Selection of DNA aptamers against polychlorinated biphenyls as potential biorecognition elements for environmental analysis.
Polychlorinated biphenyls (PCBs) have been of major concerns for decades due to their potential toxicity to human health. To trace the PCBs efficiently and sensitively, many detection methods have been developed. Aptamers, a new class of diagnostic tools, are considered to be such additional candidates for detection of pollutants. In the current study, we report the DNA aptamers, isolated by FluMag-SELEX (a modified SELEX [systematic evolution of ligands by exponential enrichment] technology), that recognize PCBs with the dissociation constants (Kd values) down to the micromolar range. Using the selected aptamers, a highly sensitive aptamer-based fluorescent assay for detection of PCBs was established using gold nanoparticles, with a widely linear range from 0.1 to 100 ng/ml. Moreover, our aptamer-based gold nanoprobe displays specificity toward 3,3',4,4'-tetrachlorobiphenyl (PCB77) compared with a few common PCB77 structural analogs. These results open the possibility of using aptamers as biorecognition elements for easy and fast environmental monitoring.


An assessment of the association between soil pH and ovine Johne's disease using Australian abattoir surveillance data.
There has long been discussion in the literature about the role of soil on ovine Johnes disease (OJD). This is especially true of soil pH, however there is very little research to support an association between pH and OJD prevalence. The primary objective of this study was to examine the hypothesis that there is an association between soil pH and OJD. Several additional hypotheses were also assessed. Sheep properties that were surveyed by the Australian National Sheep Health Monitoring Project where classified as OJD reactor positive or otherwise. A variety of explanatory variables such as soil (especially soil pH), environmental and management factors were examined. Spatial regression models were assessed using information theory to examine support for various hypotheses and to examine associations; especially that soil pH is associated with OJD. A total of 1213 properties from 10,578 were classified as OJD positive (11.5%, 95% CI: 10.9-12.1). Within the limitations of the study, only modest support was found for an association between soil pH and the presence or absence of OJD. Instead, OJD prevalence was affected by several factors concurrently, a so called multi-factorial model (hypothesis). In this supported multifactorial hypothesis soil pH was marginally associated with OJD (p=0.04) and had a relatively weak effect (OR 0.91, 95% CI 0.82 to 1.00). OJD was strongly associated with a number of biosecurity and environmental factors such as the time since infection arrived in a region, absence of biosecurity programs (such as regional biosecurity programs or state based programs) and, to a lesser extent, solar irradiation. Soil pH may play a relatively small role in explaining OJD prevalence when evaluated as part of a multifactorial model. Biosecurity and other environmental factors appear to be more strongly associated with the presence of OJD in Australia.


Novel camptothecin derivatives. Part 1: oxyalkanoic acid esters of camptothecin and their in vitro and in vivo antitumor activity.
A series of oxyalkanoic acid esters of (20S)-camptothecin derivatives was prepared by the method of acylation. Their antitumor activity was evaluated on cancer cells in vitro by the colony formation assay and in vivo. These newly synthesized derivatives show a dramatically higher chemotherapeutic activity in killing human cancer cells than the parent drug, camptothecin, and clinically available drugs, irinotecan and taxol.


Architecture of torovirus replicative organelles.
Plus-stranded RNA viruses replicate in the cytosol of infected cells, in membrane-bound replication complexes. We previously identified double membrane vesicles (DMVs) in the cytoplasm of cells infected with Berne virus (BEV), the prototype member of the Torovirus genus (Nidovirales Order). Our previous analysis by transmission electron microscopy suggested that the DMVs form a reticulovesicular network (RVN) analogous those described for the related severe acute respiratory syndrome coronavirus (SARS-CoV-1). Here, we used serial sectioning and electron tomography to characterize the architecture of torovirus replication organelles, and to learn about their biogenesis and dynamics during the infection. The formation of a RVN in BEV infected cells was confirmed, where the outer membranes of the DMVs are interconnected with each other and with the ER. Paired or zippered ER membranes connected with the DMVs were also observed, and likely represent early structures that evolve to give rise to DMVs. Also, paired membranes forming small spherule-like invaginations were observed at late time post-infection. Although resembling in size, the tomographic analysis show that these structures are clearly different from the true spherules described previously for coronaviruses. Hence, BEV shows important similarities, but also some differences, in the architecture of the replication organelles with other nidoviruses.


Bacteriophage DW-EC with the capability to destruct and inhibit biofilm formed by several pathogenic bacteria.
Biofilm formation by pathogenic bacteria is a major challenge in the food industry. Once a biofilm is established, such as on food processing equipment, it becomes more difficult to eradicate. Although physical and chemical treatments are often used to control biofilm formation, these treatments can have significant drawbacks. Alternative biofilm treatments are needed. Phage DW-EC was isolated from dawet, an Indonesian traditional Ready-To-Eat food, which has high specificity for Enterohaemorrhagic Escherichia coli (EHEC), Enteropathogenic E. coli (EPEC), and Enterotoxigenic E. coli (ETEC). Phage DW-EC produces several enzymes that can prevent the development of biofilm and biofilm eradication. Depolymerase enzymes break down the polysaccharides layer on the biofilms can lead to biofilm damage. On the other hand, endolysin and putative like-T4 lysozyme will lyse and kill a bacterial cell, thereby preventing biofilm growth. This research aims to determine the capability of previously identified phage DW-EC to inhibit and destroy biofilms produced by several foodborne pathogens. Phage DW-EC formed plaques on the bacterial lawns of EHEC, EPEC, and ETEC. The efficiency of plating (EOP) values for EHEC, EPEC, ETEC, and Bacillus cereus were 1.06, 0.78. 0.70, and 0.00, demonstrating that DW-EC was effective in controlling pathogenic E. coli populations. Furthermore, phage DW-EC showed anti-biofilm activity against foodborne pathogenic bacteria on polystyrene and stainless-steel substrates. DW-EC biofilm inhibition and destruction activities against pathogenic E. coli were significantly higher than against B. cereus biofilms, which was indicated by a lower density of the biofilm than B. cereus. Microscopic visualization verified that bacteriophage DW-EC effectively controlled EHEC, EPEC, and ETEC biofilms. The results showed that DW-EC could inhibit and destroy biofilm, making it promising to be used as an anti-biofilm candidate for polystyrene and stainless steel equipment in the food industry.


Comparative analysis of protein evolution in the genome of pre-epidemic and epidemic Zika virus.
Zika virus (ZIKV) causes microcephaly in congenital infection, neurological disorders, and poor pregnancy outcome and no vaccine is available for use in humans or approved. Although ZIKV was first discovered in 1947, the exact mechanism of virus replication and pathogenesis remains unknown. Recent outbreaks of Zika virus in the Americas clearly suggest a human-mosquito cycle or urban cycle of transmission. Understanding the conserved and adaptive features in the evolution of ZIKV genome will provide a hint on the mechanism of ZIKV adaptation to a new cycle of transmission. Here, we show comprehensive analysis of protein evolution of ZIKV strains including the current 2015-16 outbreak. To identify the constraints on ZIKV evolution, selection pressure at individual codons, immune epitopes and co-evolving sites were analyzed. Phylogenetic trees show that the ZIKV strains of the Asian genotype form distinct cluster and share a common ancestor with African genotype. The TMRCA (Time to the Most Recent Common Ancestor) for the Asian lineage and the subsequently evolved Asian human strains was calculated at 88 and 34years ago, respectively. The proteome of current 2015/16 epidemic ZIKV strains of Asian genotype was found to be genetically conserved due to genome-wide negative selection, with limited positive selection. We identified a total of 16 amino acid substitutions in the epidemic and pre-epidemic strains from human, mosquito, and monkey hosts. Negatively selected amino acid sites of Envelope protein (E-protein) (positions 69, 166, and 174) and NS5 (292, 345, and 587) were located in central dimerization domains and C-terminal RNA-directed RNA polymerase regions, respectively. The predicted 137 (92 CD4 TCEs; 45 CD8 TCEs) immunogenic peptide chains comprising negatively selected amino acid sites can be considered as suitable target for sub-unit vaccine development, as these sites are less likely to generate immune-escape variants due to strong functional constrains operating on them. The targeted changes at the amino acid level may contribute to better adaptation of ZIKV strains to human-mosquito cycle or urban cycle of transmission.


The Thrombolysis in Myocardial Infarction (TIMI) Trial phase II: additional information and perspectives.
Given the many thrombolytic agents and the number of ways in which they can be combined with mechanical revascularization, the treatment of acute myocardial infarction has been the subject of active study and lively debate, which are likely to continue for some time. Several studies, including TIMI IIA (2,3,10,22), have suggested that immediate catheterization and angioplasty offer no clinical benefit and have a greater complication rate than a more delayed invasive strategy, but TIMI II (1) and SWIFT (16) trials have suggested that an even more conservative strategy of reserving catheterization and coronary angioplasty after thrombolytic therapy for patients with recurrent spontaneous or exercise-induced ischemia may be the most desirable approach for the majority of patients similar to those entered into these trials.


Consider these exercises for chronic musculoskeletal conditions.
Exercise interventions reduce pain and improve function in knee/hip OA, chronic low back pain, shoulder pain, Achilles tendinopathy, and lateral epicondylitis.


The dualistic approach of FCA: a further insight into Ontario Lake sediments.
The investigation of object-by-attribute matrices is very common in statistics and data analysis with the aim of uncovering every possible relationship among objects and/or attributes. Formal Concept Analysis (FCA) is a method, which stems directly from partial order and lattice theory, which provides an efficient tool to symmetrically uncover linkages among objects and attributes whenever a relation stands among the two sets. It provides efficacious graphical representation and computes association rules between attributes, thus helping in the detection of possible synergism or antagonism of attributes. In this paper, FCA potentialities are discussed and described by means of a case study already investigated by other partial order techniques: the case of Lake Ontario sediment samples. Data derive from a 'test battery' for a simultaneous analysis of degradation of Lake Ontario samples, which are basically of two typologies: hygienic and toxicity tests. A multi-valued approach is adopted to cope with the ordinal feature of data. Results highlight interesting interaction among hygienic compounds and a synergism between the two toxicity tests.


A pilot randomized double-blind, placebo-controlled study on the effects of the topical application of pyridoxine on palmar-plantar erythrodysesthesia (PPE) induced by capecitabine or pegylated liposomal doxorubicin (PLD).
Palmar-Plantar Erythrodysesthesia (PPE) is a dose-limiting adverse event that commonly occurs with capecitabine and Pegylated Liposomal Doxorubicin-PLD treatment. The study aimed to test the effectiveness of a Pyridoxine (B6) treatment protocol in the management of PPE in patients receiving treatment with capecitabine or pegylated liposomal doxorubicin. This was a pilot randomized double-blind, placebo-controlled study. Patients receiving capecitabine or pegylated liposomal doxorubicin with PPE grade 1 or above were randomly allocated to receive pyridoxine or placebo. The PPE grade, Quality of Life-QoL, Pain and patients' activities of daily living were assessed. Thirty patients were assigned in the Control and 24 in the Intervention group. No statistically significant difference was found in the PPE grade between baseline and week 6 in the 2 groups (p = 0.263). The control group exhibited worst PPE-associated QoL and higher PAIN levels between baseline and week 6. Respectively, the intervention group showed improved PPE-associated QoL and lower PAIN levels. At week 6, the ECOG status in the Intervention group was improved compared to the control (p = 0.018). Patients in the Intervention group experienced better Global Health Status (p = 0.012), Physical (p = 0.003), Emotional (p = 0.008), and Social function (p < 0.001), lower Fatigue (p = 0.001) and Pain (p = 0.006) compared to Control. Topical pyridoxine was not shown to have an effect on the treatment of PPE. However, results demonstrated its effectiveness on health related QoL, QoL-associated with PPE and pain levels. Due to the high attrition rate further validation of these results in a larger population is warranted. CLINICALTRIALS. NCT02625415.


Climatic influence on the reproductive characteristics of Japanese males.
We previously performed a survey of the sperm characteristics of the partners of pregnant women in four cities in Japan. In the present study, we analyzed the sperm characteristics of these subjects and the correlations between these sperm characteristics and climatic changes or Y chromosome haplogroups. Our results showed that more haplogroup D2a1 males than O2b1 males were born in the first half of the year (January to June), whereas more O2b1 males were born in the last half of the year (July to December) (P<0.05). This was agreed and correlated with the seasonal variations in their mean sperm concentrations. The haplogroup C, D* and D2a1 males displayed lower sperm concentrations from March to May, followed by an increase in their sperm concentrations starting in June or July, while the O2b1 males displayed higher sperm concentrations in the first half of the year followed by a sudden decrease from July to August (P<0.05). We hypothesize that the Japanese climate has different effects on the sperm characteristics and reproductive seasonality of males from different lineages; and therefore, has influenced the modern population of Japan.


A study of accidental poisoning (in children) in a rural medical college hospital of West Bengal.
134 cases of accidental poisoning in children have been reported, children belonging to the age group of 1-3 years are the main victims. Kerosene has been noted as the single most important cause of poisoning. Mortality was fortunately low amounting to 5.2% of all cases.


Publication Rate and Evidence-Based Evaluation of Abstracts Presented at the American College of Veterinary Surgeon's Annual Meeting.
To document the publication rate of abstracts presented at 10 ACVS conferences and report the time required for publication and level of evidence. Literature review. All scientific abstracts published in the ACVS proceedings from 2001 to 2010 were reviewed. The level of evidence of each abstract was evaluated and scored (1-4). Publication information was determined after a broad bibliographic search through multiple online databases. The overall publication rate for ACVS abstracts (n=1,395) was 66% and 11% were published before conference presentation. The majority of abstracts focused on the dog (35%) or the horse (33%). Most (90%) abstracts were submitted to veterinary-based journals. The median time (interquartile range [IQR]) from abstract presentation to journal submission was 222 days (107-541), from journal submission to acceptance for publication was 122 days (89-185), and from acceptance to publication in a journal was 208 days (151-289). The time from abstract presentation to final publication took 449 days (238-794). Of the abstracts, 4% were of level 1 evidence, 9% level 2, 66% level 3, and 21% level 4. Studies with a higher level of evidence were submitted, accepted, and published quicker than ones with a lower level of evidence. The publication rate was 61%, 71%, 68%, and 65% for level 1, 2, 3, 4 evidence, respectively. The publication rate of scientific abstracts presented at the ACVS conferences is comparable to other biomedical conferences. The subject matter is limited in scope and focused mainly on dogs or horses. Most abstracts contained lower level of evidence. Studies with higher levels of evidence were submitted, accepted, and published more timely. However, the publication rate was similar for abstracts of all levels of evidence.


The application of single strand conformation polymorphism (SSCP) analysis in determining Hepatitis E virus intra-host diversity.
Genetic heterogeneity of RNA populations influences virus pathogenesis, epidemiology and evolution. Therefore, accurate information regarding virus genetic structure is highly important for both diagnostic and scientific purposes. For the Hepatitis E virus (HEV), the causal agent of hepatitis in humans, the intra-host population structure has been poorly investigated, mainly using the less sensitive RFLP-based approach. The objective of this study was to assess the suitability and the accuracy of single strand conformation polymorphism (SSCP) analysis, a well-established tool in genetic variation research, for the characterization of HEV quasispecies. The analysis was conducted on 50 clones of five swine isolates and 30 clones of three human HEV isolates. To identify and quantify the sequence variants present in each HEV isolate, 348bp long fragments of the amplified conserved ORF2 region were separated by cloning. Ten clones per isolate were subjected to SSCP and sequenced in a parallel experiment. The results show a high correlation of SSCP haplotype profiling with the sequencing results, confirming the sensitivity and reliability of this simple, rapid and low cost approach in the characterization of HEV quasispecies.


Preadmission usage of metformin and mortality in COVID-19 patients including the post-discharge period.
The effect of preadmission metformin usage (PMU) on the mortality of coronavirus disease-2019 (COVID-19) patients with diabetes is conflicting. Most studies have focused on in-hospital mortality; however, mortality after discharge also increases in COVID-19 patients. Examining the effect of PMU on all-cause mortality, including the post-discharge period. Patients with diabetes who were hospitalised in 2020 due to COVID-19 were included in the study. They were divided into two groups: those with a history of metformin use (MF( +)) and those without such history (MF( -)). Propensity score matching (PSM) was performed at a ratio of 1:1 for age and sex. COX regression analyses were used to demonstrate risk factors for mortality. We investigated 4103 patients hospitalised for COVID-19. After excluding those without diabetes or with chronic liver/kidney disease, we included the remaining 586 patients, constituting 293 women (50%) with an overall mean age of 66 ± 11.9 years. After PSM analysis, the in-hospital and post-discharge mortality rates were higher in the MF( -) group though not significantly different. However, overall mortality was higher in the MF( -) group (51 (42.5%) vs. 35 (29.2%), p = 0.031). For overall mortality, the adjusted HR was 0.585 (95% CI: 0.371 - 0.920, p = 0.020) in the MF( +) group. PMU is associated with reducing all-cause mortality. This effect starts from the in-hospital period and becomes more significant with the post-discharge period. The main limitations were the inability to evaluate the compliance with metformin and the effects of other medications due to retrospective nature.


Combined cystourethropexy for the treatment of type 3 and complicated female urinary incontinence.
We treated 37 women with type 3 stress urinary incontinence or with an associated complicating factor, such as morbid obesity, a large or proximal diverticulum or a urethrovaginal fistula, via combined transvaginal cystourethropexy. All women with type 3 stress incontinence had failed a previous anti-incontinence operation. Patients in both groups underwent suprapubic needle suspension and an additional bladder neck support procedure. Among 33 patients who underwent preoperative urodynamic studies 30 had stable bladders (90%), while 3 had low pressure detrusor instability (10%). The success rate in achieving continence, including cured and improved patients, was 94.6% with a followup of 3 to 72 months. Four patients (10%) required temporary intermittent catheterization for 3 to 4 weeks but none presented with long-term voiding dysfunction. The added bladder neck support improved our results in these complicated female incontinence cases compared to the standard suprapubic needle suspension procedures alone. The combined procedure currently is our method of choice for treatment of type 3 and other complicated cases of female urinary incontinence.


Temporal trends in anxiety and depression prevalence and their association with adverse outcomes in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease in Beijing, China, from 2004 to 2020.
To investigate the temporal trend in anxiety and/or depression prevalence in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Beijing and their association with adverse outcomes. Hospital admission records from 2004 to 2020 with a primary discharge diagnosis of AECOPD were retrieved from Beijing Public Health Information Centre database. The anxiety and depression were identified from discharge diagnoses of each record. Joinpoint regression was used to analyze the temporal trend and calculate the annual percentage change (APC) for the prevalence of anxiety and/or depression. Generalized linear model was used to analyze the associations between anxiety and/or depression and patients' adverse outcomes. A total of 382,125 records were included, most of which were male (66.0%) and aged ≥ 75 years (59.7%). Three segments in the temporal trend were observed, with a mild increase during 2004-2009 (APC: 5.9%, 95% CI: -14.9 to 31.7%), followed by a sharply increase during 2009-2012 (APC: 60.4%, 95% CI: 10.6 to 132.7%), then stabilized at about 3% during 2012-2020 (APC: 1.9%, 95% CI: -0.4 to 4.3%). On average, anxiety, and/or depression was more prevalent in females, the aged and those admitted in secondary hospitals (all P < 0.001). Patients with anxiety and/or depression had lower in-hospital mortality (IHM) (OR = 0.74, 95% CI: 0.63-0.88), but longer hospital stay (OR = 1.10, 95% CI: 1.07-1.13), more medical costs (OR = 1.12, 95% CI: 1.08-1.17) and higher risks of readmission for AECOPD at 30-, 90-, 180-day, and 1-year (ORs ranged from 1.22 to 1.51). The prevalence of anxiety and/or depression in patients hospitalized for AECOPD in Beijing stabilized at approximately 3% after 2012. Anxiety and/or depression is associated with a heavier burden on patients, health care, and medical insurance systems. Appropriate diagnosis and effective treatment of anxiety and depression is crucial for patients with AECOPD.


Ipsilateral breast tumor recurrence (IBTR) in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic Index.
There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast-conserving surgery plus radiotherapy (breast-conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors. The authors collected data from 375 patients who underwent BCT and received NAC and analyzed the risk of IBTR associated with undergoing BCT after NAC. The usefulness of the MD Anderson Prognostic Index (MDAPI) for IBTR also was validated using the current data set. The median follow-up was 47.8 months, and the 4-year IBTR-free survival rate was 95.6%. Multivariate analysis demonstrated that estrogen receptor (ER) status and multifocality of the residual tumor were associated significantly with IBTR-free survival. In addition, patients who had ER-positive and human epidermal growth factor 2 (HER2)-negative tumors did not develop IBTR during the observation period. Although prognostic stratification according to MDAPI was relatively good for the prediction of IBTR in the study patients, the IBTR rate in the high-risk group was not very high and was lower than that in the intermediate-risk group. Multivariate analyses demonstrated that IBTR was an independent predictive factor for overall survival. ER status and multifocality of the residual tumor after NAC were independent predictors of IBTR after BCT. The MDAPI was barely adaptable to the study patients in terms of predicting IBTR. Patients with ER-positive and HER2-negative tumors had a favorable prognosis, whereas patients who developed IBTR after NAC had significantly worse overall survival. The authors propose a new IBTR prognostic index using the 2 factors that were identified as predictive of IBTR: ER status and multifocality of the residual tumor.


Steric Mixed-Cation 2D Perovskite as a Methylammonium Locker to Stabilize MAPbI3.
The reduced dimension perovskite including 2D perovskites are one of the most promising strategies to stabilize lead halide perovskite. A mixed-cation 2D perovskite based on a steric phenyltrimethylammonium (PTA) cation is presented. The PTA-MA mixed-cation 2D perovskite of PTAMAPbI4 can be formed on the surface of MAPbI3 (PTAI-MAPbI3 ) by controllable PTAI intercalation by either spin coating or soaking. The PTAMAPbI4 capping layer can not only passivate PTAI-MAPbI3 perovskite but also act as MA+ locker to inhibit MAI extraction and significantly enhance the stability. The highly stable PTAI-MAPbI3 based perovskite solar cells exhibit a reproducible photovoltaic performance with a champion PCE of 21.16 %. Such unencapsulated devices retain 93 % of initial efficiency after 500 h continuous illumination. This steric mixed-cation 2D perovskite as MA+ locker to stabilize the MAPbI3 is a promising strategy to design stable and high-performance hybrid lead halide perovskites.


Mid-infrared wavelength multiplexer in InGaAs/InP waveguides using a Rowland circle grating.
We report the monolithic integration of a 15-channel multiplexer on indium phosphide. It covers the 7.1-to-8.5 µm wavelength range suitable for combining the outputs of several individual lasers. The fabrication is compatible with the growth of active layers, therefore enabling a fully integrate broadband laser source in the mid-infrared spectral range. Channels are accurately spaced in wavelength (97 nm) in good agreement with design.


Detectable levels of pyridinoline are present in synovial fluid from various patients with knee effusion: preliminary results.
There is a major interest for using biochemical markers of bone metabolism as a non-invasive tool for diagnostic purposes in the field of bone and joint diseases. Based upon the fact that the pyridinium cross-links of collagen are markers of bone and cartilage degradation, this study was designed to assess the presence of pyridinoline in synovial fluid samples originating from various arthritic and non-arthritic knee joints. Using a sample pooling method, significant levels of pyridinoline could be measured in synovial fluid by high performance liquid chromatography. Pyridinoline levels ranged from 19.3 +/- 5.8 pmol mL-1 (mean +/- SD) in osteoarthritic knee joints up to 32.4 +/- 14.6 pmol mL-1 in rheumatoid arthritis joints. Pyridinoline levels in synovial fluid were not significantly correlated to disease duration and synovial fluid cell count, but were correlated to erythrocyte sedimentation rate in osteoarthritic patients (r = 0.99, P = 0.002). This study demonstrates that synovial fluid originating from knee effusion contains significant levels of pyridinoline which can be quantified by high performance liquid chromatography and could, therefore, be a tool to investigate the metabolism of a single joint.


A three-step approach to close refractory persistent macular holes: a releasing-closing-tapping approach.
The aim of this study was to assess the efficacy and safety of a novel releasing-closing-tapping approach in the treatment of persistent macular holes (PMHs) after initial surgery with internal limiting membrane (ILM) peeling. We retrospectively analyzed patients with PMHs after initial surgery with ILM peeling who were treated with a novel releasing-closing-tapping approach. After repeated pars plana vitrectomy (PPV), the surgeon effectively released the adhesion between the edges and retinal pigment epithelium (RPE) by gently scraping the retinal neuroepithelium. Then, the hole was converted into a transverse slit, and the edges were gently tapped flat so that they attached to the RPE, and no space was left under the edges. Finally, air tamponade was carried out. The primary outcome measures included MH closure and the change in best-corrected visual acuity (BCVA) from preoperatively to postoperatively. The study included 11 PMH patients with a mean age of 63.82 ± 3.31 years. The mean minimum linear diameter of PMHs was 666.3 ± 208.1 μm, and the mean basal diameter was 1547.2 ± 351.8 μm. MH closure was achieved in 90.9% (10/11) of eyes, with significant improvement of visual acuity from 1.19 ± 0.30 logMAR to 0.65 ± 0.29 logMAR postoperatively. The releasing-closing-tapping approach with repeated PPV is a simple, effective, and safe surgical procedure for refractory PMHs after initial surgery with ILM peeling that can significantly improve the visual outcome and achieve a high surgical success rate.


Empirical derived AUD sub types in the US general population: a latent class analysis.
This study examined the homogenous expression of DSM-5-based alcohol use disorder (AUD) latent subtypes. Using data from the National Epidemiologic Survey of Alcohol and Related Conditions Wave 2 (n = 22,177) the typology was established utilising latent class analysis and the model was further validated by multivariate regression on a range of covariates. Three AUD classes based on a severity gradient and one non-problematic class were the most parsimonious description of the data. These classes displayed both quantitative and qualitative differences on the covariates. The resulting typology has high clinical utility, enhances AUD classification and adds to our understanding of AUD trajectories, prevention and treatment.


Amylase inhibitor from wheat: its action and clinical application.
The electrophoretic and column chromatographic characteristics of an amylase inhibitor of wheat origin were investigated. Further, the clinical usefulness of this inhibitor for determining the ratio of pancreatic to salivary isoamylase activity in serum was evaluated. Amylase inhibitor inhibits the action of salivary alpha-amylase by making an amylase-inhibitor complex, which is easily separated into its individual component during electrophoresis with full recovery of amylase activity. Using the specific inhibitory effect of this inhibitor on salivary alpha-amylase activity, the ratio of pancreatic to salivary isoamylase activity (P/S) in serum was determined. There was a good correlation in P/S ratio in serum between the results obtained with the inhibitor method and those with electrophoretic method. The P/S ratio in sera from patients with acute pancreatitis was over 8.0, whereas that in sera from patients with salivary-type hyperamylasemia such as mumps, pulmonary diseases and following surgery was less than 0.1. However, hyperamylasemia due to macroamylase or renal failure could not be identified by the inhibitor method.


Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia.
To describe the phenotypes in 2 families with vaccinia-related kinase 1 (VRK1) mutations including one novel VRK1 mutation. VRK1 mutations were found by whole exome sequencing in patients presenting with motor neuron disorders. We identified pathogenic mutations in the VRK1 gene in the affected members of 2 families. In family 1, compound heterozygous mutations were identified in VRK1, c.356A>G; p.H119R, and c.1072C>T; p.R358*, in 2 siblings with adult onset distal spinal muscular atrophy (SMA). In family 2, a novel VRK1 mutation, c.403G>A; p.G135R and c.583T>G; p.L195V, were identified in a child with motor neuron disease. VRK1 mutations can produce adult-onset SMA and motor neuron disease in children without pontocerebellar hypoplasia.


Online Safety for Children and Youth under the 4Cs Framework-A Focus on Digital Policies in Australia, Canada, and the UK.
This study analyzes the previous literature on the online safety of children and youth under "the 4Cs risk framework" concerning contact, content, conduct, and contract risks. It then conducts a comparative study of Australia, Canada, and the UK, comparing their institutions, governance, and government-led programs. Relevant research in Childhood Education Studies is insufficient both in quantity and quality. To minimize the four major online risks for children and youth in cyberspace, it is necessary to maintain a regulatory approach to the online exposure of children under the age of 13. Moreover, the global society should respond together to these online risks with "multi-level" policymaking under a "multi-stakeholder approach". At the international level, multilateral discussion within the OECD and under UN subsidiaries should continue to lead international cooperation. At the domestic level, a special agency in charge of online safety for children and youth should be established in each country, encompassing all relevant stakeholders, including educators and digital firms. At the school and family levels, both parents and teachers need to work together in facilitating digital literacy education, providing proper guidelines for the online activities of children and youth, and helping them to become more satisfied and productive users in the digital era.


Systemic alkalosis as a provocative test for coronary artery spasm in patients with infrequent resting chest pain.
Systemic alkalosis was used to detect coronary spasm in 237 patients with infrequent, resting, angina-compatible chest pain. The provocative test was performed without previous coronary arteriography but only in patients with negative submaximal exercise test results. Rapid infusion of alkaline solution followed by maximal hyperventilation raised arterial pH above the 7.65 value necessary for diagnostic significance in 196 (83%) patients. In 24 (12%) of these patients the provocative test induced significant ischemic ST segment changes. In all patients with a positive response, coronary artery disease, which was predominantly vasospastic (19 patients) or atheromatous with a vasospastic contribution (five patients), was demonstrated by coronary arteriography followed, if necessary, by ergot derivative injection. Chest pain and ECG changes were always reversed within 5 minutes by intravenous nitroglycerin. Coronary arteriography was not performed in all patients with a negative response; therefore, the sensitivity of the procedure could not be assessed. However, 36 patients with a negative response to hyperventilation underwent coronary arteriography; 33 (92%) had normal arteriograms and a negative response to ergot derivatives. Hyperventilation appears to be a safe and specific diagnostic procedure in a subset of patients in whom the probability of coronary artery disease may not be judged sufficient to warrant coronary arteriography as a primary diagnostic approach.


Complete removal of AHPS synthetic dye from water using new electro-fenton oxidation catalyzed by natural pyrite as heterogeneous catalyst.
The mineralization of a new azo dye - the (4-amino-3-hydroxy-2-p-tolylazo-naphthalene-1-sulfonic acid) (AHPS) - has been studied by a novel electrochemical advanced oxidation process (EAOP), consisting in electro-Fenton (EF) oxidation, catalyzed by pyrite as the heterogeneous catalyst - the so-called 'pyrite-EF'. This solid pyrite used as heterogeneous catalyst instead of a soluble iron salt, is the catalyst the system needs for production of hydroxyl radicals. Experiments were performed in an undivided cell equipped with a BDD anode and a commercial carbon felt cathode to electrogenerate in situ H2O2 and regenerate ferrous ions as catalyst. The effects on operating parameters, such as applied current, pyrite concentration and initial dye content, were investigated. AHPS decay and mineralization efficiencies were monitored by HPLC analyses and TOC measurements, respectively. Experimental results showed that AHPS was quickly oxidized by hydroxyl radicals (OH) produced simultaneously both on BDD surface by water discharge and in solution bulk from electrochemically assisted Fenton's reaction with a pseudo-first-order reaction. AHPS solutions with 175 mg L(-1) (100 mg L(-1) initial TOC) content were then almost completely mineralized in 8h. Moreover, the results demonstrated that, under the same conditions, AHPS degradation by pyrite electro-Fenton process was more powerful than the conventional electro-Fenton process.


Health-Related Quality of Life: The Impact on Morbidity and Mortality.
In the age of ever-expanding treatments and precision medicine, the hope for cure remains the ultimate goal for patients and providers. Equally important to many patients is the quality of life achieved during and after treatment. Evidence suggests that overall quality of life is important to patients and plays a role in determining outcomes in patients with cancer. This article examines components of health-related quality of life and cancer treatment, including physical, psychosocial, and financial burden, as well as how these components affect patients' overall wellbeing and survival.


Phaeochromocytoma in a footballer.
A young footballer with phaeochromocytoma showed classical exercise-induced symptoms. Noradrenergic clincial phenomena suggested an extra-adrenal site. The usefulness of urine metabolite estimation and of localizing procedures and the importance of preoperative alpha and beta blockade are stressed. Nitroprusside was used successfully to control hypertension during surgery. Unexplained fever after operation is reported.


In vivo differentiation of adipose-derived stem cells in an injectable poloxamer-octapeptide hybrid hydrogel.
A hybrid hydrogel (PP) composed of Polomaxer-407 (PO) and octapeptide with amino acid sequence of KFEFKFEF (PE) was prepared to make a scaffold material incorporating PO's high and tunable mechanical strength and integrity with PE's superior bioactivity. Human adipose-derived mesenchymal stem cells (hASCs) were encapsulated into PE, PO and PP hydrogels respectively and injected subcutaneously at the dorsal neck area of nude mice. Adipose-like tissue regeneration was only observed in the mice injected with cell-encapsulated PP hydrogel. No adipose regeneration was found in the mice injected with PO or PE. Immunohistochemistry analysis with mouse anti-human nuclei monoclonal antibody demonstrated that the cells in the regenerated adipose-like tissue was originated from the injected hASCs. The growth of blood capillaries indicated that the regenerated adipose-like tissue was living tissue. In addition, human-originated cells were also found in nude mice skin. These cells were positive with mouse anti-human cells keratin antibody, suggesting that the injected hASCs migrated to the skin and differentiated into epithelial cells in vivo.


Overrepresentation of 17q22-qter and 22q13 in dermatofibrosarcoma protuberans but not in dermatofibroma: a comparative genomic hybridization study.
Histopathological differentiation between dermatofibrosarcoma protuberans (DFSP) and dermatofibroma (DF) is often difficult, because both neoplasms share some clinical features and the presence of a storiform pattern. In the present study, we investigated the usefulness of comparative genomic hybridization (CGH) in the diagnosis of these entities by examining 12 DFSP and 12 DF cases. The most frequent DNA sequence copy number changes detected in 10 (83%) of 12 DFSP cases (mean, 1.9 aberrations/tumor; range, 0-3) consisted of gains of 17q22-qter (10 tumors), 22q13 (nine tumors), and 8q24.1-qter (three tumors). High-level amplification, which was detected in three tumors, was seen only in chromosome 17, with 17q23-q25 as the minimal common region. Loss of DNA sequences was not found in DFSP cases. In contrast, two (17%) of the 12 DF cases (mean, 0.5 aberrations/tumor; range, 0-4) showed DNA sequence copy number changes, although recurrent gains and losses and high-level amplifications were not observed. Gains were more common than losses in DF. Overrepresentation of 17q and 22q sequences was a common finding in DFSP but not in DF. Thus, CGH seems to be useful for distinguishing DFSP from DF in most cases.


Primary care-psychiatry interaction: a British perspective.
Three models of interaction between primary care and psychiatry in the British National Health Service are presented. Although the first two are traditional and well recognized, the third, the liaison-attachment model, is an innovation of the last decade. Two studies are described that outline the extent and nature of this form of working collaboration between specialists and generalists. Clinical, service, and educational implications are discussed in the context of the British primary care structure.


Magnetic resonance imaging appearance of oxidized regenerated cellulose in breast cancer surgery.
To describe magnetic resonance imaging (MRI) findings in patients who underwent breast-conserving surgery followed by oxidized regenerated cellulose (ORC) implantation in surgical cavity. We retrospectively reviewed 51 MRI examinations performed between January 2009 and January 2014 in 51 patients who underwent BCS with ORC implantation. In 29/51 (57 %) cases, MRIs showed abnormal findings with three main MRI patterns: (1) complex masses: hyperintense collections on T2-weighted (w) images with internal round hypointense nodules without contrast enhancement (55 %); (2) completely hyperintense collections (17 %); and (3) completely hypointense lesions (28 %). All lesions showed rim enhancement on T1w images obtained in the late phase of the dynamic study with a type 1 curve. Diffusion-weighted imaging was negative in all MRIs and, in particular, 22/29 (76 %) lesions were hyperintense but showing ADC values >1.4 × 10(-3) mm(2)/s, while the remaining 7/29 (24 %) lesions were hypointense. In four cases, linear non-mass-like enhancement was detected at the periphery of surgical cavity; these patients were addressed to a short-term follow-up, and the subsequent examinations showed the resolution of these findings. When applied to surgical residual cavity, ORC can lead alterations in surgical scar. This could induce radiologists to misinterpret ultrasonographic and mammographic findings, addressing patients to MRI or biopsy; so knowledge of MRI specific features of ORC, it is essential to avoid misdiagnosis of recurrence.


A paradigm for oncogene complementation in human breast cancer.
Multiple cellular oncogenes are amplified in malignant tumours, and it is possible to invoke gene dosage as a possible base for product activity. In vitro data have shown that two different oncogenes can cooperate in converting a normal cell into one that is tumorigenic. This suggested that multiple cooperative alterations might be involved in cancer progression. Breast cancers have a broad spectrum of clinical behaviours ranging from highly aggressive neoplasms to almost chronic diseases. Fifty months of clinical follow-up were studied in 143 patients with primary breast cancers. Uni- and multivariate analyses were performed in order to determine any synergistic effect of amplified c-myc, erbB-2 and int-2 genes on the disease-free state and overall survival. We showed that c-myc amplification was associated with early recurrence and shorter survival; in contrast, erbB-2 and int-2 extra copies resulted in later relapse events, especially in patients whose tumours showed a normal copy number of c-myc genes. This pointed out sequential activation of complex regulatory cascades within the cell. Such particular behaviour enabled us to categorize erbB-2 and int-2 oncogenes into a group showing delayed action, in contrast to c-myc involvement in rapid spread of the tumour. As expected, co-amplified c-myc and erbB-2 genes showed positive cooperation with respect to recurrence and shortening of overall survival. Finally, the harmful effects of amplified c-myc and erbB-2 oncogenes were dramatically increased in patient subgroups showing a normal copy number of the int-2 gene. Multivariate analysis was used to evaluate disease-free survival and to test for potential interactions of oncogene covariates. It pointed out multiple independent combinations which enabled us to define complementation groups with respect to clinical patient behaviour.


Construction of membrane-bound artificial cells using microfluidics: a new frontier in bottom-up synthetic biology.
The quest to construct artificial cells from the bottom-up using simple building blocks has received much attention over recent decades and is one of the grand challenges in synthetic biology. Cell mimics that are encapsulated by lipid membranes are a particularly powerful class of artificial cells due to their biocompatibility and the ability to reconstitute biological machinery within them. One of the key obstacles in the field centres on the following: how can membrane-based artificial cells be generated in a controlled way and in high-throughput? In particular, how can they be constructed to have precisely defined parameters including size, biomolecular composition and spatial organization? Microfluidic generation strategies have proved instrumental in addressing these questions. This article will outline some of the major principles underpinning membrane-based artificial cells and their construction using microfluidics, and will detail some recent landmarks that have been achieved.


An evaluation of ways of using equilibrium dialysis to quantify the binding of ligand to macromolecule.
1. The effect of systematic error (loss of ligand, complex or macromolecule) on three of the experimental designs by which equilibrium dialysis may be used to quantify the interaction of ligand and macromolecule is examined theoretically, and the design that is least sensitive to systematic error is identified. 2. Thirteen methods for fitting the binding isotherm to experimental data are compared by using them to analyse simulated data containing random error, and the most reliable method is identified.


Resection of a recurrent solid pseudopapillary neoplasm of the pancreas after duodenal sparing pancreaticoduodenectomy: A case report.
Solid Pseudopapillary Neoplasm (SPN) is a rare pancreatic neoplasm with low malignant potential and a relative indolent course. Complete resection of the SPN is curative for most cases and has a high survival rate. Recurrences, though rare, can still occur despite adequate resection. Pancreaticoduodenectomy is commonly performed to treat pancreatic head SPNs. In recent years, duodenum-preserving pancreatic head resection (DPPHR) has been reported as a less radical and acceptable alternative. We are reporting a case of 26-year old female who presented with a 7 month history of epigastric pain and increasing abdominal girth. She was diagnosed by MRI to have a huge but resectable pancreatic head mass and subsequently underwent duodenum-preserving pancreatic head resection (DPPHR) with pancreaticojejunostomy. Histopathologic examination revealed a solid pseudopapillary tumor (SPN) with lymphovascular invasion and negative margins of resection. The patient underwent hepaticojejunostomy 5 months after resection for biliary stricture. Surveillance imaging revealed tumor recurrence warranting re-exploration for recurrence 3 years after the initial surgery. Intraoperative findings revealed the mass at the distal pancreatic remnant, requiring distal pancreatectomy and splenectomy. Solid pseudopapillary neoplasms are rare pancreatic neoplasms. Surgical resection of SPNs affords long term cure with good 5-year survival rates for localized tumors Despite the low malignant potential of SPNs, relapse after resection can still occur. Complete local resection of the tumor is the treatment of choice in SPNs. DPPHR should be considered as an alternative in young patients with a localized SPN in the pancreatic head.


A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).


Improved prognostication in soft tissue sarcoma: independent information from vascular invasion, necrosis, growth pattern, and immunostaining using whole-tumor sections and tissue microarrays.
In 140 mixed primary soft tissue sarcomas with a median follow-up of 6 years, the prognostic importance of tumor size, tumor depth, grade, necrosis, vascular invasion, and peripheral growth pattern (pushing versus infiltrating) was evaluated on whole-tumor sections. Immunohistochemical expression of Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and P-glycoprotein was determined using tissue microarray from the peripheral growth zone. Local recurrences developed in 17% of the patients and correlated with necrosis, vascular invasion, and cyclin A expression. No local recurrence developed in tumors with a pushing growth pattern, regardless of tumor grade and depth. Metastasis developed in 39% of the patients. Vascular invasion was identified in 36% of the tumors and was the strongest prognostic factor for metastasis with a hazard ratio of 3.5. Growth pattern and tumor necrosis were also strong prognostic factors for metastasis, whereas malignancy grade, tumor size, and tumor depth did not have any independent prognostic value. Immunostaining showed independent prognostic information for Ki-67, beta-catenin, CD44, and P-glycoprotein. The results indicate that whole-tumor sections could facilitate identification of vascular invasion, necrosis, and peripheral growth pattern and that immunohistochemical profiling from the growth zone also provides independent prognostic information for metastasis in soft tissue sarcoma.


Energy drink intake and metabolic syndrome: A prospective investigation in young adults.
There are concerns that energy drinks (EDs) are contributing to upward trends in overweight, obesity, and cardiometabolic conditions in young people. We investigated cross-sectional and prospective associations between frequency of ED-intake in young-adults and (i) body mass index (BMI) and (ii) Metabolic Syndrome (MetS) and its components. Participants from the Raine Study at 20-years (n = 1236) and 22 years (n = 1117) self-reported ED-intake, dietary intake, and physical activity, and had blood and anthropometric measures taken. Regression modelling examined associations between ED-intake and BMI, MetS and its components. There was a positive, but not significant, cross-sectional association with BMI and likelihood of MetS with frequent ED use at 20-years (BMI: β = 0.19; MetS: OR = 1.11) and 22-years (BMI: β = 0.51; MetS: OR = 1.28). There were no associations in the prospective analysis. After adjustment, significant associations existed between occasional ED-intake and lower HDL-cholesterol (β = -0.07) and higher fasting triglycerides (β = 0.16) at 20-years, and lower fasting triglycerides at 22-years (β = -0.10), but no significant associations in the prospective analyses. No significant associations existed between frequency of ED-intake, and BMI, MetS or its individual components over two years (ages 20-22 years). Future studies should include volume of EDs consumed and longer follow-up.


Combined Impact of Telomere Length and Mitochondrial DNA Copy Number on Cognitive Function in Community-Dwelling Very Old Adults.
This study was conducted to investigate the combined impact of telomere length and mitochondrial DNA (mtDNA) copy number on cognitive function in community-dwelling very old adults. In total, 186 subjects over 75 years participated in this study. Cognitive function was assessed using the Korean Mini-Mental State Examination, and leukocyte telomere length and mtDNA copy number were measured using real-time polymerase chain reaction methods. Both the fourth quartile of telomere length and mtDNA copy number were associated with cognitive dysfunction with an adjusted odds ratio of 0.23 (95% confidence interval (CI), 0.10-0.75) and 0.18 (95% CI, 0.03-0.54), respectively. Participants in the high telomere length/high mtDNA copy number group were more likely to have cognitive dysfunction than participants in the low telomere/low mtDNA copy number group with an adjusted odds ratio of 0.19 (95% CI, 0.07-0.58). Our results collectively suggest that the combination of telomere length and mtDNA copy number may be useful for monitoring cognitive decline in older adults.


Clinical tests for screening and diagnosis of cervical spine myelopathy: a systematic review.
The purpose of this review was to investigate the diagnostic accuracy for screening and confirmation of clinical tests for cervical spine myelopathy (CSM) and to investigate the quality of the studies that have investigated these values. This study was a systematic review that used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search terms for PubMed included myelopathy; diagnosis, differential; sensitivity and specificity; and physical examination. Search terms for Cumulative Index to Nursing and Allied Health Literature were limited to myelopathy and sensitivity and specificity. Qualitative assessment included report of diagnostic accuracy metrics (sensitivity, specificity, and positive and negative likelihood ratios) and quality scores using the Quality Assessment of Diagnostic Accuracy Studies tool. Scores were created for single tests and clustered test findings. After evaluation, 12 full-text articles were selected, scored, and tabulated. Nearly all of the 18 tests demonstrated high levels of specificity and low levels of sensitivity, suggesting that they are poor screening tools. Only one study was scored as high quality. One study involved clustering of test findings but was considered low quality. Nearly all of the clinical tests for CSM seem to be poor screening tools, which implies that manually oriented clinicians may perform treatment methods in a situation of doubt or uncertainly. More high-quality studies are needed, and manual therapists need to be cognizant that the current clinical tests for CSM lack strong diagnostic accuracy measures that are necessary for clinical decision making.


Maillard products as biomarkers in cancer.
Because tumors exert increased glycolysis rates, a high intracellular carbonyl stress with the formation of Maillard products may evolve. Therefore, we studied the presence of N epsilon-(carboxymethyl)lysine (CML) modification in breast cancer tissues from 20 patients and found significant cytoplasmatic staining in tumor cells that was independent of the tumor stage, tumor type, and microanatomic localization. Studying breast cancer cell lines, we also found strong cytoplasmatic CML staining that was again independent of their invasive or metastatic behavior. Our results reveal that tumor cells show a strong cytoplasmatic immunoreactivity to CML without evident association with breast carcinoma type, differentiation, tumor stage, or intratumoral localization. We conclude that CML formation is a general tumor cell-associated process.


A novel antirecombinase gains PARIty.
In this issue, Moldovan et al. (2012) report the identification of PARI, a putative human ortholog of the yeast Srs2 protein, which potentially regulates homologous recombination repair via its ability to disrupt the function of RAD51.


[Needs and technical prerequisites of an improved supply of donor material for penetrating keratoplasty].
The supply of donor material for keratoplasty is still considered a problem in many clinics. Preservation of donor tissue makes it possible to improve material selection. As far as the grafting of typed corneas is concerned, corneal organ culture offers a valuable time interval for planning the operation. In these preservation techniques the transplanted tissue is trephined from the endothelial side. With an optimal trephining technique the number of viable endothelial cells transplanted can be increased.


Micro-determination of tolmetin in plasma by electron-capture gas chromatography.
A highly sensitive, specific and precise gas chromatographic method for the determination of the anti-inflammatory agent tolmetin in micro-samples of blood plasma is described. The pentafluorobenzyl ester derivative of tolmetin, which can be detected down to picogram levels using electron-capture detection, has been prepared. The lowest concentration of tolmetin which can be measured accurately and precisely (coefficient of variation less than 15%) in a 25-microliter plasma sample is 0.1 microgram/ml. Previously reported assays require a sample size 20--80 times larger and have a detection limit of 0.5 microgram/ml. The pentafluorobenzyl ester derivatives of both tolmetin and the internal standard have been identified from their chemical ionization mass spectra. The present method was found to be in good agreement with another published gas chromatographic assay when both methods were employed to analyze the same set of plasma samples from four juvenile reheumatoid arthritic patients.


Visualization and quantification of disease progression in multiple system atrophy.
To visualize and quantify disease progression in multiple system atrophy (MSA) from cerebellar type (MSA-C), we combined two magnetic resonance imaging (MRI) techniques, voxel-based morphometry (VBM) and 3D-based volumetry. Patients suffering from MSA-C (n = 14) were imaged twice with an interval of 2.0 +/- 0.2 years. We first applied VBM to map brain morphology changes between MSA patients and controls and to identify brain areas that showed a significant amount of atrophy. Using 3D-based volumetry, we confirmed that in MSA-C patients, the brainstem including medulla and pons, vermis and cerebellar hemispheres, caudate nucleus and putamen showed significant atrophy compared with controls. Next, we used 3D-based volumetry to analyze the atrophy rates. Atrophy rates in patients with MSA were significantly different from controls for putamen (-11.4% +/- 2.6%/year), vermis (-12.3% +/- 2.9%/year), and cerebellar hemispheres (-6.6% +/- 1.1%/year). The results show that 3D-based MRI volumetry is a tool that allows the disease progression of MSA to be followed over a time period of 2 years and suggest that it may serve as a surrogate marker in clinical trials to measure disease progression.


Changes in Secretion of the Thyroid and Pituitary Glands with a Gradual Decrease in Deuterium Body Content.
We studied changes in the secretion of thyroid hormones and pituitary thyroid-stimulating hormone (TSH) in young mature male Wistar rats during gradual decrease in deuterium body content. The rats received deuterium-depleted water ([D]=10 ppm) instead of tap water for 21 days. As soon as after 1 day, an increase in the secretion of thyroid hormones was recorded. On day 14, secondary hypothyroidism due to a sharp decrease in TSH secretion by the pituitary gland was found. By day 21, secretion of the thyroid hormones increased, and the reciprocal dependence between the concentrations of thyroid hormones and TSH was restored. Thus, the thyroid gland showed a higher sensitivity to a decrease in the deuterium content in the body than the hypothalamic-pituitary complex. The second difference was in type of response: activation of the secretory processes in the thyroid gland and a transient decrease in the secretory activity of pituitary gland thyrotropes to a decrease in deuterium content.


Proteomics in the COVID-19 Battlefield: First Semester Check-Up.
Proteomics offers a wide collection of methodologies to study biological systems at the finest granularity. Faced with COVID-19, the most worrying pandemic in a century, proteomics researchers have made significant progress in understanding how the causative virus hijacks the host's cellular machinery and multiplies exponentially, how the disease can be diagnosed, and how it develops, as well as its severity predicted. Numerous cellular targets of potential interest for the development of new antiviral drugs have been documented. Here, the most striking results obtained in the proteomics field over this first semester of the pandemic are presented. The molecular machinery of SARS-CoV-2 is much more complex than initially believed, as many post-translational modifications can occur, leading to a myriad of proteoforms and a broad heterogeneity of viral particles. The interplay of protein-protein interactions, protein abundances, and post-translational modifications has yet to be fully documented to provide a full picture of this intriguing but lethal biological threat. Proteomics has the potential to provide rapid detection of the SARS-CoV-2 virus by mass spectrometry proteotyping, and to further increase the knowledge of severe respiratory syndrome COVID-19 and its long-term health consequences.


Recombinant ferritin nanoparticles can induce dendritic cell maturation through TLR4/NF-κB pathway.
Immune response initiation and regulation require activation of dendritic cells (DCs). However, the mechanism by which ferritin, a carrier for immunogen, induces DCs maturation remains unclear. Recombinant ferritin nanoparticle (RFNp), were prepared through the baculovirus expression vector system, formed spherical and hollow cage-liked proteins with a diameter of approximately 12.17 ± 0.87 nm. They induced bone marrow-derived DC (BMDC) maturation via surface molecules up-regulation of (MHC II, CD80, CD86 and CD40), increased pro-inflammatory cytokines production (IL-6, IL-12, TNF-α, and IFN-γ), and decreased antigen capturing capacity. They positively regulated IκBα and NF-κB (p65) phosphorylation, and facilitate NF-κB (p65) translocation into mature BMDCs nuclei. Following pre-treatment of RFNp-treated BMDCs with TLR4 and NF-κB (p65) inhibitors, respectively, surface molecule expression, pro-inflammatory cytokines production, and IκBα and NF-κB (p65) activities were suppressed. RFNp-treated BMDCs can also facilitate T-cell proliferation and differentiation into Th1 and Th2. RFNps induced DCs maturation lends the potential application of RFNps as carrier platforms in DC-based vaccine.


Studies on the terminal stages of immune hemolysis. III. Distinction between the insertion of C9 and the formation of a transmembrane channel.
The intermediate product EAC1-8 released cytoplasmic components as a result of at least two sequential reactions after its interaction with C9. Binding of C9 to EAC1-8 occurred in a few minutes even at 0 degrees C. Trypsinization of EAC1-9 prepared and held at low temperature resulted in nullification of the potential hemolysis of these cells. A brief incubation at 30 or 37 degrees resulted in the formation of an intermediate whose hemolytic potential could not be nullified by trypsin. The failure of trypsin to nullify hemolysis was attributed to the insertion of C9 into the cell membrane. Studies on the effec of EDTA or low temperature suggested that the reported temperature-dependent step in E* formation described by Frank et al. was the insertion of C9. The results of the studies with 86Rb-labeled EAC1-8 indicated that a transmembrane channel was not formed until after the C9 had been inserted and a further reaction or reactions had occurred.


Getting it right when budgets are tight: Using optimal expansion pathways to prioritize responses to concentrated and mixed HIV epidemics.
Prioritizing investments across health interventions is complicated by the nonlinear relationship between intervention coverage and epidemiological outcomes. It can be difficult for countries to know which interventions to prioritize for greatest epidemiological impact, particularly when budgets are uncertain. We examined four case studies of HIV epidemics in diverse settings, each with different characteristics. These case studies were based on public data available for Belarus, Peru, Togo, and Myanmar. The Optima HIV model and software package was used to estimate the optimal distribution of resources across interventions associated with a range of budget envelopes. We constructed "investment staircases", a useful tool for understanding investment priorities. These were used to estimate the best attainable cost-effectiveness of the response at each investment level. We find that when budgets are very limited, the optimal HIV response consists of a smaller number of 'core' interventions. As budgets increase, those core interventions should first be scaled up, and then new interventions introduced. We estimate that the cost-effectiveness of HIV programming decreases as investment levels increase, but that the overall cost-effectiveness remains below GDP per capita. It is important for HIV programming to respond effectively to the overall level of funding availability. The analytic tools presented here can help to guide program planners understand the most cost-effective HIV responses and plan for an uncertain future.


Polyacrylamide gel electrophoresis: recovery of non-stained and stained proteins from gel slices.
Following electrophoresis or isoelectric focusing in gels of polyacrylamide the protein band of interest is cut out and placed above a sucrose gradient column, containing carrier ampholytes (Pharmalyte). By electrophoresis, isoelectric focusing or displacement electrophoresis the proteins migrate out of the gel slice and into the isoelectric focusing column for concentration and further purification. From this column, the proteins can be withdrawn and their isoelectric points determined. Even after staining with Coomassie Brilliant Blue at least some proteins can be recovered by this technique and used for further analyses, for instance amino acid determinations. The focusing in a pH gradient by carrier ampholytes can be replaced by an electrophoresis in a conductivity gradient column. However, in comparison with isoelectric focusing, this concentration technique has the drawback of not permitting further purification of the eluted protein.


Evaluation and Control of Thiol-ene/Thiol-epoxy Hybrid Networks.
The development of thiol-ene/thiol-epoxy hybrid networks offers the advantage of tailorable polymerization kinetics while producing a highly crosslinked, high T(g) polymer that has significantly reduced shrinkage stress. Stoichiometric mixtures of pentaerythritol tetra(3-mercaptopropionate) (PETMP)/triallyl-1,3,5-triazine-2,4,6-trione (TATATO) (thiol-ene, mixture 1) and PETMP/bisphenol a diglycidyl ether (BADGE) (thiol-epoxy, mixture 2) were prepared and hybrid mixtures of 75/25, 50/50, 25/75, and 10/90 w/w of mixtures 1 and 2 were polymerized using a combination of both radical and anionic initiation. The light exposure timing and the relative initiation conditions of the two types were used to control the order and relative rates of the radical and anionic polymerizations. The 50/50 w/w thiol-ene/thiol-epoxy hybrid material exhibited a final stress of only 0.2 MPa, which is 90 % lower than the stress developed in a control dimethacrylate resin. Kinetic analysis indicates composition affects network development in thiol-ene/thiol-epoxy hybrid networks and produces materials with robust mechanical properties.


A potential role for 5-androstene-3β,7β,17β-triol in obesity and metabolic syndrome.
Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients. Androstene-3β,7β,17β-triol (β-AET) an anti-inflammatory metabolite of DHEA, also exhibits GC-opposing and immune-modulating activity when administered to rodents. We hypothesized a role for β-AET in obesity. We now report that plasma levels of β-AET positively correlate with BMI in healthy men and women. Together with previous studies, the observations reported here may suggest a compensatory role for β-AET in preventing the development of metabolic syndrome. The β-AET structural core may provide the basis for novel pharmaceuticals to treat this disease.


AgingDB: A database for oxidative stress and calorie restriction in the study of aging.
Aging can be characterized in all living organisms as the inevitable biological changes that occur with advancing age. The aging process is time-dependent and leads to functional declines and increased incidences of disease. The underlying pathphysiologic processes of aging may best be explained using several interacting biological processes: genomic activity, oxidative stress, and age-related disease processes, all of which modify the rate and progression of aging. In this report, we describe a database, termed AgingDB, used to retrieve information on the biomolecules known to be modulated during the aging process and by the life-prolonging action of caloric restriction (CR). To enhance the usefulness of AgingDB, we include data collected from studies of CR's anti-oxidative action on gene expression, oxidative stress, and many chronic age-related diseases. We organized AgingDB into two sections A) apoptosis and the various mitochondrial biomolecules that play a role in aging; B) nuclear transcription factors known to be_sensitive to oxidative environment. AgingDB features an imagemap of biomolecular signal pathways and visualized information that includes protein-protein interactions of biomolecules. Authorized users can submit a new biomolecule or edit an existing biomolecule to reflect latest developments. By making available the most update information through AgingDB, we expect to assist researchers who are exploring the molecular basis of age-related changes modified by the life-prolonging action of CR. For the reader's convenience and accessibility, AgingDB is freely available at http://agingdb.bio.pusan.ac.kr/.


Analysis, design and development of a carbon fibre reinforced plastic knee-ankle-foot orthosis prototype for myopathic patients.
A traditional knee-ankle-foot orthosis (KAFO) for myopathic patients has been studied for the assessment of loads and fatigue resistance. Starting from this basis a thermoplastic matrix carbon fibre reinforced plastic composite (CFRP) KAFO has been developed in order to reduce the weight. A finite-element simulation programme for deformation analysis was used to compare the behaviour of conventional and CFRP orthosis. There were no breakages either of the prototype or of its parts. The CFRP orthosis allows a weight reduction of more than 40 per cent.


Clinical outcomes of immune checkpoint inhibitors to treat non-small cell lung cancer patients harboring epidermal growth factor receptor mutations.
We aimed to determine the clinical. outcomes of various immune checkpoint inhibitor (ICI) combinations for the treatment of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. The results predicted the treatment efficacy of these combinations. From July 15, 2016 to March 22, 2022, 85 NSCLC patients with EGFR mutations, enrolled at the Zhejiang Cancer Hospital, received ICI combinations after resistance to prior EGFR-tyrosine kinase inhibitors (EGFR-TKIs). These patients were diagnosed with EGFR mutations using an amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS). Survival times were analyzed using the Kaplan-Meier method and log-rank test. Patients who received ICIs combined with anti-angiogenic therapy had longer progression-free survival (PFS) and overall survival (OS) than patients who received ICIs combined with chemotherapy. There was no significant difference in survival time between patients who received ICIs combined with chemotherapy and anti-angiogenic therapy and patients who received ICIs combined with anti-angiogenic therapy or ICIs combined with chemotherapy, which was due to the limitation sample size of patients who received ICIs combined with chemotherapy and anti-angiogenic therapy. Patients with L858R mutations had a longer PFS and OS than patients with exon 19 deletions. T790M negative patients benefited more from ICI combinations, compared with T790M positive patients. In addition, there was no significant difference in PFS and OS between patients with TP53 co-mutations and patients without a TP53 co-mutation. We also found that patients with prior first-generation EGFR-TKI resistance had longer PFS and OS than prior third-generation EGFR-TKI resistance patients. There was no new adverse event in this study. EGFR-mutated patients who received ICIs combined with anti-angiogenic therapy had longer PFS and OS than patients with ICIs combined with chemotherapy. Patients with L858R or without T790M mutation benefited more from ICI combinations. Besides, patients with prior first-generation EGFR-TKI resistance could benefit more from ICIs combinations than prior third-generation EGFR-TKI resistance patients.


Inpatient prescribing errors and pharmacist intervention at a teaching hospital in Saudi Arabia.
Prescribing errors phenomena are very common within health care practice. These errors could result in adverse events and harm to patients. Pharmacist has an identified role in minimizing and preventing such errors. To detect the incidence of prescribing errors for hospitalized patient, to evaluate the clinical impact of pharmacist intervention on the detection of these errors, and to propose a program to overcome this problem in a teaching hospital. For one month period starting November until December 2009, the inpatient medication charts and orders were identified and rectified by ward and practicing pharmacists within inpatient pharmacy services in a teaching hospital at King Khalid University Hospital (KKUH) at King Saud University, Riyadh, Kingdom of Saudi Arabia on routine daily activities. Data were collected and evaluated. The causes of this problem were identified. Approximately 113 (7.1%) prescribing errors were detected during the study period out of 1580 medication orders. Wrong strength and wrong administration frequency of the prescribed drug were the most errors encountered in the study, which were 35%, and 23%, respectively. Other errors such as wrong patient, wrong drug, and wrong dose were also encountered. Lack of knowledge of prescribing skill was the main cause of such errors. Prescribing errors in teaching hospital within inpatient pharmacy services were noticed. The applied method in this project might be implemented as part of pharmacy quality assurance program for ongoing detection and monitoring of such errors. Technology in prescribing process will support the practitioner to reduce the incidence of these errors. Forcing ongoing professional communication and education within the medical team about prescribing errors now appear warranted.


Discrimination by young infants of stimuli presented discontinuously.
Four experiments are reported showing that young infants can pick up visual information from very brief displays. Pattern, edge orientation, and form can be discriminated when stimuli are presented for repeated exposures of only 300 ms.


PLIN2-induced ectopic lipid accumulation promotes muscle ageing in gregarious locusts.
Ageing plasticity represents the flexibility of the ageing process in response to non-genetic factors, occurring commonly in animals. However, the regulatory mechanisms underlying ageing plasticity are largely unclear. The density-dependent polyphenism of locusts, Locusta migratoria, displays dramatic lifespan divergence between solitary and gregarious phases, providing a useful system for studying ageing plasticity. Here, we found that gregarious locusts displayed faster locomotor deficits and increased muscle degeneration on ageing than solitary locusts. Comparative transcriptome analysis in flight muscles revealed significant differences in transcriptional patterns on ageing between two phases. RNA interference screening showed that the knockdown of the upregulated PLIN2 gene significantly relieved the ageing-related flight impairments in gregarious locusts. Mechanistically, the gradual upregulation of PLIN2 could induce the accumulation of ectopic lipid droplets and triacylglycerols in flight muscles during the ageing process. Further experiments suggested that ectopic lipid accumulation led to an ageing-related β-oxidation decline through limiting fatty acid transport and content. These findings reveal the key roles of lipid metabolism in the differences of muscle ageing between solitary and gregarious locusts and provide a potential mechanism underlying environment-induced muscle ageing plasticity.


[A case report of incomplete endocardial cushion defect with mitral stenosis in an elderly patient].
The following paper describes a mitral valve replacement (SJM 27 mm), the patch closure (EPTFE) of an ostium primum atrial septal defect and tricuspid annuloplasty (De Vega's method) in a 64-year-old female patient with an incomplete endocardial cushion defect and mitral stenosis. Surgery revealed thickened, mitral valve leaflets and the presence of a cleft, findings similar to those observed in case of rheumatic degeneration. Investigation of patient hemodynamics confirmed a diagnosis of Lutembacher syndrome and a lower with left ventricle volume. After surgery, the volume of left ventricle increased and the patients clinical course was uneventful.


Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons.
In the dorsal raphe nucleus, it is known that serotonin release activates metabotropic 5-HT1A autoreceptors located on serotonin neurons that leads to an inhibition of firing through the activation of G-protein-coupled inwardly rectifying potassium channels. We found that in mouse brain slices evoked serotonin release produced a 5-HT1A receptor-mediated inhibitory postsynaptic current (IPSC) that resulted in only a transient pause in firing. While spillover activation of receptors contributed to evoked IPSCs, serotonin reuptake transporters prevented pooling of serotonin in the extrasynaptic space from activating 5-HT1A -IPSCs. As a result, the decay of 5-HT1A -IPSCs was independent of the intensity of stimulation or the probability of transmitter release. These results indicate that evoked serotonin transmission in the dorsal raphe nucleus mediated by metabotropic 5-HT1A autoreceptors may occur via point-to-point synapses rather than by paracrine mechanisms. In the dorsal raphe nucleus (DRN), feedback activation by Gαi/o -coupled 5-HT1A autoreceptors reduces the excitability of serotoninergic neurons, which decreases serotonin release both locally within the DRN and in projection regions. Serotonin transmission within the DRN is thought to occur via transmitter spillover and paracrine activation of extrasynaptic receptors. Here, we tested the volume transmission hypothesis in mouse DRN brain slices by recording 5-HT1A receptor-mediated inhibitory postsynaptic currents (5-HT1A -IPSCs) generated by the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs). We found that in the DRN of ePET1-EYFP mice, which selectively express enhanced yellow fluorescent protein in serontonergic neurons, the local release of serotonin generated 5-HT1A -IPSCs in serotonin neurons that rose and fell within a second. The transient activation of 5-HT1A autoreceptors resulted in brief pauses in neuron firing that did not alter the overall firing rate. The duration of 5-HT1A -IPSCs was primarily shaped by receptor deactivation due to clearance via serotonin reuptake transporters. Slowing diffusion with dextran prolonged the rise and reduced the amplitude the IPSCs and the effects were potentiated when uptake was inhibited. By examining the decay kinetics of IPSCs, we found that while spillover may allow for the activation of extrasynaptic receptors, efficient uptake by serotonin reuptake transporters (SERTs) prevented the pooling of serotonin from prolonging the duration of transmission when multiple inputs were active. Together the results suggest that the activation of 5-HT1A receptors in the DRN results from the local release of serotonin rather than the extended diffusion throughout the extracellular space.


Determination of apoptosis through bax expression in cryptorchid testis: an experimental study.
The aim was to determine the expression of Bax in germ cells of rats with unilateral experimental cryptorchidism, and to evaluate the role of apoptosis in germ cell loss. Twenty-one prepubertal rats were randomly subdivided into three groups after the execution of the left cryptorchidism model. Group 1 (n=8), group 2 (n=6) and group 3 (n=7) rats were killed at the end of the first, second and third month, respectively. Bax expression was assessed in Sertoli cells, spermatogonia and spermatocytes by immunohistochemistry. Percentages of Bax expression in spermatocytes and spermatogonia were decreased in the left testicles in the 2nd and 3rd months compared to results obtained in the 1st month (p<0.05). Percentage of Bax expression in the left testicles of group 1, at the level of both spermatogonia and spermatocytes was higher than that in the right one (p<0.05). However, in groups 2 and 3, the higher Bax expression on the left side was only seen in the spermatocytes (p<0.05). In all groups, the mean weight of the left testicle was lower than that of the scrotal counterpart where the difference was significant only in groups 1 and 3 (p<0.05). The weight of the left and right testicles was increasing with time. In this model of cryptorchidism, the affected testis had a decreased weight compared to the normal one. Based on the increased Bax expression, we think that apoptosis may play a role in the germ cell loss.


Direct characterization of bulk samples by internal extractive electrospray ionization mass spectrometry.
A straight-forward analytical strategy called internal extractive electrospray ionization mass spectrometry (iEESI-MS), which combines solvent extraction of chemicals inside a bulk sample with in situ electrospray ionization mass spectrometry, has been established to directly characterize the interior of a bulk sample with molecular specificity. The method allows both qualitative and quantitative analysis of analytes distributed in a 3-dimensional volume (e.g., 1 ~ 100 mm(3)) of various synthetic and biological matrices (e.g., chewing gum, leaves, fruits, roots, pork, lung tissues) without either mashing the sample or matrix separation. Using different extraction solvents, online chromatographic separation of chemicals inside the sample volume was observed during iEESI-MS analysis. The presented method is featured by the high speed of analysis, high sensitivity, low sample consumption and minimal sample preparation and/or degradation, offering unique possibilities for advanced applications in plant science, clinical diagnosis, catalyst studies, and materials science.


Sulfated neo-clerodane diterpenoids and triterpenoid saponins from Sheareria nana S. Moore.
Three novel neo-clerodane diterpenoids Sheareria A-C (1-3) together with three known triterpenoid saponins were isolated from the whole herb of Sheareria nana S. Moore. Their structures were established by spectroscopic and chemical method. This is the first natural sulfated neo-clerodane diterpenoids. This is the first report of all these compounds from this plant. These neo-clerodane diterpenoids and triterpenoid saponins from S. nana S. Moore may be considered as chemotaxonomic markers for the genus. The compounds isolated were evaluated for their cytotoxic effects against three cancer cell lines, the test substances demonstrated selectivity toward the cancer cells. To date, this is the first report on the phytochemical and biological activity of secondary metabolites from S. nana S. Moore.


Large-scale degumming of ramie fibre using a newly isolated Bacillus pumilus DKS1 with high pectate lyase activity.
A combined (enzymatic and chemical) process using a Bacillus pumilus strain (DKS1), isolated from the soil, was used to degum ramie bast fibres. After 24 h of incubation with the isolated pectinolytic strain using a low-cost medium, the weight loss of the ramie fibre was found to be 25% under small scale. High activity of pectate lyase was detected in the culture supernatants; 400 kg of ramie fibres was degummed with 24% weight loss in large-scale degumming under field conditions. No cellulase activity was found. Microbial intervention followed by mild (0.1%) alkali treatment showed high percentage of weight loss from the ramie fibre. Bacterial degumming followed by chemical treatment resulted in an increase of single fibre tenacity (cN/tex) by more than 20.81% as compared to non-degummed (decorticated) fibre samples. Scanning electron micrographs (SEM) and fluorescence microscope showed that after Bacillus pumilus DKS1 treatment the surface of the decorticated ramie fibre becomes very smooth. These results indicate the process provides an economical and eco-friendly method for the small scale as well as large-scale degumming of decorticated ramie fibre. This study has great relevance to the textile as well as paper industry.


Baropodometric studies in patients submitted to Grice-Green operation for primary valgus pronated flat foot.
This study reports the results of a computerized baropodometric analysis of the function of primary valgus pronated flat foot submitted to talocalcanear arthrodesis according to the Grice-Green method (Grice, 1952; 1955) as modified by Vigliani et al., (1978). Our purpose was to document any anomalies in the behaviour of such feet, which up until now have been based on conventional evaluation (plantar imprints, podoscopy, etc.), which are much less sensitive than those of modern electronic systems.


Clinical Considerations for Insulin Pharmacotherapy in Ambulatory Care, Part One: Introduction and Review of Current Products and Guidelines.
In Brief This article describes available insulin products and published guidelines to aid clinicians in making treatment decisions for insulin-dependent patients with type 2 diabetes. It establishes the need for a thorough evaluation of the literature regarding ambulatory insulin dosing to further inform providers who manage insulin therapy for patients with type 2 diabetes.


Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure.
Botulinum toxin type A (BoNT/A) proved very effective in therapy for hyperactive detrusor or sphincter dysfunction of neurogenic and non-neurogenic origin. However, therapy may fail. In a search for possible reasons, we investigated the presence of BoNT/A antibodies (BoNT/A-AB) in patients who were treated more than once and correlated the presence of antibodies with clinical findings. In 25 patients (aged 11-75 years; average, 48.3 years) who had experienced at least one previous BoNT/A detrusor and/or sphincter injection, BoNT/A-AB was detected with the mouse diaphragm assay before and within 3 months after the current injection. Clinically, subjective and objective outcomes of this injection session were determined on an efficacy scale. In eight patients, BoNT/A-AB was detected; titers were clearly positive in four patients and were borderline in four patients. The subjective and objective outcomes indicated complete therapy failure in three of four patients who were positive for BoNT/A-AB. In two patients, BoNT/A-AB developed after just one injection session. Botulinum toxin type A antibodies can develop after injection of BoNT/A for urologic disorders and the antibodies can lead to therapy failure. In patients with clinically complete therapy failure in whom no obvious other causes can be determined (such as a progressive disease in a patient with multiple sclerosis), screening for BoNT/A-AB should be carried out.


Characterization of a new unshielded diode for small field dosimetry under flattening filter free beams.
To characterize the performance of a new unshielded silicon diode (Razor-IBA) for dose measurements in small flattening filter free beams. The Razor has an active volume of 0.6 mm in diameter and 20 µm in length. The detector response stability in measured dose, dose rate, dose per pulse, and dark current were evaluated. The detector response in square fields (0.6-5.0 cm) was determined using PDD curves, axial beam profiles and output ratios. The performances were compared to that of the previously available SFD-IBA and PFD-IBA diodes. The Razor short term stability relative to the SFD was much improved (<±0.1% after 1.2 kGy). The linearity was <±1% (0.05-30 Gy range) and the dose rate dependence was <±0.5% (4-24 Gy/min range). The dose per pulse dependence was <±0.7% (0.08-0.21 cGy/pulse range). The PDDs measured with Razor and PFD differed <1%. A larger dark current was observed with increase in dose (0.0025 pA/Gy) compared to the SFD (0.0002 pA/Gy). This characteristic is attributed to an increased concentration of recombination centers. The beam profile showed good agreement with the SFD. Penumbra differences were <±0.3 mm relative to PFD, with a slight overestimation of the tails (<1%), due to the absence of diode shielding. Output ratios were in good agreement for fields up to 5 × 5 cm(2) (<1%). The Razor diode has the same spatial resolution and performance reliability as its predecessor (SFD), but exhibits the additional advantage of improved stability. These features make the Razor diode detector a good candidate for small field dosimetry.


Incidental finding of migrated pacing lead fragment into pulmonary artery detected with CT.
This case shows a rare complication of a migrated atrial lead into the pulmonary artery incidentally detected during a comprehensive evaluation of coronary CT angiography.


Surface markers of cytotoxic T lymphocyte clones.
Several class II major histocompatibility complex antigen-specific murine cytolytic T cell clones express Lyt-2 but not MT4 surface antigens.


Tactivin in the regulation of dexamethasone-induced apoptosis in thymocytes.
The level of natural apoptosis in rat thymus on day 18 of embryo development attained 25%, while at subsequent terms it was about 5%. In the spleen, this parameter gradually decreased from 15 to 37% starting from day 18 of embryo development to postnatal day 30. Tactivin prevented the development of dexamethasone-induced apoptosis in thymocytes of 30-day-old rats, but had no effect on spontaneous apoptosis. Tactivin can be used as a modulator of apoptotic processes.


Systematic review of clinical practice guidelines for acne vulgaris published between January 2017 and July 2021.
Acne is very common, can cause considerable negative impact on quality of life and there is increasing concern over the use of long courses of oral antibiotics for this condition. (1) To critically appraise reporting in acne guidelines and compare this with previous systematic review of acne guidelines. (2) Examine acne treatment guidance on pre-specified acne treatments of interest and compare between acne guidelines. Searches for new or updated guidelines were carried out in MEDLINE, Embase, Google Scholar, LILACS from 1 January 2017 to 31 July 2021, supplemented by searching a guideline-specific depository and checking for updates to guidelines included in previous review. We included guidelines, consensus statements or care protocols on the medical treatment of acne vulgaris in adults and/or children and excluded those that focused on a single intervention or subgroup of acne, regional adaptations of guidelines or guidelines included in previous review. AGREE II checklist was applied to critically appraise reporting of guidelines. Results were synthesised narratively. Of 807 abstracts identified nine guidelines were identified that were eligible for inclusion. All guidelines had AGREE II scores above average in at least one domain and reporting was substantially improved compared to the systematic review of acne carried out 5 years previously. There was consensus between guidelines on the key role of topical treatments as first-line acne treatment and most recommended continuing topical treatments as maintenance therapy. There was considerable variation between guidelines on classification of severity, indications for commencing oral antibiotics and on maximum duration of oral antibiotics. However, there was consensus on the need for co-prescription of a non-antibiotic topical treatment when using oral antibiotics. There were notable differences on recommendations regarding provision of information for patients on how to use topical treatments or how to mitigate against side effects. Substantial differences in classification of acne severity hampered comparisons between guidelines. Although development and reporting of guidelines has improved over the past 5 years, differences in key recommendations remain, possibly reflecting uncertainties in the underlying evidence base. Differences between guidelines could have substantial implications for prevalence of antibiotic prescribing for acne.


Biphasic dose-response effect of baclofen on haloperidol catalepsy in the rat.
Haloperidol-induced catalepsy in rats is reduced by low dose baclofen and is potentiated by high dose baclofen. This biphasic behavioral effect is consistent with reported differences between presynaptic and postsynaptic GABA receptors. Low dose baclofen could have an anti-cholinergic effect by activating presynaptic GABA receptors that inhibit the release of acetylcholine. High dose baclofen could have an anti-dopamine effect by activating postsynaptic GABA receptors that inhibit the firing of dopamine neurons.


Specific multisubstrate adduct inhibitors of aminopropyltransferases and their effect on polyamine biosynthesis in cultured cells.
We have designed and synthesized multisubstrate adduct inhibitors for each of the three enzymes in the polyamine biosynthetic pathway (equation 1). The specific aminopropyltransferase inhibitors AdoDATO (2b) and AdoDATAD (2d) have been used to study the effects of specific polyamine depletion on cell growth. As shown in Table 2, these compounds effectively modulate the biosynthesis of Spd and Spm in vitro. However, tight regulation of the biosynthetic and degradative pathways results in little or no change in total polyamine levels in the presence of a single inhibitor (Table 2). Further studies with these aminopropyltransferase inhibitors in combination with other specific inhibitors of polyamine biosynthesis or degradation (e.g. DFMO) should shed light on the mechanism(s) underlying this tight biological regulation.


MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial.
Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.