Same-Day Versus Non-Simultaneous Extracorporeal Membrane Oxygenation Support for In-Hospital Cardiac Arrest Complicating Acute Myocardial Infarction.
Although extracorporeal membrane oxygenation (ECMO) is used for hemodynamic support for in-hospital cardiac arrest (IHCA) complicating acute myocardial infarction (AMI), there are limited data on the outcomes stratified by the timing of initiation of this strategy. Adult (>18 years) AMI admissions with IHCA were identified using the National Inpatient Sample (2000-2017) and the timing of ECMO with relation to IHCA was identified. Same-day vs. non-simultaneous ECMO support for IHCA were compared. Outcomes of interest included in-hospital mortality, temporal trends, hospitalization costs, and length of stay. Of the 11.6 million AMI admissions, IHCA was noted in 1.5% with 914 (<0.01%) receiving ECMO support. The cohort receiving same-day ECMO (N = 795) was on average female, with lower comorbidity, higher rates of ST-segment-elevation AMI, shockable rhythm, and higher rates of complications. Compared to non-simultaneous ECMO, the same-day ECMO cohort had higher rates of coronary angiography (67.5% vs. 51.3%; p = 0.001) and comparable rates of percutaneous coronary intervention (58.9% vs. 63.9%; p = 0.32). The same-day ECMO cohort had higher in-hospital mortality (63.1% vs. 44.5%; adjusted odds ratio 3.98 (95% confidence interval 2.34-6.77); p < 0.001), shorter length of stay, and lower hospitalization costs. Older age, minority race, non-ST-segment elevation AMI, multiorgan failure, and complications independently predicted higher in-hospital mortality in IHCA complicating AMI. Same-day ECMO support for IHCA was associated with higher in-hospital mortality compared to those receiving non-simultaneous ECMO support. Though ECMO-assisted CPR is being increasingly used, careful candidate selection is key to improving outcomes in this population.


Stimulation of platelet adhesion and activation by ganglioside GD3 adsorbed to plastic.
Platelet interaction with gangliosides GD3, GM3, GM1, GD1a and GT1b has been investigated. These gangliosides were previously identified in the vessel wall and ganglioside GD3 was found to accumulate selectively in the intima of atherosclerotic vessels. Gangliosides were adsorbed to plastic and incubated with 51Cr-labeled platelets. The adhesion of gel-filtered platelets to ganglioside GD3 was 3-4 times higher than to other immobilized gangliosides and to albumin-treated plastic. As was shown by scanning electron microscopy, GD3 stimulated intensive spreading of adherent platelets and formation of surface-bound aggregates, while only single unspread platelets were present on the surfaces coated with other gangliosides. GD3 isolated from milk and from human aorta possess the same stimulating activity. Platelet adhesion to GD3 decreased significantly in the presence of the stable prostacyclin analogue, carbacyclin.


Complex tunica albuginea cysts: a review of the literature.
Only 27 cases of tunica albuginea cysts have been reported. We review tunica albuginea cysts and describe the complex tunica albuginea cyst, a new entity not previously defined. A careful orderly approach to these lesions will result in a possible testicular sparing operation.


Brain oscillation recordings of the audience in a live concert-like setting.
There are only a few previous EEG studies that were conducted while the audience is listening to live music. However, in laboratory settings using music recordings, EEG frequency bands theta and alpha are connected to music improvisation and creativity. Here, we measured EEG of the audience in a concert-like setting outside the laboratory and compared the theta and alpha power evoked by partly improvised versus regularly performed familiar versus unfamiliar live classical music. To this end, partly improvised and regular versions of pieces by Bach (familiar) and Melartin (unfamiliar) were performed live by a chamber trio. EEG data from left and right frontal and central regions of interest were analysed to define theta and alpha power during each performance. After the performances, the participants rated how improvised and attractive each of the performances were. They also gave their affective ratings before and after each performance. We found that theta power was enhanced during the familiar improvised Bach piece and the unfamiliar improvised Melartin piece when compared with the performance of the same piece performed in a regular manner. Alpha power was not modulated by manner of performance or by familiarity of the piece. Listeners rated partly improvised performances of a familiar Bach and unfamiliar Melartin piece as more improvisatory and innovative than the regular performances. They also indicated more joy and less sadness after listening to the unfamiliar improvised piece of Melartin and less fearful and more enthusiastic after listening to the regular version of Melartin than before listening. Thus, according to our results, it is possible to study listeners' brain functions with EEG during live music performances outside the laboratory, with theta activity reflecting the presence of improvisation in the performances.


A gene toolbox for monitoring autophagy transcription.
Autophagy is a highly dynamic and multi-step process, regulated by many functional protein units. Here, we have built up a comprehensive and up-to-date annotated gene list for the autophagy pathway, by combining previously published gene lists and the most recent publications in the field. We identified 604 genes and created main categories: MTOR and upstream pathways, autophagy core, autophagy transcription factors, mitophagy, docking and fusion, lysosome and lysosome-related genes. We then classified such genes in sub-groups, based on their functions or on their sub-cellular localization. Moreover, we have curated two shorter sub-lists to predict the extent of autophagy activation and/or lysosomal biogenesis; we next validated the "induction list" by Real-time PCR in cell lines during fasting or MTOR inhibition, identifying ATG14, ATG7, NBR1, ULK1, ULK2, and WDR45, as minimal transcriptional targets. We also demonstrated that our list of autophagy genes can be particularly useful during an effective RNA-sequencing analysis. Thus, we propose our lists as a useful toolbox for performing an informative and functionally-prognostic gene scan of autophagy steps.


Sulfatides, L- and P-selectin ligands, exacerbate the intimal hyperplasia occurring after endothelial injury.
Leukocytes may be important in the development of intimal hyperplasia, but little is known about the participation of sulfatides (3-sulfated galactosyl ceramides) which are native ligands of L- and P-selectin. This study was designed to determine whether sulfatides affect the development of intimal hyperplasia. ICR mice were randomized to receive vehicle or sulfatides intravenously either at 1, 3, or 10 mg/kg/day for 7 days, or at 10 mg/kg/day for 1, 3, or 7 days. Endothelial damage was inflicted on the femoral artery via the photochemical reaction between rose bengal and green light. Scanning electron and light microscopic observations 3 days after the injury indicated that sulfatides-treated animals had more neutrophils adhering to the injury site than vehicle-treated controls. At 21 days, sulfatides-treated animals had a greater neointimal area than controls. In in vitro studies, sulfatides (i) increased cytosolic free calcium in mouse neutrophils, (ii) caused increases in expression of Mac-1 (CD 11 b/CD 18) on the neutrophil membrane surface in mouse whole blood. These findings suggest that neutrophil accumulation on the subendothelial matrix or adherence of platelets mediated by adhesive interactions between L- or P-selectin and sulfatides may contribute to the development of intimal hyperplasia. The neutrophil accumulation may be mediated by an increase in Mac-1 caused by the agonistic effects of sulfatides on the neutrophil membrane surface, or by an increase in L- and P-selectin ligands resulting from the binding of sulfatides onto the exposed subendothelial matrix.


Good for the heart, good for the Earth: proposal of a dietary pattern able to optimize cardiovascular disease prevention and mitigate climate change.
Human and planetary health are inextricably interconnected through food systems. Food choices account for 50% of all deaths for cardiovascular diseases (CVD) - the leading cause of death in Europe - and food systems generate up to 37% of total greenhouse gas (GHG) emissions. Based on a systematic revision of meta-analyses of prospective studies exploring the association between individual foods/food groups and the incidence of CVD, we identified a dietary pattern able to optimize CVD prevention.. This dietary pattern was compared to the current diet of the European population. The nutritional adequacy of both diets was evaluated according to the European Food Safety Authority (EFSA) recommended nutrient intake for the adult population, and their environmental impact was evaluated in terms of carbon footprint (CF). As compared to the current diet, the desirable diet includes higher intakes of fruit, vegetables, wholegrains, low glycemic index (GI) cereals, nuts, legumes and fish, and lower amounts of beef, butter, high GI cereals or potatoes and sugar. The diet here identified provides appropriate intakes of all nutrients and matches better than the current Europeans' one the EFSA requirements. Furthermore, the CF of the proposed diet is 48.6% lower than that of the current Europeans' diet. The transition toward a dietary pattern designed to optimize CVD prevention would improve the nutritional profile of the habitual diet in Europe and, at the same time, contribute to mitigate climate change by reducing the GHG emissions linked to food consumption almost by half.


Pavlov's conceptualization of unconditional reflexes, or instincts, within the framework of the theory of higher nervous activity.
According to I. P. Pavlov's theory of higher nervous activity, the establishment and dissolution of conditional reflexes enhances the higher organism's adaptation to the external environment. Pavlov asserted that, ontogenetically, conditional reflexes are based upon innate, unconditional reflexes (UR) or instincts. Pavlov did not distinguish between URs and instincts, but he preferred the former term. Phylogenetically the URs emerged out of well-established conditional reflexes during the development of higher organisms. An outgrowth of the experimental conditioning procedure, developed during the second decade of this century, was the observation and delineation of new URs. While studying human nervous and psychiatric disorders in the 1930s, Pavlov elucidated other URs. Pavlov identified 13 major URs, but he failed to formulate an exhaustive classification scheme of URs.


Siderophore biosynthesis genes of Rhizobium sp. isolated from Cicer arietinum L.
Rhizobium BICC 651, a fast-growing strain isolated from root nodule of chickpea (Cicer arietinum L.), produced a catechol siderophore to acquire iron under iron poor condition. A Tn5-induced mutant (B153) of the strain, BICC 651 impaired in siderophore biosynthesis was isolated and characterized. The mutant failed to grow on medium supplemented with iron chelator and grew less efficiently in deferrated broth indicating its higher iron requirement. The mutant produced less number of nodules than its parent strain. The Tn5 insertion in the mutant strain, B153, was located on a 2.8 kb SalI fragment of the chromosomal DNA. DNA sequence analysis revealed that the Tn5-adjoining genomic DNA region contained a coding sequence homologous to agbB gene of Agrobacterium tumefaciens MAFF301001. About 5 kb genomic DNA region of the strain BICC 651 was amplified using the primers designed from DNA sequence of agrobactin biosynthesis genes of A. tumefaciens MAFF 301001 found in the database. From the PCR product of the strain BICC 651, a 4,921 bp DNA fragment was identified which contained four open reading frames. These genes were designated as sid, after siderophore. The genes were identified to be located in the order of sidC, sidE, sidB, and sidA. Narrow intergenic spaces between the genes indicated that they constitute an operon. Phylogenetic analyses of deduced sid gene products suggested their sequence similarity with the sequences of the enzymes involved in biosynthesis of catechol siderophore in other bacteria.


Mutagenic effectiveness and efficiency of gamma rays and combinations with EMS in the induction of macro mutations in blackgram (Vigna mungo (L.) Hepper).
Blackgram, an important pulse crop of India and other Asian countries, is a rich source of protein. Genetic improvement in this crop is generally slow-paced due to the lack of wide genetic variability available for selection. To create variability for important morphological traits and yield, induced mutagenesis was attempted in a popular blackgram cultivar CO 6 using gamma rays (γ rays-60Co) and a combination of ethyl methanesulphonate (EMS) and gamma rays. In M1 generation, the mutagenic treatments of 200 Gy γ rays and 200 Gy + 20 mM EMS showed a high percentage of viable and chlorophyll mutants. However, in M2 generation, 400 Gy + 20 mM EMS generated a higher proportion of viable mutations. A broad spectrum of viable macro mutants namely variation in growth habit, duration, size of leaf and pod, nature of pod and seed, seed yield and protruded stigma mutant were observed. The combination treatments exhibited a maximum frequency of viable macro mutations. Among viable macro mutations, the growth habit mutants recorded maximum frequency, followed by leaf mutants and pod mutants. The protruded stigma mutant was isolated at the higher dose of 400 Gy of γ rays. Studies on palynological traits among fertile and sterile plants using Scanning Electron Microscopy (SEM) revealed variations in pollen and anther length and shape among the mutants. The pollen lumina and muri shape in the fertile plant were observed as polygonal and narrow straight, whereas it was collapsed in the sterile plant. The inheritance pattern for most of the viable macro mutants was true-breeding which was further confirmed in the M3 generation. These viable mutants could be used for the blackgram improvement program.


Endometrial inadequacy after treatment with human menopausal gonadotropin/human chorionic gonadotropin.
The incidence of abnormal endometrial histology in patients undergoing human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) treatment during cycles of in vitro fertilization (IVF) or gamete intrafallopian transfer has been reported to be 52% to 91%. The incidence of endometrial inadequacy, as judged by a single late luteal endometrial biopsy, has not been studied in hMG/hCG non-IVF cycles. In the current study, 30 patients (30 cycles) undergoing hMG/hCG treatment were evaluated by an endometrial biopsy. The incidence of endometrial inadequacy was found to be 27%. No preovulatory predictors for endometrial inadequacy could be identified. Therefore, luteal support for patients undergoing non-IVF hMG/hCG cycles should be considered.


Indications, clinical outcome and survival of rotating hinge total knee arthroplasty in a retrospective study of 63 primary and revision cases.
The purpose of this study is to report and compare outcome data of both primary and revision cases using a rotating hinge knee (RHK) implant. This study retrospectively analyzed 63 cases (19 primary, 44 revisions) at a mean follow-up of 34 ± 8 months after RHK implantation. Outcome parameters were stability, range of motion (ROM), loosening, Hospital of Special Surgery Score (HSS), Knee Society Score (KSS), Oxford Knee Score (OKS), EQ-5D-3L, and Visual Analog Scale (VAS) for overall function. Revision rates and implant survival are reported. Eleven percent showed medio-lateral instability < 5 mm, a mean ROM of 115° ± 17° and radiologic loosening occurred in 8% (2% symptomatic). PROMS showed the following results: HSS 79 ± 18, KSS 78 ± 27, OKS 26 ± 10, EQ-5D index 0.741 ± 0.233 and VAS 70 ± 20. Primary cases revealed better outcomes in HHS (p = .035) and OKS (p = 0.047). KSS, EQ-5D index and VAS did not differ between primary and revision cases (p = 0.070; p = 0.377; p = 0.117). Revision rate was 6.3% with an implant survival of 96.8%. RHK arthroplasty can be performed with good clinical outcome and low revision rate in revision and complex primary cases. RHK is an option in cases where standard arthroplasty and even implants with a higher degree of constraint have reached their limits. Level III, retrospective cohort study.


Denosumab Can Prevent Collapse in Patients with Early-Stage Steroid-Induced Osteonecrosis of the Femoral Head by Inhibiting Osteoclasts and Autophagy.
The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid-induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. This was a retrospective study. A total of 161 patients with steroid-induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann-Whitney U test and chi-square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2 = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627-0.973). The excellent-good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2 = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2 = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2 = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3-II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = -2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272-3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024-2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245-3.487; large necrotic area: OR = 2.211, 95% CI = 1.255-3.893). The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy.


Comparison of polymerase chain reaction and conventional methods for diagnosis of Listeria monocytogenes isolated from different clinical specimens and food stuffs.
Listeria monocytogenes has emerged as a significant food borne pathogen in recent decades. Polymerase chain reaction (PCR) is deemed to be more reliable than conventional methods of identification. This work aimed to evaluate the accuracy of PCR in comparison to conventional methods for the diagnosis of L. monocytegenes from different clinical specimens and food stuffs. This study was conducted on 66 clinical specimens and 100 different food stuffs. On the basis of colonial morphology, Gram's stain, catalase test, haemolysis on sheep blood agar, and motility test, Listeria isolates were further identified to species level by 10300 API Listeria strips. PCR was done directly for all specimens to evaluate its accuracy in comparison to conventional methods of diagnosis. A total of 5 (7.6%) same L. monocytogenes isolates were identified both by the conventional method and PCR in different clinical samples. However, PCR identified 6 (6%) L. monocytogenes isolates from food stuffs versus 4 (4%) isolates were identified by conventional methods. PCR is a rapid procedure with both sensitivity and specificity for quick detection and identification of L. monocytogenes either from clinical specimens or food stuffs.


The effects of hypnotherapy during transrectal ultrasound-guided prostate needle biopsy for pain and anxiety.
Several studies evaluating the tolerance of transrectal ultrasound (TRUS)-guided needle biopsies showed that moderate-to-severe pain was associated with the procedure. Additionally, prebiopsy anxiety or rebiopsy as a result of a prior biopsy procedure is mentioned as factors predisposing to higher pain intensity. Thus, in this study, we investigated the effects of hypnotherapy during transrectal ultrasound-guided prostate needle biopsy for pain and anxiety. Sixty-four patients presenting for TRUS-guided prostate needle biopsy were randomly assigned to receive either 10-min presurgery hypnosis session (n = 32, mean age 63.5 ± 6.1, p = 0.289) or a presurgery control session (n = 32, mean age 61.8 ± 6.8, p = 0.289). The hypnosis session involved suggestions for increased relaxation and decreased anxiety. Presurgery pain and anxiety were measured using visual analog scales (VAS), Beck Anxiety Inventory (BAI), and Hamilton Anxiety Scale (HAS), respectively. In our statistics, p < 0.05 was considered statistically significant. Postintervention, and before surgery, patients in the hypnosis group had significantly lower mean values for presurgery VAS [mean 1 (0-8); p = 0.011], BAI (6.0 vs 2.0; p < 0.001), and HAS (11.0 vs 6.0; p < 0.001). The study results indicate that a brief presurgery hypnosis intervention can be an effective means of controlling presurgical anxiety, and therefore pain, in patients awaiting diagnostic prostate cancer surgery.


Public attitudes towards bystander CPR and their association with social deprivation: Findings from a cross sectional study in North England.
Bystander cardiopulmonary resuscitation (BCPR) is undertaken in only 40% of out of hospital cardiac arrests (OHCAs) in the UK. Lower rates of BCPR and public access defibrillator (PAD) use have been correlated with lower socio-economic status (SES). The aim of this study was to examine knowledge and attitudes towards BCPR and PAD's using a study specific questionnaire, and to understand how these potentially interact with individual characteristics and SES. Cross-sectional study between July-December 2021 across areas of varying SES in North England. Six hundred and one individuals completed the survey instrument (mean age = 51.9 years, 52.2 % female). Increased age was associated with being less willing to call 999 (p < 0.001) and follow call handler advice (p < 0.001). Female respondents were less comfortable performing BCPR than male respondents (p = 0.006). Individuals from least deprived areas were less likely to report comfort performing CPR, (p = 0.016) and less likely to know what a PAD is for, (p = 0.025). Higher education level was associated with increased ability to recognise OHCA (p = 0.005) and understanding of what a PAD is for (p < 0.001). Individuals with higher income were more likely to state they would follow advice regarding BCPR (p = 0.017) and report comfort using a PAD (p = 0.029). Individual characteristics such as age and ethnicity, rather than SES, are indicators of knowledge, willingness, and perceived competency to perform BCPR. Policy makers should avoid using SES alone to target interventions. Future research should examine how cultural identity and social cohesion intersect with these characteristics to influence willingness to perform BCPR.


To run or not to run? That is the question: exercise and reduced risk of coronary heart disease.
The recent National Fitness Survey has drawn attention to the population's low level of physical (aerobic) fitness and low level of activity. About one-third of middle-aged men and one-half of middle-aged women in England are unfit for continuous walking at a normal pace of about 3 mph. Similar fitness levels were shown for the Welsh population. At the same time, coronary heart disease (CHD) accounts for about 26% of deaths in England, and for 2.5% of the NHS expenditure. The suggestion that low fitness levels and low levels of physical activity are associated with a high incidence of CHD has been widely voiced since Morris's first study, and has more recently been the subject of editorials in the British Heart Journal and the BMJ.


The acute effects of low flow oxygen and isosorbide dinitrate on left and right ventricular ejection fractions in chronic obstructive pulmonary disease.
The objectives of this study were to determine the effects of low flow oxygen and isosorbide dinitrate on rest and exercise biventricular ejection fractions in patients with chronic obstructive pulmonary disease and to relate these ejection fraction responses to changes in pressure and flow. Nine patients with stable, moderate to severe chronic obstructive pulmonary disease who had no prior history of heart failure performed supine exercise with simultaneous hemodynamic and radionuclide ventriculographic monitoring. Eight patients performed a second exercise during low flow oxygen breathing and five performed a third exercise after ingesting 10 mg oral isosorbide. Oxygen led to a decrease in exercise pulmonary artery pressure in all subjects and a decline in total pulmonary resistance in five of the seven in whom it was measured. Right ventricular ejection fraction increased 0.05 or more only in subjects who had a decrease in total pulmonary resistance. Isosorbide fed to an increase in rest and exercise right and left ventricular ejection fractions with simultaneous decreases in pulmonary artery pressure, total pulmonary resistance, blood pressure and arterial oxygen tension. These results suggest that in patients with chronic obstructive pulmonary disease but without a history of right heart failure, the right ventricular systolic functional response to low flow oxygen and isosorbide at rest and exercise is, in part, determined by changes in total pulmonary resistance. The chronic relation between right ventricular ejection fraction and pulmonary hemodynamics in patients with chronic obstructive pulmonary disease remains to be evaluated.


Sensitivity and resistance risk of Botryosphaeria dothidea causing Chinese hickory trunk canker to fludioxonil.
Hickory trunk canker (HTC), primarily caused by Botryosphaeria dothidea, is an aggravating disease that threatens an important regional economic tree species of Chinese hickory and few information is available in the control of this disease. Here, the sensitivity of 93 isolates to fludioxonil and the resistance risk were investigated. All the isolates tested were sensitive to fludioxonil and the EC50 ranged from 0.0028 to 0.0569 μg/mL. The tamed fludioxonil-resistant mutants remained highly resistant to fludioxonil even after 10 consecutive transfers to fludioxonil-free PDA plates. As for fitness penalty, the fludioxonil-resistant mutants demonstrated a reduction in conidia production and virulence as well as increased sensitivity to high osmotic stress. While, variations in mycelial growth and responses to SDS and H2O2 were not detected in all the resistant mutants. In addition, the resistant mutants demonstrated positive cross-resistance to iprodione but not to fungicides of other modes of action. Sequential analysis of BdNik1 showed that premature stop codon occurred in all the resistant mutants despite of point mutation (BD16-22R9 and BD16-22R20) or frameshift mutation (BD16-22R8, BD16-22R11 and BD16-22R18). Our study suggested that fludioxonil exhibited excellent inhibition activity on mycelial growth of B. dothidea in vitro, the resistance risk of B. dothidea to fludioxonil should be low to moderate and fludioxonil would be a nice candidate in controlling HTC caused by B. dothidea.


Neutropenia associated with dual antimalarial chemoprophylaxis--use of bone-marrow culture as an aid in further drug management.
Bone-marrow culture in soft agar was used to determine the cause of neutropenia in a visitor to Tanzania who had been taking both amodiaquine and proguanil for antimalarial prophylaxis. Desethyl-amodiaquine, a major metabolite of amodiaquine (but not amodiaquine itself, proguanil, cycloguanil or chloroquine) was implicated. Supplementary studies using amodiaquine binding techniques supported the notion that the parent compound, amodiaquine, was not the cause of the neutropenia. The bone-marrow culture technique proved useful in deciding further anti-malarial prophylaxis and in formulating the choice of curative antimalarial therapy, should this have proved necessary. The procedure may help in the managing other such patients with presumed drug-induced blood dyscrasias when the choice of appropriate and effective antimalarial drugs is limited.


Artificial intelligence based methods for hot spot prediction.
Proteins interact through their interfaces to fulfill essential functions in the cell. They bind to their partners in a highly specific manner and form complexes that have a profound effect on understanding the biological pathways they are involved in. Any abnormal interactions may cause diseases. Therefore, the identification of small molecules which modulate protein interactions through their interfaces has high therapeutic potential. However, discovering such molecules is challenging. Most protein-protein binding affinity is attributed to a small set of amino acids found in protein interfaces known as hot spots. Recent studies demonstrate that drug-like small molecules specifically may bind to hot spots. Therefore, hot spot prediction is crucial. As experimental data accumulates, artificial intelligence begins to be used for computational hot spot prediction. First, we review machine learning and deep learning for computational hot spot prediction and then explain the significance of hot spots toward drug design.


Cloning and molecular characterization of a gene coding D-xylulokinase (CmXYL3) from Candida maltosa.
To clone and identify a gene (CmXYL3) coding D-xylulokinase from Candida maltosa Xu316 and understand its physiological function. Based on the conserved regions of the known D-xylulokinase-encoding genes, a pair of degenerate primers was designed to clone the CmXYL3 gene from C. maltosa Xu316. The coding region and sequences flanking the CmXYL3 gene were obtained by PCR-based DNA walking method. Southern blotting analysis suggested that there is a single copy of the CmXYL3 gene in the genome. The open reading frame starting from ATG and ending with TAG stop codon encoded 616 amino acids with a calculated molecular mass of 68889.743 Da. The CmXYL3 gene under the control of the GPD1 promoter was heterologously expressed in Saccharomyces cerevisiae deficient in D-xylulokinase (deltaScXKS1::LEU2) activity, and restored growth on D-xylulose. The specific activity of D-xylulokinase varied during xylose fermentation and was correlated with aeration level. After growth on different pentoses and pentitols as sole carbon sources, the highest specific activity of D-xylulokinase was observed on D-xylose. The CmXYL3 gene isolated from C. maltosa Xu316 encodes a novel D-xylulokinase that plays a pivotal role in xylulose metabolism. This is the first report that describes the isolation and cloning of D-xylulokinase gene (CmXYL3) from C. maltosa Xu316. D-xylulokinase is pivotal for growth and product formation during xylose metabolism. Better understanding of the biochemical properties and the physiological function of D-xylulokinase will contribute to optimizing fermentation conditions and determining the strategies for metabolic engineering of C. maltosa Xu316 for further improvement of xylitol yield and productivity.


Adaptation and validation of a method for evaluating the bactericidal activity of ethyl alcohol in gel format 70% (w/w).
Ethyl alcohol 70% (w/w) is a broad-spectrum bactericidal agent that is mandatorily marketed as a gel in Brazil since 2002. However, there is no method described for the microbiological quality control of surface disinfectants in the form of gel, which makes it impossible to monitor the effectiveness of these products by the Health Surveillance. Thus, the present study aimed to adapt an analytical method and validate it so that it is possible to evaluate the bactericidal activity of ethyl alcohol-based disinfectants at 70% (w/w) in gel form. The proposed analytical method is an adaptation of a method developed by the Association of Official Analytical Chemists (AOAC), which is currently used to evaluate the bacterial activity of disinfectants in the form of spray and aerosol. The method consisted of challenging the disinfectant by putting it in contact with 60 carriers - previously contaminated with the test microorganism - during the contact time established by the manufacturer. The bacteria used in this work were Staphylococcus aureus CBRVS 00039 ATCC 6538, Salmonella enterica CBRVS 00028 ATCC 10708, and Pseudomonas aeruginosa CBRVS 00025 ATCC 15442. The parameters chosen for the validation of the method were: matrix effect, robustness, and repeatability. The experiments performed with a disinfectant matrix showed that there is no interference of the gel on the effectiveness of alcohol. Satisfactory results regarding the evaluation of bactericidal activity were obtained for the three microorganisms tested when the volume of 100 μL of disinfectant was applied. The method also showed good repeatability, as it proved to be robust with modification of incubation times, equipment and analysts. The development and validation of this method were extremely important for the quality monitoring of these products, besides being the first method described for the evaluation of gel disinfectants.


Acquisition of Sexually Transmitted Infections among Women Using a Variety of Contraceptive Options: A prospective Study among High-risk African Women.
In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV-1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long-acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV-1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods. MTN-020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV-1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin-based injectables or implants during follow-up. Screening for the above STIs occurred semi-annually. Over 3440 person-years of follow-up, 408 cases of C. trachomatis (incidence 11.86/100 person-years), 196 of N. gonorrhoeae (5.70/100 person-years) and 213 cases of T. vaginalis (6.19/100 person-years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users. Among African women at high HIV-1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin-based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.


Clinical relevance of Ki67 gene expression analysis using formalin-fixed paraffin-embedded breast cancer specimens.
Ki67 is a protein associated with cell cycle activity and shows a good correlation with the growth fraction, which has been proposed as a prognostic or predictive marker in breast cancer. In this study, we aimed to analyze the expression levels of Ki67 (MKI67) messenger RNA (mRNA) derived from formalin-fixed paraffin-embedded (FFPE) tissues for comparison with the immunohistochemical Ki67 labeling index, and investigate the correlation coefficients with clinical outcomes. We analyzed the data of Ki67 mRNA from FFPE and matched fresh-frozen (FF) tissues based on a real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay system in 203 cases of primary invasive breast cancer. The correlation between Ki67 mRNA expression of either FFPE or FF specimens and Ki67 labeling index was positive, as was the correlation between the FFPE and FF results (P < 0.0001). Ki67 mRNA expression of FFPE specimens was significantly associated with clinicopathological characteristics: tumor size, lymph node status, nuclear grade, hormone receptors, human epidermal growth factor receptor 2 (Her2) status, and tumor subtype. In prognostic results, Ki67 gene expression in the FFPE specimens revealed almost similar patterns of significance in Kaplan-Meier curves and univariate and multivariate relapse-free survival results as the Ki67 labeling index. Gene expression analysis of Ki67 of FFPE specimens could be successfully performed using RT-qPCR, closely resembling the significant clinical characteristics of Ki67 labeling index. These results confirm that Ki67 gene expression of FFPE specimens has potential for evaluation of cell cycle activity of breast cancer specimens.


Chromosomal regions harboring genes for the work to femur failure in mice.
The work to failure is defined as the maximum energy bone can absorb before breaking, and therefore is a direct test of the risk of fracture. To determine the genetic loci influencing work to failure, we have performed a high density genome-wide scan in 633 (MRL x SJL) F(2) female mice. Five loci ( P<0.005) with significant effects on work to failure were found on chromosomes 2, 7, 8, 9, and X, which collectively explained around 20% variance of work to femur failure in F(2) mice. Of those, only the QTL on chromosome 9 was concordant with bone mineral density (BMD) QTLs. Eight significant interactions ( P<0.01) between marker loci were identified, which accounted for an equivalent amount of F(2) variance (23%) to combined single QTL effects. Our results demonstrate that most of the genetic loci regulating work to failure are different from those for BMD in the 7-week-old female mice. If this is also true in humans, this finding will challenge the predictive value of BMD for the risk of fracture.


Urinary inhibitors of calcium phosphate formation: the inhibitory activity of normal and artificial urines.
Eelven urine samples from normal subjects inhibited the formation of calcium phosphate. In all cases the activity of the urine was identical with that of an artificial urine having the same concentration of urea, creatinine, sodium, potassium, magnesium, calcium, ammonia, sulphate, chloride, inorganic phosphate, citrate, isocitrate and pyrophosphate, and the same pH.


Thyroid function in wholly breast-feeding infants whose mothers take high doses of propylthiouracil.
Propylthiouracil (PTU) might theoretically be preferred over methimazole (MMI) during breast-feeding because of its lower milk/serum concentration ratio (0.1 vs. 1.0). The problem is that Graves' disease often relapses during the postpartum period, and high doses of PTU are sometimes needed to control maternal hyperthyroidism) during breast-feeding. However, there are virtually no data on the effects of maternal PTU on thyroid status of infants whose mothers take more than 300 mg PTU daily and who are wholly breast-feeding. To investigate whether mothers can breast-feed without adverse effects on infants' thyroid status while taking 300 mg or more daily of PTU. Eleven infants who were wholly breast-fed while their mothers took PTU 300-750 mg daily for Graves' hyperthyroidism were included in this study. In one of the 11 infants, the mother also took iodine 6 mg daily for a limited period. Thyroid status in these infants was evaluated. Free T4 (FT4), thyrotrophin (TSH), and TSH binding inhibiting antibody (TBIAb) concentrations were examined at least once in the age range 6 days to 9 months. Maternal blood was also examined for FT4 and TBIAb on the same day, or within a week, of the infants' blood tests. FT4, TSH and TBIAb concentrations at birth were examined, using cord blood, in cases where antithyroid drugs had been continued through delivery. Three of the 11 infants had TSH concentrations higher than the normal range for adults. In one of the three infants, the TSH concentration, which was determined 19 weeks after birth, was just above the normal range. In the remaining two infants whose mothers had taken PTU through delivery, TSH concentrations, determined within 7 days after birth, were distinctly high, but they became normal while maternal PTU doses were the same as or higher than those at the initial examination. Maternal PTU doses or FT4 concentrations were not significantly correlated with infants' TSH concentrations. Mothers can breast-feed while taking propylthiouracil at doses as high as 750 mg daily without adverse effects on thyroid status in their infants.


Comparison of the intrinsic kinase activity and substrate specificity of c-Abl and Bcr-Abl.
We studied the intrinsic tyrosine kinase activity and substrate specificity of c-Abl and Bcr-Abl protein tyrosine kinases (PTKs) using the peptide substrates discovered from a synthetic combinatorial peptide library. Our data indicate that the phosphorylation of these peptides by Bcr-Abl was consistently stronger than that by c-Abl. Bcr-Abl also showed substrate preference towards those peptides with one or more positive charges.


The treatment of multiple lipomas by liposuction surgery.
When lipomas reach 4 cm or more in size or are multiple, liposuction becomes an excellent alternative to excisional surgery, which is the treatment of choice for small lipomas. Two cases of multiple lipomas treated by liposuction surgery are presented.


Identification of infants at high-risk for autism spectrum disorder using multiparameter multiscale white matter connectivity networks.
Autism spectrum disorder (ASD) is a wide range of disabilities that cause life-long cognitive impairment and social, communication, and behavioral challenges. Early diagnosis and medical intervention are important for improving the life quality of autistic patients. However, in the current practice, diagnosis often has to be delayed until the behavioral symptoms become evident during childhood. In this study, we demonstrate the feasibility of using machine learning techniques for identifying high-risk ASD infants at as early as six months after birth. This is based on the observation that ASD-induced abnormalities in white matter (WM) tracts and whole-brain connectivity have already started to appear within 24 months after birth. In particular, we propose a novel multikernel support vector machine classification framework by using the connectivity features gathered from WM connectivity networks, which are generated via multiscale regions of interest (ROIs) and multiple diffusion statistics such as fractional anisotropy, mean diffusivity, and average fiber length. Our proposed framework achieves an accuracy of 76% and an area of 0.80 under the receiver operating characteristic curve (AUC), in comparison to the accuracy of 70% and the AUC of 70% provided by the best single-parameter single-scale network. The improvement in accuracy is mainly due to the complementary information provided by multiparameter multiscale networks. In addition, our framework also provides the potential imaging connectomic markers and an objective means for early ASD diagnosis.


The mutational footprints of cancer therapies.
Some cancer therapies damage DNA and cause mutations in both cancerous and healthy cells. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicity and secondary neoplasms. Nevertheless, the burden of mutation contributed by different chemotherapies has not been explored. Here we identify the mutational signatures or footprints of six widely used anticancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs as well as a previously unknown signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precise assessment of the mutational risk of different cancer therapies to understand their long-term side effects.


Prostaglandin E2 receptor EP4-selective antagonist inhibits lipopolysaccharide-induced cervical ripening in rabbits.
The purpose of this study was to examine whether EP4 as prostaglandin (PG) E2 receptor is involved in lipopolysaccharide (LPS)-induced cervical ripening. New Zealand White non-pregnant rabbits were randomly allocated to 4 equal groups and treated with vaginal suppositories containing LPS with various concentrations of EP4-selective antagonist once daily for 3 days, and then sacrificed for analysis. Analysis was performed in order to examine the inhibitory effect of EP4 antagonist on LPS-induced cervical ripening. The expression of EP4 in a cervix treated with LPS was examined immunohistochemically. The percent of cervical extensibility in the segment of cervix as the tensile strength was determined with 5.8 g of constant perpendicular stretching. The ripening area of the cervix with edematous changes in H&E sections was calculated by a microscopic system with a computer-assisted digital analyser. Type-1 collagenase activity was determined in cervical tissue using FITC-labelled type-1 collagen. Immunohistochemical study shows the positive staining of EP4 at the interstitial cells in the cervix treated with LPS. The extensibility, cervical edematous area and type-1 collagenase activity are significantly reduced in the cervix treated with LPS in the presence of EP4 antagonist compared with that treated with LPS alone. These data implicates the EP4 as the PGE2 receptor involved in LPS-induced cervical ripening.


The techniques of sphincter-saving extrasphincteric dissection and proximal segmental sphincteric excision in low rectal cancer surgery.
To define the techniques used in lower rectal cancer surgery, by transvaginal and transperineal approach; extrasphincteric dissection, proximal segmental sphincteric excision and transsphincteric rectal resection. Between 2007 and 2013, 7 patients (4 female, 3 male with lower rectal cancer were operated by sphincter-saving extrasphincteric disection and proksimal sphincteric excision techniques. After completion of the rectosigmoid dissection and total mesorectal excision up to the puborectal muscle level; extrasphincteric rectal dissection, transsphincteric rectal resection and ultra-low coloanal anastomosis were performed by using the transvaginal and transperineal approach in the sublevator phase of the operation. Seven patients were operated with sublevator access for lower rectal cancer. Bowel contiunity has been provided in all patients. One patient died due to surgical complications in the early postoperative period. One patient deceveloped anastomotic leakage and there were two patients with anastomotic stricture. Circumferential resection margin and tumoral perforation were found negative in all of the patients. Tumoral deposits at the distal resection line was observed in one patient. The techniques of sublevator rectal resection may be considered as an alternative sphincter-saving surgical method, especially in lower rectal cancer surgery.


Multidimensional reduction of multicentric cohort heterogeneity: An alternative method to increase statistical power and robustness.
Modern clinical research takes advantage of multicentric cohorts to increase sample size and gain in statistical power. However, combining individuals from different recruitment centers provides heterogeneity in the dataset that needs to be accounted for to obtain robust results. Sophisticated statistical multivariate models adjusting for center effect can be implemented, but they can become unstable and can be complex to interpret with the increasing number of covariates to consider. Here, we present a multidimensional reduction technique to identify heterogeneity in a French multicentric cohort of hematopoietic stem cell transplantations and characterize a homogeneous subgroup prior to performing simple statistical univariate analyses. The exclusion of outliers allowed the identification of two genetic factors associated with post-transplantation overall survival. We therefore provide proof-of-concept that a sample size reduction method can efficiently account for heterogeneity and center effect in multicentric cohorts while increasing statistical power and robustness for discovery of new association signals.


Molecular characterization and evaluation of the antibacterial activity of a plant defensin peptide derived from a gene of oat (Avena sativa L.).
Plant defensins are a group of small disulfide-rich cationic peptides that exhibit a broad spectrum of antimicrobial activities. In the present study, an antibacterial plant defensin peptide was successfully identified and characterized from the transcriptome of the oat (Avena sativa L.), and called AsDef1. The complete nucleotide sequence of AsDef1 was determined (321 bp) and found to contain an open reading frame (ORF) encoding a peptide of 77 aa with a putative 22 aa signal peptide sequence that addresses the mature defensin to the apoplast. Further in silico analyses revealed that the structure of the identified defensin (AsDef1) consists of the Knot1 functional domain with eight conserved cysteine residues and four disulfide bonds. The highest expression of AsDef1 was observed in the developing seeds of the A. sativa plant. AsDef1 also showed antibacterial activity against both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values ranged from 0.15625 μM to 0.625 μM. In this study, we identified and characterized an antibacterial defensin from A. sativa for the first time. The findings of the present study offer insights that can be used in producing pathogen-resistant transgenic plants and in developing potential antibacterial agents in the future using AsDef1 from A. sativa.


Rhizodegradation gradients of phenanthrene and pyrene in sediment of mangrove (Kandelia candel (L.) Druce).
A greenhouse experiment was conducted to evaluate degradation gradient of spiked phenanthrene (Ph, 10 mg kg(-1)) and pyrene (Py, 10 mg kg(-1)) in rhizosphere of mangrove Kandelia candel (L.) Druce. Rhizosphere model system was set up using a self-design laminar rhizoboxes which divided into eight separate compartments at various distances from the root surface. After 60 days of plant growth, presence of the plant significantly enhanced the dissipation of Ph (47.7%) and Py (37.6%) from contaminated sediment. Higher degradation rates of the PAHs were observed at 3mm from the root zone (56.8% Ph and 47.7% Py). The degradation gradient followed the order: near rhizosphere>root compartment>far-rhizosphere soil zones for both contaminants where mangrove was grown. Contribution of direct plant uptake and accumulation of Ph and Py were very low compared to the plant enhanced dissipation. By contrast, plant-promoted biodegradation was the predominant contribution to the remediation enhancement. The correlation analysis indicates a negative relation between biological activities (microbial biomass carbon, dehydrogenase, urease, and phosphatase activity) and residual concentrations of Ph and Py in planted soils. Our results suggested that mangrove rhizosphere was effective in promoting the depletion of aromatic hydrocarbons in contaminated sediments.


Impact of alcohol drinking on gastric cancer development according to Helicobacter pylori infection status.
Helicobacter pylori are major carcinogen of gastric cancer, but the associations among gastric cancer, H. pylori infection status, and alcohol consumption are not fully described. This study aimed to clarify how H. pylori infection status affects the association between alcohol consumption and gastric cancer risk. We selected 949 case-cohort participants from the 18,863 Korean Multi-center Cancer Cohort (KMCC) populations. Gastric cancer incidence inside and outside of the subcohort were 12 and 254 cases, respectively. Seropositivities for CagA, VacA, and H. pylori infection were determined by performing immunoblot assays. Weighted Cox regression models were used to calculate hazard ratios and 95% confidence intervals (CIs). Relative to non-drinking, heavy drinking (⩾7 times a week), and binge drinking (⩾55 g alcohol intake per occasion) showed a 3.48-fold (95% CI, 1.13-10.73) and 3.27-fold (95% CI, 1.01-10.56) higher risk in subjects not previously infected by H. pylori. There was no significant association between drinking pattern and gastric cancer risk in H. pylori IgG seropositive subjects. An increased risk for gastric cancer in heavy- and binge-drinking subjects were also present in subjects not infected by CagA- or VacA-secreting H. pylori. Heavy and binge alcohol consumption is an important risk factor related to an increasing incidence of gastric cancer in a population not infected by H. pylori.


Subcellular localization of beta-catenin and cadherin expression in the cap-stage enamel organ of the mouse molar.
We analyzed the subcellular distribution of beta-catenin in the cap-stage enamel organ and compared it with the expression of E- and P-cadherin by using confocal laser microscopy. The amounts of the molecules in the cytoplasm and the nucleus showed regional variations in the enamel organ, whereas cell surface-associated beta-catenin was ubiquitous. In both the enamel knot and the inner dental epithelium, beta-catenin was detected in the cytoplasm and in the nucleus. However, the amount of nuclear beta-catenin was apparently higher in the enamel knot than in the inner dental epithelium. P-cadherin also gave a stronger signal in the enamel knot than in other parts of the enamel organ. In the stellate reticulum, where E-cadherin was preferentially expressed, as well as in the cervical loop and outer dental epithelium, beta-catenin was localized in the cytoplasm but not in the nucleus. The nuclear localization of beta-catenin in the enamel knot suggests a specific activation of the canonical Wnt signaling pathway. A coincident upregulation of P-cadherin was observed in this area. Altogether, these observations suggest the possibility of a linkage between cell adhesion and Wnt signaling in the enamel knot.


Same day discharge does not lead to worse outcomes in patients undergoing uncomplicated laparoscopic foregut surgery.
With the advancement of minimally invasive surgical techniques surgeons have moved away from elective open foregut surgeries. Despite studies demonstrating the safety of same day discharge in appropriate patient populations, ambulatory surgery has yet to be established as the practice norm for patients undergoing uncomplicated laparoscopic foregut surgery. The ACS-NSQIP database was queried from 2005 to 2018 for patients who had undergone elective and non-emergent laparoscopic Heller myotomy, fundoplication, and paraesophageal hernia repairs with and without mesh. The primary endpoints in this study included number and severity of complications as classified by the Clavien-Dindo Classification, readmission, and return to the operating room. 6893 patients who met inclusion criteria were identified, 696 (10.1%) of which were discharged on the day of surgery. Patients who were discharged on post-operative day one were matched at a 3:1 ratio producing 2088 comparisons. There was no difference in overall morbidity (p = 0.264), readmission (OR 0.849, 95% CI 0.522-1.419), or return to the operating room (OR 1.15, 95% CI 0.531-2.761) between the two groups. Same day discharge for patients without life threatening comorbidities undergoing elective minimally invasive Heller myotomy, Nissen and Toupet fundoplication, and paraesophageal hernia repairs is safe and feasible.


Multi-targeted fluorescent probes for detection of Zn(II) and Cu(II) ions based on ESIPT mechanism.
With the rapid development of industry, it is pretty critical to detect the heavy metals. Recently, the 2-(2-hydroxyphenyl) benzothiazole derivatives with different numbers of rotatable phenyl m (m = 1,2,3) fluorescent probes HLm were synthesized. However, the theoretical analysis of the mechanism was still missing. In this work, we have systematically researched the mechanisms of excited state intramolecular proton transfer (ESIPT) and the detection of Cu(II), Zn(II) ions for the hydrogen-bond system HLm though quantum chemistry methods. By bond parameters and the minimum energy pathways analyses, the proton of this system was probed directly transfer without barrier. Bond parameters, real space function at bond critical point, the frontier molecular orbital, electron spectra and orbital interaction diagram were carried to elucidate response to Cu(II), Zn(II) ions. In addition, comparing the Gibbs free energy variation of the complexation reaction between fluorescent probes and ions, it can be proved that the number of rotatable benzene rings affects the response ability of the probe to target ions.


Evaluation of Association Between Menstrual Cycle Timing and Quantitative Background Parenchymal Enhancement on Breast MRI in Premenopausal Women.
To evaluate the influence of menstrual cycle timing on quantitative background parenchymal enhancement and to assess an optimal timing of breast MRI in premenopausal women. A total of 197 premenopausal women were enrolled, 120 of which were in the malignant group and 77 in the benign group. Two radiologists depicted the regions of interest (ROI) of the three consecutive biggest slices of glandular tissue in the unaffected side and calculated the ratio (=[SIpost - SIpre]/SIpre) in ROI from the precontrast and early phase to assess BPE quantitatively. Association of BPE with menstrual cycle timing was compared in three categories. The relationships between BPE and age /body mass index (BMI) were also explored. We found that the BPE ratio presented lower in patients with the follicular phase (day1-14) compared to the luteal phase (day15-30) in the benign group (P = .036). Also, the BPE ratio presented significantly lower in the proliferative phase (day5-14) than the menstrual phase (day1-4) and the secretory phase(day15-30) in the benign group (P = .006). While the BPE ratio was not significantly different among the respective weeks (1-4) of the menstrual cycle in the benign group (P > .05). In the malignant group, the BPE ratio did not significantly differ between/among any menstrual cycle phase or week (all P > .05). It seems more suitable for Asian women whose lesions need to follow up or are suspected of malignant to undergo breast MRI within the 1st to 14th day of the menstrual cycle, especially on the 5th to 14th day.


Improving marginal hazard ratio estimation using quadratic inference functions.
Clustered and multivariate failure time data are commonly encountered in biomedical studies and a marginal regression approach is often employed to identify the potential risk factors of a failure. We consider a semiparametric marginal Cox proportional hazards model for right-censored survival data with potential correlation. We propose to use a quadratic inference function method based on the generalized method of moments to obtain the optimal hazard ratio estimators. The inverse of the working correlation matrix is represented by the linear combination of basis matrices in the context of the estimating equation. We investigate the asymptotic properties of the regression estimators from the proposed method. The optimality of the hazard ratio estimators is discussed. Our simulation study shows that the estimator from the quadratic inference approach is more efficient than those from existing estimating equation methods whether the working correlation structure is correctly specified or not. Finally, we apply the model and the proposed estimation method to analyze a study of tooth loss and have uncovered new insights that were previously inaccessible using existing methods.


Modulated microRNA expression during adult lifespan in Caenorhabditis elegans.
MicroRNAs (miRNAs) are small, abundant transcripts that can bind partially homologous target messages to inhibit their translation in animal cells. miRNAs have been shown to affect a broad spectrum of biological activities, including developmental fate determination, cell signaling and oncogenesis. Little is known, however, of miRNA contributions to aging. We examined the expression of 114 identified Caenorhabditis elegans miRNAs during the adult lifespan and find that 34 miRNAs exhibit changes in expression during adulthood (P<or= 0.05), 31 with more than a twofold level change. The majority of age-regulated miRNAs decline in relative abundance as animals grow older. Expression profiles of developmental timing regulators lin-4 and let-7 miRNAs, as well as conserved muscle miRNA miR-1, show regulation during adulthood. We also used bioinformatic approaches to predict miRNA targets encoded in the C. elegans genome and we highlight candidate miRNA-regulated genes among C. elegans genes previously shown to affect longevity, genes encoding insulin-like ligands, and genes preferentially expressed in C. elegans muscle. Our observations identify miRNAs as potential modulators of age-related decline and suggest a general reduction of message-specific translational inhibition during aging, a previously undescribed feature of C. elegans aging. Since many C. elegans age-regulated miRNAs are conserved across species, our observations identify candidate age-regulating miRNAs in both nematodes and humans.


Fetal immunization by a DNA vaccine delivered into the oral cavity.
Infectious diseases are the main cause of neonatal morbidity and mortality in humans. The World Health Organization estimated that in 1995 approximately 8 million infants died within the first year of life from infectious diseases, including 5 million during the first week of life. Some of the salient pathogens involved include herpes simplex virus, human immunodeficiency virus, hepatitis B virus, human cytomegalovirus, group B streptococcus, hemophilus and chlamydia. Infection with these pathogens usually occurs at the end of pregnancy, during birth or by breastfeeding. To reduce the risk of disease transmission, caesarian sections, prophylactic treatment with antibiotics or maternal antiviral therapy during the last trimester are used where available, together with improved neonatal care. None of these approaches, however, completely eliminates the risk of neonatal infection. Therefore, active or passive immunization of the fetus might represent an effective approach to reduce the high risk of neonatal diseases. Here, we demonstrate that a single immunization with a DNA vaccine delivered into the amniotic fluid in the oral cavity induces high serum antibody titers and a cell-mediated immune response, combined with induction of local immunity in the oral cavities of fetal lambs.


The utilisation of intraosseous infusion in the resuscitation of paediatric major trauma patients.
Intraosseous lines are a reliable and rapid tool for obtaining vascular access in emergency situations, particularly in children. Their use is recommended when intravenous access cannot be easily secured and there is a need for fluid or pharmacological resuscitation. Training in this technique is included in the Advanced Trauma Life Support (ATLS) and Advanced Paediatric Life Support course (APLS) provider courses. The objective of this study is to analyse the national use of intraosseous lines in paediatric trauma in England and Wales. Data has been collected from the Trauma Audit and Research Network (TARN) group longitudinally over 14 years from 1988 to 2002. From 23,489 paediatric trauma cases, intraosseous lines were used in only 129 patients. Compared with the remainder of the paediatric data, we found that these were the younger (1-6 years), more severely injured patients (higher ISS, lower GCS, higher head, thorax, and abdominal AIS). The mortality of these patients was high at 64% compared with 4% overall. IO line use was greater in general than in Paediatric hospitals, perhaps due to good intravenous access skills in paediatric centres. We recommend that intraosseous line use should be a skill available to everybody involved in paediatric trauma resuscitation, particularly those who may not have refined paediatric intravenous cannulation skills.


Evaluation of Ki-67 and cyclin D1 expression in odontogenic keratocysts and orthokeratinised jaw cysts.
Orthokeratinised jaw cyst (OJC) is an entity distinct from odontogenic keratocyst (OKC) that has not been fully characterised at the molecular level. To compare the proliferative activity of the epithelial linings of OKC and OJC immunohistochemically, using Ki-67 and cyclin D1 as markers of cellular proliferation and activity. The total numbers of positively stained cells per 10 consecutive lengths of a light microscope calibration ruler were counted in each case (OKC, n = 15; OJC, n = 15) and the composite data were statistically compared. OJC showed significantly fewer Ki-67 and cyclin D1 positive cells than OKC, a finding consistent with the clinically more indolent behaviour of the OJC. Ki-67 expression was mainly detected in the suprabasal cell layers in OKC. Expression of Ki-67 was more uniform in OJC and notably without a significant predilection for the supra-basal compartment. The accumulation of Ki-67 positive cells supra-basally in OKC raises the possibility that a process of asymmetrical cell division may be operational in OKC. Expression of Ki-67 and cyclin D1 differed significantly quantitatively and by distribution pattern in OKC and OJC respectively thereby suggesting that the presence of cyclin D1 protein in OKC and OJC may not necessarily reflect production of this molecule by cycling cells.


Effects of amphetamine on the development of MTV-induced mammary tumors in female mice.
Female C3H/He mice carrying the mammary tumor virus (MTV) were monitored for mammary tumor incidence and latent periods while submitted to a daily subcutaneous injection with amphetamine (0,4 mg/kg/day). Results show that amphetamine caused an increase in incidence and a decrease in latency of tumors compared with placebo. There was also appreciated a correlation with the lethality of mice.


The p53 family and programmed cell death.
The p53 tumor suppressor continues to hold distinction as the most frequently mutated gene in human cancer. The ability of p53 to induce programmed cell death, or apoptosis, of cells exposed to environmental or oncogenic stress constitutes a major pathway whereby p53 exerts its tumor suppressor function. In the past decade, we have discovered that p53 is not alone in its mission to destroy damaged or aberrantly proliferating cells: it has two homologs, p63 and p73, that in various cellular contexts and stresses contribute to this process. In this review, the mechanisms whereby p53, and in some cases p63 and p73, induce apoptosis are discussed. Other reviews have focused more extensively on the contribution of individual p53-regulated genes to apoptosis induction by this protein, whereas in this review, we focus more on those factors that mediate the decision between growth arrest and apoptosis by p53, p63 and p73, and on the post-translational modifications and protein-protein interactions that influence this decision.


Using drug-loaded pH-responsive poly(4-vinylpyridine) microspheres as a new strategy for intelligent controlling of Lactobacillus plantarum contamination in bioethanol fermentation.
Bioethanol fermentation is usually contaminated by bacteria, especially lactic acid bacteria (LAB), thereby leading to decrease of bioethanol yield and serious economic losses. Nisin is safer for controlling of bacterial contamination than antibiotics that are widely applied in industry. Moreover, in LAB contaminative bioethanol fermentation system, consistently decreased pH value provides opportunity to realize pH value responsive material-based release of anti-bacteria substances for intelligent and persistent controlling of bacterial contamination. In this study, nisin was embedded into pH-sensitive poly(4-vinylpyridine) (P4VP) microspheres synthesized by suspension polymerization to realize intelligent controlling of Lactobacillus plantarum contamination in bioethanol fermentation. Chloramphenicol with the highest antimicrobial activity and excellent stability was chosen as the model drug to be embedded into P4VP microspheres to test the drug release behavior. The drug release curve of chloramphenicol-loaded P4VP microspheres showed sustained and pH-responsive release properties. The diameters of the microspheres ranged from 40 to 100 µm. The encapsulation efficiency of nisin into P4VP microspheres was 47.67% and the drug-loading capacity of nisin was 2.5%. Nisin-loaded P4VP microspheres were added into the simulated contaminative fermentation system, and successfully reversed the decline of bioethanol yield secondary to L. plantarum contamination. The results in this study indicated that L. plantarum contamination in bioethanol fermentation could be effectively controlled by nisin-loaded P4VP microspheres.


Effect of freeze-thaw cycles and biochar coupling on the soil water-soil environment, nitrogen adsorption and N2O emissions in seasonally frozen regions.
Freeze-thaw cycles (FTCs) usually occur in the nongrowing season of crops, and the temporal mismatch between soil nitrogen (N) supply and crop N utilization increases the risk of N loss. Crop straw burning is a seasonal air pollution source, and biochar provides new alternatives for waste biomass recycling and soil pollution remediation. To investigate the effect of biochar on N loss and N2O emissions under frequent FTCs, different biochar content treatments (0 %, 1 %, 2 %) were set, and laboratory simulated soil column FTC tests were conducted. Based on the Langmuir and Freundlich models, the surface microstructure evolution and N adsorption mechanism of biochar before and after FTCs were analyzed, and the change characteristics of the soil water-soil environment, available N and N2O emissions under the interactive effect of FTCs and biochar were studied. The results showed that FTCs increased the oxygen (O) content by 19.69 % and the N content by 17.75 % and decreased the carbon (C) content by 12.39 % of biochar. The increase in the N adsorption capacity of biochar after FTCs was related to changes in surface structure and chemical properties. Biochar can improve the soil water-soil environment, adsorb available nutrients, and reduce N2O emissions by 35.89 %-46.31 %. The water-filled pore space (WFPS) and urease activity (S-UE) were the main environmental factors determining N2O emissions. Ammonium nitrogen (NH4+-N) and microbial biomass nitrogen (MBN), as substrates of N biochemical reactions, significantly affected N2O emissions. The interaction of biochar content and FTCs in different treatments had significant effects on available N (p < 0.05). The application of biochar is an effective way to reduce N loss and N2O emissions under the action of frequent FTCs. These research results can provide a reference for the rational application of biochar and efficient utilization of soil hydrothermal resources in seasonally frozen soil areas.


Genistein affects proliferation and migration of bovine oviductal epithelial cells.
Genistein is one of the most abundant isoflavones in soybean. This molecule induces cell cycle arrest and apoptosis in different normal and cancer cells. Genistein has been of considerable interest due to its adverse effects on bovine reproduction, altering estrous cycle, implantation and fetal development and producing subfertility or infertility. The objective of this work was to study the effects of genistein on the expression of selected genes involved in the regulation of cell cycle and apoptosis. Primary cultures of bovine oviductal epithelial cells (BOEC) were treated with different genistein concentrations (0.2, 2 and 10μM) to analyze CYCLIN B1, BCL-2 and BAX gene expression by Real-time RT-PCR. Results showed that genistein down-regulated CYCLIN B1 expression, affecting cell cycle progression, and caused a decrease in the BCL-2/BAX ratio starting at 2μM of genistein. In addition, in order to determine if genistein affects BOEC migration, in vitro wound healing assays were performed. A significant reduction in cell migration after 12h of culture was observed at both 0.2 and 10μM genistein concentrations. Also, in the presence of genistein the percentage of mitotic cells decreased, although apoptotic cells percentages were not affected. These findings indicate that genistein has an inhibitory effect on BOEC proliferation and migration, suggesting that it could influence the normal physiology of the oviductal epithelium.


Endoscopic evaluation of the defunctionalized stomach by using ShapeLock technology (with video).
Patients with Roux-en-Y gastric bypass (RYGB) present a unique problem if they require diagnostic or therapeutic interventions for which the pancreatobiliary limb or the defunctionalized stomach must be accessed. Novel shape-locking guides have been reported in the literature to reduce looping during colonoscopy, and a new guide is now available to assist with enteroscopy. To use ShapeLock technology to permit evaluation of the defunctionalized stomach. Observational case series. Tertiary-care center. Nine patients with a history of RYGB referred for repeat endoscopic evaluation after initial enteroscopy failed to reach the excluded stomach. After achieving appropriate levels of sedation, a standard enteroscope was back-loaded with the ShapeLock enteroscopy guide and was inserted through the mouth. The device was moved through the gastrojejunal (GJ) anastomosis, along the Roux limb, and into the distal pancreatobiliary limb. The device was then locked, which allowed the enteroscope to be advanced to the defunctionalized stomach. The ShapeLock guide was able to be advanced to the excluded stomach and perform a thorough examination of the pancreatobiliary limb in 8 of 9 patients, without complications. In 1 patient, the diameter of the GJ anastomosis prevented passage of the device. The ShapeLock enteroscopy guide can allow access to the upper-GI tract in patients after RYGB, provided the GJ anastomosis is of adequate diameter. This study suggested that the technique is safe and has the potential to allow therapeutic interventions in the defunctionalized stomach and duodenum, including ERCP.


Molecular surveillance and phylogenetic traits of Babesia bigemina and Babesia bovis in cattle (Bos taurus) and water buffaloes (Bubalus bubalis) from Colombia.
Babesia bigemina and B. bovis are two economically important hemoparasites affecting both cattle and buffaloes involved in dairy and beef production. In Colombia, although some parasitological and serological studies suggest an endemicity of these pathogens in areas under 1000 m, little is known about its molecular prevalence in different host. The objective of this study was to estimate the prevalence and molecular traits of these parasites in cattle and buffaloes from two Colombian regions. Between 2014 and 2016, a three-point longitudinal survey was designed in farms from Caribbean and Orinoquia regions to evaluate the molecular prevalence of B. bigemina and B. bovis using a nested PCR (n-PCR) targeting hypothetical protein (hyp) and rhoptry-associated protein (RAP-1) genes, respectively. A total of 1432 cattle, 152 buffalo and 1439 Rhipicephalus microplus samples were analyzed. Moreover, phylogenetic relationship of isolates was analyzed using the 18S rRNA gene. A molecular prevalence of 31.6% (24.2% for B. bigemina and 14.4% for B. bovis), 23.6% (6.5% for B. bigemina and 17.7% for B. bovis) and 4.3% (3.5% for B. bigemina and 1.0% for B. bovis) was observed in cattle, buffaloes and Rhipicephalus microplus, respectively. Higher values of infection were observed during the wet season and late wet season; nevertheless, other variables such as age, production type, sex, breed and babesiosis control were also significantly associated with infection. Prevalence analysis showed that B. bovis infection was higher in cattle that coexist with buffaloes, when compared to those which did not. For each species, phylogenetic analyses revealed a high genetic diversity of isolates without clusters related to the isolation source. To our knowledge, this is the first longitudinal survey that evaluates through molecular methods, the infection of B. bigemina and B. bovis in two important livestock regions from Colombia. This study reveals that the prevalence of infection by Babesia spp., in cattle and buffaloes are modulated by seasonal variations, host factors and vector traits. Our results provide new insights on the epidemiological aspects of infection of Babesia spp., in cattle and buffaloes, which must be taken into consideration when babesiosis control programs are implemented in the study area.


Do not resuscitate status, not age, affects outcomes after injury: an evaluation of 15,227 consecutive trauma patients.
Despite a well-described association of age and injury with mortality and decreased functional status, inpatient mortality studies have traditionally not included analysis of do not resuscitate (DNR) status. We hypothesized that the increased likelihood of DNR status in older patients alters age-adjusted mortality rates in trauma. The trauma registry was queried for adult patients admitted to our Level I trauma center (January 2005-December 2008) and divided into eight age groups by decade. Ages 15-44 years were collapsed because of the lack of variation. We compared age, case fatality rate, and DNR status by univariate analysis and trends by χ (p < 0.05). Of the 15,227 adult patients admitted, 13% were elderly (≥65) and 7% died. DNR status was known in 75% of deaths, and 42% of those had active DNR orders on the chart at time of death. DNR likelihood increased with age (p < 0.05), from 5% to 18%. With DNRs excluded, mortality variability across all ages was markedly diminished (4-7%). DNR status among trauma patients varies significantly because of inconsistent implementation and meaning between hospitals, and successive decades are more likely to have an active DNR order at time of death. When DNR patients were excluded from mortality analysis, age was minimally associated with an increased risk of death. The inclusion of DNR patients within mortality studies likely skews those analyses, falsely indicating failed resuscitative efforts rather than humane decisions to limit care after injury.


Sonography of intrascrotal appendage torsion: varying echogenicity of the torsed appendage according to the time from onset.
The purpose of this study was to evaluate sonographic findings in torsed intrascrotal appendages and to assess the effect of the time from symptom onset on echogenicity and the relationship between the time from symptom onset and manual reduction success. Thirty-five boys (6-13 years old; mean, 9.9 years) with torsion of an intrascrotal appendage were evaluated. All had painful unilateral scrotal swelling and palpable tender nodules on physical examination and underwent sonography. Thirty-two underwent subsequent manual reduction. Before manual reduction, we assessed the size, echogenicity, appendage blood flow, periappendiceal blood flow, and scrotal swelling. Data were analyzed according to time from symptom onset. After manual reduction, the number of reduction trials, pain relief, size, and blood flow of the appendix testis were assessed. The torsed appendage was hypoechoic in all 17 boys assessed within 24 hours of symptom onset. In boys assessed more than 24 hours after onset, the torsed appendage was hypoechoic in 6, isoechoic in 4, and hyperechoic in 8. Twenty-two of 23 hypoechoic appendages showed a salt-and-pepper pattern. The echogenicity differed significantly between boys assessed within and more than 24 hours after symptom onset (P < .001). The success rates of manual reduction were 90.9% (20 of 22) for hypoechoic appendages, 75.0% (3 of 4) for isoechoic appendages, and 50.0% (3 of 6) for hyperechoic appendages. Sonography revealed increased blood flow and decreased appendage sizes in all boys with successful reduction. The echogenicity of a torsed appendage changes according to the time from onset. A hyperechoic intrascrotal appendage is associated with later sonography and is a poor predictor of manual reduction success.


Analgesic drug consumption increases after knee arthroplasty: a pharmacoepidemiological study investigating postoperative pain.
Knee arthroplasty remains the gold standard in the treatment of severe osteoarthritis. Chronic postoperative pain has been reported with a prevalence ranging from 15% to 47%. The aim of this study was to compare analgesic drug consumption before and after surgery as an indicator of pain after knee surgery. A pharmacoepidemiological method comparing analgesics and antineuropathic issues 1 year before and 1 year after surgery was used. All patients who underwent knee arthroplasty in the Midi-Pyrenees region (2.5 million inhabitants) were identified through the Health Insurance System Database. Increase of drug issues (all analgesics, antineuropathic drugs, strong opioids) was calculated and compared between several periods surrounding the surgery (12 months, 2 months, and 10 months before and after the knee arthroplasty). A multivariate logistic regression model was used to identify factors associated with chronic postoperative pain. The study included 1939 patients. An increase in analgesic, antineuropathic, and opioid drug consumption was observed the year after the surgery in 47.3%, 8.6%, and 5.6% of patients, respectively. Multivariate analysis found a significant association between type of surgery (total knee vs unicompartmental arthroplasty) and analgesic consumption 1 year after surgery, and between preoperative pain and psychiatric vulnerability and increase in neuropathic drug dispensing. Conversely, older age was considered as a protective factor. This study revealed that an increase in the issue of different analgesic drugs is present in half of patients 1 year after knee arthroplasty. Several associated factors of drug consumption (preoperative pain, type of surgery, and psychiatric disorder) were identified.


Cancers of affluence: positive social class gradient and rising incidence trend in some cancer forms.
This study shows that, unlike most diseases, some cancer forms are more common in upper social classes. All cancer cases diagnosed in Finland in 1971-75 aged 30-69 and recorded in the Finnish Cancer Registry (n = 36,500) were linked to the file of the 1970 Population Census of Finland with data on socio-economic status and education. Cancers related to both high socio-economic status and high level of education in men were colon, prostate, testis, kidney and melanoma of the skin, and in women colon, breast, and corpus uteri. Since 1953, the incidence of all these cancers had been rising, although that of the testicular cancer had levelled off in the seventies.


cAMP and Epac in the regulation of tissue fibrosis.
Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-β, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2.


Molecular photo-oscillators based on highly accelerated heterocyclic azo dyes in nematic liquid crystals.
Benzothiazole-pyrrole-based azo dyes greatly enhance their thermal isomerisation rate by up to 160 times when they are under the influence of the nematic mean field yielding the LC-based photochromic oscillators with the highest oscillation frequencies reported so far (2.6 kHz at 298 K).


Qualitative Assessment and Reporting Quality of Intracranial Vessel Wall MR Imaging Studies: A Systematic Review.
Over the last quarter-century, the number of publications using vessel wall MR imaging has increased. Although many narrative reviews offer insight into technique and diagnostic applications, a systematic review of publication trends and reporting quality has not been conducted to identify unmet needs and future directions. We aimed to identify which intracranial vasculopathies need more data and to highlight areas of strengths and weaknesses in reporting. PubMed, EMBASE, and MEDLINE databases were searched up to September 2018 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two independent reviewers screened and extracted data from 128 articles. The Strengthening the Reporting of Observational Studies in Epidemiology guidelines were used to assess the reporting quality of analytic observational studies. There has been an exponentially increasing trend in the number of vessel wall MR imaging publications during the past 24 years (P < .0001). Intracranial atherosclerosis is the most commonly studied intracranial vasculopathy (49%), followed by dissections (13%), aneurysms (8%), and vasculitis (5%). Analytic observational study designs composed 48% of the studies. Transcontinental collaborations showed nonsignificantly higher reporting quality compared with work originating from single continents (P = .20). A limitation is the heterogeneity in study designs. Investigations on the diagnostic utility of vessel wall MR imaging in less commonly studied intracranial vasculopathies such as dissections, aneurysms, and vasculitis are warranted. More consistent adherence to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines should improve transparency and maximize effective synthesis for clinical translation. Diverse collaborative teams are encouraged to advance the understanding of intracranial vasculopathies using vessel wall MR imaging.


[Can one talk of benzodiazepine "drunkenness"? About acute benzodiazepine intoxication, without suicidal or mortiferous tendencies].
When we refer to "drunkenness", more often than not, we think of alcohol or cannabis being the instigator rather than pharmacological drugs, even if outside the toxic origins, "drunkenness" may also occur without any substance intake: one can be drunk on love, poetry, music and even mania. Benzodiazepine "drunkenness" is not a classical notion in medicine. But the concept of addictology allows one to enlarge different approaches and to consider the relationship with psychoactive substances according to the same references. So, in a single fashion, between use and misuse, is it possible to resort to the same concepts for pharmacological drugs, including "drunkenness"? Any intake of a psychoactive substance, limited in time, which will take the consumer some time to recover from, can be called simple use, intoxication or drunkenness. Intoxication is rather a classical medical concept linked with poisoning, and hence the toxicological aspects prevail particularly through the concept of a toxidrome. However, little research has been done on "drunkenness" in other medical aspects, neither psychological aspects nor sociological aspects. If poisoning is defined as soon as a poison is introduced into the body, the intoxication arises after a threshold (that toxicology usually defines), but no means are available to measure the onset of the inebriation, neither any ingested amounts nor any toxic concentration in the body. It is hard to define "drunkenness" simply. At first, it is most often seen as a pathology in medicine, unlike in every day life. "Drunkenness" can be the result of physiological disturbances, notably through the effects of substances and can therefore be the manifestation of a cerebral dysfunction. Alternatively, it can arise from a variation of emotional or sensorial stimuli. If the feelings associated with drunkenness are positive and pleasant a repetition will occur in the search to reproduce enjoyable effects in reference to neurophysiological models of reward systems of the brain, and can tend to be limited to a search for pleasure. Moreover, "drunkenness" may be considered as a leak, a regression or a kind of renouncement. It may sometimes be a search for sedation, for conscious sleep, or to avoid reality. And, finally, "drunkenness" may be suicidal. Since the launch of benzodiazepines on the market during the sixties, their prescription has developed, making them so readily available in France that they are nearly as easy to obtain as alcohol. The widespread diffusion of these psychoactive substances, obtained with or without medical prescription, renders them one of the principle means of chemically modulating thought and consciousness that has become accessible to all. One of the first reasons for this is the easy and wide prescription of these drugs by almost all practitioners. Choosing between benzodiazepines or alcohol (or associating both substances) is not fortuitous. Besides intoxication with pharmacological drugs, whether voluntary or otherwise, medication overdose and iatrogenic effects, there is an incidence of a substantial use of over the counter psychoactive drugs in order to trigger other effects than suicide or self-harm. This use of pharmacological drugs, sometimes referred to as "entertaining", can lead to massive intake with dramatic behavioural response. Is it then possible to use the same term "drunkenness" for a pharmacological drug-induced state as for a state provoked by other psychoactive substances with addictive potential ? The clinical presentation of benzodiazepine "drunkenness" resembles the pharmacological effects of these drugs. If we link alcoholic and benzodiazepine "drunkenness", we can draw a parallel between the properties, the action mechanisms, the effects and the risks incurred by the consumption of these two classes of psychotropics. The similarities concern the existence of a preclinical phase, of the same biochemical or neurophysiological basis, of the same properties, notably complex relationships with anxiety. They also have the same amnesiac effects, possible paradoxical effects, or sedation potentialities that may lead to coma, respiratory depression and death. But differences exist for benzodiazepines, in the lack of disinhibition effects, the lack of cerebellar effects, the variability of elimination kinetics according to the molecules, the rarity or the lack of "recreational" intakes, and the lack of easy blood level measurements. An attempt is made to outline the definition of benzodiazepine "drunkenness", including sociological, psychological, and medical dimensions beyond the sole toxicological aspects. So, studying the misuse of benzodiazepines in more detail including the acute effects such as "drunkenness", except suicidal or mortiferous tendencies, can allow further development of its recognition, screening and prevention.


Relationship of Endothelial Microparticles to Obesity and Cardiovascular Disease Risk in Children and Adolescents.
Background Microparticles and endothelial microparticles (EMPs) are implicated in accelerating cardiovascular disease (CVD); however, data in pediatrics are limited. We examined the relationship of microparticles and EMPs with adiposity and subclinical CVD risk measures in a pediatric population to determine their potential as biomarkers of CVD risk. Methods and Results A cross-sectional study of youth (n=280; ages 8-20 years) with a range of body mass index categories was used. Microparticles, EMPs, and activated EMPs were measured by flow cytometry. %Body fat and %visceral adipose tissue were measured by dual X-ray absorptiometry. Measures of arterial stiffness and vascular wall structure were obtained. Linear regression (with log-transformed outcomes) and logistic regression were used to evaluate associations and all results were exponentiated. Youth with overweight/obesity and severe obesity had 2.50 (95% CI, 1.56-4.01) and 3.42 (95% CI, 2.15-5.43) times the geometric means of the total number of microparticles, respectively, compared with those with normal weight. Youth with overweight/obesity and severe obesity had 1.97 (95% CI, 1.09-3.55) and 2.34 (95% CI, 1.31-4.19) times the geometric means of the total number of EMPs, respectively, compared with those with normal weight. There were positive associations between the levels of both microparticles and EMPs with higher adiposity measures and poor CVD risk measures. Youth with higher adiposity showed 1.84 times the odds of having high levels of activated EMPs (%) (odds ratio, 1.84; 95% CI, 1.08-3.14) compared with those with normal weight. Conclusions Levels of microparticles, EMPs, and activated EMPs were positively associated with adiposity and poor subclinical CVD risk in a pediatric population.


[Endothelial dysfunction: role in the maternal syndrome of preeclampsia and long-term consequences for the cardiovascular system].
Preeclampsia is a pregnancy disorder being a leading cause of maternal and fetal mortality and morbidity. It is a complex multisystem disease characterized by hypertension and proteinuria. In preeclampsia the placenta releases factors into the maternal circulation which cause a systemic endothelial dysfunction. Here, we review data demonstrating the central role played by the endothelium in the development of the maternal syndrome of preeclampsia. We present also original data showing how circulating factors present in the plasma of preeclamptic women can alter the transcriptome of endothelial cells. The expression of genes involved in essential functions such as vasoregulation, oxidative stress, apoptosis and cell proliferation show differential expression when endothelial cells are exposed to preeclamptic or normal pregnancy plasma. We conclude by discussing the growing evidences that the alterations of the endothelium during preeclampsia are linked to an increased risk of cardiovascular diseases latter on life. Therefore, a better understanding of the modifications undergone by the endothelial cells during preeclampsia is essential to develop new therapeutic approaches to both, manage preeclampsia and to prevent the long-term sequelae of the disease on women cardiovascular system.


The sex pheromones of mealy plum (Hyalopterus pruni) and leaf-curl plum (Brachycaudus helichrysi) aphids: identification and field trapping of male and gynoparous aphids in prune orchards.
Mealy plum, Hyalopterus pruni, and leaf-curl plum, Brachycaudus helichrysi, aphids are the primary arthropod pests in orchards that produce dried plums (i.e., prunes). The sexual stage of their respective lifecycles occurs on prune trees in the fall, during which time males respond to sex pheromones produced by oviparous females. Air-entrainment collections confirmed that oviparous H. pruni and B. helichrysi emitted combinations of (4aS, 7S, 7aR)-nepetalactone and (1R, 4aS, 7S, 7aR)-nepetalactol. The responses of H. pruni and B. helichrysi to these compounds in ratios of 1:0, 0:1, 1:1, 2.6:1, 3.4:1, 5:1, 7:1, and 0:0 (no-pheromone control) using water traps were determined in field experiments conducted in prune orchards during the fall. The greatest number of male H. pruni was caught in traps releasing a 1:1 ratio of (4aS, 7S, 7aR)-nepetalactone and (1R, 4aS, 7S, 7aR)-nepetalactol, while male B. helichrysi were caught in similar numbers in traps releasing any of the two-component ratios tested. There was no evidence that any of the pheromone treatments influenced trap catches of gynoparae of either species. Results suggest that addition of sex pheromone lures increases trap catches of male H. pruni and B. helichrysi, and that this approach may improve monitoring and management of these pests in prune orchards. Knowledge gained from this study contributes to the understanding of the ecology of insect pests in prune orchards.