nanogenerators for Self-Powered Humidity Sensing by Finger Tapping.
Triboelectric nanogenerators (TENGs) offer an emerging market of self-sufficient power sources, converting the mechanical energy of the environment to electricity. Recently reported high power densities for the TENGs provide new applications opportunities, such as self-powered sensors. Here in this research, a flexible graphene oxide (GO) paper was fabricated through a straightforward method and utilized as the electrode of TENGs. Outstanding power density as high as 1.3 W.m-2, an open-circuit voltage up to 870 V, and a current density of 1.4 µA.cm-2 has been extracted in vertical contact-separation mode. The all-flexible TENG has been employed as a self-powered humidity sensor to investigate the effect of raising humidity on the output voltage and current by applying mechanical agitation in two forms of using a tapping device and finger tapping. Due to the presence of superficial functional groups on the GO paper, water molecules are inclined to be adsorbed, resulting in a considerable reduction in both generated voltage (from 144 V to 14 V) and current (from 23 µA to 3.7 µA) within the range of relative humidity of 20% to 99%. These results provide a promising applicability of the first suggested sensitive self-powered GO TENG humidity sensor in portable/wearable electronics.


Myelin lipids: a phylogenetic study.
The lipid composition of CNS and PNS myelin was studied in rat, Xenopus, trout and Torpedo. The main difference lay in the proportion of cerebrosides, which decreased in the sequence rat greater than Xenopus greater than Torpedo greater than trout. In addition Torpedo CNS and PNS myelins were extremely rich in sulfatides. In some respects, Torpedo appeared closer to tetrapods than trout. Otherwise the proportion of the different lipid classes did not reveal any clear evolutionary trends. The presence of hydroxylated galactolipids in CNS myelin was investigated in several additional species. Considerable amounts were found in Torpedo, Polypterus, Protopterus, lizard, and chicken, with the highest values in rat and anurans. Only very small amounts of hydroxylated cerebrosides were detected in trout and in axolotl, while newt had none. This parameter appears therefore of doubtful usefulness for phylogenetic studies. In contrast to myelin proteins, myelin lipids are of limited value for establishing phylogenetic relationships among vertebrates.


Intestinal submucous fibrovascular hamartoma: A case report.
Intestinal submucosal fibrovascular hamartoma is considered as a rare intestinal lesion. We present the case of a 63-year-old female with abdominal symptoms, bleeding, and increased serum tumor markers. The abdominal ultrasound revealed that the left abdominal intestinal wall and mesentery were thickened with enlarged multiple lymph nodes, suggesting intestinal obstruction. Other imaging findings confirmed the ultrasound findings. Histopathology of the removed lesion provided the diagnosis of intestinal submucosal fibrovascular hamartoma with hemorrhage, inflammation, and amyloidosis. Intestinal submucosal fibrovascular hamartoma is a hemorrhagic lesion with macroscopic tumor due to the abnormal mixing of the organ's normal components, which still remains a challenge for clinicians and pathologists. We consider routine abdominal ultrasonography and contrast-enhanced ultrasonography (SICUS) to be safe and effective in the diagnosis of intestinal neoplastic lesions.


Not niche: eating disorders as an example in the dangers of overspecialisation.
Labelling specific psychiatric concerns as 'niche' topics relegated to specialty journals obstructs high-quality research and clinical care for these issues. Despite their severity, eating disorders are under-represented in high-impact journals, underfunded, and under-addressed in psychiatric training. We provide recommendations to stimulate broad knowledge dissemination for under-acknowledged, yet severe, psychiatric disorders.


Catheter ablation of left-sided accessory pathways in small children.
Accessory pathways (APs) are a common reason for supraventricular tachycardia in small children. Trans-septal puncture (TSP) approach is commonly used for the ablation of left-sided APs, however it may be challenging in small children. The aim of this study was to assess the efficacy and safety of trans-septal approach radiofrequency (RF) ablation of left-sided APs in children weighing up to 30 kg. Of the 658 children who underwent catheter ablation of APs since 06/2002, 86 children had left-sided AP and weighed less than 30 kg. TSP approach guided with TEE and fluoroscopy was used for left atrium access. The mean age, height, and body weight were 7.6 ± 1.9 years, 122.4 ± 9.3 cm and 24.0 ± 4.2 kg, respectively. Forty-three children (50%) were male, 46 of 86 (53%) had manifest AP, 17 of 86 (20%) weighed less than 20 kg and in 24 of 86 children (28%) a three-dimensional system (3DS) was used to reduce fluoroscopy time. The acute success rate was 98.8% (85/86), with a recurrence rate of 2.4% (2/85) in a mean follow-up of 66.2 ± 42.7 (9.1-184.2) months. The mean procedure time and fluoroscopy time were significantly lower for the 3DS group compared to the standard fluoroscopy group 131 ± 41 (55-262) and 2.4 ± 1.5 (1-6) minutes vs 164 ± 51 (62-249) and 27 ± 13 (8-77) minutes, P < 0.01 and P < 0.0001, respectively. There were no ablation-related complications. RF ablation of left-sided APs using TSP approach in small children had an excellent efficacy and safety profile. The use of 3DS significantly reduces the procedure and fluoroscopy time.


Thiols metabolism is altered by the herbicides paraquat, dinoseb and 2,4-D: a study in isolated hepatocytes.
This report is an extension and complement of a previous study reporting the effect of three herbicides (paraquat, dinoseb and 2,4-D) on cell viability, GSH oxidation, NADH and ATP depletion (Arch. Toxicol. 68:24-31, 1994). Here we report additional data and findings aimed at a better understanding of the toxicity mechanisms induced by these herbicides. Biochemical mechanisms of cytotoxicity induced by the herbicides paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride), dinoseb (2-sec-butyl-4,6-dinitrophenol) and 2,4-D (2,4-dichlorophenoxyacetic acid) were investigated in freshly isolated rat hepatocytes. Herbicide metabolism, especially paraquat and 2,4-D, rapidly depletes GSH and protein thiols. Paraquat and 2,4-D (1-10 mM) decrease the GSH/GSSG ratio, promote loss of protein thiol contents and induce lipid peroxidation. Dinoseb, the most effective cytotoxic compound under study (used in concentrations 1000-fold lower than paraquat and 2,4-D), had moderate effects upon the GSH/GSSG ratio and lipid peroxidation, causing a depletion of protein thiols of about 20%. The results indicate that the herbicides paraquat and 2,4-D are hepatotoxic and may induce cell death by decreasing cellular GSH/GSSG ratio and protein thiols, and by inducing lipid peroxidation. The cytotoxic action of dinoseb is likely to be related with the uncoupling of oxidative phosphorylation in mitochondria. Therefore, it is likely that liver damage observed during the first phase of herbicide-intoxication is related to these metabolic processes.


Diagnostic value of measuring the talofibular space using stress sonography in chronic lateral ankle instability.
To investigate the diagnostic value of measuring the talofibular space using stress sonography for chronic lateral ankle instability (CLAI). We recruited patients who were clinically diagnosed with CLAI between October 2018 and December 2019 (CLAI group). A control group of healthy volunteers was also included for this study. Both groups underwent a preliminary stress sonographic examination. First, the ultrasonic characteristics of the anterior talofibular ligament (ATFL), including length, thickness, relaxation, calcification, and rupture, were observed using conventional sonography. Second, the talofibular space at the passive neutral position (D1) and maximum varus position (D2) was measured (by stress sonographic images), and the difference (ΔD = D1-D2) between them was determined. Third, the parameters of the two groups were statistically compared. Finally, receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were performed for parameters with significant differences. The CLAI group comprised 60 patients, yielding data on 60 ankles, whereas the control group comprised 35 participants, yielding data for 70 ankles. Differences in D1, D2, and ΔD of the talofibular space between the two groups were significant, with ΔD proving to be the best diagnostic indicator (P < 0.001). Its AUC, optimal cutoff value, sensitivity, and specificity were 0.922, 0.11 cm, 73 %, and 94 %, respectively, followed by D2 (0.850, 0.47 cm, 67 %, and 94 %, respectively; P < 0.001) and D1 (0.635, 0.47 cm, 67 %, and 94 %, respectively; P = 0.006). Measurement of talofibular space in stress sonography is a valuable diagnostic indicator for CLAI, especially the ΔD between the neutral and stress position.


Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDS-related Kaposi's sarcoma.
To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proven cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (Cmax,avg) and dose intensity. The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both Cmax,avg and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.


[Miliary tuberculosis: a report of 49 cases].
Miliary tuberculosis is a severe, acute form of tuberculosis due to lymphohaematogenous dissemination of tubercle bacilli from a focal lesion. A prospective study of was undertaken at the Pneumology Clinic of the National University Hospital Centre (CHUN) of Fann, over a period of 30 months (January 2007-June 2009), in order to assess the epidemiological, clinical, paraclinical and evolutionary aspects of miliary tuberculosis. Miliary tuberculosis accounted for 3.8% (n=49) of all diagnosed cases of tuberculosis. The sex-ratio was 1.7. The average age of patients was 37.5 years with a range of 15 to 70 years. The typical radiological appearances were present in 88% of cases whereas only 10% were positive on direct smear. HIV serology was positive in 29%. In the hospital environment, the mortality was 12.2%. Miliary tuberculosis is a severe form of the disease. The prognosis depends on early diagnosis and treatment.


Measuring lymphocyte transcription factor activity by ELISA.
Adequate immune function requires the complex interaction between cells via a series of biochemical and molecular events, culminating in altered gene expression. Initiation of transcription by sequence-specific DNA-binding proteins known as transcription factors (TFs) is the principle point at which the expression of most genes is regulated. Thus, an understanding of nuclear events affected by environmental toxicants and their mechanisms of actions is critical to understanding toxic phenomena.Colorimetric enzyme-linked immunosorbent assay (ELISA)-based procedures have been developed to detect specific transcription factor DNA-binding activity in cell extracts. Up to 96 reactions can be performed in 3 to 4 hr. Extracts are added to the 96-well plate precoated with a transcription factor DNA-binding consensus sequence and detected with an antibody specific to the transcription factor of interest. In short, ELISA provides increased speed and throughput, and allows improved sensitivity and convenience over the traditional methods.


Myositis ossificans traumatica of the thenar region.
Myositis ossificans of the hand is extremely rare. We report an unusual case of myositis ossificans of the thenar muscles and discuss the diagnostic pitfalls whereby this condition can be mistaken for malignancy or infection.


Intracellular cytokine production in peripheral blood lymphocytes: a comparison of values in infertile and fertile women.
To analyze the relation of the fertility and pregnancy of women of childbearing age to the intracellular (IC) production of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukins 2 and 4 (IL-2 and IL-4). Intracellular cytokine production in peripheral blood CD3(+) CD4(+) lymphocytes was analyzed by flow cytometry in 185 women being treated for infertility and 50 fertile women of childbearing age. Infertile women have a significantly higher IC production of TNF-α, IFN-γ, IL-2, and IL-4 and higher ratios of TNF-α/IL-2, TNF-α/IL-4, and TNF-α/IFN-γ compared to the fertile women. Cytokines produced by Th lymphocytes are important in orchestrating the immune response during conception, and Th-cell dysregulation could be a reason for infertility.


Malnutrition-induced changes of responses evoked in the rat prefrontal cortex as revealed by sensitivity to strychnine.
Susceptibility to strychnine of somatosensory responses evoked in the prefrontal cortex was studied in normal and protein-malnourished rats in three groups. (a) The normal group was from mothers fed a 21% casein diet. (b) The prenatally malnourished group was from mothers fed a 6% casein diet during 5 weeks prior to mating and throughout gestation. (c) The postnatally malnourished group born from dams fed a 6% casein diet throughout the nursing period. At 45 days of age, sensitivity of the responses to 0.5% strychnine sulfate solution was tested by measuring changes in peak-to-peak amplitude. The results showed that cortical neurons of the postnatally protein-restricted group had decreased susceptibility to strychnine, indicating functional disturbances of glycinergic synapses.


Outcome of mock embryo transfer before the first IVF cycle: A randomized control trial.
There is a lack of agreement among fertility specialists with regard to the routine use of mock embryo transfer (MET) before each in vitro fertilization (IVF) treatment cycle. While MET may be beneficial with previous difficult embryo transfer cases, its routine use before first IVF cycle has not been evaluated. To find out the effect of MET before the first IVF cycle on clinical pregnancy rate. This is a single-centre randomized controlled trial with a balanced randomization (1:1), carried out between November 2015 and October 2017, with 200 subjects at Homerton university hospital, London, randomized into either MET or control. The primary outcome was clinical pregnancy rate (detection of heart activity on the ultrasound scan), the secondary outcome measures were live birth rate, miscarriage and multiple pregnancy rates, difficult ETs, rate of blood or mucus on the catheter tip. No significant differences were observed in the baseline or cycle characteristics between the two groups. The clinical pregnancy rate was similar between the MET and control groups based on both intension to treat and per protocol analyses (p = 0.98, p = 0.92, respectively). Additionally, no significant difference was seen in the live birth rate in both groups on intension to treat and per protocol analyses (p = 0.67, p = 0.47), respectively. Our study concludes that MET prior to first IVF cycle may not improve the success rate in young women without risk factors for a difficult embryo transfer.


[Acupuncture together with cytokine depressing herbs in comparison to injection therapy with steroids in sciatic pain].
Because of their frequency and consequences sciatica remains a demanding clinical entity with significant social and economical impact. There is a high demand on therapeutic modalities, using folk medicine methods in the treatment of orthopaedic diseases. No data is available on the usefulness of methods like natural herbs in combination with acupuncture. Aim of our study was to present data on the effect of acupuncture and cytokine-inhibiting natural herbs in sciatic pain. We compared these results with nerve root infiltration by local anaesthetics and corticosteroids in our orthopaedic outpatient clinic. 278 patients with chronic pain for at least 3 months were observed. All three therapeutical modalities showed improvement of pain scores. Best results were gained with steroid injection ( n=26; 66% pain reduction), acupuncture in combination with herbs improved the pain in average of 62% ( n=230), whereas injection with local anaesthetic had a pain reduction of 48% ( n=22). Sole Mepivacain-HCl treatment had significant less pain reduction compared to the other treatment modalities. According to our results acupuncture in combination with herbs and steroid nerve blocks appear to be an effective and thus recommendable conservative therapy in cases of sciatic pain. Taking into account that patients increasingly prefer ethnomedical modalities of treatment our study gains importance for practising orthopaedists.


Autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of Oklahoma City bombing survivors 7 years after the attack.
The objective of this exploratory pilot study was to examine autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of highly exposed survivors of the 1995 Oklahoma City bombing. This study compared psychiatric diagnoses and biological stress markers (physiological reactivity and cortisol measures) in spouses of bombing survivors and matched community participants. Spouses were recruited through bombing survivors who participated in prior studies. Individuals with medical illnesses and those taking psychotropic medications that would confound biological stress measures were excluded. The final sample included 15 spouses and 15 community participants. The primary outcome measures were psychiatric diagnoses assessed with the Diagnostic Interview Schedule for DSM-IV (DIS-IV). Biological stress markers were physiological reactivity and recovery in heart rate and blood pressure responses to a trauma interview and cortisol (morning, afternoon, and diurnal variation). Compared to the community participants, spouses evidenced greater reactivity in heart rate, systolic blood pressure, and diastolic blood pressure; delayed recovery in systolic blood pressure; and higher afternoon salivary cortisol. The results support the need for further research in this area to clarify post-disaster effects on biological stress measures in the spouses of survivors and the potential significance of these effects and to address the needs of this important population which may be overlooked in recovery efforts.


What are predictors of impaired quality of life in patients with hypoparathyroidism?
Hypoparathyroidism (hypoPT) is a rare endocrine disorder. Little is known about what factors are associated with potential quality of life (QOL) impairments. HypoPT patients at a minimum of 6 months' post diagnosis were invited to participate in an online survey through their treating physician or through self-help organisations METHODS: Impairments of clinical importance in QOL were considered present if the score of the respective functioning scale of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 exceeded a pre-defined threshold. Symptom burden was assessed using the HPQ-28. Multivariate logistic regression was used to identify factors associated with impairments in QOL. Data were available for 264 hypoPT patients. Impairments of clinical importance in QOL were reported for 40.4% in role functioning (RF), 40.6% in social functioning (SF), 60.8% in physical functioning (PF), 65.5% in cognitive functioning (CF) and 76.0% in emotional functioning (EF). Higher odds for reporting impaired QOL were seen for higher symptom burden (for almost all domains) and for being unable to work (for PF, RF and SF). Surgery for thyroid cancer being the cause of hypoPT was associated with lower odds in PF for patients and in PF and CF for patients with surgery for other thyroid-related diseases being the hypoPT cause. HypoPT needs to be recognised as a disease which might be associated with impaired QOL and affect daily living. Symptom management is crucial for improving QOL in hypoPT patients but socioeconomic factors like work-ability need to be considered when treating hypoPT patients.


On the development of the pyramidal tract in the rat. II. An anterograde tracer study of the outgrowth of the corticospinal fibers.
An anterograde tracer study has been made of the developing corticospinal tract (CST) in the rat using wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP). Analysis of normal Rager stained material revealed that corticospinal axons reach upper cervical spinal cord levels at the day of birth (PO). Postnatal rats ranging in age from one (P1) to fourteen (P14) days received multiple WGA-HRP injections into the cortex of their left hemisphere and were allowed to survive for 24 h. The first labeled CST fibers caudally extend into the third thoracic spinal cord segment at P1; into the eighth thoracic segment at P3; into the first or second lumbar segment at P7 and into the second to third sacral segment at Pg. Thus the outgrowth of the leading 'pioneer' fibers of the CST is completed at P9 but later developing axons are continuously added even beyond P9. Quantitative analysis of the amount of label along the length of the outgrowing CST revealed a characteristic pattern of labeling varying with age. The most striking features of that pattern are: the formation of two standing peaks at the level of the cervical and lumbar enlargements respectively and the transient presence of a smaller running peak which moves caudally with the front of the outgrowing bundle. The standing peaks are ascribed to the branching of the axon terminals at both intumescences, whereas the running peak probably arises by the accumulation of tracer within the growth cones at the tips of the outgrowing CST axons. Factors such as the number of axons, the varying axon diameters, the branching collaterals, the presence of varicosities, the transport rate of the tracer, the uptake of the tracer at the injection site, which possibly may affect the amount of label present in both the entire bundle and in the individual axons are discussed. Current research is focused upon an analysis of the relation between the site of injection within the cortex and the pattern of labeling of the CST. A delay of two days was found between the arrival of the CST axons at a particular spinal cord level and their outgrowth into the adjacent spinal gray. However, combined HRP and electronmicroscopic experiments are necessary to determine the factors behind the maturation of the CST as well as the maturation of the spinal gray.


Metabolism and cytotoxicity of diphenylarsinic acid, a degradation product of sea-dumped chemical warfare agents, in a rainbow trout liver cell line RTL-W1.
Recent studies have found primary degradation products of phenylarsenic chemical warfare agents (CWAs) accumulating in fish tissues, while the potential effects of these dumped phenylarsenic CWAs, such as Clark I and II, in the Baltic Sea biota are poorly understood. In this study, the metabolism and cytotoxicity of diphenylarsinic acid (DPA), a primary degradation product of phenylarsenic CWA, was studied by incubating rainbow trout cell line RTL-W1 cells in media with 100 mg/L DPA. Previously undescribed metabolites were identified by ultra-high performance liquid chromatography-high resolution mass spectrometry (UPHLCHRMS). Moreover, the cytotoxicity of diphenylarsine glutathione conjugate (DPA-SG), the major metabolite of DPA, was studied. Cytotoxicity of the compounds was evaluated using the Neutral Red retention test (NRR), showing an IC50 value of 278 mg/L for DPA and 1.30 mg/L for DPA-SG, indicating that the glutathione (GSH) conjugate of DPA is more than two orders of magnitude toxic than DPA itself, suggesting that toxic properties of DPA are increased after conjugation with intracellular GSH leading enhanced toxicity after uptake. Results gained in this study give more detailed information for elucidating biological effects of dumped chemical munitions in marine environment. Moreover, the results help in assessing the environmental and health risks posed by marine munition continued presence and deterioration in the sea bottom.


Enhanced electrokinetic remediation of heavy metals contaminated soil by biodegradable complexing agents.
In this study, an electrokinetic technique for remediation of Pb2+, Zn2+ and Cu2+ contaminated soil was explored using sodium alginate (SA) and chitosan (CTS) as promising biodegradable complexing agents. The highest Cu2+ (95.69%) and Zn2+ (95.05%) removal rates were obtained at a 2 wt% SA dosage, which demonstrated that SA significantly improved the Cu2+ and Zn2+ removal efficiency during electrokinetic process. The abundant functional groups of SA allowed metal ions desorption from soil via ion-exchange, complexation, and electrolysis. Pb2+ ions were difficult to remove from soil by SA due to the higher gelation affinity with Pb2+ than Cu2+ and Zn2+, despite the Pb2+ exchangeable fraction partially transforming to the reducible and oxidizable fractions. CTS could complex metal ions and migrate into the catholyte under the electric field to form crosslinked CTS gelations. Consequently, this study proved the suitability of biodegradable complexing agents for treating soil contaminated with heavy metals using electrokinetic remediation.


The mediation roles of intermuscular fat and inflammation in muscle mitochondrial associations with cognition and mobility.
Mitochondrial dysfunction may contribute to brain and muscle health through inflammation or fat infiltration in the muscle, both of which are associated with cognitive function and mobility. We aimed to examine the association between skeletal muscle mitochondrial function and cognitive and mobility outcomes and tested the mediation effect of inflammation or fat infiltration. We analysed data from 596 Baltimore Longitudinal Study of Aging participants who had concurrent data on skeletal muscle oxidative capacity and cognitive and mobility measures of interest (mean age: 66.1, 55% women, 24% Black). Skeletal muscle oxidative capacity was assessed as post-exercise recovery rate (kPCr) via P31 MR spectroscopy. Fat infiltration was measured as intermuscular fat (IMF) via CT scan and was available for 541 participants. Inflammation markers [IL-6, C-reactive protein (CRP), total white blood cell (WBC), neutrophil count, erythrocyte sedimentation rate (ESR), or albumin] were available in 594 participants. We examined the association of kPCr and cognitive and mobility measures using linear regression and tested the mediation effect of IMF or inflammation using the mediation package in R. Models were adjusted for demographics and PCr depletion. kPCr and IMF were both significantly associated with specific cognitive domains (DSST, TMA-A, and pegboard dominant hand performance) and mobility (usual gait speed, HABCPPB, 400 m walk time) (all P < 0.05). IMF significantly mediated the relationship between kPCr and these cognitive and mobility measures (all P < 0.05, proportion mediated 13.1% to 27%). Total WBC, neutrophil count, and ESR, but not IL-6 or CRP, also mediated at least one of the cognitive and mobility outcomes (all P < 0.05, proportion mediated 9.4% to 15.3%). Skeletal muscle mitochondrial function is associated with cognitive performance involving psychomotor speed. Muscle fat infiltration and specific inflammation markers mediate the relationship between muscle mitochondrial function and cognitive and mobility outcomes. Future studies are needed to confirm these associations longitudinally and to understand their mechanistic underpinnings.


Characteristics of the genome of human infantile enteritis virus (Rotavirus).
Thermal denaturation studies and polyacrylamide gel electrophoretic analysis have shown that the genome of human infantile enteritis virus (human rotavirus) consists of approximately 11 double-stranded segments. Differences in the molecular weights of some of the corresponding genome segments are apparent between different isolates of the virus.


Factors influencing age at natural menopause.
Women who experience menopause before 45 years, have an increased risk for morbidity and mortality. We aimed to identify the factors influencing the age at natural menopause and to investigate whether tubal ligation alter age at natural menopause. This cross-sectional study was conducted on total 1660 women with natural menopause. The participants were divided into two groups as the ones having menopause before age of 45 years and after 45 years old. Positive family history, smoking and use of oral contraceptive were found to increase the risk of early menopause by 3.68, 1.34 and 1.04 times, respectively. First pregnancy at older age reduced the risk of early menopause by 0.97 and obesity reduced this risk by 0.65 (95% CI 0.47-0.90). There was no significant difference between menopausal age of patients who underwent BTL (47.46 ± 4.67 years old) and those who did not (47.68 ± 5.18 years old) (P:0.320; P > 0.05). The mean age at menopause of patients who had tubal ligation with laparoscopic cauterization and Pomeroy technique was 46.91 ± 4.07 and 47.55 ± 4.76 years old, respectively (P:0.503; P > 0.05). Besides, there was no significant difference between patients having tubal ligation at the time of cesarean section and those who did not regarding menopausal age (P:0.314; P > 0.05). We recommend identifying modifiable factors and informing women at risk of early menopause. Tubal ligation, when performed correctly, should not compromise ovarian function. If tubal ligation interferes with vascular supply to the ovaries, it may not be substantial enough to result in an earlier onset of menopause.