Cell reactions to dielectrophoretic manipulation.
The phenomenon of dielectrophoretic particle manipulation holds promise for many biotechnology applications, including cell sorting. In our system cell manipulation normally involves transient exposure (15 minutes) to radio-frequency AC electric fields generated using planar microelectrodes. The present study was designed to investigate the range of acute effects of dielectrophoretic manipulation on the normal physiology of isolated cells. Cells were suspended in isoosmotic Mannitol and exposed to a 5 MHz, 21 V (peak to peak) electric field with 100 micrometer gap electrodes. Cells were assigned to three experimental groups; non-exposed controls, exposed cells processed immediately after cessation of the field, and exposed cells processed after a time delay. SEM observations of spread cells cultured on the devices showed no apparent acute effects of field exposure on cell morphology. Cell-doubling rates in exposed cells subsequent to field-exposure or transient incubation in mannitol were no different from control cells. An MTT 'mitochondrial stress' assay indicated no alteration in the rate of oxidative respiration in exposed cells 0.5 hour after exposure to the field. Western blot analysis indicated upregulation of fos protein in cells 0.5 hour after field-exposure, which was confirmed using densitometry. Reverse transcription of cellular mRNA followed by PCR amplification, polyacrylamide gel electrophoresis and autoradiography of cDNA banding revealed differential gene expression between controls and exposed cells processed immediately after cessation of the field. Differential gene expression persisted in exposed cells at least 0.5 hours after removal from the field. Observations indicated that temperature fluctuation in the mannitol solution was minimal, suggesting that upregulated mRNA may not have been related to thermally-induced heat shock protein. The present study has indicated that exposure to AC fields during dielectrophoretic cell manipulation is associated with upregulation of the intermediate-early gene cfos and also transcription of other as yet unidentified genes. These transcriptional events were not manifest as gross changes in cell morphology or cell-cycle dynamics.


An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication.
Dengue virus (DENV) causes dengue fever, a major health concern worldwide. We identified an amphipathic helix (AH) in the N-terminal region of the viral nonstructural protein 4A (NS4A). Disruption of its amphipathic nature using mutagenesis reduced homo-oligomerization and abolished viral replication. These data emphasize the significance of NS4A in the life cycle of the dengue virus and demarcate it as a target for the design of novel antiviral therapy.


Women's needs and wants when seeing the GP in relation to menopausal issues.
To explore women's needs and wants when seeing the GP in relation to menopausal issues. A qualitative interview study. The study was part of a larger project, targeting menopause. It included in-depth interviews of 24 women aged 52-53 years who came from all over Denmark. The women showed a great variety of menopausal experience of symptoms and treatment. An acquaintance with the women's agendas when seeing the GP about menopausal issues. Women consulting their GPs either wanted to discuss treatment for menopausal symptoms, to have an examination for diseases or to get a risk assessment. Their needs for medication or examination were satisfied but several women wanted more information, especially about the pros and cons of hormone therapy (HT). Risk assessment, if not requested, indicated problems, with some women feeling uncomfortable if the GPs started a discussion about HT and osteoporosis, if they only wanted an examination to be reassured that everything was normal. The authors' findings indicate that GPs encounter a subtle balance in considering the question of risk information to menopausal women who do not request it.


[Correlation of serum uric acid levels with coronary flow in patients with ST-segment elevation myocardial infarction undergoing primary coronary intervention].
To explore the association of the uric acid levels and coronary blood flow in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). A total of 276 STEMI patients undergoing primary PCI were enrolled and divided into 2 groups based upon the Thrombolysis in Myocardial Infarction (TIMI) flow grade. No-reflow was defined as TIMI Grade 0, 1 and 2 flows. The association of uric acid levels on admission with TIMI flow grade after PCI was assessed by multivariate Logistic regression. Major adverse cardiac events (MACE) were defined as death, non-fatal myocardial infarction and need for repeat percutaneous revascularization or coronary artery bypass grafting. The uric acid level was significantly higher in the no-reflow group (n = 57) than that of the normal-flow group (n = 219, 372 ± 111 vs 303 ± 102, P < 0.01). In-hospital MACEs were significantly higher in the patients with no reflow (8.8% vs 1.8%, P = 0.016). A uric acid level ≥ 345 mmol/L measured on admission had a 61.2% sensitivity and 77.5% specificity in predicting no-reflow at ROC curve analysis. At multivariate analyses, high plasma uric acid (OR 1.01, 95%CI 1.01 - 1.01, P < 0.01), neutrophil count (OR 1.02, 95%CI 1.00 - 1.06, P < 0.01), admission plasma glucose (OR 1.14, 95%CI 1.08 - 1.21, P < 0.01), time from pain to PCI (OR 1.67, 95%CI 0.46 - 5.97, P = 0.012), pre PCI thrombus score ≥ 4 (OR 2.67, 95%CI 1.29 - 5.13, P = 0.008), collateral circulation grade ≤ 1 (OR 1.86, 95%CI 1.27 - 2.73, P = 0.008), and Killip classes (OR 2.01, 95%CI 1.01 - 3.94, P = 0.042) were independent predictors of no-reflow post primary PCI. The plasma level of uric acid on admission is a strong and independent predictor of poor coronary blood flow following at post-primary PCI among STEMI patients. Uric acid levels may be a useful biomarker of risk stratification.


[Sándor Ferenczi's theoretical achievement].
The Hungarian Sándor Ferenczi has not only been a very close friend of Sigmund Freud and an outstanding representative of the psychoanalytic movement, but also an excellent man of early "Tiefenpsychologie". In the most valuable part of his research - the investigation of the sense of reality - he made a step into future tendencies of psychoanalysis, the ego-psychoanalysis. He was able to modify the analytic technique, a fact which in those days caused quite a bit of criticism by the psychoanalytic movement and by Freud himself too.


The Need for Improved Detection of Urinary Tract Infections in Young Children.
An estimated 400,000 urinary tract infections (UTIs) are diagnosed annually in children aged <3 years in the United States; yet >50% of febrile UTIs may be missed in this population. Here, we explored possible barriers to diagnosing febrile UTIs in very young children through social research of community pediatricians. Following qualitative interviews, a quantitative survey was developed that included a high-risk case for febrile UTI, presented before prompting for the topic of the survey, to gauge practice of delayed testing. Factors associated with delay were explored using univariate logistic regression. The final survey link was sent to three populations via email, with the largest response from a survey sent to pediatricians in Pennsylvania, which formed the basis of our primary results. Of the 218 evaluable responses, 59.6% of physicians would initially test urine in the high-risk case patient, while 21.6% would choose to continue fever reducer and follow-up in 2 days. In the knowledge-based questions, 67.5, 34.0, and 35.6% of respondents identified the correct prevalences in total population, Caucasian girls, and uncircumcised boys, respectively. Many pediatricians (59.5%) believed that delays in detection are common in clinical practice. Physicians who chose to delay testing were more likely to be female, in practice for <25 years, to underestimate prevalence of febrile UTIs and have greater number of children seen per week (all P ≤ 0.02). Our findings support the need for improved communication and education about prevalence in higher risk populations, outcomes associated with delayed diagnosis, and optimal skills for collection of urine in young patients.


Periprosthetic hip and knee fractures: the scope of the problem.
This review covers the present incidence, site, and outcome of periprosthetic fractures of the hip and the knee. Fractures can occur intraoperatively or postoperatively as an early or a late complication. Late postoperative fractures are related to osteolysis secondary to wear debris. These late fractures will become more prevalent with time. Intraoperative fractures can be avoided by careful technique and improved instrument design. Fractures can affect the acetabulum, femur, and trochanter of hip replacements: and the femur, tibia, and patella of knee replacements. The femur is most commonly involved for both joints. Stress fractures have been described as a rare complication of both sites of arthroplasty. If the fracture is recognized and the bone stock is good, a good outcome can be achieved if rigid fixation is obtained Unfortunately poor bone stock is often present, leading to late periprosthetic fractures, which compromise the outcome.


P450s controlling metabolic bifurcations in plant terpene specialized metabolism.
Catalyzing stereo- and regio-specific oxidation of inert hydrocarbon backbones, and a range of more exotic reactions inherently difficult in formal chemical synthesis, cytochromes P450 (P450s) offer outstanding potential for biotechnological engineering. Plants and their dazzling diversity of specialized metabolites have emerged as rich repository for functional P450s with the advances of deep transcriptomics and genome wide discovery. P450s are of outstanding interest for understanding chemical diversification throughout evolution, for gaining mechanistic insights through the study of their structure-function relationship, and for exploitation in Synthetic Biology. In this review, we highlight recent developments and examples in the discovery of plant P450s involved in the biosynthesis of industrially relevant monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids, throughout 2016 and early 2017. Examples were selected to illustrate the spectrum of value from commodity chemicals, flavor and fragrance compounds to pharmacologically active terpenoids. We focus on a recently emerging theme, where P450s control metabolic bifurcations and chemical diversity of the final product profile, either within a pathway, or through neo-functionalization in related species. The implications may inform approaches for rational assembly of recombinant pathways, biotechnological production of high value terpenoids and generation of novel chemical entities.


Surgery for brain metastases from nonsmall cell lung carcinomas and tissue cultures from the resected specimens.
Between 1978 and 1989, 44 patients underwent 44 thoracotomies and 55 craniotomies for nonsmall cell lung carcinoma (NSCLC) and its brain metastases. Patients ages ranged from 20 to 75 years. There were no intraoperative mortalities. The 2-, 3-, and 5-year survival rates following the initial craniotomy were 23%, 10%, and 10%, respectively. Patient survival did not differ with respect to solitary or multiple metastases or the sequence of surgery for primary lesion and brain metastases. Moreover, there was no significant difference in survival between patients treated by surgery alone and those receiving surgery followed by whole brain radiotherapy. After 1985, in vitro tissue culture was attempted using freshly resected specimens of brain metastases obtained from 30 consecutive cases. Of those specimens, nine (30%) were successfully established as permanent cell lines. Eight of those cell lines revealed DNA-aneuploid pattern on flow cytometric analysis. The remaining cell line was not analyzed. Karyotype analysis was also performed in eight of nine established cell lines. Two adenocarcinoma cell lines showed the presence of +3p- chromosome, and three showed +7q- chromosome as recurrent chromosomal abnormalities. These findings provide new evidence concerning the presence of 3p- and/or 7q- marker chromosomes in certain adenocarcinoma cell lines established from brain metastases. The prognosis was poorer in the group with in vitro tumor growth than that in the group showing no in vitro tumor growth. These cell lines established from brain metastases may be useful materials not only for studying the biological characteristics and chemo-sensitivity testing, but also for estimating prognoses after resection of brain metastases.


Short-term vitamin A supplementation does not affect bone turnover in men.
Limited data in humans and animals indicate that excess vitamin A stimulates bone resorption and inhibits bone formation, effects that over time might lead to bone loss and fracture. Thus, it is possible that vitamin A supplementation is a currently unrecognized risk factor for the development of osteoporosis. To further evaluate this possibility, a prospective, randomized, single-blind study of vitamin A supplementation was conducted in 80 healthy men age 18-58 y. One half received 7576 microg (25,000 IU) of retinol palmitate daily with their evening meal; the others took a placebo. Blood was collected from fasting subjects and serum prepared at baseline and after 2, 4 and 6 wk of supplementation. Serum bone specific alkaline phosphatase (BSAP) and N-Telopeptide of type 1 collagen (NTx) were measured at all time points. Serum osteocalcin (Oc) was measured at baseline and after 6 wk of supplementation. BSAP, NTx and Oc did not differ between the supplemented and placebo-treated groups over the course of the study. In conclusion, short-term vitamin A supplementation at this dosage in healthy men does not alter serum markers of skeletal turnover. Thus, it is unlikely that short-term administration of vitamin A would contribute to the development of osteoporosis. Whether long-term vitamin A supplementation might have adverse skeletal effects remains to be determined.


Enhanced disruption of the blood brain barrier by intracarotid mannitol injection during transient cerebral hypoperfusion in rabbits.
Fairly large volumes of intracarotid mannitol (20% to 25%) are required to disrupt the blood brain barrier (BBB), that is, 200 to 300 mL/30 s in humans or 10 mL/40 s in rabbits. During transient cerebral hypoperfusion blood flow to the rabbit brain is decreased to 0.2 to 0.3 mL/30 s. We therefore hypothesized that if the disruption of the BBB by intracarotid mannitol was primarily due to its osmotic effects, injection of 0.2 to 0.3 mL of mannitol during transient cerebral hypoperfusion will be sufficient to disrupt the BBB, thereby dramatically (by 20-folds) decrease the dose requirements compared with injections during normal blood flow. After preliminary studies, 4 doses of intracarotid mannitol were first tested: (1) 2 mL with cerebral hypoperfusion, (2) 4 mL with cerebral hypoperfusion, (3) 4 mL without cerebral hypoperfusion, and (4) 8 mL without cerebral hypoperfusion. Next, we compared the extent to which methods of drug delivery (infusion vs. bolus injection) affected BBB disruption in 12 rabbits. Finally, we assessed the duration of BBB disruption with intracarotid mannitol in another 12 rabbits. We observed that BBB disruption during injection of 4 mL of mannitol with cerebral hypoperfusion was comparable to 8 mL mannitol without cerebral hypoperfusion. Bolus injections of 4 mL mannitol were more effective than steady-state infusions. The BBB disruption with intracarotid mannitol lasted for 60 minutes postinjection. We conclude that cerebral hypoperfusion decreases the dose of intracarotid mannitol by a modest 2-fold. Our results suggest that mechanical factors may play a significant role in the osmotic disruption of the BBB by intracarotid mannitol.


Spatial and temporal patterns in Canadian COVID-19 crowdfunding campaigns.
Online charitable crowdfunding has become an increasingly prevalent way for Canadians to deal with costs that they would otherwise not be able to shoulder on their own. With the onset of COVID-19 and related lockdown measures, there is evidence of a surge in crowdfunding use relating to the pandemic. This study gathered, classified, and analysed Canadian crowdfunding campaigns created in response to COVID-19 from GoFundMe.com, a popular crowdfunding platform. Spatio-temporal analysis of classified campaigns allowed for observation of emergent trends in the distribution of pandemic-related need incidence and financial support throughout the pandemic. Campaigns raising money on behalf of established charities were the most common in the sample, and accounted for the greatest portion of funding raised, while campaigns for businesses made up a small proportion. Dense metropolitan areas accounted for the vast majority of campaign locations, and total sample funding was disproportionately raised by campaigners in Ontario and British Columbia.


Effectiveness of Digital Medicines to Improve Clinical Outcomes in Patients with Uncontrolled Hypertension and Type 2 Diabetes: Prospective, Open-Label, Cluster-Randomized Pilot Clinical Trial.
Hypertension and type 2 diabetes mellitus are major modifiable risk factors for cardiac, cerebrovascular, and kidney diseases. Reasons for poor disease control include nonadherence, lack of patient engagement, and therapeutic inertia. The aim of this study was to assess the impact on clinic-measured blood pressure (BP) and glycated hemoglobin (HbA1c) using a digital medicine offering (DMO) that measures medication ingestion adherence, physical activity, and rest using digital medicines (medication taken with ingestible sensor), wearable sensor patches, and a mobile device app. Participants with elevated systolic BP (SBP ≥140 mm Hg) and HbA1c (≥7%) failing antihypertensive (≥2 medications) and oral diabetes therapy were enrolled in this three-arm, 12-week, cluster-randomized study. Participants used DMO (includes digital medicines, the wearable sensor patch, and the mobile device app) for 4 or 12 weeks or received usual care based on site randomization. Providers in the DMO arms could review the DMO data via a Web portal. In all three arms, providers were instructed to make medical decisions (medication titration, adherence counseling, education, and lifestyle coaching) on all available clinical information at each visit. Primary outcome was change in SBP at week 4. Other outcomes included change in SBP and HbA1c at week 12, and low-density lipoprotein cholesterol (LDL-C) and diastolic blood pressure (DBP) at weeks 4 and 12, as well as proportion of patients at BP goal (<140/90 mm Hg) at weeks 4 and 12, medical decisions, and medication adherence patterns. Final analysis included 109 participants (12 sites; age: mean 58.7, SD years; female: 49.5%, 54/109; Hispanic: 45.9%, 50/109; income ≤ US $20,000: 56.9%, 62/109; and ≤ high school education: 52.3%, 57/109). The DMO groups had 80 participants (7 sites) and usual care had 29 participants (5 sites). At week 4, DMO resulted in a statistically greater SBP reduction than usual care (mean -21.8, SE 1.5 mm Hg vs mean -12.7, SE 2.8 mmHg; mean difference -9.1, 95% CI -14.0 to -3.3 mm Hg) and maintained a greater reduction at week 12. The DMO groups had greater reductions in HbA1c, DBP, and LDL-C, and a greater proportion of participants at BP goal at weeks 4 and 12 compared with usual care. The DMO groups also received more therapeutic interventions than usual care. Medication adherence was ≥80% while using the DMO. The most common adverse event was a self-limited rash at the wearable sensor site (12%, 10/82). For patients failing hypertension and diabetes oral therapy, this DMO, which provides dose-by-dose feedback on medication ingestion adherence, can help lower BP, HbA1c, and LDL-C, and promote patient engagement and provider decision making. Clinicaltrials.gov NCT02827630; https://clinicaltrials.gov/show/NCT02827630 (Archived by WebCite at http://www.webcitation.org/6rL8dW2VF).


A longitudinal study of Salmonella and Campylobacter jejuni isolates from day of hatch through processing by automated ribotyping.
Comparisons of bacterial populations over long periods of time allow researchers to identify clonal populations, perhaps those responsible for contamination of farms or humans. Salmonella and Campylobacter can cause human illness, and our objective was to use a library typing system to track strains that persist in the poultry house and through the processing plant. Two farms, over four consecutive flocks, were studied. Multiple samples were taken of the poultry house environment, feed mill, transport crates, and carcasses in the processing plant. Sample collection on the farm took place on chick placement day, midgrowout, and the day of harvest. This study found that 80.3% of isolates belonged to a single strain of Salmonella Kentucky that persisted in several environmental samples for all flocks at both farms, from chick placement day to the final product at the plant. Surgical shoe covers produced most isolates (n = 26), and processing day yielded the highest recovery (n = 68). Additional serotypes were recovered, but the Salmonella Kentucky-positive eggshells and chick mortality appeared to be the source of the organism for both farms. All Campylobacter isolates recovered were identified as C. jejuni. Most Campylobacter isolates (90.1%) belonged to one of three core strains. C. jejuni was not recovered on chick placement day. Cecal droppings yielded all nine strains. Most isolates (98.2%) were from one farm. Cluster analysis grouped C. jejuni and Salmonella isolates into four and six distinct clusters, respectively, on the basis of a similarity level of 80%.


Primary mucosa-associated lymphoid tissue lymphoma of the hilar bile duct resulting in fluctuant jaundice: A case report.
Primary mucosa-associated lymphoid tissue (MALT) lymphomas rarely originate in the hilar bile duct. Preoperative diagnosis of a primary MALT lymphoma of the hilar bile duct is difficult owing to the rarity of this disease. Differentiating between obstructive jaundice caused by MALT lymphoma of the hilar bile duct and hilar cholangiocarcinoma (the most common form of bile duct cancer) is challenging. A 57-year-old man presented to our hospital in August 2012 with fluctuant obstructive jaundice. Contrast-enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography showed a hilar liver mass measuring 23 × 28 mm along with intrahepatic biliary dilatation indicating hilar bile duct obstruction with a high index of suspicion for hilar cholangiocarcinoma. Based on frozen section examination, he was intraoperatively diagnosed with chronic nonspecific inflammation. Histopathological and immunohistochemical examinations confirmed a diagnosis of malignant lymphoma, specifically classified as an extranodal marginal zone B-cell lymphoma of MALT type. A primary MALT lymphoma of the bile duct should be considered among the differential diagnosis in patients with a hilar tumor who present with fluctuating jaundice and are preoperatively diagnosed with suspected hilar cholangiocarcinoma, and/or an intraoperative diagnosis of chronic nonspecific inflammation (based on frozen section examination) assessed for stenosis or obstruction of the bile duct.


Inhibition of staphylococcal alpha-toxin. A kinetic evaluation of aromatic polysulphonic acids as inhibitors of haemolysis.
1. The effect of a number of aromatic polysulphonic acids on the kinetics of haemolysis of rabbit erythrocyte suspensions by crude staphylococcal alpha-toxin was studied at pH8.6 and 6.8. 2. All of the inhibitory compounds caused an increase in the prelytic lag time (tau) of the sigmoid haemolysis curves, an increase in the time to reach 50% haemolysis (t((1/2))) and a decrease in the maximum rate of haemolysis (R(max.)). The most inhibitory compounds caused a 50% decrease in R(max.) at concentrations between 0.1 and 0.2mm. 3. The effect of pH varied considerably: compounds (I) and (II) were almost equally inhibitory at both pH values, compounds (IV) and (IX) were more inhibitory at pH6.8 than at pH8.6, and compounds (VII), (VIII), (X), (XI) and (XII) were more inhibitory at pH8.6. 4. Increased time of premixing alpha-toxin with compound (I) caused increased inhibition. 5. An attempt was made, where possible, to relate the inhibitory activity to the structure of the test compound.


A comparison of the binding characteristics of the beta-adrenoceptor antagonists 3H-dihydroalprenolol and 125I-iodocyanopindolol in rat liver.
The binding characteristics of 3H-dihydroalprenolol and 125I-iodocyanopindolol have been compared in a particulate fraction from regenerating rat liver. When total 3H-dihydroalprenolol binding and inhibition of total 3H-dihydroalprenolol binding by (-)isoprenaline, (-)alprenolol and (+/-)cyanopindolol was investigated, it was found that all agents were bound to two classes of saturable binding sites. In the inhibition studies, the presence of two binding components was not obvious until the data were transformed into Hofstee plots and these were decomposed, except in the case of (+/-)cyanopindolol. Only (+/-)cyanopindolol was found to distinguish clearly between the two saturable binding sites identified by 3H-dihydroalprenolol, as indicated by a broad plateau in the inhibition curve. When 125I-iodocyanopindolol was used as radioligand, only one saturable binding site was identified, even in the presence of less selective inhibiting ligands. The lower affinity component of 3H-dihydroalprenolol binding could be inhibited by 10 microM phentolamine. However, binding experiments with 3H-prazosin indicated that the lower affinity component was not identical with the alpha-adrenoceptor. Phentolamine did not influence 125I-iodocyanopindolol binding. Thus, due to its higher specific activity and a high degree of selectivity, 125I-iodocyanopindolol appears to be the ligand of choice.


Effect of different γ-subunit isoforms on the regulation of AMPK.
AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. AMPK activation results in a wide range of downstream responses, many of which are associated with improved metabolic outcome, making AMPK an attractive target for the treatment of metabolic diseases. AMPK is a heterotrimeric complex consisting of a catalytic subunit (α) and two regulatory subunits (β and γ). The γ-subunit harbours the nucleotide-binding sites and plays an important role in AMPK regulation in response to cellular energy levels. In mammals, there are three isoforms of the γ-subunit and these respond differently to regulation by nucleotides, but there is limited information regarding their role in activation by small molecules. Here, we determined the effect of different γ-isoforms on AMPK by a direct activator, 991. In cells, 991 led to a greater activation of γ2-containing AMPK complexes compared with either γ1 or γ3. This effect was dependent on the long N-terminal region of the γ2-isoform. We were able to rule out an effect of Ser108 phosphorylation, since mutation of Ser108 to alanine in the β2-isoform had no effect on activation of AMPK by 991 in either γ1- or γ2-complexes. The rate of dephosphorylation of Thr172 was slower for γ2- compared with γ1-complexes, both in the absence and presence of 991. Our studies show that activation of AMPK by 991 depends on the nature of the γ-isoform. This finding may have implications for the design of isoform-selective AMPK activators.


Metal-Free Syntheses of α-Ketothioamide and α-Ketoamide Derivatives from Sulfoxonium Ylides.
An efficient base, additive and metal-free synthetic methods for α-ketothioamide and α-ketoamide derivatives from readily available sulfoxonium ylides have been described. Sulfoxonium ylides with primary or secondary amines afforded α-ketothioamides in the presence of elemental sulfur, whereas α-ketoamides were produced when I2 and TBHP were present. The reaction proceeded well at room temperature and generated the corresponding molecules in good to excellent yields. The reaction can be scaled-up and tolerated by a range of functional groups with simple operational procedures.


Prebiotic and Probiotic Regulation of Bone Health: Role of the Intestine and its Microbiome.
Recent advances in our understanding of how the intestinal microbiome contributes to health and disease have generated great interest in developing strategies for modulating the abundance of microbes and/or their activity to improve overall human health and prevent pathologies such as osteoporosis. Bone is an organ that the gut has long been known to regulate through absorption of calcium, the key bone mineral. However, it is clear that modulation of the gut and its microbiome can affect bone density and strength in a variety of animal models (zebrafish, rodents, chicken) and humans. This is demonstrated in studies ablating the microbiome through antibiotic treatment or using germ-free mouse conditions as well as in studies modulating the microbiome activity and composition through prebiotic and/or probiotic treatment. This review will discuss recent developments in this new and exciting area.


The Molecular and Mechanistic Insights Based on Gut-Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement.
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most frequent classification of liver disease around the globe. Along with the sequencing technologies, gut microbiota has been regarded as a vital factor for the maintenance of human and animal health and the mediation of multiple diseases. The modulation of gut microbiota as a mechanism affecting the pathogenesis of NAFLD is becoming a growing area of concern. Recent advances in the communication between gut and hepatic tissue pave novel ways to better explain the molecular mechanisms regarding the pathological physiology of NAFLD. In this review, we recapitulate the current knowledge of the mechanisms correlated with the development and progression of NAFLD regulated by the gut microbiome and gut-liver axis, which may provide crucial therapeutic strategies for NAFLD. These mechanisms predominantly involve: (1) the alteration in gut microbiome profile; (2) the effects of components and metabolites from gut bacteria (e.g., lipopolysaccharides (LPS), trimethylamine-N-oxide (TMAO), and N,N,N-trimethyl-5-aminovaleric acid (TMAVA)); and (3) the impairment of intestinal barrier function and bile acid homeostasis. In particular, the prevention and therapy of NAFLD assisted by nutritional strategies are highlighted, including probiotics, functional oligosaccharides, dietary fibers, ω-3 polyunsaturated fatty acids, functional amino acids (L-tryptophan and L-glutamine), carotenoids, and polyphenols, based on the targets excavated from the gut-liver axis.


Using mathematical modeling as a resource in clinical trials.
In light of recent clinical developments, the importance of mathematical modeling in cancer prevention and treatment is discussed. An exist- ing model of cancer chemotherapy is reintroduced and placed within current investigative frameworks regarding approaches to treatment optimization. Areas of commonality between the model predictions and the clinical findings are investigated as a way of further validating the model predictions and also establishing mathematical foundations for the clinical studies. The model predictions are used to propose additional ways that treatment optimization could enhance the clinical processes. Arising out of these, an expanded model of cancer is proposed and a treatment model is subsequently obtained. These models predict that malignant cells in the marrow and peripheral blood exhibit the tendency to evolve toward population levels that enable them to replace normal cells in these compartments in the untreated case. In the case of dose-dense treatment along with recombinant hematopoietic growth factors, the models predict a situation in which normal and abnormal cells in the marrow and peripheral blood are obliterated by drug action, while the normal cells regain their growth capabilities through growth-factor stimulation.


DNA Breaks in Ig V Regions Are Predominantly Single Stranded and Are Generated by UNG and MSH6 DNA Repair Pathways.
Antibody diversity is initiated by activation-induced deaminase (AID), which deaminates cytosine to uracil in DNA. Uracils in the Ig gene loci can be recognized by uracil DNA glycosylase (UNG) or mutS homologs 2 and 6 (MSH2-MSH6) proteins, and then processed into DNA breaks. Breaks in switch regions of the H chain locus cause isotype switching and have been extensively characterized as staggered and blunt double-strand breaks. However, breaks in V regions that arise during somatic hypermutation are poorly understood. In this study, we characterize AID-dependent break formation in JH introns from mouse germinal center B cells. We used a ligation-mediated PCR assay to detect single-strand breaks and double-strand breaks that were either staggered or blunt. In contrast to switch regions, V regions contained predominantly single-strand breaks, which peaked 10 d after immunization. We then examined the pathways used to generate these breaks in UNG- and MSH6-deficient mice. Surprisingly, both DNA repair pathways contributed substantially to break formation, and in the absence of both UNG and MSH6, the frequency of breaks was severely reduced. When the breaks were sequenced and mapped, they were widely distributed over a 1000-bp intron region downstream of JH3 and JH4 exons and were unexpectedly located at all 4 nt. These data suggest that during DNA repair, nicks are generated at distal sites from the original deaminated cytosine, and these repair intermediates could generate both faithful and mutagenic repair. During mutagenesis, single-strand breaks would allow entry for low-fidelity DNA polymerases to generate somatic hypermutation.


Asymmetric inhibition of spicule formation in sea urchin embryos with low concentrations of gadolinium ion.
As gastrulation proceeds during sea urchin embryogenesis, primary mesenchyme cells (PMCs) fuse to form syncytial cables, within which calcium is deposited as CaCO₃, and a pair of spicules is formed. Earlier studies suggested that calcium, previously sequestered by primary mesenchyme cells, is secreted and incorporated into growing spicules. We examined the effects of gadolinium ion (Gd(3+)), a Ca(2+) channel blocker, on spicule formation. Gd(3+) did not lead to a retardation of embryogenesis prior to the initiation of gastrulation and did not inhibit the ingression of PMCs from the blastula wall or their migration along the inner blastocoel surface. However, when embryos were raised in seawater containing submicromolar to a few micromolar Gd(3+), of which levels are considered to be insufficient to block Ca(2+) channels, a pair of triradiate spicules was formed asymmetrically. At 1-3 μmol/L Gd(3+), many embryos formed only one spicule on either the left or right side, or embryos formed a very small second spicule. Induction of the spicule abnormality required the presence of Gd(3+) specifically during late blastula stage prior to spicule formation. An accumulation or adsorption of Gd(3+) was not detected anywhere in the embryos by X-ray microanalysis, which suggests that Ca(2+) channels were not inhibited. These results suggest that Gd(3+) exerts an inhibitory effect on spicule formation through a mechanism that does not involve inhibition of Ca(2+) channels.


Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report.
An 82-year-old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune-related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine-based immunosuppressant was effective against irAE hepatitis, therefore thiopurine-based immunosuppressants may be effective against steroid-refractory hepatitis.


Knowledge of post-concussional syndrome in naïve lay-people, general practitioners and people with minor traumatic brain injury.
Expectations about effects of minor traumatic brain injury (MTBI) may play a role in maintaining symptoms, the ability to simulate post-concussion syndrome (PCS) and the extent to which professionals might associate patient complaints with MTBI. In turn, expectations will be related to knowledge about MTBI. This study investigates knowledge of PCS in people with MTBI compared with general practitioners (GPs) and lay-people, using recall (a vignette) and symptom guessing or recognition (checklists). Thirty GPs, 30 people with MTBI, and 30 lay-people generated symptoms from a vignette describing a MTBI. They then completed a PCS checklist or a checklist containing PCS and 'bogus' items pertaining to the vignette. Only 1 of 90 participants reported enough PCS symptoms to indicate 'caseness' from the vignette alone. Using checklists, more GPs (60%) than controls (20%) ticked enough symptoms to attain PCS 'caseness'. Few people with MTBI who did not themselves achieve PCS 'caseness' by self-report using checklists achieved 'caseness' using the vignette and checklists. The frequency of non-physical symptom reporting was higher than for physical symptom reporting. The addition of 'bogus' items to checklists did not affect responding. It is unlikely that pre-injury expectations about MTBI maintain PCS symptoms. PCS was difficult to simulate without prompting, even by GPs and PCS 'cases'. The use of 'caseness', rather than simple symptom scores, and further development of checklists with 'bogus' items may provide a more valid assessment of MTBI effects. GPs may benefit from further information about PCS and available treatments.


Highly stereoselective benzylation of N-sulfinylketimines.
The benzylation of N-sulfinyl ketimines with 2-(p-tolylsulfinyl)ethylbenzene and LDA afford t-alkylamines in good yields. The configuration at each one of the new chiral centers simultaneously created in this reaction is controlled by the configuration of the sulfinyl groups at the nucleophile and electrophile, respectively. Thus, the reactions of the (S)-sulfoxide 6 with the N-(S)-sulfinylketimines 3 only yield the anti diastereoisomers 18, whereas the syn diastereoisomers 19 are exclusively formed in reactions of (S)-6 with N-(R)-sulfinylketimines 3. After a two-step desulfinylation process ((i) TFA, (ii) Ra-Ni), this reaction provides a procedure for synthesizing any epimer of alpha,alpha-dibranched beta-alkylarylamines in optically pure form by choosing the configuration of the starting materials. A similar behavior is observed for carbanions derived from the O-protected 2-(p-tolylsulfinyl) benzyl alcohol 7 thus allowing the synthesis of the optically pure anti- and syn-1,2-amino alcohols containing a chiral quaternary carbon adjacent to the nitrogen.


Divalent germanium compound with a radical-anionic ligand: molecular structures of (dpp-BIAN)*- GeCl and its hydrochloration products [(dpp-BIAN)(H)2]*+ [GeCl3]- and [[(dpp-BIAN)(H)2*+]2(Cl-)]+ [GeCl3]- (dpp-BIAN=1,2-Bis[(2,6-diisopropylphenyl)imino]acenaphthene).
The germanium(II) compound (dpp-BIAN)GeCl (1), which contains the radical anion of dpp-BIAN can be prepared either by reacting free dpp-BIAN ligand with 2 equiv of GeCl2(1,4-dioxane) in Et2O or by metathetical reaction of the sodium salt of dpp-BIAN with germanium dichloride in Et2O or benzene. The reaction of benzene solutions of 1 with 2 or 3 equiv of HCl led to protonation of the dpp-BIAN ligand affording [(dpp-BIAN)(H)2]*+[GeCl3]- (2) and [[(dpp-BIAN)(H)2*+]2(Cl-)]+ [GeCl3]- (3), which incorporate the radical cation of the protonated ligand. Compounds 1-3 have been characterized by elemental analysis, IR, UV-vis, and electron spin resonance (ESR) spectroscopy. Molecular structures of 1-3 were determined by single-crystal X-ray diffraction. In molecule 1, the Ge atom is positioned at the apex of the slightly distorted trigonal pyramid. The Ge-N bond lengths in 1 are 2.0058(19) and 2.004(2) A. The molecular structure of 2 consists of contact ions [(dpp-BIAN)(H)2]+ and [GeCl3]-. In the molecular structure of 3, two radical cations of [(dpp-BIAN)(H)2]+ are "coordinated" by the chlorine anion. The ESR signal of 1 indicates the presence of a dpp-BIAN radical anion and shows a hyperfine structure due to the coupling of an unpaired electron to 14N, 73Ge, 35Cl, 37Cl, and 1H nuclei (AN=0.48 (2 N), AGe=0.96, ACl=0.78 (35Cl), ACl=0.65 (37Cl), AH=0.11 (4 H) mT, g=2.0014). Both 2 and 3 reveal ESR signals of radical cation [(dpp-BIAN)(H)2]*+ (septet, AN=0.53, AH=0.48 mT, g=2.0031).


Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders.
Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.


Product Processing Quality Classification Model for Small-Sample and Imbalanced Data Environment.
With the rapid development of machine learning technology, how to use machine learning technology to empower the manufacturing industry has become a research hotspot. In order to solve the problem of product quality classification in a small sample data and imbalanced data environment, this paper proposes a data generation model called MSMOTE-GAN, which is based on Mahalanobis Synthetic Minority Oversampling Technology (MSMOTE) and Generative Adversarial Network (GAN). Among them, MSMOTE is proposed to solve the problem of the sample biased to the majority class expanded by methods such as GAN in a sample imbalanced environment. Based on the traditional SMOTE method, the sample distance measurement method is modified from Euclidean distance to Mahalanobis distance, taking into account the correlation between attributes and the influence of dimensions on the sample distance. In the data generation model, MSMOTE is used to balance the positive and negative samples in the data. GAN generates fake data with the same distribution as the original data based on a balanced data set and expands the sample size to solve the problems of overfitting and insufficient model expression ability that occur when the sample size is too small. The quality classification framework of water heater liner based on the data generation model and Random Forest is constructed, and the process of the quality classification of water heater liner under the environment of small sample data and imbalanced data is fully described. This paper compares the MSMOTE-GAN model, Bootstrap, and tableGAN on the water heater liner production line data set and the public data set. The experimental result shows that the expanded data set of the MSMOTE-GAN model can effectively improve the performance of the classification model.


Quantitative analysis of diaphragm motion during fluoroscopic sniff test to assist in diagnosis of hemidiaphragm paralysis.
The current imaging gold standard for detecting paradoxical diaphragm motion and diagnosing hemidiaphragm paralysis is to perform the fluoroscopic sniff test. The images are visually examined by an experienced radiologist, and if one hemidiaphragm ascends while the other descends, then it is described as paradoxical motion, which is highly suggestive of hemidiaphragm paralysis. However, diagnosis can be challenging because diaphragm motion during sniffing is fast, paradoxical motion can be subtle, and the analysis is based on a 2-dimensional projection of a 3-dimensional surface. This paper presents a case of chronic left hemidiaphragm elevation that was initially reported as mild paradoxical motion on fluoroscopy. After measuring the elevations of the diaphragms and modeling their temporal correlation using Gaussian process regression, the systematic trend of the hemidiaphragmatic motion along with its stochastic properties was determined. When analyzing the trajectories of the hemidiaphragms, no statistically significant paradoxical motion was detected. This could potentially change the prognosis if the patient was to consider diaphragm plication as treatment. The presented method provides a more objective analysis of hemidiaphragm motions and can potentially improve diagnostic accuracy.


Exploring Workers' Subjective Experiences of Habit Formation in Cybersecurity: A Qualitative Survey.
Employee behaviors remain at the center of the cybersecurity of workplaces, despite the challenges they face in doing so. Time pressures and competing demands mean that users tend to rely on habitual behaviors that often run counter to good cybersecurity practice. One possible solution may be to encourage positive habit formation. Designing such interventions, however, relies on knowledge of the perception and experience of habit formation in the context of cybersecurity. To this end, a qualitative survey containing open-ended questions was completed by 195 participants (mean age = 35.51, 53 percent female) recruited via an online participant panel. Participants were asked what cybersecurity behaviors they perform at work and how they believe any habits were prompted, formed, and maintained. Thematic analysis identified three over-arching themes: (a) forming habits unavoidably or unconsciously (some were mandated, or formed without conscious awareness), (b) consciously cultivating habits (including the roles of intrinsic motivation and external prompts), and (c) social and organizational influences (including the influence of occupational culture, social modeling, previous experiences, and information gathering practices). Based on these findings, we present guidelines for supporting workplace cybersecurity habit formation reflecting these subjective experiences, namely introducing automatic solutions, facilitating external cues, fostering interest in cybersecurity issues among employees, creating a positive cybersecurity occupational culture and highlighting positive behavior, and providing access to accessible cybersecurity information to employees. These results constitute a first step in identifying how habits can be exploited for positive cybersecurity behavior change in a way that accounts for the reliance on habitual behaviors in busy, time-pressured workplaces.


Transition of chemical management in Japan -Shift to self-regulation and measures for small businesses.
Increased variety and use of chemicals and the number of chemical disasters have changed chemical management. Europe and the United States have adopted self-regulation in chemical management; furthermore, countries worldwide must comply with the relevant United Nations recommendations and international standards for chemical management. Japan has experienced numerous pollution incidents and occupational disasters, resulting in the development of laws and regulations on chemical management; however, these policies are inconsistent with international trends. In particular, the shift from a compliance approach to self-regulation and measures for small businesses remain as challenges. This paper discusses the current situation and issues in chemical management in Japan, focusing on international trends.


Systemic Inflammation after Aneurysmal Subarachnoid Hemorrhage.
Aneurysmal subarachnoid hemorrhage (aSAH) is one of the most severe neurological disorders, with a high mortality rate and severe disabling functional sequelae. Systemic inflammation following hemorrhagic stroke may play an important role in mediating intracranial and extracranial tissue damage. Previous studies showed that various systemic inflammatory biomarkers might be useful in predicting clinical outcomes. Anti-inflammatory treatment might be a promising therapeutic approach for improving the prognosis of patients with aSAH. This review summarizes the complicated interactions between the nervous system and the immune system.


A Practical Approach to Recalcitrant Face and Neck Dermatitis in Atopic Dermatitis.
Face and neck dermatitis in the atopic dermatitis patient is a diagnostically challenging entity with broad differential diagnoses. Recent case reports reporting face and neck dermatitis in patients on dupilumab therapy have added further complexity to diagnosis and management. Herein, we discuss a broad diagnostic algorithm and practical management strategy for recalcitrant face and neck dermatitis in the atopic patient with an emphasis on face and neck dermatitis associated with dupilumab therapy. Our aim is to raise awareness about the probable entity of drug-associated face and neck dermatitis and share a practical management strategy that may also be applied broadly to atopic dermatitis patients presenting with face and neck dermatitis.


Engaging Agribusinesses: Feasibility and Cost of an ATV Safety Poster Project.
All-terrain vehicle (ATV)-related deaths and injuries continue to be a significant problem. Influential change agents such as agribusinesses could be important partners for improving safety behaviors among rural ATV users. Our objective was to determine how effectively an injury prevention project could engage agribusinesses through the postal service and to assess their willingness to display a safety poster. One thousand two hundred forty-four agribusinesses received an ATV safety poster and a postcard survey by mail. A randomized sampling of these businesses was surveyed by telephone 4-7 weeks later. Telephone survey questions included whether they recalled receiving the poster, and if so, whether, where and how long the poster was displayed. One hundred six postcards were returned. Of the 192 eligible business persons contacted by telephone, 89% agreed to participate. Approximately one-third of telephone survey participants recalled receiving the poster. Among these, 81% with walk-in customers posted it, and 74% still had it displayed 1 month later. Of participants who did not recall receiving the poster, 83% stated they would have displayed the poster. The cost of displaying each poster in a business was 16.6 cents/day during the first month. Final costs/day would be much less because of continued display. A high percentage of agribusinesses displayed or would have displayed an ATV safety poster, and most displayed it beyond 1 month. Unfortunately, participant recruitment via postal delivery alone was challenging. Nevertheless, mass mailing of injury prevention materials to be displayed in the retail setting may be a low cost method for raising safety awareness.


Expanding midwifery care in the United States: Implications for clinical outcomes and cost.
This study compared clinical and financial outcomes for low-risk birthing people between those attended by midwives and those attended by obstetricians during hospital births. We conducted a retrospective cohort analysis of births from January 1, 2016 to December 31, 2020 at hospitals participating in a perinatal quality improvement collaborative, Obstetrical Care Outcomes Assessment Program (OB COAP), in the Northwest region of the United States and estimated risk ratios using a multivariate regression approach with a modified Poisson binomial for mode of delivery, labor interventions, and newborn outcomes comparing midwife-led to obstetrician-led care. Using publicly available data on average costs of vaginal and cesarean births, we then extrapolated the cost differences in care between midwives and obstetricians. Births in the midwife group were less likely to be associated with induction (17.6% vs. 20.3% RR 0.74; 95% CI 0.70-0.78), epidural use (58.9% vs. 76.3% RR 0.78; 95% CI 0.77-0.80), and episiotomy (2.2% vs. 3.4% RR 0.68; 95% CI 0.58-0.81). Cesarean birth was also lower in the midwifery group (7.8% vs. 12.3% RR 0.68, 95% CI 0.62-0.73), without a corresponding increase in risk in adverse neonatal outcomes. We estimated that expanding midwifery care to 100% of low-risk births across the United States could save as much as $340 million per year. Midwifery care is associated with a lower risk of cesarean birth and other interventions versus care provided by obstetricians and is therefore likely lower-cost.


Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait.
Infants born to women with depressive symptoms are at higher risk for insecure attachment and behavioral problems. Thus current medical practice is to continue psychotropic medication of pregnant women with depression despite concerns about its behavioral teratology. There are few animal studies focused on long-term behavioral effects of prenatal antidepressant exposure; in addition, studies have not looked at individual differences in baseline affective state as a source of response variability. In this study, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was administered to male and female rat pups from postnatal days 2-7 to model exposure to antidepressants in the human third trimester. Four behavioral measures were conducted from the neonatal to adult age periods in Low and High lines selectively bred for their rate of ultrasonic vocalizations after brief maternal separation. Neonatal fluoxetine administration decreased distress calls in both lines, but to a greater extent in High line rats than Low line. Neonatal fluoxetine also impaired motor coordination in neonates. Neonatal fluoxetine administration decreased social behavior in both juvenile and adult subjects. Fluoxetine-related reductions in anxiety behavior were not observed at the two older ages. As expected, High line subjects displayed more anxiety behavior than Low line subjects at all three test ages. These results suggest that there are may be significant behavioral consequences of antidepressant use during late pregnancy on offspring maternal attachment and social behavior, with implications for increased risk of autism spectrum disorders.


New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations.
The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an α-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show this allylic covalent inhibitor has different catalytic proficiencies for pseudoglycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools.


Status of ongoing collaborative efforts.
T-cell lymphomas are the rarest of all non-Hodgkin lymphomas (NHLs) and may therefore be the least understood. The aim of the T-Cell Project is to pool prospective data from centers around the world to improve understanding of the more frequent and the uncommon subtypes of T-cell lymphomas. To be eligible for enrollment in this study, patients must have previously untreated, de novo peripheral T-cell lymphoma (PTCL) or natural killer (NK)/T-cell lymphoma and be at least 18 years of age. As of October 2009, 479 patients from 13 centers were enrolled, and 454 of these cases were validated. The patients are evaluated for their responses to treatment, progression-free and overall survival, and treatments received.


Bromine-rich Zinc Bromides: Zn6Br12(18-crown-6)2×(Br2)5, Zn4Br8(18-crown-6)2×(Br2)3, and Zn6Br12(18-crown-6)2×(Br2)2.
The bromine-rich zinc bromides Zn6Br12(18-crown-6)2×(Br2)5 (1), Zn4Br8(18-crown-6)2×(Br2)3 (2), and Zn6Br12(18-crown-6)2×(Br2)2 (3) are prepared by reaction of ZnBr2, 18-crown-6, and elemental bromine in the ionic liquid [MeBu3N][N(Tf)2] (N(Tf)2 = bis(trifluoromethylsulfonyl)amide). Zn6Br12(18-crown-6)2×(Br2)5 (1) is formed instantaneously by the reaction. Even at room temperature, compound 1 releases bromine, which was confirmed by thermogravimetry (TG) and mass spectrometry (MS). The release of Br2 can also be directly followed by the color and density of the title compounds. With controlled conditions (2 weeks, 25 °C, absence of excess Br2) Zn6Br12(18-crown-6)2×(Br2)5 (1) slowly releases bromine with conconcurrent generation of Zn4Br8(18-crown-6)2×(Br2)3 (2) (in ionic liquid) and Zn6Br12(18-crown-6)2×(Br2)2 (3) (in inert oil). All bromine-rich zinc bromides contain voluminous uncharged (e.g., Zn3Br6(18-crown-6), Zn2Br4(18-crown-6)) or ionic (e.g., [Zn2Br3(18-crown-6)](+), [(Zn2Br6)×(Br2)2](2-)) building units with dibromine molecules between the Zn oligomers and partially interconnecting the Zn-containing building units. Due to the structural similarity, the bromine release is possible via crystal-to-crystal transformation with retention of the crystal shape.


Endoscopic variceal ligation: an effective method of variceal obliteration.
Endoscopic variceal ligation was performed in 20 patients with portal hypertension of varied etiology. Variceal obliteration was achieved in 18 patients (90%) while recurrence of bleeding occurred in two patients (10%). The average number of bands required was four per patient and average number of sessions required for variceal obliteration was two. We found the procedure to be cheap, safe and effective in achieving early variceal obliteration.


Bilateral First-Ray Amputation of the Foot Due to Severe Tophaceous Gout Complicated by Infection and Discharged Sinus A Case Report.
Gout is a purine metabolism disease. Tophaceous gout may cause joint destruction and other systemic problems and sometimes may be complicated by infection. Infection and sinus with discharge associated with tophaceous gout are serious complications, and treatment is difficult. We present a patient with tophaceous gout complicated by infection and discharging sinus treated by bilateral amputation at the level of the first metatarsus. A 43-year-old man previously diagnosed as having gout, and noncompliant with treatment, presented with tophaceous gout associated with discharging sinus and infection on his left first metatarsophalangeal joint. Because of the discharging sinus associated with the tophaceous deposits, the soft-tissue and bony defects, and the noncompliance of the patient, amputation of the first ray was undertaken, and a local plantar fasciocutaneous flap was used to close the defect. After 8 months, the patient was admitted to the emergency department with similar symptoms in his right foot, and the same surgical procedure was performed. One year after the second surgery, the patient had no symptoms, there was no local inflammatory reaction over the surgical areas, and laboratory test results were normal. Gout disease with small tophi often can be managed conservatively. However, in patients with extensive lesions, risk of superinfection justifies surgical treatment. Results of complicated cases are not without morbidity; therefore, early surgical treatment may prevent extremity loss and further complications. In severe cases, especially with compliance issues, amputation provides acceptable results.


Synaptonemal Complex in Human Biology and Disease.
The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC mediates the synapses of the homologous chromosomes, leading to the formation of bivalents, and physically supports the formation of programmed double-strand breaks (DSBs) and their subsequent repair and maturation into crossovers (COs), which are essential for genome haploidization. Defects in the assembly of the SC or in the function of the associated meiotic recombination machinery can lead to meiotic arrest and human infertility. The majority of proteins and complexes involved in these processes are exclusively expressed during meiosis or harbor meiosis-specific subunits, although some have dual functions in somatic DNA repair and meiosis. Consistent with their functions, aberrant expression and malfunctioning of these genes have been associated with cancer development. In this review, we focus on the significance of the SC and their meiotic-associated proteins in human fertility, as well as how human genetic variants encoding for these proteins affect the meiotic process and contribute to infertility and cancer development.


Assembly of Microparticles to Patterned Trenches Using the Depletion Volume Effect.
In this paper, we demonstrate that 20 μm microbeads can be preferentially assembled into substrate trenches of similar width by employing a polymer (depletant) that induces the depletion volume effect (depletion attraction). In previous works, we proved that this strategy is useful to assemble mesoscale parts in a site-specific manner. Here, we show that it is also applicable to assemble functional parts, such as fluorescent particles, into trenches engraved on the surface of two- and three-dimensional template components. A convenient advantage of this strategy is that it is independent of material properties for assembling mesoscale functional components into desired patterns.


Selective modulation of charge-carrier transport of a photoanode in a photoelectrochemical cell by a graphitized fullerene interfacial layer.
We show that a graphitic carbon interfacial layer, derived from C70 by annealing at 500 °C, results in a significant increase in the attainable photocurrent of a photoelectrochemical cell that contains a WO3 -functionalized fluorine-doped tin oxide (FTO) photoanode. Time-resolved photoluminescence spectroscopy, photoconductive atomic force microscopy, Hall measurements, and electrochemical impedance spectroscopy show that the increase in photocurrent is the result of fast and selective electron transport from optically excited WO3 through the graphitic carbon interfacial layer to the FTO-coated glass electrode. Thus the energy efficiency of perspective solar-to-fuel devices can be improved by modification of the interface of semiconductors and conducting substrate electrodes by using graphitized fullerene derivatives.


The association of Id-1, MIF and GSTpi with acquired drug resistance in hormone independent prostate cancer cells.
Most patients with prostate cancer respond to androgen ablation therapy, but the tumor eventually progresses to an androgen-independent stage with multiple anti-cancer drug resistance. Novel therapeutic strategies for hormone independent prostate cancer need to be developed. The genes for Id-1, MIF and GSTpi were up-regulated in drug resistant cells of hormone independent prostate cancer cells using cDNA microarray gene expression analysis. In this study we aimed to investigate whether constitutive overexpression of these candidate genes in cells can affect cellular resistance to chemotherapeutic agents. The mRNA expression was determined by reverse transcriptase-polymerase chain reaction, and the Id-1, MIF and GSTpi protein contents in these cell lines were measured by Western blotting. Susceptibility of the cells to chemotherapeutic agents including doxorubicin, paclitaxel and cyclophosphamide was determined by microculture tetrazolium bromide assay. The analysis of apoptosis was assessed by annexin V assay. The cytotoxity assay results demonstrated that cells overexpressing the Id-1 gene increased in their resistance to doxorubicin, paclitaxel and cyclophosphamide. MIF expression can drive cells to increase in their resistance to paclitaxel, and GSTpi expression confers drug resistance to doxorubicin and cyclophosphamide. The induction of mdr1 gene expression was noted in up-regulation of MIF and GSTpi. Our findings suggest that overproduction of the Id-1, MIF and GSTpi proteins and coinduction of mdr-1 play an important role in the development of acquired drug resistance to various drugs of prostate cancer cells.


Surgical management of posteriorly dislocated silicone plate haptic intraocular lenses.
To report a large series of delayed posterior dislocation of silicone plate haptic intraocular lenses after Nd:YAG laser capsulotomy and discuss the surgical management of this complication. We reviewed the records of 11 consecutive patients (11 eyes) with delayed onset of posterior dislocation of a plate haptic silicone intraocular lens. The cause of the posterior capsular defect, time to dislocation, surgical management techniques, complications, and visual outcome were recorded. In eight of the 11 eyes, the silicone plate haptic intraocular lens dislocated an average of 1.8 months (range, 0 to 6.5 months) after Nd:YAG posterior capsulotomy. The other three eyes had surgical complications at the time of cataract extraction that compromised posterior capsular or zonular integrity and led to silicone plate haptic intraocular lens dislocation from 9 weeks to 6 months (mean, 3.6 months) postoperatively. Surgical management consisted of pars plana vitrectomy with intraocular lens repositioning (six eyes) or exchange (five eyes). The average follow-up period after intraocular lens repositioning or exchange was 6.5 months (range, 1 to 14 months). Best-corrected visual acuity at the last follow-up examination measured 20/40 or better in all but one eye that had preexisting macular disease. Cataract surgeons and patients should be aware of the potential for plate haptic silicone intraocular lenses to undergo delayed posterior dislocation through capsular defects. This complication can be managed effectively with vitrectomy and either repositioning or exchange of the implant. Postoperative visual acuity is generally excellent, and complications are minimal.


Effects of packing on the postoperative hearing after middle ear surgery.
The changes of hearing by packing after middle ear surgery should be anticipated and carefully interpreted. To evaluate the amount and patterns of hearing loss resulting from packing in middle ear cavity (MEC) and external auditory canal (EAC) after middle ear surgery. We obtained pure tone thresholds by bone (BC) and air conduction (AC) up to 12 weeks after middle ear surgery in 17 patients who had minimal middle ear pathology. To observe the effects of packing only in the EAC as in cases of explorative tympanotomy or stapes surgery, BC and AC threshold were obtained after packing only in the EAC in 18 volunteers. The changes of BC and AC thresholds in terms of pure tone average (PTA) and high frequency PTA were analyzed. PTA by AC increased significantly by a maximal value of 38.7 dB at the second postoperative day, by 35.0 dB at 1 week after middle ear surgery. PTA by BC also increased maximally at the second postoperative day by 4.8 dB. The elevation of BC threshold at high frequencies (2, 3, 4 kHz) was more pronounced. Packing of EAC without MEC packing resulted in elevation of AC threshold by 43.0 dB, with similar patterns of BC threshold changes as MEC and EAC packing.


Effect of nickel titanium file design on the root surface strain and apical microcracks.
The aim of this study was to determine the effect of nickel titanium file design on the root surface strain generated and apical microcracks caused during canal shaping. Thirty-three mandibular incisors were distributed into LightSpeed X, FlexMaster and a control group. A strain gauge was fixed apically on the proximal root surface to determine the maximum strain during canal shaping. Except for the control group, all root canals were enlarged to size 50. Images were taken after removing the apical 1 and 2 mm of the root end. Mean maximum strain values and presence of microcracks were statistically compared using the t-test and chi-square test, respectively. During canal shaping, the strain increased cumulatively with mean maximum strains of 808.2 ± 228.8 and 525.1 ± 168.9 microstrain in LightSpeed X and FlexMaster, respectively (P = 0.004). Both systems caused comparable microcracks. Although LightSpeed X produced higher maximum strain, no difference in microcrack development was found between both systems.


Pesticidal and pest repellency activities of rhizomes of Drynaria quercifolia (J. Smith) against Tribolium castaneum (Herbst).
Tribolium castaneum (Herbst) is a harmful pest of stored grain and flour-based products in tropical and subtropical region. In the present study, rhizome of Drynaria quercifolia (J. Smith) was evaluated for pesticidal and pest repellency activities against T. castaneum, using surface film method and filter paper disc method, respectively. In addition, activity of the isolated compound 3,4-dihydroxybenzoic acid was evaluated against the pest. Chloroform soluble fraction of ethanol extract of rhizome of D. quercifolia showed significant pesticidal activity at doses 0.88 to 1.77 mg/cm(2) and significant pest repellency activity at doses 0.94 to 0.23 mg/cm(2). No pesticidal and pest repellency activity was found for petroleum ether, ethyl acetate and methanol soluble fractions of ethanol extract as well as for 3,4-dihydroxybenzoic acid. Considering our findings it can be concluded that chloroform soluble fraction of rhizome of D. quercifolia is useful in controlling T. castaneum of stored grain and flour-based products.


[Effects of Microplastics Addition on Soil Organic Carbon Mineralization in Citrus Orchard].
To investigate the effects of microplastics on soil organic carbon mineralization and the changes in soil enzyme activities, an incubation experiment was conducted whereby single applications of either microplastics or straw, and combined application of both, were added to Dangyang citrus orchard soil. The results showed that the combined application of straw and microplastics significantly affected organic carbon mineralization in the soil, but the single addition of microplastics had no significant effect. Compared with straw alone, the application of a small combined amount of microplastics and straw significantly increased soil organic carbon mineralization by 8.20%, while medium and high amounts of the combined application significantly inhibited soil organic carbon mineralization. The lowest amount of organic carbon mineralization occurred with the highest amount of combined microplastics and straw, 10.13% lower than with straw alone. The addition of microplastics significantly reduced the activity of β-glucosidase. In particular, a high amount of microplastics significantly decreased the activity of β-glucosidase, compared with the control, by 20.52%, 43.93%, and 17.79% on the day 1, 6, and 35, respectively. However, straw application alleviated the inhibition effect of microplastic application on soil β-glucosidase activity. The soil organic carbon mineralization rate was significantly positively correlated with DOC, MBC and β-glucosidase activity.


MicroRNA-543 suppresses liver cancer growth and induces apoptosis via the JAK2/STAT3 signaling pathway.
The aim of the present study was to investigate the function of microRNA-543 on liver cancer cell proliferation and apoptosis, and also to identify whether the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was a direct target of microRNA-543. When compared with paracarcinoma tissue, microRNA-543 expression in tissue samples from patients with liver cancer was identified to be decreased. Furthermore, overall survival of patients with high microRNA-543 expression was increased compared with patients with low microRNA-543 expression. Inhibition of microRNA-543 expression increased cell proliferation and decreased apoptosis of liver cancer cells. It also activated the protein expression of phosphorylated JAK2, phosphorylated STAT3, c-Myc and B-cell lymphoma 2 (Bcl-2) in liver cancer cells. However, activation of microRNA-543 expression in turn decreased cell proliferation and increased apoptosis of liver cancer cells. The results of the present study highlight the pivotal function of microRNA-543 as an inhibitor in liver cancer cell proliferation by observing JAK2/STAT3/c-Myc/Bcl-2 in liver cancer.


Decreased Expression of Retinoid X Receptors During Human and Azoxymethane-induced Colorectal Carcinogenesis in the Rat.
The family of retinoid X receptors (RXRs) including RXRα, β and γ, is involved in regulating cell proliferation, differentiation, apoptosis and development. In order to characterize the role of RXRs during colorectal carcinogenesis, the expression of RXRs in human and azoxymethane (AOM)-induced rat colorectal tumors was profiled by immunohistochemistry. Both human and rat normal colorectal epithelia and hyperplasia exhibited strong nuclear, but weak cytoplasmic staining for all three proteins. Expression of RXRα, β and γ was significantly reduced in rat carcinomas compared to high-grade dysplasia whether in aberrant crypt foci or in adenomas. All three proteins displayed dramatically reduced nuclear expression in both human adenomas and carcinomas. Reduced expression of RXRα and RXRγ seems more significant than RXRβ in both human and rat carcinomas. Reduced expression of RXRs is associated with colorectal carcinogenesis in both humans and AOM-treated rats.


GMP-Compliant Production of Autologous Adipose-Derived Stromal Cells in the NANT 001 Closed Automated Bioreactor.
In recent years mesenchymal stromal cells (MSCs) have received a great deal of interest for the treatment of major diseases, but clinical translation and market authorization have been slow. This has been due in part to a lack of standardization in cell manufacturing protocols, as well as a lack of biologically meaningful cell characterization tools and release assays. Cell production strategies to date have involved complex manual processing in an open environment which is costly, inefficient and poses risks of contamination. The NANT 001 bioreactor has been developed for the automated production of small to medium cell batches for autologous use. This is a closed, benchtop system which automatically performs several processes including cell seeding, media change, real-time monitoring of temperature, pH, cell confluence and cell detachment. Here we describe a validation of the bioreactor in an environment compliant with current good manufacturing practice (cGMP) to confirm its utility in replacing standardized manual processing. Stromal vascular fraction (SVF) was isolated from lipoaspirate material obtained from healthy donors. SVF cells were seeded in the bioreactor. Cell processing was performed automatically and cell harvesting was triggered by computerized analysis of images captured by a travelling microscope positioned beneath the cell culture flask. For comparison, the same protocol was performed in parallel using manual methods. Critical quality attributes (CQA) assessed for cells from each process included cell yield, viability, surface immunophenotype, differentiation propensity, microbial sterility and endotoxin contamination. Cell yields from the bioreactor cultures were comparable in the manual and automated cultures and viability was >90% for both. Expression of surface markers were consistent with standards for adipose-derived stromal cell (ASC) phenotype. ASCs expanded in both automated and manual processes were capable of adipogenic and osteogenic differentiation. Supernatants from all cultures tested negative for microbial and endotoxin contamination. Analysis of labor commitment indicated considerable economic advantage in the automated system in terms of operator, quality control, product release and management personnel. These data demonstrate that the NANT 001 bioreactor represents an effective option for small to medium scale, automated, closed expansion of ASCs from SVF and produces cell products with CQA equivalent to manual processes.


[Inhibition of tumor cell invasion and induction of apoptosis by ubenimex].
This study is to investigate the effects of ubenimex on tumor cell invasion and apoptosis, dose relationship and mechanism. Immunofluorescence staining was performed to detect the expression of CD13 in HT-1080 cells. MTT assay was used to analyze the effect of ubenimex on cell proliferation. Annexin V-EGFP/PI was used to detect apoptotic cells by flow cytometry. Cell cycle was analyzed using flow cytometry. Ala-pNA was used as substrate to evaluate the effect of ubenimex on the aminopeptidase activity. Transwell assay was used to analyze the effect of ubenimex on cell invasion and migration ability. Western blotting was used to detect the expression level of CD13. MMP activity was analyzed using gelatin zymography. The results showed that ubenimex at high concentration inhibited the proliferation of HT-1080 cells (IC50: 3.8 mg x mL(-1)), and induced cell apoptosis. Cell cycle was blocked at G1 phase. Ubenimex at low concentration inhibited the aminopeptidase activity of HT-1080 cells (IC50: 8.3 microg x mL(-1)) and inhibited cell invasion, but it had no effects on the cell migration and proliferation. Ubenimex had no effects on CD13 expression and MMP activity. In conclusion, ubenimex at low concentration can inhibit the invasion ability of tumor cells by directly inhibiting the aminopeptidase activity; ubenimex at high concentration can inhibit the proliferation of tumor cells and induce cell apoptosis by a CD13-independent pathway.


Impact of different frequencies of controlled breath and pressure-support levels during biphasic positive airway pressure ventilation on the lung and diaphragm in experimental mild acute respiratory distress syndrome.
We hypothesized that a decrease in frequency of controlled breaths during biphasic positive airway pressure (BIVENT), associated with an increase in spontaneous breaths, whether pressure support (PSV)-assisted or not, would mitigate lung and diaphragm damage in mild experimental acute respiratory distress syndrome (ARDS). Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 hours, animals were randomly assigned to: 1) BIVENT-100+PSV0%: airway pressure (Phigh) adjusted to VT = 6 mL/kg and frequency of controlled breaths (f) = 100 bpm; 2) BIVENT-50+PSV0%: Phigh adjusted to VT = 6 mL/kg and f = 50 bpm; 3) BIVENT-50+PSV50% (PSV set to half the Phigh reference value, i.e., PSV50%); or 4) BIVENT-50+PSV100% (PSV equal to Phigh reference value, i.e., PSV100%). Positive end-expiratory pressure (Plow) was equal to 5 cmH2O. Nonventilated animals were used for lung and diaphragm histology and molecular biology analysis. BIVENT-50+PSV0%, compared to BIVENT-100+PSV0%, reduced the diffuse alveolar damage (DAD) score, the expression of amphiregulin (marker of alveolar stretch) and muscle atrophy F-box (marker of diaphragm atrophy). In BIVENT-50 groups, the increase in PSV (BIVENT-50+PSV50% versus BIVENT-50+PSV100%) yielded better lung mechanics and less alveolar collapse, interstitial edema, cumulative DAD score, as well as gene expressions associated with lung inflammation, epithelial and endothelial cell damage in lung tissue, and muscle ring finger protein 1 (marker of muscle proteolysis) in diaphragm. Transpulmonary peak pressure (Ppeak,L) and pressure-time product per minute (PTPmin) at Phigh were associated with lung damage, while increased spontaneous breathing at Plow did not promote lung injury. In the ARDS model used herein, during BIVENT, the level of PSV and the phase of the respiratory cycle in which the inspiratory effort occurs affected lung and diaphragm damage. Partitioning of inspiratory effort and transpulmonary pressure in spontaneous breaths at Plow and Phigh is required to minimize VILI.


The impact on eating habits of temporary translocation from a Mediterranean to a Northern European environment.
To assess the effect of temporary translocation from a Mediterranean to a Northern European environment on the eating habits of a group of foreign students. Cross-sectional survey of eating habits before and after moving from Greece to Glasgow, Scotland. University of Glasgow. Eighty post-graduate Greek students. A self-administered questionnaire comprising of three major sections: (1) general eating habits; (2) frequency of eating selected food items; (3) opinion of food availability in Glasgow. After moving to Glasgow, significant decreases were reported in the frequency of consuming fresh fruit, raw vegetables, fish, legumes, meat, poultry and fresh fruit juice. The frequency of eating biscuits, savoury snacks, soft/fizzy drinks, alcoholic drinks and mayonnaise, dips and sauces increased. The estimated median daily consumption of fruit and vegetables decreased from 363 g in Greece to just 124 g in Glasgow, well below the Scottish and WHO dietary target of 400 g/day. The main perceived barriers to maintaining customary eating habits were the price of food, the lack of familiar tastes, the greater availability of convenience food and the limited variety of food available in Glasgow, when compared to Greece. These findings highlight the difficulties that migrant populations face in retaining traditional, often healthier, eating habits when migrating to a foreign country. Barriers of high cost, limited availability and poor quality of familiar foods, need to be addressed in order for migrants to maintain their customary eating patterns. Furthermore, these barriers need to be addressed before nutritionists can expect to see the widespread adoption of the Mediterranean diet by Western populations less familiar with this eating pattern.


Batch cultivation of Methylosinus trichosporium OB3b. I: Production of soluble methane monooxygenase.
Methanotrophs have promising applications in bioremediation and in the production of fuel-related chemicals due to their nonspecific enzyme, methane monooxygenase (MMO). The optimal conditions for cell growth and production of the soluble from of MMO (sMMO) were determined from batch cultivations of an obligatory methanotrophs, Methylosinus trichosporium OB3b, in shake flasks and a 5-L bioreactor. It was confirmed that a copper deficiency is essential for the formation of the cytoplasmic sMNO. Optimum cell growth without added copper was observed at pH 6.0-7.0, temperature of 30-34 degrees C, and phosphate concentration of 10-40 mM. In the bioreactor experiments, external CO(2) addition eliminated the long lag period observed in the absence of added CuSO(4), i.e., prior to the exponential cell growth phase. When methane was continuously supplied, the profile of the cell growth showed two different phases depending on the availability of nitrate, an initial fast exponential growth phase (specific growth rate, micro = 0.08 h(-1)) and a later slow growth phase (micro = 0.008 h(-1)). The cell density at the transition from a fast to a slow growth rate was proportional to the initial medium nitrate concentration in the range 5-20 mM and cell yield was estimated to be 7.14 g dry cell wt/g N. Whole-cell sMNO activity remained essentially constant regardless of the growth rate unit cell growth stopped. With an initial medium iron concentration below 40 mM, an abrupt decrease in sMNO activity was observed. The lower sMNO activity could be restored by supplying additional iron to the bioreactor culture. Cell yield on iron was estimated to be 1.3 x 10(3) g dry cell wt/g Fe.


Quantification of Plasmodium malariae infection in mosquito vectors.
Plasmodium malariae occurs in various tropical regions throughout the world and causes low, yet significant, levels of morbidity in human populations. One means of studying the ecology and frequency of this parasite is by measuring sporozoite loads in the salivary glands of infected mosquitoes. An effective, species-specific test that can be used to detect the presence of sporozoites in mosquitoes is the circumsporozoite ELISA. The aim of the present study was to standardize the circumsporozoite ELISA for P.malariae, by setting quantification parameters using, as antigen, either a synthetic peptide or extracts of whole sporozoites. The standard quantification curves produced indicated that the assay had a lower threshold of sensitivity of 250 sporozoites in a 50-microl sample, equivalent to about 1250 sporozoites in a mosquito.


Validation and Comparison of PROMISE and CONFIRM Model to Predict High-Risk Coronary Artery Disease in Symptomatic and Diabetes Mellitus Patients.
The identification of high-risk coronary artery disease (HRCAD) is important in diabetes mellitus (DM) patients. However, the reliability of current models to predict HRCAD has not been fully investigated. Thus, we aimed to validate and compare CONFIRM and PROMISE high-risk model (CHM and PHM) in DM patients. 5936 symptomatic DM patients who underwent coronary computed tomographic angiography (CCTA) were identified. Probability of HRCAD for each patient was estimated based on CHM and PHM, respectively. We used Area under the receiver operating characteristic curve (AUC), integrated discrimination improvement (IDI), net reclassification improvement (NRI) and Hosmer-Lemeshow (H-L) test to evaluate model's predictive accuracy. Overall, 470 (8%) patients had HRCAD on CCTA. There was no difference between the AUC for CHM and PHM (0.744 v.s. 0.721, p = 0.0873). Compared to CHM, PHM demonstrated a positive IDI (3.08%, p < 0.0001), positive NRI (12.50%, p < 0.0001) and less discrepancy between observed and predicted probabilities (H-L χ2 for CHM: 35.81, p < 0.0001; H-L χ2 for PHM: 23.75, p = 0.0025). Compared to CHM, PHM was associated with a more accurate prediction for HRCAD and might optimize downstream management strategy in symptomatic patients with DM. ClinicalTrials.gov (NCT04691037).


Quantum chaotic scattering in microwave resonators.
In a frequency range where a microwave resonator simulates a chaotic quantum billiard, we have measured moduli and phases of reflection and transmission amplitudes in the regimes of both isolated and of weakly overlapping resonances and for resonators with and without time-reversal invariance. Statistical measures for S -matrix fluctuations were determined from the data and compared with extant and/or newly derived theoretical results obtained from the random-matrix approach to quantum chaotic scattering. The latter contained a small number of fit parameters. The large data sets taken made it possible to test the theoretical expressions with unprecedented accuracy. The theory is confirmed by both a goodness-of-fit-test and the agreement of predicted values for those statistical measures that were not used for the fits, with the data.


Determination of Curcuminoids in Turmeric Raw Materials and Dietary Supplements by HPLC: Single-Laboratory Validation, First Action 2016.16.
The AOAC Expert Review Panel (ERP) approved a method for the quantitation of curcuminoids for consideration for First Action Official MethodSM status. The previously published method summarized a single-laboratory validation of three individual curcuminoinds-curcumin, demethoxycurcumin, and bis-demethoxycurcumin-in raw materials and finished products. Method performance was compared with AOAC Standard Method Performance Requirement 2016.003. With repeatability precision ranging from 0.3 to 5.5% and recoveries from 96.6 to 103.3% in the different product matrixes, the ERP adopted the method and provided recommendations for achieving Final Action status.


One versus 2 years of CMFVP adjuvant chemotherapy in axillary node-positive and estrogen receptor-negative patients: a Southwest Oncology Group study.
To determine if prolonged adjuvant treatment (2 years v 1 year) with combination chemotherapy (cyclophosphamide, methotrexate, fluorouracil [5-FU], vincristine, and prednisone [CMFVP]) in poor-prognosis breast cancer patients (estrogen receptor [ER]-negative, stage II to IIIA) would result in improved disease-free and overall survival rates. Four hundred forty-five women with ER-negative node-positive breast cancer were enrolled by the Southwest Oncology Group (SWOG) over a period of 5 years (1979 to 1984). Randomized assignments were made to either 1 or 2 years of adjuvant CMFVP. Doses were daily oral cyclophosphamide 60 mg/m2, intravenous (i.v.) weekly methotrexate 15 mg/m2, i.v. weekly 5-FU 400 mg/m2, i.v. weekly vincristine .625 mg/m2 for the first 10 weeks, and prednisone weeks 1 through 6 with doses decreasing from 30 mg/m2 to 10 mg/m2. The median follow-up duration is 8.6 years, with a maximum of 11.3 years. Treatment arms were not significantly different as regards either survival or disease-free survival rates (P = .33 and P = .24, respectively). The five-year survival rate is 57% on the 1-year arm and 62% on the 2-year arm. Patients with three or fewer nodes and premenopausal status were associated with improved survival. Compliance on the 2-year arm was poor, with only 37% completing the full 2 years of treatment. SWOG grade 3 to 4 toxicity was experienced by 47% of patients on the 1-year arm and by 52% on the 2-year arm. There were no treatment-related deaths. We conclude that 2-year adjuvant treatment with CMFVP is not an improvement over 1-year treatment. Moreover, 2 years of CMFVP is difficult to complete. However, the results are not definitely negative. A moderate improvement attributed to prolonged chemotherapy, especially among patients with four or more positive nodes, cannot be ruled out.


Phase I study of PM00104 (Zalypsis®) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors.
PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.


Social and psychosocial factors predicting depression in old age: a longitudinal study.
The predictive value of social and psychosocial factors for the occurrence of depression in elderly Finns is described using a longitudinal design. A population determined as not being depressed in an epidemiological study in 1984-1985 was clinically interviewed and examined in a follow-up study in 1989-1990 (N = 679). The potential predictive factors for depression were analyzed by contrasting the persons depressed in 1989-1990 with the ones not depressed. In men, depression was predicted by a poor relationship with one's wife and feelings about low appreciation of old persons or of the participant himself during the initial study and the loss of a mother while under 20 years of age. Certain changes and life events during the follow-up were related to the occurrence of depression in men, such as a change in the relationship with one's wife into a poorer direction, a decrease in the amount of hobbies, getting married, a grandchild's divorce, separation from someone important, moving into long-term institutional care, giving up hobbies or a position in a voluntary organization, and alcohol problems of a close person. In women, depression was predicted by living together with one's husband, living with other people, and a low activity in participating in religious events during the initial study and a loss of father while under 20 years of age. The risk of women living alone was lower compared to women not living alone. Also, certain changes and life events during the follow-up were associated with a high risk of depression in women, including a change in the relationship with one's neighbors into a poorer direction, an increase in the amount of time spent alone, a decline of the social activity level, getting married, occurrence of serious marital problems, separation from someone important, giving up hobbies or a position in a voluntary organization, alcohol problems of a close person, and a small number of social growth events. The results support the hypothesis about psychosocial factors playing a role in the etiology of depression in old age.


Prevalence and Factors Associated With Second Eye Cataract Surgery and the Trend in the Time Interval Between the Two Eye Surgeries Based on the Malaysian National Eye Database.
To study the prevalence of second eye cataract surgery (SECS), trend in time interval between subsequent surgeries over the years, and factors associated with SECS utilization among patients who underwent cataract surgeries in the Ministry of Health (MOH), Malaysia. Secondary cross-sectional analysis of the Malaysian National Eye Database (NED) data. The Malaysian Cataract Surgery Registry collected data on patients who had cataract surgery from 2002-2004 and 2007-2012. Data collected included demography, operative events, time interval between 2 surgeries, and postoperative visual outcomes. Descriptive analysis was performed. Total surgeries increased from 11,954 in 2002 to 30,265 in 2012 with a proportionate increase in SECS (30.7% in 2002 to 34.3% in 2012). Poor vision (<6/12) was reduced from 81.1% to 14.2% after surgery. With improved data capturing, missing data reduced from 29.22% to 1.05%. The time interval between surgeries was 10.58 months in 2002 and 14.49 months in 2012. Malays (40.2%) and those aged 61-70 years (38.1%) had the highest number of SECS. Those aged 40-50 years (10.96 months) and with poorer vision (9.97 months) had the shortest time interval between the 2 surgeries. The commonest surgical method was phacoemulsification (72.3%). Negeri Sembilan State had the highest SECS rate (35.91%) and Melaka had the shortest interval between surgeries (10.15 months). Despite an increase in the number of SECS, the time interval is still long. Poor presenting second eye vision and disparity among different states warrants the health authority's attention and intervention.


An immersive virtual reality system for ecological assessment of peripersonal and extrapersonal unilateral spatial neglect.
Unilateral spatial neglect (USN) is a debilitating neuropsychological syndrome that often follows brain injury, in particular a stroke affecting the right hemisphere. In current clinical practice, the assessment of neglect is based on old-fashioned paper-and-pencil and behavioral tasks, and sometimes relies on the examiner's subjective judgment. Therefore, there is a need for more exhaustive, objective and ecological assessments of USN. In this paper, we present two tasks in immersive virtual reality to assess peripersonal and extrapersonal USN. The tasks are designed with several levels of difficulty to increase sensitivity of the assessment. We then validate the feasibility of both assessments in a group of healthy adult participants. We report data from a study with a group of neurologically unimpaired participants (N = 39). The results yield positive feedback on comfort, usability and design of the tasks. We propose new objective scores based on participant's performance captured by head gaze and hand position information, including, for instance, time of exploration, moving time towards left/right and time-to-reach, which could be used for the evaluation of the attentional spatial bias with neurological patients. Together with the number of omissions, the new proposed parameters can result in lateralized index ratios as a measure of asymmetry in space exploration. We presented two innovative assessments for USN based on immersive virtual reality, evaluating the far and the near space, using ecological tasks in multimodal, realistic environments. The proposed protocols and objective scores can help distinguish neurological patients with and without USN.