Analysis of trace levels of sulfonamides in surface water and soil samples by liquid chromatography-fluorescence.
Methods are reported for determining six sulfonamides used as veterinary drugs in water and soil samples. Analytes are isolated from water samples by solid-phase extraction on HBL cartridges and pre-concentration factors of up to 250 were obtained. Soil samples are treated using microwave-assisted extraction of analytes with acetonitrile and further clean up by solid-phase extraction. Determination is carried out by high-performance liquid chromatography using fluorimetric detection with precolumn derivatization with fluorescamine. The separation of the derivatized sulfonamides is performed on an octadecyl column using binary gradient elution with acetate buffer/acetonitrile mixtures. For water analysis, the detection limits of the whole process are in the low nanogram per liter level and recovery rates range from 70 to 104%, with standard deviations 2-11%. For soil analysis, extraction efficiency is evaluated using three soil samples with different physicochemical characteristics. Recovery rates range from 60 to 98% and detection limits are between 1 and 6ngg(-1).


Mitochondrial leader sequence--plasmid DNA conjugates delivered into mammalian cells by DQAsomes co-localize with mitochondria.
In the last decade the increase in therapeutic strategies aimed at mitochondrial targets has resulted in the need for novel delivery systems for the selective delivery of drugs and DNA into mitochondria. In this study, we have continued our efforts towards the development of the first mitochondriotropic drug and DNA delivery system (DQAsomes). Prepared from derivatives of the self-assembling mitochondriotropic bola-amphiphile dequalinium chloride, these vesicles bind and transport DNA to mitochondria in living mammalian cells where upon they have been shown to release the DNA on contact with mitochondrial membranes. We present data to demonstrate that oligonucleotides as well as plasmid DNA conjugated to a mitochondrial leader sequence (MLS) co-localize with mitochondria when delivered into mammalian cells by DQAsomes. In contrast to a commercially available DNA delivery vector, our vesicles appear to have a pronounced specificity for mitochondria. Further, the data strongly suggest that linear conjugates might be better suited to delivery into mitochondria and that in the absence of a mitochondria specific vector, the presence of a MLS-peptide conjugated to the DNA is alone not sufficient to direct the accumulation of DNA at mitochondria.


[Analysis of the causes and potential avoidability of readmissions in an acute patients' hospital].
Rates of hospital readmissions are used as indicators of quality of health care. Yet specific causes of readmissions have not been sufficiently studied and an unified definition of such an indicator is lacking. Our goal was to determine the causes and potential avoidability of readmissions in our hospital and to identify a suitable definition of this indicator. Cross sectional study. Hospital Costa del Sol (Marbella, Málaga). Subjects of study: Random sample of hospital discharges followed by a new admission within the next 6 months (n = 363). Determination of the causes and potential avoidability of readmissions, by means of a peer-review of medical records. Descriptive and logistic regression analysis of the variables contained in the Minimum Basic Data Set (MBDS) and related to the avoidability of readmissions. 19% (95% CI: 15.0-23.0) of hospital readmissions within 6 months after hospital discharge were attributed to potentially avoidable situations if the applied medical care had been modified during the previous episode. This figure reached 37% (95% CI: 27.4-47.3) for surgical services, 13% (95% CI: 8.7-17.6) for medical services and 12% (95% CI: 2.9-20.6) for obstetrics. The MBDS variables related to the potential avoidability of readmissions were, for the whole hospital, 1) the shorter interval from the previous discharge and 2) the difference of diagnosis between both episodes. Most hospital readmissions are due to non-avoidable situations if the applied medical care had been modified during the previous episode. In order to detect potentially avoidable situations, definitions of readmission rates should only include early readmissions with a chief diagnosis other than that in the previous admission.


[Significance of hemodilution and deferred autotransfusions in spinal surgery in the child and the adolescent].
Homologous blood transfusions may involve immunological risks, as much as the risk of transmitting viral bacterial or parasitic illnesses. 140 children and adolescents having been operated for scoliosis were evaluated in order to compare hemodilution plus deferred auto-transfusion against standard transfusion techniques. By combining hemodilution and deferred autotransfusion, pre and post-surgery transfusions drop from 2725 to 370 ml of homologous blood, on the average. The combined use of these two techniques thus reduces the need for new homologous blood most significantly.


Handling polypharmacy -a qualitative study using focus group interviews with older patients, their relatives, and healthcare professionals.
On average, older patients use five or more medications daily. A consequence is an increased risk of adverse drug reactions, interactions, or medication errors. Therefore, it is important to understand the challenges experienced by the patients, relatives, and healthcare professionals pertinent to the concomitant use of many drugs. We conducted a qualitative study using focus group interviews to collect information from patients, relatives, and healthcare professionals regarding older patients' management of prescribed medicine. We interviewed seven patients using five or more medications daily, three relatives, three general practitioners, nine nurses from different healthcare sectors, one home care assistant, two hospital physicians, and four pharmacists. The following themes were identified: (1) Unintentional non-adherence, (2) Intentional non-adherence, (3) Generic substitution, (4) Medication lists, (5) Timing and medication schedule, (6) Medication reviews and (7) Dose dispensing/pill organizers. Medication is the subject of concern among patients and relatives. They become confused and insecure about information from different actors and the package leaflets. Therefore, patients often request a thorough medication review to provide an overview, knowledge of possible side effects and interactions, and a clarification of the medication's timing. In addition, patients, relatives and nurses all request an indication of when medicine should be taken, including allowable deviations from this timing. Therefore, prescribing physicians should prioritize communicating information regarding these matters when prescribing.


Effect of potential probiotic Leuconostoc mesenteroides FB111 in prevention of cholesterol absorption by modulating NPC1L1/PPARα/SREBP-2 pathways in epithelial Caco-2 cells.
Mustard kimchi consumption reduces cholesterol levels in rats. To identify lactic acid bacteria (LAB) in kimchi which exert this effect, 20 LAB isolates were evaluated for cholesterol reduction in an in vitro screen. The FB111 strain showed the highest cholesterol-lowering activity and was identified as Leuconostoc mesenteroides. This strain was characterized as a potential probiotic through sequential analyses for resistance to gastrointestinal digestion and bile salts, and adhesion to Caco-2 cells. The Caco-2 cells treated with L. mesenteroides FB111 (6-8 log CFU/mL) showed toxicological effect. The reduction of cholesterol uptake in these cells was inhibited by 48.6% compared to the control and significantly higher than that of the Lactobacillus rhamnosus GG (LGG) strain-treated group after 2-h incubation. The levels of NPC1L1, ABCG5, ABCG8, SREBP-1, SREBP-2, and PPARα gene expression were determined by reverse transcription-quantitative polymerase chain reaction analysis. The L. mesenteroides FB111 and LGG inhibited the mRNA expression of NPC1L1 (P < 0.05), whereas the expression of PPARα was increased. Moreover, the FB111 strain also inhibited the expression of SREBP-2 mRNA. Overall, we found that L. mesenteroides FB111 has efficient cholesterol-lowering effects and might be useful as a probiotic in the food industry.


Aortic atresia with a solitary and indeterminate ventricle.
A male infant having aortic atresia and double inlet to a solitary and indeterminate ventricle, presented a clinical picture of "hypoplastic left heart syndrome". Haemodynamic consequences are described and comparison made to other types of aortic atresia. Cross-sectional echocardiography was found to be reliable in determining both atrioventricular and ventriculo-arterial connections in the presence of aortic atresia and a solitary ventricle.


Identification and characterization of IKKε gene from grass carp Ctenopharyngodon idella.
IKKε is an IKK-related kinase implicated in antiviral immune response in higher vertebrates. To elucidate the function of IKKε in teleost fish, grass carp IKKε (gcIKKε) has been cloned and characterized in this paper. The full-length cDNA of gcIKKε is composed of 2529 nucleotides and encodes a polypeptide of 723 amino acids. The mRNA transcription of gcIKKε was constitutively detected in all the selected tissues and the gcIKKε mRNA level increased at 36 h after GCRV infection. Western blot data of both HEK293T cells and EPC cells demonstrated that gcIKKε was around 80 KDa; and immunofluorescence staining data of both NIH3T3 cells and EPC cells determined gcIKKε was a cytosolic protein. The mRNA level of gcIKKε in CIK cells was increased more than 150 times right after poly(I:C) treatment and PMA treatment triggered gcIKKε mRNA transcription in CIK cells more than 100 times. Over-expression of gcIKKε in EPC cells activated the promoter activity of both zebrafish IFN and fathead minnow IFN. gcIKKε mRNA transcription level in CIK cells was increased from 48 h post GCRV infection with different MOIs. All the data support the idea that gcIKKε is a novel teleost IκB kinase recruited in the IFN-mediated antiviral immunity of grass carp.


Methodological aspects of DNA image cytometry in formalin-fixed paraffin-embedded material from pancreatic adenocarcinoma.
Deparaffinized and disintegrated material from conventionally formalin-fixed and paraffin-embedded surgical specimens of 100 cases of ductal adenocarcinoma of the pancreas was Feulgen-stained, and the cytochemical DNA distribution patterns of at least 100 single tumour cells and 50 "control" cells (fibrocytes) were assessed by means of image cytometry (ICM). In 77 cases a sufficient number of neoplastic cells could be obtained for these DNA assessments. The fairly high number (23) of cases that had to be excluded due to too small amounts of disintegrated cells or cell nuclei may be explained by the high content of connective tissue stroma in these pancreatic adenocarcinomas. The tumour cell nuclei in 76 of these 77 cases showed cytochemically a clear-cut "non-diploid" DNA distribution pattern. This observation reflects the well-known highly malignant growth potential of this carcinoma. Despite the fact that about 1/4 of the tumours had to be excluded, the main result of our methodological study is, after all that conventionally formalin-fixed paraffin-embedded specimens of most pancreatic adenocarcinomas can be successfully used for the deparaffinization-disintegration procedure preceding the nuclear DNA assessments by means of ICM. Additional studies are, however, required to obtain the diagnostic and prognostic impact of the results of such cytochemical analyses of the DNA distribution pattern in adenocarcinomas of the pancreas.


1-(4-Amino-2-hydroxyphenyl)ethanone from Phomopsis liquidambari showed quorum sensing inhibitory activity against Pseudomonas aeruginosa.
Phomopsis liquidambari S47 is an endophytic fungus isolated from the leaves of Punica granatum. Here, we are the first to report a quorum sensing (QS) inhibitor 1-(4-amino-2-hydroxyphenyl)ethanone (AHE) isolated and identified from the metabolites of P. liquidambari S47. Exposure to AHE at sub-MIC concentrations notably suppressed the secretion of acyl-homoserine lactones and virulence factors in Pseudomonas aeruginosa PAO1. To investigate the metabolic variations of P. aeruginosa PAO1 exposed to AHE, magnetic resonance imaging-based metabolomic analysis was performed. AHE treatment created a disturbance in the QS system by suppressing the expressions of QS-related genes. The disturbed QS system resulted in the inhibited activity of antioxidant enzymes and thus enhanced oxidative stress. The vegetable infection assay showed that the virulence of P. aeroginosa PAO1 was attenuated which could be due to the impacts to the amino acid and nucleotide metabolism by enhanced oxidative stress. These findings suggest that AHE has a potential to become an antivirulence "agent" to tackle P. aeruginosa infection. KEY POINTS: • AHE treatment inhibited AHL secretion and virulence factors production. • AHE treatment aggravated oxidative stress and disturbed metabolism. • AHE suppressed QS-related gene expressions and reduced virulence of P. aeruginosa.


Association of latent class analysis-derived subphenotypes of acute kidney injury with mortality in critically ill patients with cardiovascular disease: a retrospective cohort study.
To explore the potential heterogeneity of acute kidney injury (AKI) and evaluate the prognostic differences among AKI subphenotypes in critically ill patients with cardiovascular diseases. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database. Latent class analysis (LCA) was used to explore the potential subphenotypes of AKI in critically ill patients with cardiovascular diseases. The number of classes was identified by the Bayesian information criterion and entropy. The differences in prognostic ability among the AKI subphenotypes were evaluated by logistic regression analysis. A total of 7738 AKI patients were enrolled in this study. Using LCA, AKI patients were divided into 4 heterogeneous subphenotypes, which were obviously different from the Kidney Disease: Improving Global Outcomes (KDIGO) stages. Interestingly, class 3 classified by LCA was dominated by stage 2, while the mortality rate in class 3 was significantly different from that in class 1 (15.2% vs. 1.6%, p < 0.05). After further adjustment, the mortality rate in class 3 remained higher than that in class 1, with an odds ratio of 12.31 (95% confidence interval, 8.96-16.89). LCA was feasible for AKI classification in critically ill patients with cardiovascular disease, and 4 distinct subphenotypes of AKI patients with different prognoses were identified. Our results highlighted the potential heterogeneity of AKI patients, which is worthy of further investigation.


Concentrations and fluxes of organic carbon substrates in the aquatic environment.
Data concerning concentrations and fluxes of dissolved organic compounds (DOC) from marine and lacustrine environments are reviewed and discussed. Dissolved free amino acids and carbohydrates comprised the main fraction in the labile organic carbon pool. Dissolved free amino acids in marine waters varied between 3-1400 nM and those of fresh waters between 2.6-4124 nM. Dissolved free carbohydrates varied between 0.4-5000 nM in marine systems and between 14-111 nM in fresh waters, The turnover times of both substrate pools varied in marine waters between 1.4 hours and 948 days and in fresh waters between 2 hours and 51 days. Measurements of stable 12/13C-ratio and 14C-isotope dating in ocean deep water samples revealed DOC turnover times between 2000-6000 years. Studies on carbon flows within the aquatic food webs revealed that about 50% of photosynthetically fixed carbon was channelled via DOC to the bacterioplankton. Excreted organic carbon varied between 1-70% of photosynthetically fixed carbon in marine waters and between 1-99% in fresh waters. The labile organic carbon pool represented only 10-30% of the DOC. The majority (70-90%) of the DOC was recalcitrant to microbial assimilation. Only 10-20% of the DOC could be easily chemically identified. Most of the large bulk material represented dissolved humic matter and neither the chemical structure nor the ecological function of the DOC is as yet clearly understood.


Marrow-middle ear connections: a potential cause of otogenic meningitis.
We hypothesize that the connections between the hematopoietic bone marrow and middle ear is a potential cause of childhood otogenic meningitis. Although it is known that there is a causal relationship between otitis media and bacterial meningitis, the relationship has never been satisfactorily established. Human fetal and infant temporal bones prepared for light microscopic evaluation revealed direct connections between the hematopoietic bone marrow and middle ear. We noted this difference in anatomy between the infant middle ear and the adult middle ear. We studied 10 temporal bones from 5 infants in each group: meningitis group with otitis media who died of meningitis, control Group 1 without otitis media, and control Group 2 with otitis media who died of diseases other than meningitis. A quantitative analysis of the frequency of connections between the hematopoietic bone marrow and middle ear was performed. The correlation between unabsorbed mesenchyme and otitis media also was investigated. The frequency of connections was significantly higher in order of the meningitis group, control Group 2, and control Group 1. The degree of unabsorbed mesenchyme tended to be more severe in order of the meningitis group, control Group 2, and control Group 1. The prevalence of connections between the hematopoietic bone marrow and middle ear in patients with meningitis and otitis media is high. A higher prevalence of connections in infants with otitis media could increase the risk for otogenic meningitis in them.


Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes.
In little more than 30 years, Lyme disease, which is caused by the spirochaete Borrelia burgdorferi, has risen from relative obscurity to become a global public health problem and a prototype of an emerging infection. During this period, there has been an extraordinary accumulation of knowledge on the phylogenetic diversity, molecular biology, genetics and host interactions of B. burgdorferi. In this Review, we integrate this large body of information into a cohesive picture of the molecular and cellular events that transpire as Lyme disease spirochaetes transit between their arthropod and vertebrate hosts during the enzootic cycle.


Neoplasms of terminally differentiated B lymphocytes.
The pathophysiology of, and diagnostic criteria for, multiple myeloma are discussed. There is evidence that the malignant cell population in multiple myeloma may retain at least some capacity for immune modulation/inhibition. As the molecular biology of this disease progresses, clinical access to proliferation manipulation may become possible.


Characterization of the lipopolysaccharide O-antigen of Cronobacter turicensis HPB3287 as a polysaccharide containing a 5,7-diacetamido-3,5,7,9-tetradeoxy-D-glycero-D-galacto-non-2-ulosonic acid (legionaminic acid) residue.
Cronobacter turicensis, previously known as Enterobacter sakazakii, is a Gram-negative opportunistic food-borne pathogen that has been reported as a cause of life-threatening neonatal infections. From chemical and physical analyses involving composition analysis, methylation, two-dimensional high-resolution nuclear magnetic resonance, and mass spectrometry methods, the antigenic O-polysaccharide in the smooth-type lipopolysaccharide of C. turicensis (strain HPB 3287) was determined to be a high molecular mass polymer of a repeating pentasaccharide unit composed of D-galactose, D-glucose, 2-acetamido-2-deoxy-D-galactose, and 5,7-diacetamido-3,5,7,9-tetradeoxy-D-glycero-D-galacto-non-2-ulosonic acid (legionaminic acid), in a molar ratio 2:1:1:1, and having the structure: [see formula in text].


Intestinal cancer in patients with Crohn's disease.
Surveillance of intestinal cancer in Crohn's disease (CD) has often been advocated. To date, no clear evidence exists whether CD patients are at special risk for intestinal cancer. An increased incidence of small bowel adenocarcinoma is suggested. However, recent figures also suggest an increased risk of CD associated colorectal cancer. We report our experience with 10 cases of CD complicated by intestinal adenocarcinoma. Our institutional database included 330 patients treated for CD between 1988-2005. Data of patients that developed carcinoma within Crohn's lesions of either small or large bowel were analyzed. Ten patients were diagnosed with CD complicated by carcinoma. In nine patients, cancer was present in the colorectum and in one, in Crohn's ileitis. Tumors were in conjunction with fistulae in three and developed within strictures in five patients. Mean age at the time of diagnosis of CD was 43 years. Mean duration of CD until diagnosis of cancer was 14 years. Only five patients were diagnosed for cancer preoperatively. Staging revealed advanced tumors in almost all patients. Mean survival after surgery was 29 months (2-149 months). Cancer risk in CD and especially in Crohn's colitis may still be underestimated. Delayed diagnosis resulted in a poor prognosis. The value of colonoscopy as surveillance tool is questioned by the fact that in our patients, carcinoma was diagnosed in some patients preoperatively by routine colonoscopy. Therefore, additional markers should be identified to detect CD patients at risk.


Detection of melanoma, breast cancer and head and neck squamous cell cancer sentinel lymph nodes by Tc-99m Tilmanocept (Lymphoseek®).
Technetium-99m-labeled Tilmanocept or Lymphoseek® (Cardinal Health, Dublin, Ohio) is a soluble, synthetic molecule with a small diameter (7 nm), which is comprised of technetium-99m chelated to a dextran backbone containing multiple units of mannose ligands with a high affinity for CD206, a receptor located on the surface of macrophages and dendritic cells that are found in high concentration in lymph nodes. It enables quick transit from the injection site and rapid lymph node accumulation. The binding of mannose ligand and CD206 results in the internalization of the ligand and receptor into the cell. Once the Technetium-99m-labeled Tilmanocept (Lymphoseek®) reaches the lymph node, it is readily internalized by the macrophages and dendritic cells within the draining lymph nodes. Technetium-99m-labeled Tilmanocept (Lymphoseek®) has been extensively studied as a radioisotope for detection of sentinel lymph nodes in melanoma, breast cancer and head and neck squamous cell carcinoma in clinical trials. Based on its safety and ability to detect sentinel lymph nodes satisfactorily, it has been approved by the FDA to use as a radioisotope for preoperative lymphoscintigraphy for identification of sentinel lymph nodes in these types of cancer. Further, the FDA has expanded approval of Technetium-99m-labeled for sentinel lymph node mapping of all solid tumors as well as in pediatric patients.


Using artificial intelligence to analyze emotion and facial action units following facial rejuvenation surgery.
There remains a lack of standards in facial rejuvenation procedures, which may be attributed to the subjective measures used to determine surgical outcomes and success. The aim of this study was to evaluate the use of machine learning technology, i.e. FaceReader™, to objectively measure facial rejuvenation surgery outcomes. Using a retrospective study design, we enrolled a cohort of patients undergoing high SMAS facelift with/without additional procedures during a one-year interval. The predictor variable was surgery done (pre- vs. postoperative). The outcome variables were 28 facial action units, happiness, and sadness emotions, detected by FaceReader™. Appropriate statistics were calculated at α = 0.05. The sample comprised of 15 patients (11 females, 15 Caucasians, mean age of 55.7 years). There was an average increase in detected happy emotion from 1.03% to 13.17% (p>0.01). Conversely, the average angry emotion detected decreased from 14.66% to 0.63% (p<0.05). There were no other distinct action unit patterns across the operation. Despite a small sample size, the results of this study suggest that FaceReader™ can be used as an objective outcome assessment tool in patients undergoing high SMAS facelift with/without its adjuncts.


High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients.
The prognostic significance of BRCA2 mRNA levels in tumor tissues was studied in sporadic breast cancer patients. BRCA2 mRNA levels were determined by real-time PCR. Histologic grade III tumors showed significantly (p = 0.001) higher BRCA2 mRNA levels (0.828 +/- 0.102 BRCA2/beta-glucuronidase mRNA ratio, mean +/- SE) than histologic grade I and II tumors (0.438 +/- 0.055) and estrogen receptor (ER)-negative tumors (0.773 +/- 0.102) showed a nonsignificant (p = 0.072) trend toward an increase in BRCA2 mRNA levels compared to ER-positive tumors (0.541 +/- 0.079). Other clinicopathologic parameters, such as menopausal status, lymph node status and tumor size, were not significantly associated with BRCA2 mRNA levels. Patients with high BRCA2 mRNA levels showed a significantly (p = 0.006) lower 5-year disease free survival rate (63%) than those with low levels (94%). Lymph node metastases, ER negativity and high histologic grade were also significantly (p < 0.05) associated with poor prognosis. Multivariate analysis revealed that BRCA2 mRNA levels were a significant prognostic factor, being independent of the other conventional prognostic factors. Our results suggest that BRCA2 mRNA levels might serve as a clinically useful prognostic factor in breast cancer patients.


[A man with a swelling next to his nose].
A 61-year old male presented himself at the department of dermatology with an asymptomatic node next to the nose, which appeared to be a first manifestation of sarcoidosis.


Babesia bovis (argentina): observations of coagulation parameters, fibrinogen catabolism and fibrinolysis in intact and splenectomized cattle.
The results of this paper indicate that cattle infected with B. bovis (argentina) have a markedly altered and activated coagulation system. A degree of thrombin activation occurs due partly to release of thromboplastin-like substances from lysed erythrocytes but due primarily to activation of kallikrein by babesial proteases. This produces a hyperfibrinogenaemia, particularly in intact cattle, with soluble fibrin complexes constituting up to one-third of the total fibrinogen concentration. High molecular weight non-coagulable fibrinogen-like proteins are detected terminally but more so in splenectomized cattle. Plasminogen concentration decreases in splenectomized but not intact cattle while low molecular weight fibrinogen degradation products are not easily detected. It is suggested that a hypercoagulable intermediate state with little or no fibrin deposition occurs rather than terminal disseminated intravascular coagulation.


Riverine dissolved organic matter (DOM) as affected by urbanization gradient.
Rapid urbanization has considerably altered carbon biogeochemical cycle and river hydrology. However, the influences of urban land use and urban-induced nutrient increase on dissolved organic matter (DOM) characteristics are poorly understood. Here we hypothesize that the alterations significantly change sources and levels of DOM in river systems that drain the urban areas. To test the hypothesis, we investigated DOM in headwater rivers with varied urban intensities in the Three Gorges Reservoir Area (TGRA), China, through field sampling conducted in the dry and wet seasons. We found positive relationships of urban land (%Urban) with DOC concentration and chromophoric DOM (CDOM) absorption coefficients a254, a280 and a350, as well as fluorescence index (FI370), indicating the significantly increased levels of DOM and autochthonous sources along an urbanization gradient. A stepwise regression analysis demonstrated that occurrences of DOC and CDOM can be predicted by %Urban, while increasing autochthonous source is predictable by the increase in riverine nitrogen. Moreover, a254, a280 and FI370 values showed distinct seasonal variations, with significantly higher CDOM concentration in the wet season and with much higher autochthonous signal in the dry season with high nitrogen loading. Based on the findings, we conclude that urbanization influences occurrences and sources of DOM, with increasing urbanization making an important and direct contribution to DOM, and an indirect effect of urban induced nutrient enrichment, i.e., enhanced nutrient loadings increase autochthonous DOM production in rivers.


[Validation of a syndromic surveillance system of acute respiratory tract diseases in preschools of Schleswig-Holstein (SHARE)].
To obtain reliable, regionalized, and timely data for the spread of seasonal influenza in various age groups, which are preferentially affected by the influenza virus, a syndromic surveillance system for acute respiratory tract infections in Schleswig-Holstein (SHARE) was established in preschools and nurseries starting in 2006. The Schleswig-Flensburg district with 12 of 114 preschools and nurseries and 850 of 5,750 supervised children served as a pilot district. The weekly rates of sickness absenteeism correlated most strongly with the onset of seasonal influenza and with population density during the first half of the year. Mean annual sickness absenteeism levels of above 6% occurred more frequently above a population density of 200 inhabitants/km(2) than below this density (relative risk 2.50, 95% confidence interval 1.18-5.32). By analysis of the receiver-operating characteristic curve, the diagnostic performance of the SHARE system as a classifier for seasonal influenza was determined. The sensitivity was 83% and the specificity was 79% when sickness absence rates exceeded 5%. The performance of the SHARE system correlated with the size of the kindergarten. In 2008, 13 of 15 districts of Schleswig-Holstein participated with 157 of 1,684 kindergarten and 10,300 of 113,000 children. The evaluation for 2008 confirmed that the SHARE system is suitable for the surveillance of seasonal influenza at the district and state levels.


Brain-derived neurotrophic factor in experimental autoimmune neuritis.
Long-term disability in Guillain-Barré syndrome (GBS) is associated with axonal, and some neuronal, degeneration. Brain-derived neurotrophic factor (BDNF) can prevent neuronal death following damage to motor axons and we have therefore examined the ability of BDNF to ameliorate the effects of experimental autoimmune neuritis (EAN), a model of GBS. Treatment of Lewis rats with BDNF (10 mg/kg/day) did not significantly affect the neurological deficit, nor significantly improve survival, motor function or motor innervation. The weight of the urinary bladder was significantly increased in control animals with EAN, but remained similar to normal in animals treated with BDNF. With the exception of a possibly protective effect indicated by bladder weight, this study suggests that BDNF may not provide an effective therapy for GBS, at least in the acute phase of the disease.


Speciation and leachability of copper in mine tailings from porphyry copper mining: influence of particle size.
Mine tailing from the El Teniente-Codelco copper mine situated in VI Region of Chile was analysed in order to evaluate the mobility and speciation of copper in the solid material. Mine tailing was sampled after the rougher flotation circuits, and the copper content was measured to 1150 mg kg (-1) dry matter. This tailing was segmented into fractions of different size intervals: 0-38, 38-45, 45-53, 53-75, 75-106, 106-150, 150-212, and >212 microm, respectively. Copper content determination, sequential chemical extraction, and desorption experiments were carried out for each size interval in order to evaluate the speciation of copper. It was found that the particles of smallest size contained 50-60% weak acid leachable copper, whereas only 32% of the copper found in largest particles could be leached in weak acid. Copper oxides and carbonates were the dominating species in the smaller particles, and the larger particles contained considerable amounts of sulphides.


A concurrent occurrence of cutis laxa, Dandy-Walker syndrome and immunodeficiency in a girl.
We report on a 17-y-old girl with inherited cutis laxa, immunodeficiency and Dandy-Walker syndrome. Immunodeficiency manifested itself by decreased and fluctuating levels of IgG, IgA and IgM and intermittent leucopenia causing increased susceptibility to respiratory tract infections. Dandy-Walker syndrome (agenesis of the cerebellar vermis with a large posterior fossa cyst communicating with an enlarged 4th ventricle) was shown on a CT scan but with the exception of macrocrania, no typical signs or symptoms were observed at the age of 17. Loose hyperextensible skin with pendulous skinfolds as a manifestation of cutis laxa was observed from birth. Anomalies of the right pulmonary artery, abnormal branching of the left arteria subclavia (arteria lusoria) from the left aortic arch and bicuspidal aortic valve were also present. The combination of the rare disorders cutis laxa, Dandy-Walker syndrome and immunodeficiency is reported here for the first time.


A novel training model for the loop electrosurgical excision procedure: an innovative replica helped workshop participants improve their LEEP.
We wanted to evaluate the feasibility and effect of a hands-on loop electrosurgical excision procedure (LEEP) 2.5-day intensive surgical skills workshop, using a novel training model on porcine tissue. Hands-on simulation-based training was conducted to emphasize colposcopy, local anesthesia, uterine cervix and vulva punch biopsy, LEEP, and complication management. Performance of 51 participants' technical skills was assessed before and after training completion. LEEP performance was significantly better after completion of the training (P < .001). Before and after training mean scores (SD) of 18.0 (3.5) and 23.4 (2.1) were assessed. Multivariate analysis revealed that the training effects were independent of previous surgical expertise. The LEEP workshop was feasible and effective and we recommend implementing hands-on LEEP training into gynecology training programs.


Deciphering essential cistromes using genome-wide CRISPR screens.
Although millions of transcription factor binding sites, or cistromes, have been identified across the human genome, defining which of these sites is functional in a given condition remains challenging. Using CRISPR/Cas9 knockout screens and gene essentiality or fitness as the readout, we systematically investigated the essentiality of over 10,000 FOXA1 and CTCF binding sites in breast and prostate cancer cells. We found that essential FOXA1 binding sites act as enhancers to orchestrate the expression of nearby essential genes through the binding of lineage-specific transcription factors. In contrast, CRISPR screens of the CTCF cistrome revealed 2 classes of essential binding sites. The first class of essential CTCF binding sites act like FOXA1 sites as enhancers to regulate the expression of nearby essential genes, while a second class of essential CTCF binding sites was identified at topologically associated domain (TAD) boundaries and display distinct characteristics. Using regression methods trained on our screening data and public epigenetic profiles, we developed a model to predict essential cis-elements with high accuracy. The model for FOXA1 essentiality correctly predicts noncoding variants associated with cancer risk and progression. Taken together, CRISPR screens of cis-regulatory elements can define the essential cistrome of a given factor and can inform the development of predictive models of cistrome function.


The fecundity and long-term variability in abundance of noctuid moths (Lepidoptera, Noctuidae).
The relationship between fecundity and long-term adult fluctuations of 29 temperate noctuid moths was investigated and is explained in terms of the r- and K-selection strategies. The potential population growth rate per year (PGR) and the "rate of return to equilibrium" (sensu Pimm 1982) have been calculated and correlated with generation-to-generation fluctuations. A highly significant correlation was found between PGR and the coefficient of generation-to-generation variation. The r-strategy species possess the highest PGR, the highest generation-to-generation coefficient of variation and their larvae are polyphagous. Species with typical features of K-strategists exhibit the lowest PGR values and the lowest generation-to-generation coefficients of variation. Their larvae seem to be exclusively oligophagous.


Comparative activation states of tumor-associated and peritoneal macrophages from mice bearing an induced fibrosarcoma.
Balb/c mice bearing a methylcholanthrene-induced fibrosarcoma were used to compare the activation levels of tumor-associated and peritoneal macrophages. Two stages of tumor growth were examined, namely "small" and "large" tumors, with average diameters of 10 and 30 mm, respectively. The activation state, determined by measurement of both phagocytic index and beta-glucuronidase content, was found to be markedly higher in tumor-associated macrophages than in their peritoneal counterparts and it was, in addition, independent of tumor progression. The percentage of tumor-associated macrophages, which were detected on the basis of Fc receptor expression, remained constant in the growing neoplasm, at approximately 23% of total cell population. None of these parameters were affected by inoculation with an immunopotentiating dose of heat-killed Candida albicans which, on the other hand, seemed not to alter the course of the tumor. These data suggest that within the tumor microenvironment macrophages would somehow be maintained at a constant proportion and at a highly activated state, while outside the tumor they would be at a lower activation level. Our results also suggest that TAM would not possess antitumor activity in vivo, although we have found this activity in vitro.


Electrostatic interactions at the plasma membrane.
Hydrogen-ion titration has been used to detect the presence of charged groups on the human red-cell plasma membrane. The findings are discussed in terms of the effect of the local environment on electrostatic interactions between the charged groups.


Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation.
Aberrant overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been reported in a variety of tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell proliferation, acting concurrently as an nicotinamide adenine dinucleotide (NAD+) synthase and, unexpectedly, as an extracellular signaling molecule for several tumor-promoting pathways. Although previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers the possibility to simultaneously disrupt NAMPT's enzyme activity and ligand capabilities. Here we report the development of two highly selective proteolysis-targeting chimeras (PROTACs) that promote NAMPT degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions like NAMPT, which is not easily achieved by conventional enzymatic inhibitors.


Early pregnancy loss in in vitro fertilization (IVF) is a positive predictor of subsequent IVF success.
To determine the significance of biochemical pregnancy losses and clinical spontaneous abortion (SAB) on outcomes of future IVF cycles. Retrospective cohort study. Academic IVF program. Women with a history of unsuccessful IVF attempts undergoing IVF. None. Clinical pregnancy rate. Patients with an early pregnancy loss had a greater ongoing clinical pregnancy rate in the immediate next cycle when compared with those women who had a negative pregnancy test (37.3% vs. 27.3%). Patients with a history of a biochemical pregnancy or a clinical spontaneous abortion had an ongoing clinical pregnancy rate in the next cycle of 38.4% and 42.3%, respectively, compared with 27.3% in women who had a history of a negative pregnancy test. The cumulative pregnancy rate after the first IVF attempt was 54.1% in patients with a previous biochemical pregnancy loss, 61.4% in those with a previous clinical SAB, and 46.5% in women with a previous negative pregnancy test. Women who experience an early pregnancy loss after IVF have a greater likelihood of success in subsequent IVF cycles when compared with patients who fail to conceive.


[Gender-specific manifestations of daily physical activity and sedentary behaviour in elderly people of Surgut].
Objective of the study was to establish gender-specific characteristics of physical activity (PA) and sedentary behavior in elderly people living in Yugra North. 295 residents of Surgut (102 men aged 62,9±5,3 years, 35%; 193 women aged 61,9±3,8 years, 65%) were subject to a IPAQ-RU questionnaire. The study revealed the gender-specific differences in body length and mass, body mass and body fat indices. It was detected that more energy is spent on the housework and physical activity in the country (moderate-intensity physical activity for women and high-intensity one for men). The study data showed no statistically significant gender-specific differences in general physical activity. Sedentary behavior is more popular among men rather than women (2543 vs 2441 min/week). 47% of low-active men and 56% of women reported the sitting times of 6-9 hours per day, 42% - 9-12 hours per day. Actions need to be taken to increase physical activity which is low at the moment and decrease sedentary behavior which is currently on the high level.


Utilisation of thrombolytic therapy in older patients with myocardial infarction.
Empirical evidence from many countries, obtained from sampling populations of patients admitted to hospital with acute myocardial infarction, has confirmed that elderly patients are significantly less likely to receive thrombolytic therapy. This difference persists after controlling for confounding factors such as admission delay and contraindications to thrombolysis. However, evidence supporting the efficacy of thrombolysis in reducing mortality after acute myocardial infarction is less clear cut in patients aged 75 years or above than in younger patients. These older patients are substantially under-represented in the clinical trials although they constitute one third of the clinical population. Observational studies indicate that older patients are at slightly higher risk than younger patients of experiencing haemorrhagic stroke after thrombolysis. It is, however, unlikely that efficacy and tolerability considerations alone account for the low use of thrombolytics in the elderly as similar trends are seen for other modalities of treatment of acute myocardial infarction. Since older patients have the highest mortality risk after myocardial infarction, they have the greatest potential gain from thrombolytic treatment, assuming a uniform treatment effect across age. The estimated cost effectiveness (cost per quality-adjusted life-year gained) improves with increasing age. It is concluded that patient age should not influence the treatment decision concerning thrombolysis. To ensure that elderly patients receive maximum benefit from this therapeutic advance requires attention to referral patterns from the community, speed of assessment in hospital and a clear treatment policy without age constraints. The effectiveness of these measures should be routinely audited.


Bacteroides thetaiotaomicron relieves colon inflammation by activating aryl hydrocarbon receptor and modulating CD4+T cell homeostasis.
Inflammatory bowel disease (IBD) is a form of nonspecific chronic intestinal inflammation associated with gut microbiome dysbiosis. Modulating the composition of the intestinal flora may be a viable means of alleviating such inflammatory pathology. Bacteroides thetaiotaomicron (B. thetaiotaomicron) is a symbiotic intestinal microbe that has been associated with IBD, although the mechanistic basis for this association remains to be clarified. In this present study, we determined that B. thetaiotaomicron can alleviate colonic inflammation through mechanisms associated with the modulation of tryptophan metabolism and T cell subsets within inflamed intestinal tissues. Specifically, we found that B. thetaiotaomicron promotes the preferential differentiation of anti-inflammatory Treg/Th2 cells while suppressing the relative differentiation of pro-inflammatory Th1/Th17 cells, thereby decreasing inflammation within the colon. At a molecular level, B. thetaiotaomicron treatment was linked to altered CpG methylation within the Foxp3 promoter that was associated with enhanced Treg cell functionality. In a murine dextran sulfate sodium (DSS) colitis model system, B. thetaiotaomicron increased the levels of the aryl hydrocarbon receptor (AHR) ligands indole metabolites-indole acetic acid (IAA) and indole propionic acid (IPA), thereby increasing AHR activation that is related to changes of transcription factor expression profiles within T cells. In summary, our data suggest that B. thetaiotaomicron can activate AHR and modulate CD4+ T cell differentiation profiles in a murine DSS colitis model system, suggesting that this bacterium may be of therapeutic relevance for the treatment of IBD.


Manipulation of porous poly(l-lactide-co-ε-caprolactone) microcarriers via microfluidics for C2C12 expansion.
The growth and repair of skeletal muscle are due in part to activation of muscle precursor cells, commonly known as satellite cells or myoblasts. In order to acquire enough cells for neoskeletal muscle regeneration, it is urgent to develop microcarriers for skeletal myoblasts proliferation with a considerable efficiency. The current study was thus proposed to develop a microfluidic technology to manufacture porous poly(l-lactide-co-ε-caprolactone) (PLCL) microcarriers of high uniformity, and porosity was manipulated via camphene to suit the proliferation of C2C12 cells. A co-flow capillary microfluidic device was first designed to obtain PLCL microcarriers with different porosity. The attachment and proliferation of C2C12 cells on these microcarriers were evaluated and the differentiation potential of expanded cells were verified. The obtained porous microcarriers were all uniform in size with a high mono-dispersity (CV < 5 %). The content of camphene rendered effects on the size, porosity, and pore size of microcarriers, and porous structure addition produced a softening of their mechanical properties. The one of 10 % camphene (PM-10) exhibited the superior expansion for C2C12 cells with the number of cells after 5 days of culture reached 9.53 times of the adherent cells on the first day. The expanded cells from PM-10 still retained excellent myogenic differentiation performance as the expressions of MYOD, Desmin and MYH2 were intensively enhanced. Hence, the current developed porous PLCL microcarriers could offer as a promising type of substrates not only for in vitro muscular precursor cells expansion without compromising any multipotency but also have the potential as injectable constructs to mediate muscle regeneration.


Impact of acute and sub-acute exposure of magnesium oxide nanoparticles on mrigal Cirrhinus mrigala.
This experiment was conducted to investigate the impact of acute and sub-acute exposure of magnesium oxide nanoparticles on Mrigal Cirrhinus mrigala. For sub-acute tests 1/100,1/50,1/10 were selected based on the LC50 at 96 h s. Protein, carbohydrate, and lipid, Aspartate aminotransferase, alanine transaminase, lactate dehydrogenase and DPPH, HRSA assays were analyzed in the gill, muscle, and liver of Mrigal. Protein and lipid levels increased on the 7th,14th day compared to control. Carbohydrate levels decreased on the 7th,14th day of exposure, and the enzymatical changes increased on the 7th,14th day. Antioxidant levels highly increased in DPPH assay compared to the HRSA assay. This study provides the biochemical, antioxidant, and behavioral changes in relation to the exposure of MgO NPs.


Immunocytochemical detection of progesterone receptor in breast cancer with monoclonal antibody. Relation to biochemical assay, disease-free survival, and clinical endocrine response.
A new immunocytochemical assay for progesterone receptor (PgR-ICA) employing the monoclonal antibody JZB 39 was used to study tumors from two series of patients with breast cancer. In Series 1 assay results were in agreement with those of biochemistry in 76% of 338 cases (P less than 0.001) and in 54% of 101 cases in Series 2 (P less than 0.001). Agreement was better in Series 1 because it included fresher, previously untouched specimens. There were 70 patients in Series 1 with known clinical endocrine response. A negative assay correlated with disease progression in 45 of 57 patients, significantly better than with biochemistry (P = 0.013). In comparing 39 women with rapid disease progression with 39 free of disease at 5.1 years, those with PgR-ICA-positive tumors were over four times more likely to remain disease-free than those with negative results (P = 0.007). Product moment life-table analysis of 79 patients from Series 2 showed a significantly better cumulative survival for those with PgR-ICA-positive tumors (P = 0.047). These findings indicate that PgR-ICA should be of value in planning therapy and predicting disease course in breast cancer patients.


Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene.
A retrospective cohort study was carried out in a cardboard factory in Germany to investigate the association between exposure to trichloroethene (TRI) and renal cell cancer. The study group consisted of 169 men who had been exposed to TRI for at least 1 year between 1956 and 1975. The average observation period was 34 years. By the closing day of the study (December 31, 1992) 50 members of the cohort had died, 16 from malignant neoplasms. In 2 out of these 16 cases, kidney cancer was the cause of death, which leads to a standard mortality ratio of 3.28 compared with the local population. Five workers had been diagnosed with kidney cancer: four with renal cell cancers and one with a urothelial cancer of the renal pelvis. The standardized incidence ratio compared with the data of the Danish cancer registry was 7.97 (95% CI: 2.59-18.59). After the end of the observation period, two additional kidney tumors (one renal cell and one urothelial cancer) were diagnosed in the study group. The control group consisted of 190 unexposed workers in the same plant. By the closing day of the study 52 members of this cohort had died, 16 from malignant neoplasms, but none from kidney cancer. No case of kidney cancer was diagnosed in the control group. The direct comparison of the incidence on renal cell cancer shows a statistically significant increased risk in the cohort of exposed workers. Hence, in all types of analysis the incidence of kidney cancer is statistically elevated among workers exposed to TRI.(ABSTRACT TRUNCATED AT 250 WORDS)


The protective effect of curcumin administration on carbon tetrachloride (CCl4)-induced nephrotoxicity in rats.
The aim of the present study was to examine the protective effect of curcumin (CUR) on carbon tetrachloride (CCl4)-induced nephrotoxicity to evaluate the detailed mechanisms by which CUR exerts its protective action. Thirty male Wistar-Albino rats weighing 250-300 g were randomly divided into three groups: administrations of olive oil (control, po), CCl4 (0.5mg/kg in olive oil sc) every other day for 3 weeks, and CCl4 (0.5mg/kg in olive oil sc) plus CUR (200mg/kg) every day for 3 weeks. Administration of CCl4 significantly (p<0.001) increased the levels of renal function test such as creatinine and blood urea nitrogen (BUN). Furthermore, treatment of CCl4 significantly elevated the oxidant status of renal tissues while decreasing its anti-oxidant status (p<0.001). CUR displayed a renal protective effect as evident by significant decrease in inflammation and apoptosis during histopathological examination. The administration of CCl4 resulted in an increase in malondialdehyde (MDA) production due to an increase in membrane lipid peroxidation; however, the administration of CUR attenuated this, probably via its antioxidant and free radical scavenging properties. The finding of our study indicates that CUR may have an important role to play in protecting the kidney from oxidative insult.


The distribution of power and heat produced by interstitial microwave antenna arrays: II. The role of antenna spacing and insertion depth.
The distribution of power and temperature generated by 915 MHz interstitial microwave antenna arrays was studied in static muscle-equivalent phantoms and both perfused and non-perfused canine thigh muscle. These arrays, which would form the geometric basis of larger volume implants, consisted of four parallel antennas oriented such that transverse to their long axes they formed the corners of a square. Arrays with 2 and 3 cm sides were compared at various depths of insertion where the nodes for all four antennas were coincident at the same depth. The position relative to the antenna nodes of the maximum power and highest temperature within the array volume varied with the depth of insertion of the antennas. Though power dropped rapidly distal to the nodes at all depths, a shift in the location of the maximum power proximal to the nodes resulted in an increase in the effective heating volume at certain insertion depths. For 2 cm array spacing the highest power and temperature were measured along the central axis of the array at all insertion depths. However, arrays using 3 cm spacing generated their maximum power adjacent to the antennas with only 50% of this level occurring along the central axis. When the temperature produced by 3 cm arrays was measured in phantoms midway through simulated 30-minute hyperthermia treatments, the effect of thermal conduction on the temperature distribution was evident. Though power was only 50% centrally, the highest temperatures occurred there. This same pattern of central heating occurred in perfused canine muscle demonstrating the importance of conductive and convective heat redistribution in reducing thermal gradients within the array volume.


Science can be an anxiety-ridden road. It's best to develop coping strategies early in the journey.
Early adoption of coping strategies can help smooth the ups and downs of science and life.


Identified and potential internalization signals involved in trafficking and regulation of Na+/K+ ATPase activity.
The sodium-potassium pump (NKA) or Na+/K+ ATPase consumes around 30-40% of the total energy expenditure of the animal cell on the generation of the sodium and potassium electrochemical gradients that regulate various electrolyte and nutrient transport processes. The vital role of this protein entails proper spatial and temporal regulation of its activity through modulatory mechanisms involving its expression, localization, enzymatic activity, and protein-protein interactions. The residence of the NKA at the plasma membrane is compulsory for its action as an antiporter. Despite the huge body of literature reporting on its trafficking between the cell membrane and intracellular compartments, the mechanisms controlling the trafficking process are by far the least understood. Among the molecular determinants of the plasma membrane proteins trafficking are intrinsic sequence-based endocytic motifs. In this review, we (i) summarize previous reports linking the regulation of Na+/K+ ATPase trafficking and/or plasma membrane residence to its activity, with particular emphasis on the endocytic signals in the Na+/K+ ATPase alpha-subunit, (ii) map additional potential internalization signals within Na+/K+ ATPase catalytic alpha-subunit, based on canonical and noncanonical endocytic motifs reported in the literature, (iii) pinpoint known and potential phosphorylation sites associated with NKA trafficking, (iv) highlight our recent studies on Na+/K+ ATPase trafficking and PGE2-mediated Na+/K+ ATPase modulation in intestine, liver, and kidney cells.


Neuropsychological and behavioral disorders as presentation symptoms in two brothers with early-infantile Niemann-Pick type C.
Niemann-Pick disease type C (NPC) is a lysosomal storage disease caused by mutations in NPC1 or NPC2 genes. We present two brothers with the same compound heterozygous variants in exon 13 of the NPC1 gene (18q11.2), the first one (c.1955C> G, p. Ser652Trp), inherited from the mother, the second (c.2107T>A p.Phe703Ile) inherited from the father, associated to the classical biochemical phenotype of NPC. The two brothers presented unspecific neurologic symptoms with difference in age of onset: one presented dyspraxia and motor clumsiness at age 7 years, the other showed a systemic presentation with hepatosplenomegaly noted at the age of two months and neurological symptoms onset at age 4 with speech disturbance. Clinical evolution and neuroimaging data led to the final diagnosis. Systemic signs did not correlate with the onset of neurological symptoms. Miglustat therapy was started in both patients. We highlight the extreme phenotypic heterogeneity of NP-C in the presence of the same genetic variant and the unspecificity of neurologic signs at onset as previously reported. We report some positive effects of miglustat on disease progression assessed also with neuropsychological follow-up, with an age-dependent response.


In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low-frequency-ultrasound-induced blood-brain barrier opening in swine.
To verify that low-frequency planar ultrasound can be used to disrupt the BBB in large animals, and the usefulness of MRI to quantitatively monitor the delivery of superparamagnetic iron oxide (SPIO) nanoparticles into the disrupted regions. Two groups of swine subjected to craniotomy were sonicated with burst lengths of 30 or 100 ms, and one group of experiment was also performed to confirm the ability of 28-kHz sonication to open the BBB transcranially. SPIO nanoparticles were administered to the animals after BBB disruption. Procedures were monitored by MRI; SPIO concentrations were estimated by relaxivity mapping. Sonication for 30 ms created shallow disruptions near the probe tip; 100-ms sonications after craniotomy can create larger and more penetrating openings, increasing SPIO leakage ∼3.6-fold than 30-ms sonications. However, this was accompanied by off-target effects possibly caused by ultrasonic wave reflection. SPIO concentrations estimated from transverse relaxation rate maps correlated well with direct measurements of SPIO concentration by optical emission spectrometry. We have also shown that transcranial low-frequency 28-kHz sonication can induce secure BBB opening from longitudinal MR image follow up to 7 days. This study provides valuable information regarding the use low-frequency ultrasound for BBB disruption and suggest that SPIO nanoparticles has the potential to serve as a thernostic agent in MRI-guided ultrasound-enhanced brain drug delivery.


An in vitro test for endocytotic activation of murine epidermal Langerhans cells under the influence of contact allergens.
Several in vivo and in vitro studies have shown that contact sensitizing agents induce enhanced internalization of cell membrane constituents by epidermal Langerhans cells (LC). However the intracellular distribution of the internalized material has not yet been clearly defined. For this reason we investigated the uptake of gold-labeled antibodies against MHC class II molecules by cultured murine LC under the influence of various contact sensitizing agents, non-sensitizing analogues, and irritants. Antigen-antibody complexes were visualized by light microscopy using the silver enhancement technique and by pre-embedding electron microscopy. Viability was monitored by staining dead cells with propidium iodide. For light-microscopic evaluation of the intracellular distribution pattern of gold particles, a stimulation index was defined and used for the assessment of endocytotic activation. Untreated and solvent treated (control) cells exhibited an accumulation of internalized gold complexes into large aggregates composed of few intracellular vesicles. Cytoplasmic staining was absent and few gold particles were detectable in the endocytotic organelles under these conditions. In contrast to the non-sensitizing compounds DCNB and DNBSO3, which had no effect at all, treatment with subtoxic concentrations of the contact sensitizing agents DNFB, DNCB, TNCB, K2Cr2O7, NISO4 and p-phenylenediamine resulted in diffuse intracellular staining which was most pronounced in the submembraneous region. This was due to the numerous endocytotic vesicles which were closely associated with the cell membrane. Consequently a significant increase in the stimulation index was noted for these compounds. An irritant such as sodium lauryl sulphate used in subtoxic concentrations did not influence the intracellular distribution of internalized gold particles whereas toxic amounts of this compound induced a diffuse intracellular staining pattern indicative of membrane destruction. This approach represents a practical and reliable test for endocytotic activation of murine LC and may be useful for in vitro tests of the activating and possibly sensitizing properties of new chemical compounds.


Development of a subtidal epibenthic community: factors affecting species composition and the mechanisms of succession.
Macroinvertebrate grazers and temporal variability were found to strongly influence species composition of communities that developed subtidally on plexiglas panels. On panels exposed to the naturally high densities of sea urchins and sea stars, only grazer-resistant algal crusts, a diatom/blue-green algal film and short-lived filamentous algae became abundant. On those panels protected from grazers, however, other algae and sessile invertebrates were also common. Both the effects of grazing and the abundance of individual taxa differed on panels immersed at different times of the year.Resident species also affected subsequent recruitment. Some colonists were found more frequently on panels with established communities than on recently immersed plates. Others became more abundant on younger than on older panels. Considerable small-scale spatial variation in the abundance of species was also found among panels within treatments and appeared to persist throughout the 13 months of the study.I suggest that since the interactions that determine which mechanisms are important in succession occur between individuals (generalized here to species), not between successional stages, factors such as those examined that can determine which species will interact, indirectly determine the mechnaisms that are important in the development of a community. Models that deal with interactions between successional stages may lack the detail neccessary to predict or explain changes in species composition in diverse communities.


Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential.
AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (-9.5 kcal/mol) and ERK2 (-9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN-/- cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 μM within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.


Effects of ionic liquids on the survival, movement, and feeding behavior of the freshwater snail, Physa acuta.
Room-temperature ionic liquids (ILs) are being promoted as environmentally friendly alternatives to volatile organic solvents currently used by industry. Because ILs are novel and not yet in widespread use, their potential impact on aquatic organisms is unclear. We studied the effects of several ILs on the survivorship and behavior (movement and feeding rates) of the freshwater pulmonate snail, Physa acuta. Median lethal concentrations (LC50s) of ILs with imidazolium- and pyridinium-based cations and Br- and PF6- as anions ranged from 1 to 325 mg/L. Toxicity was greatest for ILs with eight-carbon alkyl chains attached to both imidazolium and pyridinium rings and declined with shorter alkyl chains, indicating a positive relationship between alkyl chain length and toxicity. Compared to controls, snails moved more slowly when exposed to butyl- and hexyl-cation ILs at 1 to 3% of LC50 concentrations but were not affected at higher IL concentrations (4-10% of LC50), which is characteristic of U-shaped dose-response curves. Snail movement was not affected by ILs with octyl alkyl groups. Grazing patterns, however, indicated that snails grazed less at higher IL concentrations. Physa acuta egestion rates were reduced in the presence of ILs at 3 to 10% of LC50 concentrations. Thus, nonlethal IL concentrations affected P. acuta behaviors, potentially impacting individual fitness and food web interactions. These results provide initial information needed to assess the potential hazards of ILs should they reach freshwater ecosystems.


Synthesis of a GlcNAcylated arginine building block for the solid phase synthesis of death domain glycopeptide fragments.
Herein we describe the synthesis of glycopeptide fragments from the death domains of TRADD and FADD bearing the recently discovered Nω-GlcNAc-β-arginine post-translational modification. TRADD and FADD glycopeptides were accessed through the use of a suitably protected synthetic glycosylamino acid 'cassette' that could be directly incorporated into conventional solid phase peptide synthesis (SPPS) protocols.


Predicting future risk of exacerbations in Japanese patients with adult asthma: A prospective 1-year follow up study.
To avoid future risk is a definitive goal of long-term asthma management. Exacerbations are considered to be the most relevant future risk in real life asthma management. Few comparative studies have evaluated the risk factors associated with exacerbations in Japanese patients with asthma. We performed the prospective 1-year follow up study in Japanese patients with adult asthma. A total of 189 patients with asthma were enrolled and followed up for 1 year. Finally, 181 patients completed the study protocol. Of 181 patients, 43 patients (23.8%) had exacerbations during the follow-up period. Among the 45 patients who had exacerbations during the preceding year, 32 patients (71.1%) had exacerbations. Prevalence of patients with previous exacerbations and those with previous admissions were significantly higher in patients with exacerbations than those with no exacerbation. Logistic regression analysis also identified a significant association between exacerbations during the follow-up period and exacerbations during the preceding year, admissions during the preceding 3 years, ACT score below 20, low %FVC (<80%), or low FEV1 (<70%), respectively. Of the 55 patients with severe asthma, 29 patients (52.7%) had exacerbations. Among the 36 patients with severe asthma with previous exacerbations, 26 patients (72.2%) had exacerbations. The history of exacerbations during the preceding year was associated with a significantly increased risk of exacerbations both among the patients with severe asthma and those with non-severe asthma. This study implicated that exacerbations during the preceding year reliably predict future risk of exacerbations in Japanese patients with asthma.


Supraclavicular first rib resection and total scalenectomy: technique and results.
The supraclavicular approach has been a successful route for thoracic outlet decompression. It permits many more options than the transaxillary route. Anterior and middle scalenectomy, together with brachial plexus neurolysis can be performed with excellent exposure. The same incision can be used to perform cervical or first rib resection, although the success rate is not significantly improved by removing ribs. The 5-year success rate for scalenectomy with or without first rib resection using life table methods is approximately 70%.


A case of non-agglutinable vibrio gastroenteritis with anuria.
A case of non-agglutinable vibrio (Heiberg Group II) gastroenteritis is presented. The patient, an alcoholic, acquired this infection in Australia and recovered fully. The need to use selective vibrio media when diarrhoeal stools are cultured is emphasized.


Rapid brain cooling in intubated pigs through nasal flushing with oxygen: prevention of brain hyperthermia.
Local cooling of the brain by the respiratory air is found in many animal species. The mechanism is based on cooling of the nasal vein blood and heat transfer in the cavernous sinus/carotid artery complex and is therefore not active in anaesthetised, intubated animals. The present experiment was made to investigate the effects of oxygen flushing of the nasal cavities in such animals. Nine anaesthetised, intubated male pigs were used. The temperatures in the third ventricle and rectum were measured continuously. Oxygen was infused into the nasal cavities during 10 min periods interrupted by 10 min without flow. The nasal oxygen flow constantly induced a rapid, reversible and flow dependant decrease in brain temperature: 0.25 degree C +/- 0.04, (n = 2) (mean +/- SD, n) at < 4 l/min; 1.35 degrees C +/- 0.78, (n = 20) at 4-6 l/min; and 1.44 degrees C +/- 0.62, (n = 6) at > 6 l/min. The ventricle temperature decreased 0.59 degree C +/- 0.23, (n = 8) when the animals were transferred to spontaneous respiration and the tracheal tube removed. It may be possible to protect the brain in intubated animals and humans from heat-induced damages by establishment of nasal flushing.


Ecotypic changes of alpine birds to climate change.
In endotherm animals, several traits are related to climate. For example, Bergmann's rule predicts a decrease in body size within species and across closely related species with increasing temperature, whereas Gloger's rule states that birds and mammals should be darker in humid and warm environments compared to colder and drier areas. However, it is still not clear whether ecotypic responses to variation in the local environment can also apply to morphological and colouration changes through time in response to climate change. We present a 100-year-long time series on morphological and melanin-based colours of snowfinch (325 Montifringilla, 92 Pyrgilauda and 30 Onychostruthus) museum specimens. Here we show that the tarsus length of the species has decreased and the saturation of the melanin-based colour has increased, which was correlated with the increase of temperature and precipitations. As ecotypic variations are tightly linked to individual behavioural and physiological responses to environmental variations, differently sized and coloured individuals are expected to be differently penalized by global changes. This study opens the pertinent question about whether ecotypic responses can enhance population persistence in the context of global change.


Expression of androgen receptor through androgen-converting enzymes is associated with biological aggressiveness in prostate cancer.
The association between the expression of androgen receptor (AR) or androgen-converting enzymes and malignant potential in prostate cancer (PCa) was examined. PCa specimens from 44 cases of stage II, 10 cases of stage III, four cases of stage IV and two recurrent cases were semi-quantitatively studied with immunohistochemistry for AR and androgen-converting enzymes. The expression scores for AR, 5alpha-reductase type 1 (SRD5A1), 5alpha-reductase type 2 (SRD5A2), and aldo-keto reductase family 1 member C3 (AKR1C3) in the metastatic lesion of stage IV or recurrent cancer (n = 6) were 284.2 (30.1), 300 (0.0), 279.2 (51) and 254.2 (74.9), respectively; these scores were significantly higher than the respective scores of 121.8 (82.1), 135.1 (59.7), 167.0 (66.4) and 150.5 (62.8) for stage II and III cancer (n = 54) (p<0.001, p<0.001, p = 0.002 and p = 0.018, respectively). The expression scores for AR and SRD5A1 in stage II and III cancer with Gleason score 7 (n = 19) were 128.7 (72.3) and 150.5 (52.9); these were significantly higher than the scores of 78.8 (67.2) and 100.0 (39.6), respectively, for cancers with a Gleason score of < or =6 (n = 20) (p = 0.032 and p = 0.002, respectively). The expression scores for AR, SRD5A1 and AKR1C3 in stage II and III cancer with primary Gleason pattern > or =4 (n = 21) were 158.1 (84.3), 158.3 (61.1) and 173.8 (64.8); these were significantly higher than the scores of 98.6 (72.8), 120.3 (54.7) and 135.6 (57.6), respectively, for cancers with primary Gleason pattern < or =3 (n = 33) (p = 0.011, p = 0.026 and p = 0.034, respectively). Within Gleason score 9 cancer, the expression scores for AR and SRD5A1 in the primary lesion of stage IV (n = 3) were 276.7 (5.8) and 283.3 (28.9); these scores were significantly higher than the scores of 182.1 (86.0) and 140.0 (56.6), respectively, for stage II and III cancer (n = 7) (p = 0.027 and p = 0.001, respectively). Both AR and androgen-converting enzymes were upregulated in high-grade or advanced PCa.


Effect of delayed mating and prolonged engorgement on the reproductive fitness of female Amblyomma limbatum (Acari: Ixodidae) in marginal population areas.
Reptile ticks mate while females are attached to their host. Following mating, females engorge, detach and then lay their eggs. This study examines whether the time that females of the reptile tick Amblyomma limbatum spend on hosts prior to mating and the time they take to engorge on hosts after mating influence their reproductive fitness, as measured by the number of viable eggs they produce. When compared with females that experienced no temperature-induced delay in mating, females attached for an initial period to hosts with body temperatures too low to induce mating had no decline in their reproductive fitness, once provided with suitable temperatures for mating. However, on hosts with suitable body temperatures for mating, female ticks that took longer to mate, took longer to engorge and had reduced reproductive fitness. In addition, females that spent more than 20 days feeding on hosts after mating had reduced reproductive fitness, irrespective of the time they spent on hosts prior to mating compared with females with shorter feeding periods. Thus, the time that A. limbatum females spent on hosts prior to mating and/or after mating has a significant bearing on the number viable progeny produced. The ecological implications of these results are discussed in relation to females colonizing marginal population areas at the edge of their distributional range.


Factors associated with COVID-19 vaccine uptake among foreign migrants in China.
The COVID-19 outbreak created unique policy challenges for vaccinating special groups like migrants. As part of sustainable development goals, the equitable distribution of the COVID-19 vaccine can contribute to ensuring health for all. This study examined COVID-19 vaccine uptake among foreign migrants in China based on sociodemographics, cultural beliefs, past vaccine behaviors, and psychosocial factors. An online cross-sectional survey was conducted among foreign migrants in mainland China via social media platforms from 21 November through 20 December 2021. Bivariate (unadjusted odd-ratio) and multivariate logistic regression analyses were performed to establish the correlates of COVID-19 vaccine uptake. Surveyed foreign migrants that are culture neutral (AOR: 2.5, CI: 95%, 1.02-5.90, p = 0.044), willing to pay for vaccination (AOR: 2.27, CI: 95%, 1.18-3.98, p = 0.012), believe in vaccine efficacy (AOR: 3.00, CI: 95%, 1.75-5.16, p < 0.000), have poor psychological health (AOR: 1.96, CI: 95%, 1.14-3.38, p = 0 0.014), and have higher perceived seriousness of COVID-19 (AOR: 2.12, CI: 95%, 1.26-3.57, p = 0.005) are more likely to receive COVID-19 vaccine. Those migrants with a history of declining vaccination (AOR: 0.34, CI: 95%, 0.18-0.65, p = 0.000) and middle-income earners $1701-3500 (AOR: 0.43, CI: 95%, 0.23-0.82, p = 0.010) are less likely to receive the COVID-19 vaccine. This study brings a unique perspective to understanding vaccine behavior among international migrants in China. There is an urgent call from the World Health Organization and countries for complete vaccination and efforts to improve vaccine coverage. However, fewer studies have been conducted globally on the vaccination of migrant populations. The current study provides empirical information to increase the knowledge of the correlates of vaccine behavior among immigrants in countries around the globe. Future studies should conduct cross-country comparisons to understand the factors associated with increasing vaccination rates among immigrant populations to formulate a strong policy to increase vaccine coverage among immigrant populations across countries.


No more the same: the lives of adolescents in Taiwan who have lost fathers.
This article offers a reconstruction of the life worlds of 30 adolescents, aged 9 to 18, from 20 families who have lost their fathers through death. Through interviews designed to measure the impact of culture on adolescent coping, six themes on rebuilding their lives, "no more the same," were identified: (1) isolation from death, (2) incompleteness, (3) staying inside, (4) worrying with mother, (5) building connections with fathers, and (6) restructuring the family. By exploring the lives of fatherless adolescents in Taiwan, the findings of this study illustrate a metaphor "no more the same" to represent life after father's death in such culture.


Feasibility of Concussion Rehabilitation Approaches Tailored to Psychological Coping Styles: A Randomized Controlled Trial.
To evaluate the feasibility of a clinical trial involving participants with concussion randomized to treatments designed to address fear avoidance or endurance coping, which are risk factors for disability. A secondary objective was to evaluate whether each treatment could affect selective change on targeted coping outcomes. Randomized controlled trial. Outpatient concussion clinics. Adults (N=73, mean age=42.5y) who had persistent postconcussion symptoms and high avoidance or endurance behavior were enrolled at a mean of 12.9 weeks post injury. Ten participants did not complete treatment. Participants were randomized to an interdisciplinary rehabilitation program delivered via videoconferencing and tailored to avoidance coping (graded exposure therapy [GET]) or endurance coping (operant condition-based pacing strategies plus mindfulness training [Pacing+]). Feasibility outcomes included screening efficiency, accrual, credibility, treatment fidelity, adherence, and retention. Avoidance was measured with the Fear Avoidance Behavior after Traumatic Brain Injury Questionnaire and endurance behavior with the Behavioral Response to Illness Questionnaire. Screening efficiency, or the proportion of clinic patients who were assessed for eligibility, was 44.5% (275 of 618). A total of 65.8% (73 of 111) of eligible patients were randomized (37 to GET, 36 to Pacing+), meeting accrual targets; 91.7% (55 of 60) of participants perceived treatment as credible. Therapists covered a mean of 96.8% of essential prescribed elements, indicating excellent fidelity. The majority (71.2%; 47 of 66) of participants consistently attended treatment sessions and completed between-session homework. Retention was strong, with 65 of 73 (89%) randomized participants completing the outcome assessment. GET was associated with greater posttreatment reductions in avoidance behavior compared with Pacing+ (Cohen's drepeated measures, 0.81), whereas the treatment approach-specific effect of Pacing+ on endurance behavior was less pronounced (Cohen's drepeated measures, 0.39). These findings support a future efficacy-focused clinical trial. GET has the potential to selectively reduce fear avoidance behavior after concussion, and, via this mechanism, to prevent or reduce disability.


Virus-like structures in the skin in the course of chronic lupus erythematosus.
Six skin biopsies of one patient, from foci of chronic lupus erythematosus in different stages of development of the disease and from unchanged skin were examined by electron microscope. The aim of the investigations performed was to check the presence of reticulotublar structures in these samples. Reticulotublar structures appeared in numerous quantities in early foci, while in scarred foci, as in structurally unchanged skin, they were, although always present, rare.


Immunohistologic identification of trophoblast populations in early human pregnancy with the use of monoclonal antibodies.
Three murine monoclonal antibodies (H315, H316, and NDOG1) have been used in a peroxidase-antiperoxidase technique on formalin-fixed paraffin-embedded tissues to identify populations of fetal trophoblast cells by their expression of membrane antigens in chorionic and decidual tissue from the first trimester of normal human pregnancy. H315 and H316 showed comparable staining of placental villous syncytiotrophoblast and cytotrophoblast and were also able to distinguish subpopulations of nonvillous trophoblast in the placental bed, including perivascular and endovascular trophoblastic cells as well as cytotrophoblastic elements within the decidua and myometrium. H315 and H316 also showed cytoplasmic staining of columnar epithelium of endometrial glands throughout the first trimester. In contrast, NDOG1 stained chorionic syncytiotrophoblast but not villous cytotrophoblast and also did not react with any cytotrophoblastic elements in the placental bed. NDOG1 distinguished these different subpopulations of trophoblast as early as 13 to 15 days after ovulation.


A bibliometric analysis of publications on trauma-related hemorrhagic shock from 2012 to 2022: Research landscape and future trends.
Trauma-related hemorrhagic shock is a global problem. This study aimed to analyze the knowledge domain and frontiers of trauma-related hemorrhagic shock research through a bibliometric analysis. Articles on trauma-related hemorrhagic shock published between 2012 and 2022 were retrieved from the Web of Science Core Collection, and a bibliometric analysis was conducted using CiteSpace and VOSviewer. A total of 3116 articles and reviews were analyzed. These publications primarily came from 441 institutions in 80 countries, with the USA having the highest number of publications, followed by China. Among the publications, Ernest E. Moore published the most papers, whereas John B. Holcomb had the most co-citations. The most productive institution was the University of Pittsburgh in the USA. The keyword burst and reference clustering analysis indicated that "reboa," "whole blood," "exsome," "glycocalyx," "endotheliopathy," and "predictor" are new trends and developing areas of interest. With the help of CiteSpace and VOSviewer, this study provides a deeper understanding of the research landscape, frontier hotspots, and future trends in trauma-related hemorrhagic shock over the last decade. "Whole blood" instead of "component therapy" shows potential advantage while "REBOA" is increasingly discussed in rapid hemostasis. This study provides important clues for researchers to understand the knowledge domain and frontiers of this study field.


Angioedema With Normal Complement Studies: What Do We Know?
Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.


Late Adiposity Rebound and the Probability of Developing and Reversing Childhood Obesity.
To evaluate the associations between late adiposity rebound (at or after 7.0 years of age) and the probability of developing and reversing obesity during elementary school years. Using nationally representative cohorts from Early Childhood Longitudinal Studies, Kindergarten Class of 1998-1999 and 2010-2011, weighted extended Cox hazard models were used to assess the probability of developing and reversing obesity (cut-offs for extended models were 6 and 12 months after kindergarten entry, respectively). Measurements used in the study were collected 6 times between kindergarten and fifth grade (Early Childhood Longitudinal Studies, Kindergarten Class of 1998-1999) and 8 times between kindergarten through fourth grade (Early Childhood Longitudinal Studies, Kindergarten Class of 2010-2011). Among children with obesity at kindergarten entry, within 6 months, the risk of developing obesity was 73% and 76% lower for boys with late adiposity rebound than their classmates without late adiposity rebound (hazard ratio 0.27 and 0.24). Six months after entering kindergarten, similar association was observed for both boys and girls. Among children without obesity at kindergarten entry, within 12 months, the probability of reversing obesity was 52% and 54% higher for boys with late adiposity rebound than their peers without late adiposity rebound (hazard ratio 1.52 and 1.54). Twelve months after entering kindergarten, the probability of reversing obesity among both sexes with late adiposity rebound was 6-8 times that among children without late adiposity rebound. Late adiposity rebound was significantly associated with a decreased risk of developing obesity and an increased probability of reversing obesity among kindergarteners.


Modulation of GABA binding to rat brain membranes by alkyl beta-carboline-3-carboxylate esters.
The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid were assessed on low affinity binding of GABA to rat brain membranes, and the enhancement of such binding by diazepam. The propyl ester acted as a benzodiazepine agonist in enhancing low affinity GABA binding, while the methyl and ethyl esters acted as benzodiazepine antagonists in reversing the stimulation of GABA binding by diazepam. These effects on low affinity GABA binding in vitro are consistent with pharmacological and behavioural actions of these esters in vivo and support the hypothesis that such actions are mediated via a GABA-benzodiazepine receptor complex.


Perceived muscular tension, emotional stress, psychological demands and physical load during VDU work.
The aim of this study was to investigate whether perceived muscular tension, psychological demands and emotional stress were associated with physical load or working technique during visual display unit (VDU) work. Subjects (28 women and 29 men) from two different organisations volunteered to participate in the study. The study design was cross-sectional, and the data were assessed when the subjects performed their usual work tasks at their usual work place. Multivariate linear and logistic regression models were used to investigate possible associations. The different outcome variables were: median muscle activity and muscular rest in the trapezius muscle bilaterally, wrist movements and working technique. The different explanatory variables were: perceived muscular tension (binary), emotional stress (binary), psychological demands (binary), organisation (binary) and gender (binary). Age (continuous) and present musculoskeletal pain (binary) were also controlled for in the multivariate models. Electromyography (EMG) and electrogoniometers were used to assess the physical load, and the data collection time was 15 min. An ergonomic checklist was used to assess working technique, i.e. work with lifted shoulders. Subjects who perceived muscular tension at least a few times per week the month before the measurements were made worked with higher muscle activity [expressed as per cent of a reference voluntary electrical activity (% RVE)] in the trapezius muscle bilaterally (5% RVE, P=0.05). High emotional stress during the measurement was associated with higher muscle activity in the trapezius muscle on the side not operating the computer mouse (8% RVE, P=0.006). Subjects who reported high levels of emotional stress worked more often with lifted shoulders (odds ratio 6.0, 95% CI 1.2-28.9). However, when present musculoskeletal pain was included in the multivariate model the odds ratio for high emotional stress decreased to 4.5 (95% CI 0.9-23.2). Perceived muscular tension and emotional stress were associated with physical load, in terms of muscle activity in the trapezius muscles, during VDU work in ordinary occupational settings.


Lipoprotein (a): Does It Play a Role in Pediatric Ischemic Stroke and Thrombosis?
The goal of this paper is to describe the current understanding of lipoprotein (a) (Lp(a)), clinical practice guidelines, and the potential pathophysiological mechanisms that appear to increase the risk of cardiovascular and thromboembolic events, specifically within the pediatric population. The proatherogenic and pro-thrombotic properties of Lp(a) may increase the risk of atherothrombotic disease. In adults, atherosclerotic plaques increase thrombotic risk, but antifibrinolytic and proinflammatory properties appear to have an important role in children. Although it is not well established in neonates, recent studies indicate the risk of incident thrombosis and ischemic stroke are approximately fourfold higher in children with elevated Lp(a) which also increases their risk of recurrent events. Despite this higher risk, Pediatric Lp(a) screening guidelines continue to vary among different medical societies and countries. The inconsistency is likely related to inconclusive evidence outside of observational studies and the lack of specific therapies for children with elevated levels. Additional research is needed to improve understanding of the pro-thrombotic mechanisms of Lp(a), appropriate screening guidelines for Lp(a) in the pediatric population, and to elucidate the short and long term effects of elevated Lp(a) on the risk of pediatric thrombosis and stroke.


Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells.
The glutamylation of methotrexate has been evaluated in H35 hepatoma cells in vitro as a function of the conditions of culture. Glutamylation yields methotrexate polyglutamate with two to five additional glutamate residues and is a saturable process. The rate of glutamylation increases little above 10 microM extracellular methotrexate which corresponds to an intracellular concentration of approximately 4 microM. The rate of glutamylation measured over a 6-h period was stimulated by a reduction in cellular folates and prior incubation of the cells with insulin. Glutamylation was also more rapid in dividing cultures than in confluent cells. The combination of insulin inclusion and folate reduction, which was additive, caused approximately a fourfold increase in the rate of glutamylation over control cells under the conditions tested. The maximal rate of methotrexate glutamylation, which was 100 nmol/g/h, occurred in folate-depleted, insulin-supplemented cells. Supplementing folate-depleted cells with reduced folate coenzymes caused the glutamylation to be reduced by more than 90%. The turnover of methotrexate polyglutamates in cells saturated with these derivatives occurred at approximately one-half the rate of net synthesis and was stimulated to nearly the same extent by folate depletion and insulin. In addition to showing that folates can modify the rates of methotrexate polyglutamate formation, data are presented suggesting that methotrexate polyglutamates can regulate their own synthesis. The consequences of the formation of these retained forms of methotrexate in H35 hepatoma cells (M. Balinska, J. Galivan, and J.K. Coward (1981) Cancer Res. 41,2751-2756) and the effects of potential regulators of this process are discussed in terms of the glutamylation of folates in the cells and the chemotherapeutic effects of antifolates.


Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor.
LH-21 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole) was previously reported as a neutral antagonist at the cannabinoid CB1 receptor which, despite its reported poor ability to penetrate into the brain, suppressed food intake and body weight in rats by intraperitoneal administration. In the present study, we studied the mechanism of action of LH-21 by characterizing its in vitro pharmacological properties and in vivo efficacy. LH-21 inhibited the binding of [3H]CP55940 to cloned human and rat CB1 receptors with IC50 values of 631+/-98 nM, and 690+/-41 nM, respectively, and acted as an inverse agonist in a cAMP functional assay using cultured cells expressing human, rat or mouse CB1 receptor. The compound was shown to be brain-penetrant in rats by intravenous administration. Importantly, a single dose of LH-21 (60 mg/kg, i.p.) caused a similar suppression of overnight food intake and body weight gain in wild-type and CB1 receptor knockout mice. Our results suggest that LH-21 is a low affinity inverse agonist for the CB1 receptor and does not act on the CB1 receptor to inhibit food intake in mice.


Review: Diagnostic accuracy of PCR-based detection tests for Helicobacter Pylori in stool samples.
Although different methods have been established to detect Helicobacter pylori (H. pylori) infection, identifying infected patients is an ongoing challenge. The aim of this meta-analysis was to provide pooled diagnostic accuracy measures for stool PCR test in the diagnosis of H. pylori infection. In this study, a systematic review and meta-analysis were carried out on various sources, including MEDLINE, Web of Sciences, and the Cochrane Library from April 1, 1999, to May 1, 2016. This meta-analysis adheres to the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses report (PRISMA Statement). The clinical value of DNA stool PCR test was based on the pooled false positive, false negative, true positive, and true negative of different genes. Twenty-six of 328 studies identified met the eligibility criteria. Stool PCR test had a performance of 71% (95% CI: 68-73) sensitivity, 96% (95% CI: 94-97) specificity, and 65.6 (95% CI: 30.2-142.5) diagnostic odds ratio (DOR) in diagnosis of H. pylori. The DOR of genes which showed the highest performance of stool PCR tests was as follows: 23S rRNA 152.5 (95% CI: 55.5-418.9), 16S rRNA 67.9 (95%CI: 6.4-714.3), and glmM 68.1 (95%CI: 20.1-231.7). The sensitivity and specificity of stool PCR test are relatively in the same spectrum of other diagnostic methods for the detection of H. pylori infection. In descending order of significance, the most diagnostic candidate genes using PCR detection were 23S rRNA, 16S rRNA, and glmM. PCR for 23S rRNA gene which has the highest performance could be applicable to detect H. pylori infection.