Empiric amphotericin B therapy: the need for a reappraisal.
Neutropenic patients are at high risk of developing invasive fungal diseases. A number of studies, both randomized and historical, have demonstrated that empiric therapy with amphotericin B in neutropenic patients with fever, refractory to antibiotics, results in a decrease in the frequency and mortality of deep fungal infections. Recent years have seen a number of advances in the management of neutropenic patients. Reasonably effective antifungal prophylaxis now exists and in many centres forms part of the routine care of neutropenic patients. Other centres advocate the use of selective decontamination and/or protective isolation. Furthermore the duration of neutropenia can be reduced with the use of haematopoetic growth factors. The impact of empiric amphotericin B in patients already benefiting from such treatments has not been adequately studied. The optimum dose of empiric amphotericin B is not defined. The criteria for commencing amphotericin B therapy in febrile neutropenic patients must therefore be redefined on the basis of further studies carried out in the context of these developments. We offer an approach to the use of empiric amphotericin B based on risk factors and prophylaxis.


Adverse effects of unconventional therapies in the elderly: A systematic review of the recent literature.
Unconventional therapies are increasingly popular, not least in populations of elderly individuals. This review summarizes the evidence regarding the risk unconventional therapies may entail for the elderly. Computerized literature searches were performed to locate all reports with original data on this topic. Most of the evidence found was anecdotal by nature and thus has obvious limitations. The results show that elderly patients can suffer harm from unconventional therapies. Herbal treatments are associated most frequently with adverse events. They can cause both direct toxicity and unwanted herb-drug interactions. Acupuncture, spinal manipulation and even massage therapy have also been implicated. Indirect risks exist if unconventional therapies are employed as a substitute for conventional treatments. It is concluded that unconventional therapies are not risk-free for elderly patients. All parties involved ought to be educated with a view of minimizing this risk, and more research is needed to increase our understanding of this area.


Assay method for the carboxylic acid metabolite of clopidogrel in human plasma by gas chromatography-mass spectrometry.
This paper describes a GC-MS method for the analysis of the carboxylic acid metabolite (SR26334, II) of methyl (+)-(S)-alpha-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5( 4H)-acetate hydrogensulfate (clopidogrel, SR 25990, I) in plasma and serum. The analytical procedure involves a robotic liquid-liquid extraction with diethyl ether followed by a solid-liquid extraction on C18 cartridges. The derivatization process was performed using n-ethyl diisopropylethylamine and alpha-bromo-2,3,4,5,6-pentafluoro toluene. A structural analogue (III) of II, was used as internal standard. The 1/X2; weighted calibration curve obtained in the range 5-250 ng/ml was well described by a quadratic equation. The extraction efficiency was better than 48% over the range studied; for the internal standard it averaged 51% at 50 ng/ml. Precision ranged from 3.6 to 15.8%, and accuracy was between 92 and 114%. Dilution has no influence on the performance of the method which could then be used to quantitate plasma samples containing up to 25000 ng/ml. The limit of quantification was 5 ng/ml. The method validation results indicate that the performance characteristics of the method fulfilled the requirements for assay methods for use in pharmacokinetic studies.


On the effect of computed tomography resolution to distinguish between abdominal aortic aneurysm wall tissue and calcification: A proof of concept.
The purpose of this study is to determine the optimal target CT spatial resolution for accurately imaging abdominal aortic aneurysm (AAA) wall characteristics, distinguishing between tissue and calcification components, for an accurate assessment of rupture risk. Ruptured and non-ruptured AAA-wall samples were acquired from eight patients undergoing open surgical aneurysm repair upon institutional review board approval and informed consent was obtained from all patients. Physical measurements of AAA-wall cross-section were made using scanning electron microscopy. Samples were scanned using high resolution micro-CT scanning. A resolution range of 15.5-155μm was used to quantify the influence of decreasing resolution on wall area measurements, in terms of tissue and calcification. A statistical comparison between the reference resolution (15.5μm) and multi-detector CT resolution (744μm) was also made. Electron microscopy examination of ruptured AAAs revealed extremely thin outer tissue structure <200μm in radial distribution which is supporting the aneurysm wall along with large areas of adjacent medial calcifications far greater in area than the tissue layer. The spatial resolution of 155μm is a significant predictor of the reference AAA-wall tissue and calcification area measurements (r=0.850; p<0.001; r=0.999; p<0.001 respectively). The tissue and calcification area at 155μm is correct within 8.8%±1.86 and 26.13%±9.40 respectively with sensitivity of 87.17% when compared to the reference. The inclusion of AAA-wall measurements, through the use of high resolution-CT will elucidate the variations in AAA-wall tissue and calcification distributions across the wall which may help to leverage an improved assessment of AAA rupture risk.


Influence of nanosized delivery systems with benzyl nicotinate and penetration enhancers on skin oxygenation.
Many novel nanosized delivery systems have been designed for topical application of drugs since they can overcome the skin barrier and improve drug bioavailability. The increased absorption is often a consequence of a reversibly disrupted barrier function of the skin by the vehicle itself or by specific ingredients that act as penetration enhancers. This paper reports the effects of two nanosized systems (microemulsion and liposomes), in the presence and absence of penetration enhancers (PE), on the topical delivery of a lipophilic drug in vivo and compares that to classical hydrogel formulation. A vasodilator benzyl nicotinate (BN), which increases the blood flow of the skin, was incorporated into the formulations, and skin oxygenation was followed by electron paramagnetic resonance oximetry. It was found that microemulsions and liposomes (with or without PE) accelerate the rate of BN action when compared to hydrogel. However, incorporation of PE in microemulsion also improves the effectiveness of BN action. To understand why PE enhances the action of BN, its effect on the structure of the stratum corneum was investigated in vitro. The increased fluidity of the stratum corneum lipids provides an explanation for the greater penetration of BN into the skin when the drug and PE are together incorporated into the appropriate formulation.


New insights into cortical development and plasticity: from molecules to behavior.
The human brain contains 100 billion neurons, and each neuron can have up to 200,000 connections to other neurons. Recent advancements in neuroscience-ranging from molecular studies in animal models to behavioral studies in humans-have given us deeper insights into the development of this extraordinarily intricate system. Studies show a complex interaction between biological predispositions and environment; while the gross neuroanatomy and low-level functions develop early prior to receiving environmental inputs, functional selectivity is shaped through experience, governed by the maturation of local excitatory and inhibitory circuits and synaptic plasticity during sensitive periods early in development. Plasticity does not end with the closing of the early sensitive period - the environment continues to play an important role in learning throughout the lifespan. Recent work delineating the cascade of events that initiates, controls and ends sensitive periods, offers new hope of eventually being able to remediate various clinical conditions by selectively reopening plasticity.


Shift work and nonalcoholic fatty liver disease incidence among Chinese rail workers: a 4-year longitudinal cohort study.
Occupational harmful factors, such as shift work, are attracting increasing attention as a potential cause of nonalcoholic fatty liver disease (NAFLD). In this study, we aimed to identify the association between shift work and NAFLD incidence in Chinese rail population. A cohort study was conducted among 14,112 rail workers for 4-year follow-up. Shift work frequency and other potential variables were recorded by questionnaires, including demographic, lifestyle, and occupation information. Besides, body mass index, blood pressure, fasting blood glucose, total cholesterol, triglyceride, alanine aminotransferase, and aspartate aminotransferase were measured by anthropometric measurement and blood test. Diagnosis of new NAFLD case was based on abdominal ultrasonography. Cox proportional hazards regression model was used to determine whether shift work has effect on occurrence of NAFLD. The incidence of NAFLD was 30.43% in total subjects. After adjustment for possible confounders, the RRs of NAFLD were 1.069 (95% CI 0.998-1.146) and 1.179 (95% CI 1.059-1.312) in occasionally shift work group and frequently shift work group respectively, compared to the seldom shift work group. In stratified analyses, the RRs of NAFLD incidence linked to shift work exposure seems increase among female and elder. The results of three sensitivity analyses were similar with main analysis. This research provided further evidence of positive harmful effect of shift work on NAFLD incidence in Chinese rail workers, particularly in frequently shift work population. The risk estimate of shift work on NAFLD was higher in female and elder.


Forty-two supernumerary marker chromosomes (SMCs) in 43,273 prenatal samples: chromosomal distribution, clinical findings, and UPD studies.
Fluorescence in situ hybridization (FISH) analyses were performed on supernumerary marker chromosomes (SMCs) detected in 43,273 prenatal diagnoses over a period of 11 years, 1993-2003. A total of 42 pregnancies with SMC were identified, indicating a prevalence of one in 1032. A total of 15 SMCs were endowed with detectable euchromatin (prevalence, 1/2884), including six SMCs containing the cat eye critical region (CECR) on chromosome 22q11.21 (1/7212). De novo SMCs were found in 29 pregnancies (1/1492), including 14 euchromatic SMCs (48.2%). Follow-up studies were available for 24 cases. Nine pregnancies (37.5%) were terminated; two children (8.3%) were born with Pallister-Killian syndrome and cat eye syndrome (CES), respectively; 13 children (54.1%) showed apparently normal development. Familial SMCs were identified in 13 pregnancies (1/3328) from 11 unrelated women. They were all acrocentric. In all, 10 were heterochromatic and one was an extra der(22)t(11;22) chromosome. A total of 12 cases were available for follow-up. One pregnancy was terminated due to anhydramnios, spina bifida, and cystic-dysplastic kidneys; one child suffered from a der(22) syndrome; 10 children (83.3%) appeared unaffected. Studies for uniparental disomy were performed on seven pregnancies and revealed a case of maternal heterodisomy for chromosome 22. So far this is the largest FISH study of prenatally ascertained SMCs and the first study with detailed data on the prevalence. Findings illustrate the spectrum and clinical outcomes of prenatally diagnosed SMCs, and indicate a higher frequency of SMCs than generally assumed.


Ferroelectric 2D ice under graphene confinement.
We here report on the direct observation of ferroelectric properties of water ice in its 2D phase. Upon nanoelectromechanical confinement between two graphene layers, water forms a 2D ice phase at room temperature that exhibits a strong and permanent dipole which depends on the previously applied field, representing clear evidence for ferroelectric ordering. Characterization of this permanent polarization with respect to varying water partial pressure and temperature reveals the importance of forming a monolayer of 2D ice for ferroelectric ordering which agrees with ab-initio and molecular dynamics simulations conducted. The observed robust ferroelectric properties of 2D ice enable novel nanoelectromechanical devices that exhibit memristive properties. A unique bipolar mechanical switching behavior is observed where previous charging history controls the transition voltage between low-resistance and high-resistance state. This advance enables the realization of rugged, non-volatile, mechanical memory exhibiting switching ratios of 106, 4 bit storage capabilities and no degradation after 10,000 switching cycles.


Intracardiac electrophysiological effects of lorcainide in man.
The electrophysiological effects of lorcainide 1.25 or 2.5 mg/kg given iv over 2 or 4 min, were studied in 21 patients with normal and diseased impulse formation and conduction, by means of intracardiac recording and stimulation. Sinus rate and the effective atrial refractory period rose following both doses of lorcainide. The corrected sinus node recovery time rose only after lorcainide 2.5 mg/kg and then most markedly in patients with sinus node dysfunction. The P-A interval remained unchanged following the drug. The A-H interval during sinus rhythm, and the pooled A-H intervals during atrial pacing, increased slightly, and the functional and effective A-V nodal refactory period changed variably. Wenckebach periods above the bundle of His occurred at lower atrial pacing rates following both doses of lorcainide in 7 patients, at the same atrial pacing rate in 9 and at higher rates in 3. H-V intervals, pooled H-V intervals and QRS-width lengthened in all patients, most markedly in cases with a conduction delay below the His bundle, who had received lorcainide 2.5 mg/kg. Thus, lorcainide shares some electrophysiological properties with procainamide and aprindine. Higher doses should be used with caution in patients with pre-existing conduction delay below the bundle His.


Efficacy of Phase 1 of Life Goals Programme on symptom reduction and mood stability for bipolar disorder.
Life Goals Programme (LGP) was developed as a psychological intervention for bipolar disorder, with its structured 6-session psychoeducation phase (Phase 1) targeting understanding of the disorder, medication adherence, early warning signs, and coping with symptoms and triggers. The present study tested the efficacy of Phase 1 of the LGP on symptom recovery and moment-by-moment mood stability, as well as medication adherence and quality of life. Adults with bipolar disorder were randomly allocated to the LGP condition (six weekly group sessions) or the waitlist condition (six weeks of standard care, followed by the same LGP intervention). Participants were assessed before and after treatment, and at 6-month follow up. Waitlist participants were additionally assessed at baseline. Assessment included a clinical interview (SCID, MADRS, YMRS, and HAM-A), self-reported questionnaires, and 6-day experience sampling assessment on a mobile device. 64 out-patients with bipolar disorder (44 Bipolar I and 20 Bipolar II subtypes) participated in this study. LGP was well received and attended. Following LGP, there were significant improvements in knowledge about illness and level of anxiety, which were of large effect sizes and sustained at 6-month follow-up. Experience sampling assessment revealed small but significant improvements in moment-by-moment mood stability. Improvement in medication adherence was significant at 6 months and was of a moderate-to-large effect size. Changes in anxiety and mood stability were significantly greater following LGP than standard care. Our results warrant further testing against active control. There was a robust improvement in emotional regulation following the 6-week LGP.


Five genes influenced by obesity may contribute to the development of thyroid cancer through the regulation of insulin levels.
Previous studies indicate that obesity is an important contributor to the proceeding of thyroid cancer (TC) with limited knowledge of the underlying mechanism. Here, we hypothesize that molecules affected by obesity may play roles in the development of TC. To test the hypothesis above, we first conducted a large-scale literature-based data mining to identify genes influenced by obesity and genes related to TC. Then, a mega-analysis was conducted to study the expression changes of the obesity-specific genes in the case of TC, using 16 independent TC array-expression datasets (783 TC cases and 439 healthy controls). After that, pathway analysis was performed to explore the functional profile of the selected target genes and their potential connections with TC. We identified 1,036 genes associated with TC and 534 regulated by obesity, demonstrating a significant overlap (N = 176, p-value = 4.07e-112). Five out of the 358 obesity-specific genes, FABP4, CFD, GHR, TNFRSF11B, and LTF, presented significantly decreased expression in TC patients (LFC<-1.44; and p-value < 1e-7). Multiple literature-based pathways were identified where obesity could promote the pathologic development of TC through the regulation of these five genes and INS levels. The five obesity genes uncovered could be novel genes that play roles in the etiology of TC through the modulation of INS levels.


The biogenesis and regulation of telomerase holoenzymes.
Chromosome stability requires a dynamic balance of DNA loss and gain in each terminal tract of telomeric repeats. Repeat addition by a specialized reverse transcriptase, telomerase, has an important role in maintaining this equilibrium. Insights that have been gained into the cellular pathways for biogenesis and regulation of telomerase ribonucleoproteins raise new questions, particularly concerning the dynamic nature of this unique polymerase.


Human papillomavirus vaccine policy and delivery in Latin America and the Caribbean.
Cervical cancer caused by human papillomavirus (HPV) is a major preventable public health problem. Two vaccines are now available for primary prevention of HPV infection and their introduction offers new opportunities to enhance comprehensive cervical cancer prevention and control. Currently, HPV vaccine price is a significant barrier to rapid vaccine introduction and access. Therefore, making evidence-based decisions about whether and how to introduce HPV vaccine into the immunization schedule in the countries of Latin America and the Caribbean (LAC) requires a rigorous analysis of several factors. These include: estimates of disease burden, cost-effectiveness, operational feasibility of reaching a population of adolescent females and other key analyses that have been used in recent years to support the introduction of other vaccines, such as rotavirus and pneumococcal conjugate vaccines. Given the large number of public health priorities that are competing for limited public resources, developing and using a sound evidence base is of particular importance for vaccines, like HPV, which are currently available only at prices higher than other vaccines now in use. HPV vaccination provides the opportunity to dramatically improve women's health and partnerships must also be broad-based and effectively coordinated. This can be achieved by developing programs based on the lessons learned from vaccination strategies used to eliminate rubella and neonatal tetanus and for scaling up influenza vaccination in countries of LAC.


Value of the Controlling Nutritional Status score in predicting the prognosis of patients with lung cancer: A multicenter, retrospective study.
The body's immune-nutrition status affects prognosis in patients with lung cancer. The Controlling Nutritional Status (CONUT) score is an immune-nutrition-related index associated with prognosis in other tumors. We aimed to assess the value of CONUT scores in predicting prognosis in patients with lung cancer. In this retrospective, multicenter study, 1339 patients with lung cancer were divided into low and high CONUT score groups. The relationship between CONUT scores and overall survival (OS) was assessed by survival curves and Cox proportional hazards regression modeling. A nomogram, including CONUT scores and other clinical variables, was established. There were 659 (49.2%; mean age, 59.91 years) low and 680 (50.8%; mean age, 62.23 years) high CONUT score patients. OS was significantly worse in patients with high than in those with low CONUT scores (P < 0.001), even after stratification by pathological types (non-small-cell lung cancer and small-cell lung cancer) and Tumor, Node, Metastasis (TNM) stages. A high CONUT score independently predicted risk in patients with lung cancer (adjusted hazard ratio, 1.48; 95% CI, 1.26-1.73; P < 0.001). The CONUT-based nomogram could predict prognosis well (C-index, 0.701), with better resolution and accuracy than TNM staging for predicting OS at 1, 2, and 3 years (area under the receiver operating characteristic curve, 0.735 vs 0.678, 0.742 vs 0.696, and 0.768 vs 0.743, respectively). The CONUT score can predict prognosis in patients with lung cancer. A CONUT-based nomogram can improve the accuracy of survival prediction in such patients.


Light and dark bars; contrast discrimination.
Contrast increment thresholds were measured for light and dark bars as a function of the base contrast of the bars. The bars were superimposed on a uniform field of 340 cd/m2. They had either rectangular or Gaussian luminance profiles, varied in width from 0.1 degree to 10 degrees, and in duration from 10 to 200 msec. For the 200-msec presentations, the resulting contrast discrimination functions all had approximately the same shape when contrast was defined as (Lmax - Lmin)/(Lmax + Lmin), and closely resembled corresponding results for sine-wave gratings. The similarity in shape of contrast discrimination functions for light and dark bars is attributed to a retinal nonlinear intensity transformation. The 10 msec contrast discrimination functions differed from the 200-msec functions in ways that can be explained by differences in temporal integration.


Utilization of isolated microbe and treated wastewater for enhanced growth of Jatropha curcas for bioremediation of fly ash amended soil.
The generation of Fly Ash (FA) waste is continuously piling up with the increasing energy demand. Recent research is focused towards reutilizing this fly ash waste through bioremediation practices. But fly ash retards the growth of plants and holds back to support the bioremediation process due to a deficiency of essential main nutrients. The present research envisages overcoming this problem by providing a novel concept of inducing isolated microbes and treated wastewater which provides necessary nutrients and promotes better plant growth and metal extraction. A pot experimental study was executed with treatments T1 (FA amended soil), T2 (FA with isolated microbe), and T3 (FA with microbes and treated wastewater). As an outcome of the present research, T3 gained relatively higher morphological characteristics viz. Leaf area (29.8%), absolute growth rate (61.7%), plastochron index (18.6%), biomass yield (47.3%) and enhanced metal extraction for Fe (34.4%), Al (27.1%), Mn (72.0%), Zn (17.5%) in comparison to the control. Treatment T3 also gained higher Remediation Efficiency (RE) and Bio-Concentration Factor (BCF) values for Al, Fe, and Mn. The involvement of nutrients via treated wastewater energizes the process mechanism and increases the working zone for the microbes thereby, enhancing the bioremediation.


Studies on the effects of piperidine derivatives on blood pressure and smooth muscles contractions.
Ten substituted phenacyl derivatives of 4-hydroxypiperidine were synthesized and studied for their effects on the mean arterial blood pressure (MABP) in normotensive anaesthetized rats and smooth muscles contractions of isolated rabbit jejunum. Two derivatives caused fall in blood pressure at the dose of 10-20 mg/kg and one rise in blood pressure at the dose of 20 mg/kg. Two compounds exhibited biphasic response (hypotensive followed by hypertensive) and one gave triphasic response at 10 mg/kg dose. Rest of four derivatives were found devoid of any effect on mean arterial blood pressure up to the dose of 30 mg/kg. All the derivatives except two caused relaxant effect on the spontaneous contraction of rabbit jejunum at the dose range of 0.1-2 mg/kg.


Preparation and sustainable release of modified konjac glucomannan/chitosan nanospheres.
Biodegradable and biocompatible polymer nanospheres are useful materials for controlled drug delivery. In the present study, novel composite nanospheres were prepared from carboxymethyl konjac glucomannan (CKGM) and 2-hydroxypropyl trimethyl ammonium chloride chitosan (HACC) as a vaccine delivery vehicle by electrostatic complexation in a neutral aqueous solution without the use of chemical crosslinkers. By altering the CKGM and HACC concentrations, the average CKGM/HACC particle size could be tuned from approximately 600nm to 1460nm and the zeta potential from 39mV to 50mV. Furthermore, using ovalbumin (OVA) as a model molecule for vaccines, various parameters were determined to affect the CKGM/HACC nanosphere encapsulation efficiency and in vitro controlled release properties. Under optimum conditions, the OVA encapsulation efficiency of CKGM/HACC nanospheres was 71.8%, while sustained and continuous in vitro OVA release over a period of more than 24h was observed. Therefore, CKGM/HACC nanospheres are novel drug delivery carriers with great potential for medical applications.


Updates in the Management of Relapsed and Refractory Acute Lymphoblastic Leukemia: An Urgent Plea for New Treatments Is Being Answered!
The treatment of acute lymphoblastic leukemia (ALL) has dramatically changed over the past three decades. However, relapsed and/or refractory ALL still remains with a very low survival and high morbidity associated with its treatment. Here, we will review the outstanding progress that has been made in the treatment of relapsed and/or refractory ALL and discuss future directions and challenges that require further investigation.


LINAC-based radiosurgery for functional and psychiatric disorders: Problems and their solutions.
Stereotactic radiosurgery (SRS) is practically non-invasive treatment option, and its application for ablative procedures in functional and psychiatric brain disorders seems rather promising. In such cases, gamma knife surgery (GKS) is considered a standard option due to its proved accuracy in targeting and dosimetry. However, modern linear accelerators (LINAC), which are the most commonly used radiosurgical device, provide comparable treatment preciseness. Although at present experience with LINAC-based SRS of functional brain disorders is rather limited, from the technological viewpoint it definitely seems possible and theoretically may be of the similar efficacy as established with GKS for the same indications. However, widespread introduction of such practice requires resolution of several important methodological issues, particularly related to establishment of specific treatment standards, development of dedicated training for involved medical professionals, and creation of the data accumulation and outcome analysis systems.


Investigation of umbilical cord serum miRNAs associated with childhood obesity: A pilot study from a birth cohort study.
We investigated umbilical cord serum microRNA (miRNA) profiles to identify biomarkers of a risk for obesity later in life. Participating children were divided into high- and low-risk groups of obesity based on the timing of adiposity rebound and the body mass index (BMI) at 5 years and randomly selected from each group for this study. 3D-Gene® Human miRNA Oligo Chip was performed using cord serum in five children of both groups. The most relevant miRNAs were confirmed in 33 children of the groups using the TaqMan® microRNA assay. We detected five cord serum miRNAs differentially expressed in children at high risk of obesity compared with the levels in children at low risk, namely, miR-516-3p and miR-130a-3p with increased levels and miR-1260b, miR-4709-3p, and miR194-3p with decreased levels. This study provides the first identification of altered umbilical cord serum miRNAs in childhood obesity.


Carpal tunnel syndrome observed after an arbovirus infection: A preliminary case series report.
Report a case series study of individuals who, after having a suspected arboviral disease during an epidemic outbreak in north-eastern Brazil, presented symptoms of acroparesthesia. A retrospective evaluation of patients with acroparesthesia undertaken between December 2015 and October 2016 following a clinical picture suggestive of an arboviral infection. Clinical and electrophysiological data were obtained from 29 individuals. 13% were male. All presented a main complaint of numbness in the hands, with 86% presenting bilateral symptoms. The symptoms started within 60 days of the clinical picture in 62% of cases. The electrophysiological study demonstrated CTS in 54 median nerves. It was classified as mild in 24.1% of cases, moderate in 32.7%, severe in 24.1%, very severe in 6.8% and extremely severe in 5.1%. The best explanation for the presence of acroparesthesia following an arboviral infection may be the narrowing of the carpal tunnel caused by the inflammatory joint process usually observed in cases of chikungunya infection. This is the first study with electrophysiological data that associates arboviral infection with CTS.


Gastric cancer cell-derived extracellular vesicles elevate E2F7 expression and activate the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.
Cancer cell-derived extracellular vesicles (EVs) have extensive application in the formation of their environment, including metastasis. This study explored the ability of gastric cancer (GC) cell-derived EVs-mediated microRNA-129-5p/E2F transcription factor 7/mitogen-activated protein kinase/extracellular regulated protein kinase (miR-129-5p/E2F7/MAPK/ERK) axis to affect the peritoneal metastasis of GC by delivering lncRNA small nucleolar RNA host gene 12 (SNHG12). EV-derived lncRNA and SNHG12/miR-129-5p/E2F7 network were determined by bioinformatics analysis. The regulatory relationship among SNHG12, miR-129-5p, and E2F7 was verified using a combination of dual-luciferase reporter gene, RNA immunoprecipitation, and RNA pull-down assays. The SNHG12, miR-129-5p, and E2F7 expression was measured by RT-qPCR. After GC cell-derived EVs were isolated and co-cultured with human peritoneal mesothelial cells (HPMCs), the uptake of EVs by HPMCs was observed under laser scanning confocal microscopy. Cell viability and apoptosis were examined using cell counting kit-8 and flow cytometry, respectively. Western blot analysis was performed to measure the mesothelial-mesenchymal transition (MMT)-related protein expression. The pathological and morphological characteristics of metastatic tumors in nude mice were observed by hematoxylin-eosin staining. A high SNHG12 expression was correlated with the poor prognosis of patients with GC. GC-derived EVs led to increased HPMC apoptosis and MMT by transferring SNHG12, whereas the knockdown of SNHG12 annulled the aforementioned results. SNHG12 sponged miR-129-5p to boost E2F7 expression and activate the MAPK/ERK signaling, thus inducing HPMC apoptosis and MMT. In vivo experiments further verified that EVs derived from GC cells promoted peritoneal metastasis in nude mice. GC cell-derived EVs elevated the E2F7 expression and activated the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.


The current understanding of germline predisposition in non-syndromic sagittal craniosynostosis: a systematic review.
The objective of this literature review was to provide a comprehensive and up-to-date overview of the current understanding of the genetic etiology for non-syndromic sagittal craniosynostosis. Using the PubMed database and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we systematically reviewed relevant records on germline genetics in children with non-syndromic sagittal craniosynostosis. Two hundred two records were identified, of which 25 were included following title and abstract screening and subsequent full-text review. The 25 records in combination included 829 children with non-syndromic sagittal craniosynostosis. A likely pathogenic or pathogenic germline variant was reported for 9.8% of the 827 patients for whom germline genetic testing was performed. The reported variants were distributed across 50 different genes, with more than one variant detected in 13 genes. Based on the existing literature, genetic predisposition is likely to play a role in at least 9% of children with non-syndromic sagittal craniosynostosis. Future studies will benefit from international consensus in terms of diagnostic nomenclature and a higher level of standardization across study methodologies and bioinformatic approaches.


Characterization of Size and Aggregation for Cellulose Nanocrystal Dispersions Separated by Asymmetrical-Flow Field-Flow Fractionation.
Cellulose nanocrystals (CNCs) derived from various types of cellulose biomass have significant potential for applications that take advantage of their availability from renewable natural resources and their high mechanical strength, biocompatibility and ease of modification. However, their high polydispersity and irregular rod-like shape present challenges for the quantitative dimensional determinations that are required for quality control of CNC production processes. Here we have fractionated a CNC certified reference material using a previously reported asymmetrical-flow field-flow fractionation (AF4) method and characterized selected fractions by atomic force microscopy (AFM) and transmission electron microscopy. This work was aimed at addressing discrepancies in length between fractionated and unfractionated CNC and obtaining less polydisperse samples with fewer aggregates to facilitate microscopy dimensional measurements. The results demonstrate that early fractions obtained from an analytical scale AF4 separation contain predominantly individual CNCs. The number of laterally aggregated "dimers" and clusters containing 3 or more particles increases with increasing fraction number. Size analysis of individual particles by AFM for the early fractions demonstrates that the measured CNC length increases with increasing fraction number, in good agreement with the rod length calculated from the AF4 multi-angle light scattering data. The ability to minimize aggregation and polydispersity for CNC samples has important implications for correlating data from different sizing methods.


Public stigma toward fatigue-do social characteristics of affected persons matter? Results from the SOMA.SOC study.
Although public stigma imposes a great burden on those affected with manifold negative consequence there is not much known about public stigma related to fatigue. Therefore, this study addresses the following research questions: (1) What is the magnitude of public stigma toward individuals with fatigue? (2) Are there differences in public stigma depending on the social characteristics of the affected person (sex, occupation, and migration)? Analyses are based on a national telephone survey in Germany (N = 1,209). A vignette describing a person with symptoms of fatigue was presented to the respondents. Vignettes were varied according to sex, occupational status, and migration status. Stigma toward the person presented in the vignette was measured by stereotypes and negative emotional reactions (anger). Of the stereotypes under study, "hypersensitive" was most frequently endorsed by the respondents (35.7%), followed by "weak will" (27.2%). About 15-20% of the respondents agreed that they react with anger, annoyance or incomprehension. There were considerable differences in fatigue stigma according to the social characteristics of the affected person. In two social groups public stigma was particularly pronounced: (1) male persons with a low occupational status and a migration background; (2) female persons with a high occupational status and without a migration status. In contrast, women with a low occupational status and a migration background were less stigmatized. Individuals suffering from fatigue symptoms are confronted with stereotypes and negative emotional reactions by the public. Magnitude of public stigma considerably varies according to social characteristics of the afflicted person. Future studies should consider applying an intersectional approach to identify groups that are at risk of multiple stigma.


Retracted: MicroRNA-424-5p Alleviates Isoflurane Anesthesia-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons by Targeting FASN.
[This retracts the article DOI: 10.1155/2022/2517463.].


Development of vasoactive-intestinal-polypeptide-immunoreactive neurons in the rat occipital cortex: a combined immunohistochemical-autoradiographic study.
The postnatal development of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons, previously labeled with [3H]thymidine on embryonic days E14-E22, has been studied in the rat occipital cortex. Immuno-histochemistry combined with autoradiography showed very little evidence of an "inside-out" pattern of maturation. Most VIP neurons are generated between E17 and E21 and are found in layers II-IV of the cortex, but their position within these layers is not dictated by their date of birth. There is evidence of a temporal maturation since E17 VIP neurons were seen first (at day 7) and E21 last. Peak numbers of VIP neurons were generated on E19. The numbers of VIP-immunoreactive neuronal somata detected in the cortex increased from the first week after birth to the third week and declined thereafter. However VIP-immunoreactive dendrites were still visible, suggesting that VIP levels in the cell bodies were very low, and not that there was a loss of neurons.


Application of perovskite oxides and their composites for degrading organic pollutants from wastewater using advanced oxidation processes: Review of the recent progress.
In the recent years, perovskite oxides are gaining an increasing amount of attention owing to their unique traits such as tunable electronic structures, flexible composition, and eco-friendly properties. In contrast, their catalytic performance is not satisfactory, which hinders real wastewater remediation. To overcome this shortcoming, various strategies are developed to design new perovskite oxide-based materials to enhance their catalytic activities in advanced oxidation process (AOPs). This review article is to provide overview of basic principle and different methods of AOPs, while the strategies to design novel perovskite oxide-based composites for enhancing the catalytic activities in AOPs have been highlighted. Moreover, the recent progress of their synthesis and applications in wastewater remediation (pertaining to the period 2016-2022) was described, and the related mechanisms were thoroughly discussed. This review article helps scientists to have a clear outlook on the selection and design of new effective perovskite oxide-based materials for the application of AOPs. At the end of the review, perspective on the challenges and future research directions are discussed.


Assessment of DNA fragmentation and aneuploidy on poor quality human embryos.
In human assisted reproduction, low embryo quality due to retarded growth and abnormal cellular morphology results in fewer embryos suitable for transfer. This study aimed to assess the extent of DNA fragmentation and aneuploidy in spare slow growing or arrested human embryos. In 19 assisted reproduction cycles, a total of 57 embryos unsuitable for embryo transfer were used for simultaneous apoptosis and aneuploidy assessment. Among them, 31 (54.3%) showed DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling (TUNEL) analysis. Among 26 embryos that were negative for TUNEL, interpretable fluorescence in-situ hybridization (FISH) results were obtained for 25 embryos (96.2%). Sixteen embryos were detected to be chromosomally abnormal (64.0%); three were found to be chaotic, six had complex aneuploidy, six had complete monosomy and one was polyploid. The results show that a high level of DNA fragmentation and aneuploidy are common in embryos with slow growth and/or low quality. More detailed studies are needed to assess the effect of factors such as ovarian stimulation regimens and in-vitro culture conditions. Moreover, application of simultaneous TUNEL and FISH techniques can be informative regarding DNA integrity and aneuploidy.


Identification of two novel highly inducible promoters from Bacillus licheniformis by screening transcriptomic data.
Bacillus licheniformis TCCC11148 is an important industrial strain used to produce alkaline protease. In this study, the transcriptome of B. licheniformis TCCC11148 was analyzed by high throughput RNA sequencing (RNA-Seq) to identify genes that are expressed differentially in the different phases were detected using RNA-Seq. In total, 440 differentially expressed genes between the 12 h and 48 h groups were identified, including 267 up- and 173 downregulated genes. Additionally, 198 differentially expressed genes were identified in the 48 h vs. the 60 h group, including 182 up- and 16 downregulated genes. To screen for novel inducible promoters, an alkaline protease reporter gene was used to test 24 promoters from 66 candidate genes with obviously higher expression levels (RPKM values) than the control group based on the transcriptome data of B. licheniformis in different phases. Gene 707, related to coenzyme transport and metabolism, and gene 1004, related to posttranslational modification were identified as likely having inducible promoters. The expression level of recombinant strains with reporter genes under the control of promoters p707 and p1004 were 8 times higher than that of the control group. This study contributes a method for finding useful inducible promoters for industrial use based on transcriptomic data.


Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition.
Glioblastoma multiforme is the most common glioma in adults and carries a poor prognosis, due to tumor recurrence despite aggressive treatment. Such relapse has been attributed to the persistence of glioma stemlike cells (GSCs), a subpopulation of glioma cells with stem cell properties. Thus, targeting these cells will be critical to achieving meaningful improvement in glioblastoma multiforme survival. We investigated the role of β1-integrin signaling as one such potential target. We used GSCs isolated from primary human gliomas and maintained in stem cell conditions. We manipulated β1-integrin signaling using a self-assembling peptide amphiphile (PA) displaying the IKVAV (isoleucine-lysine-valine-alanine-valine) epitope as well as lentiviral overexpression, and we assayed the effects on downstream effectors and apoptosis using immunofluorescence. We show that β1-integrin expression correlates with decreased survival in glioma patients and that β1-integrin is highly expressed by GSCs. The IKVAV PA potently increases immobilized β1-integrin at the GSC membrane, activating integrin-linked kinase while inhibiting focal adhesion kinase (FAK). The IKVAV PA induces striking apoptosis in GSCs via this FAK inhibition, which is enhanced in combination with inhibition of epidermal growth factor receptor (EGFR). Conversely, lentiviral overexpression of β1-integrin renders GSCs resistant to EGFR inhibition, which was overcome by FAK inhibition. These observations reveal a role for β1-integrin signaling through FAK in GSC treatment resistance and introduce self-assembling PAs as a novel new therapeutic approach for overcoming this resistance.


A comprehensive identification-evidence based alternative for HIV/AIDS treatment with HAART in the healthcare industries.
The HIV/AIDS-related issue has given rise to a priority concern in which potential new therapies are increasingly highlighted to lessen the negative impact of highly active anti-retroviral therapy (HAART) in the healthcare industry. With the motivation of "medical applications," this study focuses on the main advanced feature selection techniques and classification approaches that reflect a new architecture, and a trial to build a hybrid model for interested parties. This study first uses an integrated linear-nonlinear feature selection technique to identify the determinants influencing HAART medication and utilizes organizations of different condition-attributes to generate a hybrid model based on a rough set classifier to study evolving HIV/AIDS research in order to improve classification performance. The proposed model makes use of a real data set from Taiwan's specialist medical center. The experimental results show that the proposed model yields a satisfactory result that is superior to the listed methods, and the core condition-attributes PVL, CD4, Code, Age, Year, PLT, and Sex were identified in the HIV/AIDS data set. In addition, the decision rule set created can be referenced as a knowledge-based healthcare service system as the best of evidence-based practices in the workflow of current clinical diagnosis. This study highlights the importance of these key factors and provides the rationale that the proposed model is an effective alternative to analyzing sustained HAART medication in follow-up studies of HIV/AIDS treatment in practice.


Persistent left superior vena cava remnant causing cyanosis in a post-Fontan patient.
We report the successful surgical closure of a persistent left superior vena cava remnant draining into the pulmonary venous circulation causing cyanosis in a post-Fontan patient who had previously undergone Damus-Kaye-Stansel and bidirectional superior cavopulmonary connection followed by a transcatheter coil occlusion of his persistent left superior vena cava.


Late preterm birth has direct and indirect effects on infant gut microbiota development during the first six months of life.
Preterm infants display aberrant gut microbial colonisation. We investigated whether the differences in gut microbiota between late preterm and full-term infants results from prematurity or external exposures. This study comprised 43 late preterm infants (340/7 -366/7 ) and 75 full-term infants based on faecal samples collected following birth and at two to four weeks and six months of age. We assessed clinically relevant bacteria using quantitative polymerase chain reaction. Logistic regression analyses were performed to determine whether the observed differences in gut microbiota were attributable to prematurity or perinatal exposure. The prevalence of bifidobacteria differed in the intestinal microbiota of the full-term and late preterm neonates. Differences in the presence of specific species were detected at the age of six months, although the microbiota alterations were most prominent following delivery. As well as prematurity, the mode of birth, intrapartum and neonatal antibiotic exposure, and the duration of breastfeeding had an additional impact on gut microbiota development. The gut microbiota composition was significantly different between late preterm and full-term infants at least six months after birth. Antibiotic exposure was common in late preterm infants and modulated gut colonisation, but preterm birth also affected gut microbiota development independently.


An improved and simplified protocol to combine Golgi-Cox staining with immunofluorescence and transmission electron microscopy techniques.
Approaches utilizing multiple analysis techniques on a single sample are highly desirable in research, especially to reduce the number of animals and obtain the maximum information. Golgi-Cox staining is a widely used method for characterizing axon and dendritic morphology and several attempts to combine this technique with immunofluorescence and transmission electron microscopy have been proposed. With few exceptions, most of the protocols were characterized by a high degree of complexity and low reproducibility. Here we show a simplified procedure of perfusion, fixation and staining of brain tissues that allows Golgi-Cox staining, immunofluorescence and transmission electron microscopy in the same sample, to obtain high-quality images with a low-cost procedure. The main novelty in this protocol is the possibility of performing Golgi-Cox staining after the perfusion and post-fixation of brain tissue with a buffered solution containing, not only formaldehyde, but also glutaraldehyde. This renders the tissue suitable for electron microscopy, but it is also compatible with immunofluorescence staining. This combined protocol can be used in most neuroscience laboratories as it does not require special equipment and skills. This protocol will be useful in a broad range of neuroscience topics to study morphological changes during brain development and plasticity in physiological and pathological conditions.


Transcript array analysis in rheumatology.
Transcript array analysis is a novel technique that examines the expression of thousands of genes simultaneously. Transcript array analyses are being used to clarify the diagnosis and prognosis of malignancies, and to understand the underlying pathogenesis of complex human disorders such as the rheumatic diseases. In this review, the authors will outline the use of transcript arrays to simultaneously assess gene activation of hundreds or thousands of genes, and their potential use in understanding and managing rheumatic disorders. The authors focus on the use of transcript arrays to confirm and refine disease diagnoses, to generate new hypotheses regarding pathophysiology of rheumatic diseases, and to the possible profiling of patients with respect to their likely response to therapies.


A modified directional atherectomy catheter for resection of calcified atherosclerotic plaques.
The purpose of this study was to determine the feasibility of resecting calcified atherosclerotic plaques in human cadaveric vessels by using a modified directional coronary atherectomy catheter and to correlate these results with bench tests using an in-vitro sea coral model. The conventional directional coronary atherectomy catheter was modified by changing the cutter blade to a tungsten carbide material and by increasing the torsional strength of the drive cable. The performance of the modified directional coronary atherectomy (DCA) catheter was compared with the conventional catheter using a sea coral model to simulate calcified material. Then, 10 human ex-vivo arteries (eight with calcification) were treated with both conventional and modified catheters, and the results studied with intravascular ultrasound and confirmed by histologic examination. Using the modified directional coronary atherectomy catheter it was possible to perform effective and consistent longitudinal cutting, and to resect a significantly larger amount of coral (1.0 +/- 0.1 mm2 versus 0.2 +/- 0.1 mm2 with conventional cutter, P < 0.0001). In heavily calcified ex-vivo arteries, the modified catheter was more effective in removing calcified plaques (13 +/- 11 mg versus 3.7 +/- 1.4 mg with conventional cutter, P = 0.07). Intravascular ultrasound confirmed the effective atherectomy (residual area stenosis 28 +/- 16% versus 47 +/- 10% with the conventional device, P < 0.05), and histologic examination showed calcified nodules in the atherectomy samples obtained with the modified cutter (area of calcium 1.43 +/- 0.89 mm2 versus 0.93 +/- 0.83 mm2 with the conventional cutter). The modified directional coronary atherectomy catheter effectively removed both non-calcified and calcified plaques in the ex-vivo human cadaveric arteries, thus demonstrating the feasibility of directional coronary atherectomy of calcified plaques. This modified device shows promise for treating calcified coronary lesions, especially in larger vessels.


Synergistic inhibition of platelet aggregation by endothelium-derived relaxing factor and prostacyclin.
The anti-aggregatory effect of endothelium-derived relaxing factor (EDRF) on aggregation of washed, aspirin-treated platelets was compared with that of nitric oxide. Nitric oxide produced a dose-dependent inhibitory effect on PAF-induced aggregation: the antiaggregatory activity was unstable and was completely preventable by pretreating the platelets with haemoglobin (10 mumol/l). Bovine aortic endothelial cells (EC) were grown to confluence on microcarrier beads, pretreated with aspirin (1 mmol/l), and their addition to the platelet cuvette also caused a dose-dependent inhibition of aggregation induced by PAF, thrombin and A23187. The inhibitory effect of the EC on platelet aggregation was partly prevented in the presence of haemoglobin (10 mumol/l). Both nitric oxide and EC showed synergy with prostacyclin, in that the latter potentiated the anti-aggregatory action of both these factors against PAF-induced platelet aggregation. Thus cultured endothelial cells release a non-prostanoid anti-aggregatory factor, which, like nitric oxide, shows a synergistic interaction with prostacyclin and is blocked by haemoglobin. This anti-aggregatory factor has the characteristics of EDRF.


Molecular characterization, expression and anti-tumor function analysis of yak IFITM2 gene.
IFITM2 is interferon-induced transmembrane protein 2, which plays an extremely key role in anti-tumor and anti-virus diseases. In this study, the 602 bp cDNA sequence of the yak (Bos grunniens) IFITM2 (BgIFITM2) gene was obtained. Moreover, the prokaryotic expression vector of BgIFITM2 protein was constructed and expressed successfully, with a molecular weight of 33.680 kDa. The proliferation activities and migration abilities of HepG2 cells were significantly inhibited after treatment with BgIFITM2 protein (0.1 and 1 μg/mL) (P < 0.05). The expressions of B cell lymphoma-2 (BCL2)/BCL2-associated X (BAX) and molecular target of rapamycin (mTOR) genes were significantly decreased, but the expressions of BAX gene were significantly increased after treatment with BgIFITM2 protein (0.1 and 1 μg/mL) (P < 0.05). The expression of BAX protein was also significantly increased after treatment with 1 μg/mL BgIFITM2 protein (P < 0.05). Finally, the addition of BgIFITM2 protein attenuated the formation of tumor lesions in mice, and the pathological damage of the lung was less than that in the model group. The expression of Ki67 protein in the model group was significantly higher than that in the control group (P < 0.05), but the expression of Ki67 protein in the BgIFITM2 group was significantly lower than that in the model group (P < 0.05). Taken together, BgIFITM2 protein could inhibit the proliferative activity of HepG2 cells by regulating apoptosis-related genes, and reduce the invasiveness of HepG2 cells in mice lung tissue. These results facilitate further studies on the function of BgIFITM2 protein.


Digital design of multimaterial photonic particles.
Scattering of light from dielectric particles whose size is on the order of an optical wavelength underlies a plethora of visual phenomena in nature and is a foundation for optical coatings and paints. Tailoring the internal nanoscale geometry of such "photonic particles" allows tuning their optical scattering characteristics beyond those afforded by their constitutive materials-however, flexible yet scalable processing approaches to produce such particles are lacking. Here, we show that a thermally induced in-fiber fluid instability permits the "digital design" of multimaterial photonic particles: the precise allocation of high refractive-index contrast materials at independently addressable radial and azimuthal coordinates within its 3D architecture. Exploiting this unique capability in all-dielectric systems, we tune the scattering cross-section of equisized particles via radial structuring and induce polarization-sensitive scattering from spherical particles with broken internal rotational symmetry. The scalability of this fabrication strategy promises a generation of optical coatings in which sophisticated functionality is realized at the level of the individual particles.


The environmental influence of national savings in D-8 countries: Empirical evidence using an ARDL model.
Extensive theoretical and empirical evidence supports the crucial role of savings in driving a nation's economic growth and development. However, previous studies have not considered their potential environmental implications. This study aims to explore the influence of savings and remittances on the Developing-8 countries (D-8) from 1989 to 2019, using the panel autoregressive distributed (ARDL) model. The findings reveal that national savings and remittances, in the long run, help mitigate environmental degradation in the D-8 countries but energy use and population growth stimulate carbon dioxide (CO2) emissions. In contrast, economic growth does not significantly affect these countries' environmental quality in the long run. However, none of the explanatory variables have any significant relationship with CO2 emissions in the short run. Therefore, policymakers in the D-8 countries are strongly encouraged to prioritize the enhancement of national savings across the three economic agents to maximize the positive effects of savings on environmental quality. Government savings can be increased by reducing deficits and borrowings, while corporate savings can be encouraged by implementing investment tax credits and promoting research and development. Additionally, governments can embark on public enlightenment campaigns on financial education and provide incentives to encourage household savings.


Incidence trends of female breast cancer in Saskatchewan, 1932-1990.
Using a log-linear model, we examined the 59-year incidence trends (1932-1990) of breast cancer by age, sex, and birth cohort in Saskatchewan, Canada. The incidence of breast cancer showed a continuously increasing trend since the 1930s. The trend was age dependent--in general, the 60 years and older age group had greater increases in incidence rates than did younger age groups. The increase in incidence rates in the 45 years and older age group was consistent over time and the incidence rates for those younger than 45 years increased until the 1960s, with a decline in trend following the 1960s. Birth cohort was a significant factor in the incidence of breast cancer. The major birth cohort effect can be described for those born from 1852 to 1927--in every age group breast cancer incidence increased as the birth years advanced. For those born after 1927, the incidence of breast cancer was unchanged as the birth cohort changed and was sustained at a high level. Whether this phenomenon suggests that the risk factors for breast cancer ceased to increase over time needs to be confirmed by further studies.


Fibroblast growth factor receptors contain a conserved HAV region common to cadherins and influenza strain A hemagglutinins: a role in protein-protein interactions?
The first extracellular domain of the cadherins has been shown to exhibit extensive sequence homology with the amino termini of the HA1 chains of influenza strain A hemagglutinins. These regions of homology are known to be functionally important in both the cadherins and the hemagglutinins. The homologous regions harbor the tripeptide HAV, which has been identified as being the cadherin cell adhesion recognition sequence. Here we report that members of the rapidly expanding family of fibroblast growth factor receptors also possess HAV-containing regions. These regions are homologous to the HAV-containing regions present within both the hemagglutinins and the cadherins and appear to be involved in regulating the function of the fibroblast growth factor receptors. We speculate that the HAV motif may represent an evolutionarily conserved amino acid sequence that will prove to be functionally important in a wide variety of proteins.


Colonization and infection with fluoroquinolone-resistant Escherichia coli among cancer patients: clonal analysis.
Escherichia coli with high-level fluoroquinolone resistance were isolated from feces and/or various body sites of 16 cancer patients who were on oral fluoroquinolone prophylaxis. Population analysis of fecal isolates in 11 patients showed that fluoroquinolone-resistant E. coli was the only aerobic gram-negative bacillus present and exhibited a relatively homogenous fluoroquinolone MIC distribution. Molecular typing by pulsed field gel electrophoresis of chromosomal DNA digests or by random amplified polymorphic DNA fingerprinting confirmed the clonal nature of gastrointestinal tract colonization with E. coli. Genotyping of ten colonies picked from the same fecal culture demonstrated identical strains in four of four patients examined. Identical genotypes from the same patient were isolated over prolonged periods of time in 12 of 12 cases examined, with one patient (with the longest follow-up of 14 months) who lost his initial genotype and became persistently colonized with a new genotype. In the 11 patients who developed infection due to fluoroquinolone-resistant E. coli, molecular typing also indicated that fecal colonization was associated with, and presumably preceded infection due to an indistinguishable genotype of fluoroquinolone-resistant E. coli.


A three-level model for therapeutic drug monitoring of antimicrobials at the site of infection.
The silent pandemic of bacterial antimicrobial resistance is a leading cause of death worldwide, prolonging hospital stays and raising health-care costs. Poor incentives to develop novel pharmacological compounds and the misuse of antibiotics contribute to the bacterial antimicrobial resistance crisis. Therapeutic drug monitoring (TDM) based on blood analysis can help alleviate the emergence of bacterial antimicrobial resistance and effectively decreases the risk of toxic drug concentrations in patients' blood. Antibiotic tissue penetration can vary in patients who are critically or chronically ill and can potentially lead to treatment failure. Antibiotics such as β-lactams and glycopeptides are detectable in non-invasively collectable biofluids, such as sweat and exhaled breath. The emergence of wearable sensors enables easy access to these non-invasive biofluids, and thus a laboratory-independent analysis of various disease-associated biomarkers and drugs. In this Personal View, we introduce a three-level model for TDM of antibiotics to describe concentrations at the site of infection (SOI) by use of wearable sensors. Our model links blood-based drug measurement with the analysis of drug concentrations in non-invasively collectable biofluids stemming from the SOI to characterise drug concentrations at the SOI. Finally, we outline the necessary clinical and technical steps for the development of wearable sensing platforms for SOI applications.


The fertility of women after cervical laser surgery.
To retrospectively survey our population of women who had undergone cervical laser surgery to determine if it adversely affected their ability to conceive or to carry a pregnancy to term. Women who had undergone laser surgery during the period 1979-1989 were contacted and surveyed regarding each of their pregnancies. Information obtained included their age at the time of each pregnancy, pregnancy outcome, how long they were trying to conceive, and their use of contraception. The post-laser experience of the study group was matched individually for age and parity with a control population taken from the pre-laser interval of the same patients. We contacted 1069 women; 512 responded to the survey and 433 were matched with controls. The mean study interval was 3.8 years. The study group had significantly more total pregnancies (277 versus 177 for controls, P < .001), total births (163 versus 112 for controls, P < .002), full-term pregnancies (145 versus 100 for controls, P < .005), and terminations of pregnancy (75 versus 28 for controls, P < .001). There was no significant difference in the number of spontaneous abortions (31 for the study group and 33 for controls), premature deliveries (18 for the study group and 12 for controls) or ectopic pregnancies (eight for the study group and four for controls). There was no difference in the pregnancy rate (compared with controls) between laser vaporizations and excisions. Cervical laser surgery does not appear to impair a woman's ability to conceive or carry a pregnancy to term. There is no difference in the effect on fertility between laser vaporization and laser excisional cone biopsies.


5-Hydroxytryptamine evokes three distinct responses on the rat superior cervical ganglion in vitro.
In addition to the 5-HT3-mediated fast depolarisation, 5-hydroxytryptamine (5-HT) evoked two additional responses on the rat superior cervical ganglion: a hyperpolarisation and a slow depolarisation. These responses appeared to be direct actions on 5-HT receptors since they were present in a low calcium medium containing tetrodotoxin and were not abolished by a variety of non-serotonin antagonists. The hyperpolarisation was not antagonised by 5-HT3 or 5-HT2 antagonists. The 5-HT1 ligands 5-carboxamidotryptamine (5-CT) and 8-OH-DPAT also evoked a hyperpolarisation. The hyperpolarisation was antagonised by six 5-HT1A antagonists including WB-4101 and spiroxatrine. It was therefore concluded to be mediated by a 5-HT1A receptor. The slow depolarisation was only evoked by 5-HT. The receptor involved in this response, however, could not be determined. We conclude that in addition to 5-HT3 receptors the rat superior cervical ganglion possesses 5-HT1A receptors and another uncharacterised 5-HT receptor.


Measurement of IgE to hazelnut allergen components cannot replace hazelnut challenge in Dutch adults.
Component-resolved diagnostics (CRD) help predict hazelnut allergy (HA) in children, but are of unknown diagnostic value in adults. This study aimed to evaluate the diagnostic accuracy of IgE to hazelnut extract and components in adults. A Dutch population of consecutively presenting adults suspected of HA, who underwent a double-blind placebo-controlled food challenge, were included. Serum IgE to hazelnut extract and Cor a 1, 8, 9, and 14 was measured on ImmunoCAP. Diagnostic accuracy was assessed by area under the curve (AUC) analysis. Of 89 patients undergoing challenge, 46 had challenge-confirmed HA: 17 based on objective and 29 based on subjective symptoms. At commonly applied cutoffs 0.1 and 0.35 kUA /L, high sensitivity was observed for IgE to hazelnut extract and Cor a 1 (range 85-91%), and high specificity for IgE to Cor a 8, 9 and 14 (range 77-95%). However, the AUCs for hazelnut extract and components were too low for accurate prediction of HA (range 0.50-0.56). Combining hazelnut extract and component IgE measurements did not significantly improve accuracy. Higher IgE levels to Cor a 9 and 14 were tentatively associated with HA with objective symptoms, but the corresponding AUCs still only reached 0.68 and 0.63, respectively. Although hazelnut allergic adults are generally sensitized to hazelnut extract and Cor a 1, and hazelnut tolerant adults are usually not sensitized to Cor a 8, 9, or 14, challenge testing is still needed to accurately discriminate between presence and absence of HA in adults from a birch-endemic country.


An estimate of the fertility potential of the fractions of the split ejaculate in terms of the motile sperm count.
The motile sperm count is a simple index which is equivalent to the product of sperm density (millions of sperm per milliliter) and percentage of motility (motile sperm per 100 sperm x 0.01). Since other studies have demonstrated a positive correlation between this index and the pregnancy rate, it has been hypothesized that the motile sperm count could be useful for expressing the potential fertility of individual semen specimens. Collection of semen by the split ejaculate technique and subsequent artificial insemination homologous (AIH) with the best split fraction has been used for the treatment of oligospermia. We calculated the motile sperm count for whole semen and the first fraction of split ejaculates from 45 men who were studied for infertility. Subsequently, 15 couples agreed to AIH with the first fraction of the split ejaculate. The data indicate that the motile sperm count may be a reasonable index for comparing the potential fertility of the semen specimens and thereby estimating the chances of successful AIH.


MRI of nigrosome-1: A potential triage tool for patients with suspected parkinsonism.
Susceptibility-weighted imaging (SWI) of nigrosome-1 is an emerging and clinically applicable imaging marker for parkinsonism, which can be derived from routinely performed brain MRI. The purpose of the study was to assess whether SWI can be used as a triage tool for more efficient selection of subsequent Dopamine Transporter Scan (DaTSCAN) single-photon emission computed tomography (SPECT). We examined 72 consecutive patients with suspected parkinsonism with both DaTSCAN SPECT and SWI (48 in Philips Ingenia, 24 in GE Signa). Additionally, we examined 24 healthy controls with SWI (14 in Philips Ingenia, 10 in GE Signa). Diagnostic performance of SWI and DaTSCAN SPECT was assessed on the basis of clinical diagnosis, in terms of sensitivity, specificity, and diagnostic accuracy. A total of 54 parkinsonism patients (69 years ± 9, 32 men), 18 nonparkinsonism patients (69.4 years ± 9, 10 men), and 24 healthy controls (62 years ± 8, 10 men) were recruited. SWI had a specificity of 92% and a sensitivity of 74%, whereas DaTSCAN SPECT had 83% and 94%, respectively. By preselecting patients with abnormal or inconclusive SWI, the diagnostic performance of DaTSCAN SPECT improved (specificity 100%, sensitivity 95%). Scans from Philips were associated with significantly lower image quality compared to GE (p < .001). The experienced rater outperformed the less experienced one in diagnostic accuracy (82% vs. 68%). SWI can be used as triage tool because normal SWI can in most cases rule out parkinsonism. However, the performance of SWI depends on acquisition parameters and rater's experience.


Electrospun interconnected Fe-N/C nanofiber networks as efficient electrocatalysts for oxygen reduction reaction in acidic media.
One-dimensional electrospun nanofibers have emerged as a potential candidate for high-performance oxygen reduction reaction (ORR) catalysts. However, contact resistance among the neighbouring nanofibers hinders the electron transport. Here, we report the preparation of interconnected Fe-N/C nanofiber networks (Fe-N/C NNs) with low electrical resistance via electrospinning followed by maturing and pyrolysis. The Fe-N/C NNs show excellent ORR activity with onset and half-wave potential of 55 and 108 mV less than those of Pt/C catalyst in 0.5 M H2SO4. Intriguingly, the resulting Fe-N/C NNs exhibit 34% higher peak current density and superior durability than generic Fe-N/C ones with similar microstructure and chemical compositions. Additionally, it also displays much better durability and methanol tolerance than Pt/C catalyst. The higher electroactivity is mainly due to the more effective electron transport between the interconnected nanofibers. Thus, our findings provide a novel insight into the design of functional electrospun nanofibers for the application in energy storage and conversion fields.


The G209A mutation in the alpha-synuclein gene is not detected in familial cases of Parkinson disease in non-Greek and/or Italian populations.
To determine whether the G-to-A substitution at nucleotide 209 (G209A) mutation in the alpha-synuclein gene is responsible for familial Parkinson disease (PD) in the US population. Polymerase chain reaction-based DNA analysis of consecutive patients with PD and family history of PD. A university-affiliated movement disorder clinic and a Veterans Affairs clinical research laboratory. Forty-four patients with PD and family history of PD and 29 patients with sporadic PD, all with no known Greek and/or Italian background. None of the DNA samples showed the G209A mutation. The G209A mutation is rare in US patients with familial PD.


Experience by children and adolescents of more than one type of maltreatment: Association of different classes of maltreatment profiles with clinical outcome variables.
Most victims of child abuse have experienced more than one type of maltreatment, yet there is a lack of understanding of the impact of specific combinations of types of maltreatment. This study aimed to identify meaningful classes of maltreatment profiles and to associate them with short-term clinical outcomes. A total of 358 German children and adolescents aged 4-17 with a known history of child maltreatment were included in the study. Through interviews and questionnaires, information was obtained from participants and their primary caregivers on history of maltreatment, sociodemographics, psychopathology, level of psychosocial functioning, and health-related quality of life. Types of abuse were categorized into six major groups: sexual abuse in general, sexual abuse with penetration, physical abuse, emotional abuse, neglect, and exposure to domestic violence. A latent class analysis (LCA) was performed to determine distinct multi-type maltreatment profiles, which were then assessed for their associations with the sociodemographic and clinical outcome variables. The LCA revealed that participants could be categorized into three meaningful classes according to history of maltreatment: (1) experience of multiple types of maltreatment excluding sexual abuse (63.1%), (2) experience of multiple types of maltreatment including sexual abuse (26.5%), and (3) experience of predominantly sexual abuse (10.3%). Members of Class 2 showed significantly worse short-term outcomes on psychopathology, level of functioning, and quality of life compared to the other classes. Three distinct profiles of multiple types of maltreatment were empirically identified in this sample. Exposure to multiple types of abuse was associated with poorer outcomes.


Effects of chromium and copper depletion on lymphocyte reactivity to mitogens in diabetes-prone BHE/cdb rats.
The purpose of this study was to measure effects of chromium (Cr) and copper (Cu) depletion on lymphocyte reactivity to mitogens in diabetes-prone BHE/cdb rats. A 2 x 2 factorial research design was used, and 40 BHE/cdb rats were fed with Cr- and/or Cu-depleted diets or adequate Cr and/or Cu diets for 21 wk. Cr and Cu concentrations in diets and mineral concentrations of tissues of BHE/cdb rats were measured by using flame and graphite furnace atomic absorption spectrometry. Three glucose tolerance tests were performed to monitor the development of diabetes or glucose intolerance at weeks 12, 18, and 21. Splenocytes (2 x 10(6)) were incubated with phytohemagglutinin-l (PHA-L), concanavalin A (ConA), and lipopolysaccharides (LPSs), respectively, for 72 h. Four hours before the end of the incubation, splenocytes were pulsed with 3H-thymidine. The 3H-thymidine uptake by lymphocytes was used to calculate a stimulation index. According to glucose tolerance tests, these rats did not develop diabetes or impaired glucose tolerance throughout the study. Average Cr concentrations were 0.98 to 1.03 mg Cr/kg of diet in adequate Cr diets and 8.2 to 14 micrograms Cr/kg of diet in Cr-depletion diets. Average Cu concentrations were 3.6 to 6.4 mg Cu/kg of diet in adequate Cu diets and 1.1 to 1.3 mg Cu/kg of diet in Cu-depletion diets. Organ weights did not differ significantly among treatment groups at the end of the study. Cr or Cu depletion significantly affected iron, zinc, and magnesium concentrations in the liver. A significant interactive effect of Cr and Cu was observed on lymphocyte proliferation with PHA-L stimulation at 25 micrograms/mL (P < 0.006). However, there were no significant effects of dietary treatment on lymphocyte proliferation with 10 micrograms/mL of PHA-L, ConA, or LPS stimulations. When Cr and Cu were adequate in the diets, there was an enhanced effect of Cu or Cr on lymphocyte proliferation. However, when Cr was depleted in the diet, there was a suppressive effect of Cu on lymphocyte proliferation. This result indicates that adequate amounts of Cr and Cu in the diet support the immune system.


The time first-response fire fighters have to initiate care in a midsize city.
The objective of this study was to determine whether simultaneously dispatched first-response firefighters (fire) arrive before transporting EMS providers (ambulance) and the amount of time fire has on scene to initiate care. Fire and ambulance dispatch records were obtained for all 9-1-1 responses from four 1-month intervals. Only incidents to which both agencies had been simultaneously dispatched were included. Response time for each agency was determined by subtracting the time of dispatch from the time of arrival. The difference between fire and ambulance response time was the time fire had to initiate care. Both agencies were simultaneously dispatched to 4752 incidents. Average response time for all incidents was 4.0 +/- 2.6 min for fire and 5.3 +/- 2.0 min for ambulance. Fire had 1.3 +/- 3.2 min on average to initiate care. Fire arrived before ambulance for 69% (3262) of requests and for these calls had 2.8 +/- 1.7 min on average to initiate care. Utilization of densely staged first-response fire apparatus in a midsize city may be appropriate because firefighters frequently arrive before ambulances and may have adequate time to initiate lifesaving interventions.


DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines.
Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance. We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA. The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness. We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells.


Surveillance for long-term health effects associated with depleted uranium exposure and retained embedded fragments in US veterans.
To ensure that all veterans with retained embedded fragments are properly monitored for potential health effects of embedded materials. Urine biomonitoring and health surveillance programs were developed to gather information about health risks associated with chemicals released from embedded fragments. Elevated systemic exposure to depleted uranium (DU) that continues to occur in veterans with DU fragments remains a concern, although no clinically significant DU-related health effects have been observed to date. Other metals and local tissue reactions to embedded fragments are also of concern. Knowledge gained from these programs will help to develop guidelines for surgical removal of tissue-embedded fragments.


Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability.
Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32-p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.


Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer's disease-related inhibitory circuit dysfunction in adults with Down syndrome.
Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ1-42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-fluorodeoxyglucose positron emission tomography). Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r2 = 0.2, p = 0.003), adults with DS (r2 = 0.4, p < 0.0001) and sporadic AD (r2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ1-42 (r2 > 0.3, p < 0.006), low CSF t-tau (r2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05). Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.


Isoprenaline and forskolin increase evoked vasopressin release from rat pituitary.
Isolated neurointermediate lobes of rat pituitaries were incubated in Krebs solution. The vasopressin release evoked by electrical stimulation (0.2 ms, 80 V, 15 Hz, 10 s trains at 10 s intervals for a total of 10 min) was completely inhibited by tetrodotoxin. Isoprenaline increased the evoked vasopressin release to a maximum of 60% (EC50 10 nM) and this effect was antagonized surmountably by propranolol. Forskolin increased the vasopressin release by 98%. These results suggest the presence within the neurohypophysis of a beta-adrenoceptor-linked adenylate cyclase facilitating vasopressin secretion.


Haemodynamic effects of a new dihydropyridine calcium entry blocker, S-12968-(-), in a rat model of cardiovascular calcium overload.
1. The haemodynamic effects of S-12968-(-), a new dihydropyridine calcium entry blocker (enantiomer of S-11568), were compared with those of the stereoisomer, S-12967-(+), nifedipine, and sodium nitroprusside. 2. A first experiment was performed in conscious, young male rats chronically implanted with femoral artery and vein cannula and repeated in rats previously treated with vitamin D3 and nicotine. Such treatment produces marked vascular calcium overload, especially of the compliance arteries, with no overt sign of toxicity as far as can be judged from the plasma profile. 3. In conscious rats the hypotensive effects of S-12968-(-), nifedipine and sodium nitroprusside were of similar potency. The falls in blood pressure produced by nifedipine and sodium nitroprusside were accompanied by reflex tachycardia which was less marked in the vascular calcium overload model. S-12968-(-) did not induce reflex tachycardia. S-12967-(+) increased blood pressure in both models. 4. A second experiment was performed in open-chest pentobarbitone-anaesthetized rats with electromagnetic flowprobes on the ascending aorta. In controls the falls in blood pressure produced by low doses (0.1 and 0.3 mg kg-1, i.v.) of S-12968-(-) were accompanied by falls in total peripheral resistance. The higher dose (1 mg kg-1, i.v.) of S-12968-(-) produced no change in total peripheral resistance, and in rats pretreated with vitamin D3 and nicotine, cardiac output fell. 5. In conclusion, S-12968-(-) appears to have a dual action and to lower blood pressure at higher doses at least in part by a cardiac effect. This phenomenon is more pronounced in rats pretreated with vitamin D3 and nicotine.6. S-12967-(+) resembles a calcium channel activator in this model.


Cells capture and antimicrobial effect of hydrophobically modified chitosan coating on Escherichia coli.
Hydrophobically modified chitosan (HMCS), prepared by reacting alkyl aldehyde with chitosan was demonstrated to be an effective antimicrobial and transparent coating. The grafted alkyl chains exist as protruded hydrophobic tails on the HMCS coating surface. In contact with E. coli cells, HMCS coating captured and immobilized the cells via these hydrophobic tails. The hydrophobic tails could also kill the cells captured on the coating surface as visualized by fluorescence microscope. More than 50% of the initially loaded cells (2.5×104 CFU) could be killed after 2h contact with HMCS coating. The cells capture and killing effects of the coating surface could be completely neutralized by treating with α-cyclodextrin to sequester the protruded hydrophobic tails. The facile coating of antimicrobial HMCS on surface also enabled the easy fabrication of patterned E. coli cells arrays.


Incidence and remission of type 2 diabetes in relation to degree of obesity at baseline and 2 year weight change: the Swedish Obese Subjects (SOS) study.
The aim of this work was to analyse the rates of incidence and remission of type 2 diabetes in relation to baseline BMI and weight change in the prospective, controlled Swedish Obese Subjects (SOS) study. Three-thousand four-hundred and eighty-five obese individuals receiving bariatric surgery or conventional treatment were grouped into four baseline BMI categories (<35, 35-40, 40-45 or ≥ 45 kg/m(2)) and five weight-change categories according to their BMI at 2 years (increase [≥ 1 BMI unit increase], no change [less than 1 BMI unit change], minor reduction [-1 to -9 BMI units], medium reduction [-10 to -14 BMI units] and major reduction [< -15 BMI units]). The incidence and remission of diabetes at 2 years was assessed. Among individuals with no weight change, diabetes incidence rates were 5.5%, 7.4%, 8.3% and 5.2%, in the four baseline BMI categories, respectively. In those with an initial BMI of 35-40, 40-45 and ≥ 45 kg/m(2) who attained a minor reduction in weight, the corresponding rates were 1.3%, 1.2% and 3.4%, respectively. In both the medium- and major-weight-reduction groups, diabetes incidence was ≤ 0.5%. Among individuals with diabetes at baseline, the remission rates were 15.3-26.9% in the no-weight-change groups, and 48.1-70% for individuals who attained a minor weight reduction. In the medium- and major-weight-reduction groups, the remission rate was 77-97%. There were no differences in 2 year incidence and remission rates between different baseline BMI groups that achieved the same degree of weight reduction. In obese individuals, the favourable effect of weight reduction on type 2 diabetes incidence and remission is independent of initial BMI. Trial registration ClinicalTrials.gov number NCT01479452.


Glycosylation in SARS-CoV-2 variants: A path to infection and recovery.
Glycan is an essential molecule that controls and drives life in a precise direction. The paucity of research in glycobiology may impede the significance of its role in the pandemic guidelines. The SARS-CoV-2 spike protein is heavily glycosylated, with 22 putative N-glycosylation sites and 17 potential O-glycosylation sites discovered thus far. It is the anchor point to the host cell ACE2 receptor, TMPRSS2, and many other host proteins that can be recognized by their immune system; hence, glycosylation is considered the primary target of vaccine development. Therefore, it is essential to know how this surface glycan plays a role in viral entry, infection, transmission, antigen, antibody responses, and disease progression. Although the vaccines are developed and applied against COVID-19, the proficiency of the immunizations is not accomplished with the current mutant variations. The role of glycosylation in SARS-CoV-2 and its receptor ACE2 with respect to other putative cell glycan receptors and the significance of glycan in host cell immunity in COVID-19 are discussed in this paper. Hence, the molecular signature of the glycan in the coronavirus infection can be incorporated into the mainstream therapeutic process.


Amenable mortality inequalities and their changes by place of residence during 1990-2019: the case of Lithuania.
The aim of this study was to analyze inequalities of amenable mortality by place of residence and its changes in Lithuania during 1990-2019. A record-linked cohort study. Information on deaths was obtained from Statistics Lithuania and the Institute of Hygiene. Mortality rates from amenable causes of death by urban and rural among men and women were calculated per 100,000 population and were standardized by age. Inequalities in mortality were assessed using rate differences. For the assessment of the trends of mortality and its inequalities during 1990-2019, joinpoint regression analysis was applied. During 1990-2019, amenable mortality of men and women in rural areas was higher compared to urban areas (P < 0.05). Changes in men's and women's mortality and its inequalities between rural and urban areas were characterized by three cut-off points (P < 0.05). However, not all the periods between the cut-off points were characterized by statistically significant changes in mortality. A reduction in amenable mortality was more evident in women, especially those living in rural areas. During 1990-2004 and in 2006, the differences in amenable mortality were greater among rural and urban women than among men. However, during 2013-2019, the differences were smaller (P < 0.05). Inequalities of men's mortality decreased during 1990-2001 and 2005-2012, and inequalities of women's mortality decreased during 1993-2006, 2006-2017, and 2017-2019 (P < 0.05). Inequalities of men's mortality decreased most rapidly during 2005-2012 (on average, by 10.24% per year), while inequalities of women's mortality decreased most rapidly during 2017-2019 (on average by 18.32% per year) (P < 0.05). During 1990-2019, inequalities and a decline of inequalities in amenable mortality among rural and urban men and women were identified in Lithuania. The amenable mortality of the residents of Lithuania remained high, changed unevenly, and no significant sharp decrease was observed. Further reduction of inequalities in amenable mortality between rural and urban inhabitants with a special focus on men remain the health policy challenges in Lithuania.


Endoscopic full-thickness dissection (EFTD) in the rectum: a case series.
Rectal endoscopic full- thickness dissection (EFTD) using a flexible colonoscope is an alternative to the well-established trans-anal endoscopic microsurgery (TEM) and the trans-anal minimally invasive surgery (TAMIS) techniques for resecting dysplastic or malignant rectal lesions. This study evaluated EFTD safety by analyzing outcomes of the first patients to undergo rectal EFTD at the University Hospital of North-Norway. The first 10 patients to undergo rectal EFTD at the University Hospital of North-Norway April, 2016 and January, 2021, were included in the study. The procedural indications for EFTD were therapeutic resection of non-lifting adenoma, T1 adenocarcinoma (AC), recurrent neuroendocrine tumor (NET) and re-excision of a T1-2 AC. EFTD rectal specimen histopathology revealed three ACs, five adenomas with high-grade dysplasia (HGD), one NET and one benign lesion. Six procedures had negative lateral and vertical resection margins and in three cases lateral margins could not be evaluated due to piece-meal dissection or heat damaged tissue. Two patients experienced delayed post-procedural hemorrhage, one of whom also presented with a concurrent post-procedural infection. No serious complications occurred. Preliminary results from this introductory trial indicate that EFTD in the rectum can be conducted with satisfactory perioperative results and low risk of serious complications.


Prurigo pigmentosa in Korea: clinicopathological study.
Prurigo pigmentosa (PP) is an inflammatory dermatosis characterized by recurrent pruritic erythematous papules, mainly located on the trunk. It was first described by Nagashima in 1971 in Japan. Since then, more than 300 cases have been reported in Japan, but reports from other parts of the world are quite rare. We studied clinical and histopathological data from six patients with PP diagnosed in our hospital and 43 patients (18 reports) who were diagnosed with PP in Korea between 1988 and 2008. The number of Korean patients reported in recent years is higher than the number of other non-Japanese patients reported. Clinicopathological characteristics in Korean patients were not significantly different from those previously reported. Therapeutic results with minocycline were successful in our patients. We suspect that PP is not uncommon in Korea, and the disease may be underestimated. Strict restriction of diet as well as known associated factors like wet condition are suggested as one of the important factors contributing to the occurrence of PP in Korea.


Congenital cholesteatoma: clinical features and growth patterns.
The clinical features and patterns of growth, relative to age, were examined in patients with congenital cholesteatoma to investigate disease progression and site of origin. We retrospectively reviewed 72 children younger than 15 years with intraoperatively confirmed congenital cholesteatoma diagnosed using the inclusion criteria of Levenson et al. Patient demographics, history, and otoscopic and operative findings were evaluated. Correlation between mass volumetric and operation age was analyzed in patients with closed-type masses. Parameters of disease extent of middle ear quadrant, ossicular erosion, attic involvement, invasion of the mastoid cavity, and type of mass were assessed relative to age at operation. Mean patient age was 63.1 months (range, 20-179 months), with 51 patients (70.8%) being asymptomatic and diagnosed incidentally. Nineteen patients (26.4%) had closed-type cystic masses, and 53 (73.6%) had open-type lesions. The volume of closed-type masses was linearly correlated with age at operation. Logistic regression showed that increased age at operation was associated with a lower proportion of anterosuperior quadrant lesions, resulting in uncertainty about the site of origin. The possibility of open-type masses also increased according to age at operation. Congenital cholesteatoma shows growth and extension over time. Early detection and intervention are necessary to avoid advanced disease.