Safety Indices of Ultrasound: Adherence to Recommendations and Awareness During Routine Obstetric Ultrasound Scanning.
To analyze bioeffect safety indices and assess how often operators look at these indices during routine obstetric ultrasound. Automated analysis of prospectively collected data including video recordings of full-length ultrasound scans coupled with operator eye tracking was performed. Using optical recognition, we extracted the Mechanical Index (MI), Thermal Index in soft tissue (TIs), and Thermal Index in bone (TIb) values and ultrasound mode. This allowed us to report the bioeffect safety indices during routine obstetric scans and assess adherence to professional organization recommendations. Eye-tracking analysis allowed us to assess how often operators look at the displayed bioeffect safety indices. A total of 637 ultrasound scans performed by 17 operators were included, of which 178, 216, and 243 scans were first, second, and third-trimester scans, respectively. During live scanning, the mean and range were 0.14 (0.1 to 3.0) for TIb, 0.2 (0.1 to 1.2) for TIs, and 0.9 (0.1 to 1.3) for MI. The mean and standard deviation of TIb were 0.15 ± 0.03, 0.23 ± 0.09, 0.32 ± 0.24 in the first, second, and third trimester, respectively. For B-mode, the highest TIb was 0.8 in all trimesters. The highest TIb was recorded for pulsed-wave Doppler mode in all trimesters. The recommended exposure times were maintained in all scans. Analysis of eye tracking suggested that operators looked at bioeffect safety indices in only 27 (4.2 %) of the scans. In this study, recommended bioeffect indices were adhered to in all routine scans. However, eye tracking showed that operators rarely assessed safety indices during scanning.


Intracellular pH is increased after transformation of Chinese hamster embryo fibroblasts.
These studies reveal that a series of tumorigenic Chinese hamster embryo fibroblast (CHEF) cell lines maintain an internal pH (pHi) that is 0.12 +/- 0.04 pH unit above that of the nontumorigenic CHEF/18 parental line. This increase of pHi in the tumorigenic CHEF cells is not due to autocrine growth factor production or to the persistent activation of pathways previously shown to modulate Na+/H+-antiporter activity present in the CHEF/18 line. These findings suggest that the defect in pHi regulation in the tumorigenic CHEF/18 derivatives lies in the Na+/H+ antiporter itself. Further studies to determine the biological significance of an increased pHi show that the external pH (pHo)-dependence curve for initiation of DNA synthesis in the tumorigenic CHEF lines is shifted by approximately 0.2 pH unit toward acidic values relative to that of the nontumorigenic CHEF/18 parent. These data show a critical role for pHi in the regulation of DNA synthesis in Chinese hamster embryo fibroblasts and demonstrate that aberrations in pHi can contribute to the acquisition of altered growth properties.


Sedentary behaviour in relation to ovarian cancer risk: a systematic review and meta-analysis.
Sedentary behaviour is an emerging risk factor for several site-specific cancers. Ovarian cancers are often detected at late disease stages and the role of sedentary behaviour as a modifiable risk factor potentially contributing to ovarian cancer risk has not been extensively examined. We systematically searched relevant databases from inception to February 2020 for eligible publications dealing with sedentary behaviour in relation to ovarian cancer risk. We conducted a systematic review and meta-analysis, calculating summary relative risks (RR) and 95% confidence intervals (CI) using a random-effects model. We calculated the E-Value, a sensitivity analysis for unmeasured confounding. We tested for publication bias and heterogeneity. Seven studies (three prospective cohort studies and four case-control studies) including 2060 ovarian cancer cases were analysed. Comparing highest versus lowest levels of sedentary behaviour, the data indicated a statistically significant increase in the risk of ovarian cancer in relation to prolonged sitting time (RR = 1.29, 95% CI = 1.07-1.57). Sub-analyses of prospective cohort studies (RR = 1.33, 95% CI = 0.92-1.93) and case-control studies (RR = 1.28, 95% CI = 0.98-1.68) showed statistically non-significant results. Sensitivity analysis showed that an unmeasured confounder would need to be related to sedentary behaviour and ovarian cancer with a RR of 1.90 to fully explain away the observed RR of 1.29. Our analyses showed a statistically significant positive association between sedentary behaviour and ovarian cancer risk.


Addictive Potential of Online-Gambling. A Prevalence Study from Austria.
There are hints, that online-gambling has a higher addictive potential than offline-gambling. In this study prevalence and sociodemographic distribution of online- vs. offline-gambling in Austria are gathered and possible relations discussed. Problematic gambling-behavior was assessed via Lie-and-Bet questionnaire from Johnson. The results indicate a tendency of younger gamblers and particularly problematic gamblers towards online-gambling. Considering the substantial addictive potential of online-gambling and hints of a future trend away from offline- towards online-gambling, preventive measures like public restrictions for online providers and awareness campaigns for consumers about the dangers of online-gambling offers are reasonable.


Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial.
High serum levels of testosterone and estradiol, the bioavailability of which may be increased by Western dietary habits, seem to be important risk factors for postmenopausal breast cancer. We hypothesized that an ad libitum diet low in animal fat and refined carbohydrates and rich in low-glycemic-index foods, monounsaturated and n-3 polyunsaturated fatty acids, and phytoestrogens, might favorably modify the hormonal profile of postmenopausal women. One hundred and four postmenopausal women selected from 312 healthy volunteers on the basis of high serum testosterone levels were randomized to dietary intervention or control. The intervention included intensive dietary counseling and specially prepared group meals twice a week over 4.5 months. Changes in serum levels of testosterone, estradiol, and sex hormone-binding globulin were the main outcome measures. In the intervention group, sex hormone-binding globulin increased significantly (from 36.0 to 45.1 nmol/liter) compared with the control group (25 versus 4%,; P < 0.0001) and serum testosterone decreased (from 0.41 to 0.33 ng/ml; -20 versus -7% in control group; P = 0.0038). Serum estradiol also decreased, but the change was not significant. The dietary intervention group also significantly decreased body weight (4.06 kg versus 0.54 kg in the control group), waist:hip ratio, total cholesterol, fasting glucose level, and area under insulin curve after oral glucose tolerance test. A radical modification in diet designed to reduce insulin resistance and also involving increased phytoestrogen intake decreases the bioavailability of serum sex hormones in hyperandrogenic postmenopausal women. Additional studies are needed to determine whether such effects can reduce the risk of developing breast cancer.


Redistributed charge and dipole schemes for combined quantum mechanical and molecular mechanical calculations.
Special care is needed in carrying out combined quantum mechanical and molecular mechanical (QM/MM) calculations if the QM/MM boundary passes through a covalent bond. The present paper discusses the importance of correctly handling the MM partial point charges at the QM/MM boundary, and in particular, it contributes in two aspects: (1) Two schemes, namely, the redistributed charge (RC) scheme and the redistributed charge and dipole (RCD) scheme, are introduced to handle link atoms in QM/MM calculations. In both schemes, the point charge at the MM boundary atom that is replaced by the link atom is redistributed to the midpoint of the bonds that connect the MM boundary atom and its neighboring MM atoms. These redistributed charges serve as classical mimics for the auxiliary orbitals associated with the MM host atom in the generalized hybrid orbital (GHO) method. In the RCD scheme, the dipoles of these bonds are preserved by further adjustment of the values of the redistributed charges. The treatments are justified as classical analogues of the QM description given by the GHO method. (2) The new methods are compared quantitatively to similar methods that were suggested by previous work, namely, a shifted-charge scheme and three eliminated-charge schemes. The comparisons were carried out for a series of molecules in terms of proton affinities and geometries. Point charges derived from various charge models were tested. The results demonstrate that it is critical to preserve charge and bond dipole and that it is important to use accurate MM point charges in QM/MM boundary treatments. The RCD scheme was further applied to study the H atom transfer reaction CH3 + CH3CH2CH2OH --> CH4 + CH2CH2CH2OH. Various QM levels of theory were tested to demonstrate the generality of the methodology. It is encouraging to find that the QM/MM calculations obtained a reaction energy, barrier height, saddle-point geometry, and imaginary frequency at the saddle point in quite good agreement with full QM calculations at the same level. Furthermore, analysis based on energy decomposition revealed the quantitatively similar interaction energies between the QM and the MM subsystems for the reactant, for the saddle point, and for the product. These interaction energies almost cancel each other energetically, resulting in negligibly small net effects on the reaction energy and barrier height. However, the charge distribution of the QM atoms is greatly affected by the polarization effect of the MM point charges. The QM/MM charge distribution agrees much better with full QM results than does the unpolarized charge distribution of the capped primary subsystem.


In situ Gel of Metoprolol Tartrate: Physicochemical Characterization, In vitro Diffusion and Histological Studies.
The purpose of the present investigation was to prepare an intranasal in situ gel with increased nasal residence time in order to improve bioavailability of metoprolol tartrate. The in situ gel systems containing carbopol, hydroxypropyl methylcellulose K4M and K15M in different concentrations were prepared. The samples were characterized for viscosity, rheological behavior, gelation behavior, gel strength, and mucoadhesion. The formulations F10 (0.4% w/v carbopol, 1% w/v hydroxylpropyl methylcellulose K15M) and F13 (0.3% w/v carbopol, 1% w/v hydroxypropyl methylcellulose K15M) showed gel strength of 40.33±0.47 and 43.00±1.41, respectively, and mucoadhesion strength 31.48±0.14×10(3) and 32.12±0.05×10(3) dyne/cm(2), respectively. In vitro release profiles showed initial burst followed by slow release. F10 and F13 released 88.08±0.98 and 91.18±1.09% drug in 8 h. R(2) value for F10 (0.9953) and F13 (0.9942) was maximum for Higuchi, showing mixed order kinetics while n value obtained on treatment with Korsemayer Pappas equation were near to 0.5, suggesting release by fickian diffusion mechanism. The nasal permeability of formulations F10 and F13 were found to be 0.057 and 0.063 cm/s, respectively. Histopathological examination revealed slight degeneration of nasal epithelium with increased vascularity by F10 but no inflammation by formulation F13. Thus, a pH triggered in situ gel system containing low concentration (0.3% w/v) of carbopol demonstrated sustained release of metoprolol tartrate without any destructive effect on the mucosa.


Assessment of heart neurons in dilated (congestive) cardiomyopathy.
Pathological studies in seven hearts from patients with dilated cardiomyopathy have shown that the number of neurons is significantly reduced in these compared with five hearts from normal subjects. The number of ganglion cells was counted in a strip of right atrial wall between the venae cavae and sectioned serially. The mechanism responsible for the neuronal depopulation in this type of cardiomyopathy could not be determined. Previous viral infection may be causally related. Three hearts of patients suffering from chronic Chagas's heart disease were also studied. Depopulation of neurons was most severe in the hearts with Chagas's disease and less severe in those with dilated cardiomyopathy, though neurons were still significantly reduced in number in the latter compared with normal controls. Despite the lack of a specific, definite cause for the depopulation of neurons, physiological evidence of parasympathetic impairment in patients with dilated cardiomyopathy is in agreement with the pathological findings. It is suggested that on the basis of our findings neuronal depopulation in some patients with dilated cardiomyopathy may be of aetiological significance.


CRISPR/Cas9-Mediated Multiple Knockouts in Abscisic Acid Receptor Genes Reduced the Sensitivity to ABA during Soybean Seed Germination.
Abscisic acid (ABA) is an important plant hormone that regulates numerous functions in plant growth, development, and stress responses. Several proteins regulate the ABA signal transduction mechanism in response to environmental stress. Among them, the PYR1/PYL/RCAR family act as ABA receptors. This study used the CRISPR/Cas9 gene-editing system with a single gRNA to knock out three soybean PYL genes: GmPYL17, GmPYL18, and GmPYL19. The gRNA may efficiently cause varying degrees of deletion of GmPYL17, GmPYL18, and GmPYL19 gene target sequences, according to the genotyping results of T0 plants. A subset of induced alleles was successfully transferred to progeny. In the T2 generation, we obtained double and triple mutant genotypes. At the seed germination stage, CRISPR/Cas9-created GmPYL gene knockout mutants, particularly gmpyl17/19 double mutants, are less susceptible to ABA than the wild type. RNA-Seq was used to investigate the differentially expressed genes related to the ABA response from germinated seedlings under diverse treatments using three biological replicates. The gmpyl17/19-1 double mutant was less susceptible to ABA during seed germination, and mutant plant height and branch number were higher than the wild type. Under ABA stress, the GO enrichment analysis showed that certain positive germination regulators were activated, which reduced ABA sensitivity and enhanced seed germination. This research gives a theoretical basis for a better understanding of the ABA signaling pathway and the participation of the key component at their molecular level, which helps enhance soybean abiotic stress tolerance. Furthermore, this research will aid breeders in regulating and improving soybean production and quality under various stress conditions.


Mirror visual feedback alleviates deafferentation pain, depending on qualitative aspects of the pain: a preliminary report.
Following lesions in somatosensory pathways, deafferentation pain often occurs. Patients report that the pain is qualitatively complex, and its treatment can be difficult. Mirror visual feedback (MVF) treatment can improve deafferentation pain. We sought to classify the qualities of the pain in order to examine whether the potential analgesic effect of MVF depends on these qualities. Twenty-two patients with phantom limb pain, or pain related to spinal cord or nerve injury, performed a single MVF procedure. Before and after the MVF procedure, we evaluated phantom limb awareness, movement representation of the phantom or affected/paralysed limb, pain intensity on an 11-point numerical rating scale (0-10) and the qualities of the pain [skin surface-mediated (superficial pain) vs deep tissue-mediated (deep pain)] using lists of pain descriptors for each of the two categories. Fifteen of the patients perceived the willed visuomotor imagery of the phantom or affected/paralysed limb after the MVF procedure. In most of the patients, a reduction in pain intensity and a decrease in the reporting of deep-pain descriptors were linked to the emergence of willed visuomotor imagery. In this pilot study, we roughly classified the pain descriptor items into two types for evaluating the qualities of deafferentation pain. We found that visually induced motor imagery by MVF was more effective for reducing deep pain than superficial pain. This suggests that the analgesic effect of MVF treatment does depend on the qualities of the pain. Further research will be required to confirm that this effect is a specific consequence of MVF.


Collaboration at risk: registered nurses' experiences on orthopaedic wards.
To extract meaning from registered nurses' lived experiences in their professional collaboration with orthopaedic surgeons. Interprofessional collaboration between registered nurses and orthopaedic surgeons faces challenges on many levels. The literature offers theories on collaboration, but reality seems to be in conflict with theory, especially in somatic hospitals. Little empirical research on lived experience has been conducted in these settings. I conducted narrative interviews with five registered nurses who work on orthopaedic wards in two different hospitals in Norway. I analysed the data using a phenomenological hermeneutical method inspired by Ricoeur's theory of interpretation. The registered nurses emphasised disparate expectations and priorities when they described collaboration. They felt their performance was hindered and had difficulty in being assertive about their own area of work. Collaboration was perceived from the perspective of relations with orthopaedic surgeons, which were perceived as difficult as indicated by the themes identified: disparate expectations and priorities; feeling emotionally burdened; keeping a distance; accepting difficult relations; and being confident in difficult relations. Registered nurses seem to focus on relations in work settings where chaos and unpredictability set the background for collaboration. They perceived relations through their focus on behaving responsibly. This highlights their resources and their ability to see and to meet others, as well as difficulties they experience in asserting the importance of their own professional sphere. Acknowledging strengths and weaknesses could help to strengthen nursing identity and make it more explicit. Both resources and weaknesses are revealed that could be used by all healthcare workers to improve collaboration with colleagues, thereby enhancing patient care.


Petroleum hydrocarbon remediation in frozen soil using a meat and bonemeal biochar plus fertilizer.
Petroleum hydrocarbon (PHC) degradation slows significantly during the winter which substantially increases the time it takes to remediate soil in Arctic landfarms. The aim of this laboratory trial was to assess the potential of a meat and bonemeal (MBM) biochar to stimulate PHC degradation in contaminated soil collected from Iqaluit, Canada. Over 90 days, 3% (w/w) MBM biochar significantly increased F3- (equivalent nC16-C34) PHC degradation rate constants (k) in frozen soils when compared to the fertilizer (urea and monoammonium phosphate) control. Taking into consideration extensive variability within treatments and negative k values, this difference may not reflect significant remediation. Decreasing C17/Pr and C18/Ph ratios in the frozen soil suggest that this reduction is a result of microbial degradation rather than volatilization. Amendment type and application rate affected the immediate abiotic losses of F2 and F3-PHC in sterile soils, with the greatest losses occurring in compost-amended treatments in the first 24 h. In frozen soils, MBM biochar was found to increase liquid water content (θliquid) but not nutrient supply rates. Under frozen but not thawed conditions, genes for aromatic (C2,3O and nahAc) but not aliphatic (alkB) PHC degradation increased over time in both biochar-amended and control treatments but total viable PHC-degrading populations only increased in biochar-amended soils. Based on these results, it is possible that PHC degradation in biochar-amended soils is active and even enhanced under frozen conditions, but further investigation is required.


Patient narratives representing patient voices to inform research: a pilot qualitative study.
We are investigating the feasibility and effectiveness of establishing a library of patient narratives to inform patient-centered research in the U.S. Veterans Affairs organization. Using qualitative methods, we conducted a needs assessment of 15 researchers and then interviewed and videotaped 11 veterans with traumatic brain injury or diabetes. We developed a method for displaying the narratives to researchers modeled after a UK initiative called DIPEx and then performed preliminary usability testing. We found that it is not only feasible to provide researchers with patient narratives that could help guide their research, but that similar narratives might be useful to practitioners, health system decision makers, and other patients as well.


Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures.
Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague-Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signal-regulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethyl rhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (DeltaPsi(m)). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 h) also significantly (p<0.01) dissipates the DeltaPsi(m) in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways.


Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy.
Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. We evaluated 415 patients with AML-MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML-MRC, therapy type and mutation profile. Criteria for AML-MRC included: cytogenetic abnormalities (AML-MRC-C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML-MRC-H) and 28 (7%) with previously treated MDS (AML-MRC-TS), and 97 (23%) with multilineage dysplasia (AML-MRC-M). Median age was 70 years (range 18-94). Among 95 evaluable patients, a total of 37 (39%) had secondary-type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML-MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML-MRC-M (HR 0.56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions.


Immobilization of cesium-resistant bacterial cells by radiation polymerization and their bioremoval efficiency.
Biological approaches for the removal of heavy metals and radionuclides from contaminated water are reported. The present study was carried out with the objective of identifying bacterial strains for the uptake of cesium that could be used for bioremediation. Polymer carriers prepared by radiation polymerization were used for the immobilization of bacteria and the efficiency of free cells and immobilized cells for the removal of cesium was evaluated. Thirty-five bacterial isolates were screened for resistance to cesium and five bacterial isolates based on resistance to cesium (BR-3, BR-6, BR-21, BR-39, BR-40) were selected for immobilization. Polymer carriers were prepared using 10, 20, 30, 40 and 50% acrylamide at different doses of 1 to 5 kGy gamma radiation. The polymer carriers prepared using 30% and 40% acrylamide at 5 kGy were found to be suitable based on gel fraction and absorption capacity for the immobilization of bacterial cells. Bioremoval of cesium by free and immobilized bacterial cells was evaluated. Significant reductions of 76-81% cesium were observed with bacterial cells immobilized by radiation polymerization.


Rationalising the influence of solvent choice on the porosity of conjugated microporous polymers.
Conjugated microporous polymers (CMPs) synthesised in different solvents give different surface areas dependent on the solvent choice. No one solvent results in a high surface area across a range of different CMP materials. Here, we present an investigation into how the porosity of CMPs is affected by solvent polarity. It is seen that the trends differ depending on the respective monomer dipole moments and whether hydrogen bonding groups are present in the monomers and are able to interact with the respective solvent via hydrogen bonding. It is believed that this methodology could be used to influence future materials design of both structure and synthesis strategy.


A competitive inhibitory circuit for selection of active and passive fear responses.
When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses. Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents. However, rodents also exhibit active responses such as flight under natural conditions. The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established. Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF+) mediate conditioned flight, and activation of somatostatin-positive (SOM+) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF+ and SOM+ neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.


Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies.
Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration. Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age. Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells. Early IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration.


Hypertrophy and hyperplasia in the endocrine and exocrine pancreas of rats fed soybean trypsin inhibitor or repeatedly injected with pancreozymin.
Rats were 1) fed raw soybeans for 30 days, 2) given trypsin inhibitor as drinking water for 7 days, or 3) repeatedly injected with cholecystokinin-pancreozymin (CCK-PZ) for 7 days. After all these treatments the pancreas of the animals was markedly enlarged. Microscopic examination revealed, besides hypertrophy of acinar cells, increased mitotic figures in the acinar, centro-acinar, intercalated portion and excretory duct cells. The islets of Langerhans were found conspicuously enlarged due to mitotic proliferation of B cells. The endogenous CCK-PZ released by the intraluminal trypsin inhibitor and the exogenous CCK-PZ given by injections thus exerts not only secretagogous, but also trophic effects upon the endocrine and exocrine pancreas. The exocrine pancreas likely is affected also by the increased release of insulin from the B cells stimulated by CCK-PZ.


'Clickable' 2,5-diketopiperazines as scaffolds for ligation of biomolecules: their use in Aβ inhibitor assembly.
The synthesis of 1,3,6-trisubstituted-2,5-diketopiperazine scaffolds bearing up to three 'clickable' sites for further oxime bond or alkyne-azide cycloaddition ligations is described. The orthogonally Boc/Alloc protected DKP precursors prepared from L-lysine residues and an aminohexyl arm are efficiently prepared on a gram scale by sequentially using Fukuyama-Mitsunobu alkylation, dipeptide coupling and diketopiperazine ring formation as key steps. These scaffolds, with their glyoxylyl, aminooxy, alkynyl or azido functions, are "ready-to-use" platforms for biomolecular assembly. Their potentiality in this field was proved through the chemoselective ligation of Aβ-binding motifs, the KLVFFA peptide and the curcumin molecule. The inhibitory effect of these conjugates on Aβ amyloid fibril formation is reported using thioflavin T fluorescence assays and AFM observation.


Improving animal well-being through genetic selection.
This paper reviews the possibilities of adapting laying hens to cages by means of genetic selection. By selecting separately for rate of lay and longevity using a kin selection method, a strain of laying hen has been developed that shows much less feather pecking and cannibalism than a control strain, and with no decrease in productivity. This experimental strain enjoys a higher level of welfare in cages because it does not require beak trimming.


The need for culture in tegumentary leishmaniasis diagnosis in Bolivia: a comparative evaluation of four parasitological techniques using two sampling methods.
Leishmaniases are zoonotic diseases caused by protozoa of the genus Leishmania. In Bolivia, leishmaniasis occurs mainly in the cutaneous form (CL) followed by the mucosal or mucocutaneous form (ML or MCL), grouped as tegumentary leishmaniosis (TL), while cases of visceral leishmaniasis (VL) are rare. The cases of TL are routinely diagnosed by parasitological methods: Direct Parasitological Exam (DPE) and axenic culture, the latter being performed only by specialized laboratories. The aim of the present study was to optimize the parasitological diagnosis of TL in Bolivia, using two sampling methods. Samples from 117 patients with suspected TL, obtained by aspiration (n=121) and scraping (n=121) of the edge of the lesion were tested by: direct parasitological exam, culture in TSTB medium, and miniculture and microculture in Schneider's medium. A positive laboratory result by any of the four techniques evaluated using either of the two sampling methods was considered the gold standard. Of the 117 suspected patients included, TL was confirmed in 96 (82%), corresponding 79 of the confirmed cases (82.3%) to CL and 16 (16.7%) to ML. Parasitological techniques specificity was 100% and their analytical sensitivity was greater with scraping samples in TSTB culture (98%). Scraping samples in TSTB and miniculture correlated well with the reference (Cohen's kappa coefficient=0.88) and showed good reliability (Cronbach's alpha coefficient ≥0.91). Microculture provided positive results earlier than the other culture methods (mean day 4.5). By day 14, 98% of positive cultures had been detected. Scraping sampling and miniculture were associated with higher culture contamination (6% and 17%, respectively). Bacterial contamination predominated, regardless of the sampling and culture method, while filamentous fungi and mixed contamination were more frequently observed in cultures from scraping samples. In conclusion: (i) scraping samples proved more suitable for the diagnosis of TL as they increased analytical sensitivity, are less traumatic for the patient and are safer for laboratory personnel than aspirates; (ii) culture, mainly in TSBT medium, should be used for the diagnosis of TL due to its high sensitivity (doubling the number of cases diagnosed by DPE) and its low cost compared to other culture media.


Haematemesis related to orthodontic treatment with Nance palatal arch: a case report.
Haematemesis is a worrying sign, generally related to acute upper gastrointestinal bleeding and potentially life-threatening condition. We present a case of a 15-year-old Caucasian girl who was belatedly diagnosed with oral bleeding because it was not related to the most common aetiologic factors. In fact, she was undergoing orthodontic treatment with a Nance palatal arch, an appliance used to reinforce anchorage during teeth movements. In her case haematemesis was a sign of inflammation and necrosis occurring in the palatal mucosa, under the acrylic button of palatal arch. The appliance was removed; antibiotic and Chlorhexidine 0.12% were recommended. After a 6-week follow-up, no pathological signs were present and the orthodontic treatment was resumed. Both physicians and dentists should be aware of the possible side effect of the Nance palatal arch use; this could help in achieving a diagnosis and providing a correct treatment. Orthodontists should avoid excessive compression over the palatal mucosa and check the appliance condition during every follow-up in order to avoid necrosis of the palatal mucosa.


Effects of visual processing and congenital nystagmus on visually guided ocular motor behaviour.
The aim of this study was to compare visually guided ocular motor behaviour in children with visual processing and/or motor deficits with an age-matched comparison group and an adult group. Visual stimuli were shown to 28 children with visual processing and/or motor deficits (11 females, 17 males; mean age 7y 5mo, SD 2y 9mo, range 2-14y;) and an age-matched comparison group of 213 typically developing children (115 females, 98 males; mean age 5y 8mo, SD 3y 5mo, range 0-12y). The adult group consisted of nine females and two males with (mean age of 24y 4mo, SD 4y 8mo). Individuals who had a likely diagnosis of cerebral visual impairment (CVI), an opticopathy with unknown location, nystagmus, glaucoma, or a cataract were included in the study. Exclusion criteria were a visual acuity below 0.2, a developmental age under 1 year, and the presence of brain tumours, autism, and anxiety disorders. Orientating eye movements to large cartoons were quantified using the reaction time to fixation (RTF) and gaze fixation area (GFA). A Mann-Whitney U test was used to compare the differences between groups and Bonferroni post-hoc testing was used to analyse age dependence of RTF and GFA values within the comparison group. Individuals with CVI showed significantly prolonged RTF values; those with congenital nystagmus showed significantly increased GFA values. In the comparison group, RTF was significantly longer in children under the age of 2 years than in children aged 4 years and older (290 and 200 ms respectively; p < 0.001). No developmental change was found for GFA values. Increased RTF values in individuals with CVI relate to visual processing deficits. The data suggest that visually guided ocular motor responses mature during the first 3 years of life.


Umbilical Cord Milking Versus Delayed Cord Clamping in Infants 28 to 32 Weeks: A Randomized Trial.
To determine whether rate of severe intraventricular hemorrhage (IVH) or death among preterm infants receiving placental transfusion with UCM is noninferior to delayed cord clamping (DCC). Noninferiority randomized controlled trial comparing UCM versus DCC in preterm infants born 28 to 32 weeks recruited between June 2017 through September 2022 from 19 university and private medical centers in 4 countries. The primary outcome was Grade III/IV IVH or death evaluated at a 1% noninferiority margin. Among 1019 infants (UCM n = 511 and DCC n = 508), all completed the trial from birth through initial hospitalization (mean gestational age 31 weeks, 44% female). For the primary outcome, 7 of 511 (1.4%) infants randomized to UCM developed severe IVH or died compared to 7 of 508 (1.4%) infants randomized to DCC (rate difference 0.01%, 95% confidence interval: (-1.4% to 1.4%), P = .99). In this randomized controlled trial of UCM versus DCC among preterm infants born between 28 and 32 weeks' gestation, there was no difference in the rates of severe IVH or death. UCM may be a safe alternative to DCC in premature infants born at 28 to 32 weeks who require resuscitation.


Cognitive Dysfunction Among Primi gravidae Attending an Ante Natal Clinic in Kano, Northwest Nigeria.
Cognitive deficits among pregnant women have been reported, though the evidence is equivocal. Cognitive dysfunction during pregnancy may have negative consequences on maternal and child health. Yet, very little is known about cognitive function of pregnant women in general and primi gravidae in particular in the area under study. This study aimed to evaluate cognitive function among primi gravidae. About 120 primi gravidae were studied in a large urban hospital in Kano. Mini-Mental State Examination (MMSE) was used to evaluate cognitive function; socio-demographic and clinical data were obtained. Data were processed using IBM SPSS statistics version 20.0. Significant values of P were those < 0.05. The median age of the primi gravidae was 20.0 (3) years; 80 % of them had secondary school education, 88.3 % were in their third trimester of pregnancy and 42.5 % did not have any medical complaints at the time of presentation. The median MMSE score of the primi gravidae was 22.00 (19.0), indicating mild cognitive impairment. Majority of the women (88.3%) had either mild (58.3%) or severe (30%) cognitive dysfunction. The cognitive dysfunction was influenced by level of education (X2 = 11.961, P = 0.003) and type of presenting complaints (X2 = 13.514, P = 0.036). There was significant association between the mild cognitive impairment and level of education (X2 = 11.426, P = 0.022). This study concluded that the primi gravidae had mild cognitive impairment; with majority (88.3%) of them having cognitive dysfunction, which was significantly associated with level of educational attainment and was influenced by the level of education and presenting complaints.


Craniotomy vs. craniectomy for posterior fossa tumors: a prospective study to evaluate complications after surgery.
Posterior fossa surgery traditionally implies permanent bone removal. Although suboccipital craniectomy offers an excellent exposure, it could lead to complications. Thus, some authors proposed craniotomy as a valuable alternative to craniectomy. In the present study we compare postoperative complications after craniotomy or craniectomy for posterior fossa surgery. We prospectively collected data for a consecutive series of patients who underwent either posterior fossa craniotomy or craniectomy for tumor resection. We divided patients into two groups based on the surgical procedure performed and safety, complication rates and length of hospitalization were analyzed. Craniotomies were performed with Control-Depth-Attachment(®) drill and chisel, while we did craniectomies with perforator and rongeurs. One-hundred-fifty-two patients were included in the study (craniotomy n =100, craniectomy n =52). We detected no dural damage after bone removal in both groups. The total complication rate related to the technique itself was 7 % for the craniotomy group and 32.6 % for the craniectomy group (<0.0001). Pseudomeningocele occurred in 4 % vs. 19.2 % (p =0.0009), CSF leak in 2 % vs. 11.5 % (p =0.006) and wound infection in 1 % vs. 1.9 % (p =0.33), respectively. Post-operative hydrocephalus, a multi-factorial complication which could affect our results, was also calculated and occurred in 4 % of the craniotomy vs. 9.6 % of the craniectomy group (p =0.08). The mean length of in-hospital stay was 9.3 days for the craniotomy group and 11.8 days for the craniectomy group (p =0.10). The present study suggests that fashioning a suboccipital craniotomy is as effective and safe as performing a craniectomy; both procedures showed similar results in preserving dural integrity, while post-operative complications were fewer when a suboccipital craniotomy was performed.


Implantable microchip: the futuristic controlled drug delivery system.
There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized.


Comprehensive stroke center quality metrics.
Recent advances in stroke treatment created a need for a consensus statement by industry experts detailing elements of quality stroke care. In 2005, the brain attack coalition published recommendations outlining elements constituting the highest level of stroke care, the comprehensive stroke center. Unlike primary level stroke care, comprehensive center recommendations have not resulted in creation of a corresponding national certification process-largely owing to difficulties in establishing quality metrics. The authors proposed 13 comprehensive quality measures and assessed them at a tertiary referral, teaching hospital in Houston, Texas. Proposed metrics were derived from the 2005 brain attack coalition's comprehensive center guidelines. Outcomes measures included morbidity and mortality rates for stroke, cerebral aneurysm, carotid endarerectomy, and stent patients. Process measures included timeliness of brain imaging interpretation, timeliness and consideration of antiplatelet treatment regimes for carotid stent patients, and documentation of National Institutes of Health Stroke Score. Metrics were defined by international classification of disease codes with accompanying inclusion and exclusion criteria. Internal quality was benchmarked against Primary Stroke Center, research literature, and University Health Consortium rates. Baseline data revealed significant opportunities for improvement in the categories of imaging interpretation timeliness and National Institutes of Health Stroke Score documentation. All other measures fell within expected ranges. Assessment of quality outcomes is the basis for disease-specific certification. Institutions that claim comprehensive capabilities must demonstrate high standards of performance on uniform validated quality metrics. The authors demonstrate the feasibility of operationalizing the metrics outlined in Brain Attack Coalition's comprehensive stroke center recommendations.


Fracture resistance of structurally compromised premolar roots restored with single and accessory glass or quartz fiber posts.
Glass and quartz fiber posts are used in restoration of structurally compromised roots. Accessory fiber posts are recently introduced to enhance the fiber post adaptation. This study evaluated the effectiveness of glass versus quartz accessory fiber posts. In this experimental study, 40 mandibular premolar roots with similar dimension (radius of 3.5 ± 0.2 mm and length of 13 ± 0.5 mm) were selected and their root canals were flared until 1.5 mm of dentin wall remained. They were randomly assigned to four groups (n = 10) and restored as follows: Exacto glass fiber post (EX), Exacto glass fiber post + 2 Reforpin accessories (EXR), D. T. Light quartz fiber post (DT), and D. T. Light quartz fiber post + 2 Fibercone accessories (DTF). All posts were cemented with Duo-Link resin cement and the cores were built with the particulate filler composite. Following 1-week water storage, specimens were subjected to fracture loads in a universal testing machine. The maximum loads and failure modes were recorded and analyzed with the two-way analysis of variance (ANOVA) and Fisher's exact tests (α = 0.05). The mean fracture resistance values (N) were 402.8 (EX), 378.4 (EXR), 400.1 (DT), and 348.5 (DTF). Two-way ANOVA test showed neither reinforcing method (P = 0.094), nor post composition (P = 0.462) had statistically significant differences on fracture resistance of the structurally compromised premolar teeth. Fisher's exact test also demonstrated no statistically significant difference regarding two variables (P = 0.695). Core fracture was the most common failure mode (62.5%). Glass and quartz fiber posts with or without accessories restored the weakened premolar roots equally.


Genomic biomarkers of pulmonary exposure to tobacco smoke components.
Associations between smoking and the development of tobacco-related diseases in humans have historically been assessed by epidemiological studies. These studies are further complicated by the number of chemicals used in tobacco and individual smoking habits. An alternative approach is required to assess the biological responses. Toxicogenomics was carried out to identify early molecular markers for events in pulmonary injury resulting from tobacco smoke components (TSC) exposure. EpiAirway-100 cells were exposed at the air/liquid interface to representative particle (nicotine; cadmium) and vapour phase [formaldehyde (FA) and ethyl carbamate] components of cigarette smoke. Microarray technology was used to compare expression profiles of human genes associated with toxicity and drug resistance, from control and TSC-treated respiratory epithelium (n=5/dose). Using the GEArray 'toxicology and drug resistance' microarray followed by significance analysis of microarray analysis, 42 mRNA transcripts were found to be significantly altered by the TSC exposure. The vapour [ethyl carbamate, FA and particle (nicotine, cadmium)] phase TSC exhibited differential transcriptional responses that could not be attributed to their chemical phase. The transcriptional changes could be classified according to a functional family, where ethyl carbamate, FA and cadmium classified as carcinogens, demonstrated the highest gene homology when compared with the noncarcinogen, nicotine. Analysis of the microarray data and further confirmation (reverse transcriptase-PCR) identified three potential biomarkers for TSC-induced injury. These three genes (CYP7A1, HMOX1 and PTGS1) are highly upregulated and have been linked with mechanistic pathways of disease.


KDR receptor: a key marker defining hematopoietic stem cells.
Studies on pluripotent hematopoietic stem cells (HSCs) have been hindered by lack of a positive marker, comparable to the CD34 marker of hematopoietic progenitor cells (HPCs). In human postnatal hematopoietic tissues, 0.1 to 0.5% of CD34(+) cells expressed vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR). Pluripotent HSCs were restricted to the CD34+KDR+ cell fraction. Conversely, lineage-committed HPCs were in the CD34+KDR- subset. On the basis of limiting dilution analysis, the HSC frequency in the CD34+KDR+ fraction was 20 percent in bone marrow (BM) by mouse xenograft assay and 25 to 42 percent in BM, peripheral blood, and cord blood by 12-week long-term culture (LTC) assay. The latter values rose to 53 to 63 percent in LTC supplemented with VEGF and to greater than 95 percent for the cell subfraction resistant to growth factor starvation. Thus, KDR is a positive functional marker defining stem cells and distinguishing them from progenitors.


Evaluation of Anticancer and Anti-Inflammatory Activities of Some Synthetic Rearranged Abietanes.
Synthesis of the rearranged abietane diterpenes pygmaeocins C and D, viridoquinone, saprorthoquinone, and 1-deoxyviroxocine has been successfully achieved. The anticancer and anti-inflammatory activities of selected orthoquinonic compounds 5, 7, 13, and 19, as well as pygmaeocin C (17), were evaluated for the first time. The antitumor properties were assessed using three cancer cell lines: HT29 colon cancer cells, Hep G2 hepatocellular carcinoma cells, and B16-F10 murine melanoma cells. Compounds 5 and 13 showed the highest cytotoxicity in HT29 cells (IC50 = 6.69 ± 1.2 µg/mL and IC50 = 2.7 ± 0.8 µg/mL, respectively). Cytometric studies showed that this growth inhibition involved phase S cell cycle arrest and apoptosis induction, possibly through the activation of the intrinsic apoptotic pathway. Morphological apoptotic changes, including nuclear fragmentation and chromatin condensation, were also observed. Furthermore, the anti-inflammatory activity of these compounds was evaluated on the basis of their ability to inhibit nitric oxide production on the lipopolysaccharide activated RAW 264.7 macrophage cell line. Although all compounds showed high anti-inflammatory activity, with percentages between 40 and 100%, the highest anti-inflammatory potential was obtained by pygmaeocin B (5) (IC50NO = 33.0 ± 0.8 ng/mL). Our results suggest that due to their dual roles, this type of compound could represent a new strategy, contributing to the development of novel anticancer agents.


Effects of network development on attitudes towards work and well-being at work among health care staff in northern Finland.
To assess the effects of network development between primary and special health care units on attitudes towards work and well-being at work among health care staff. A prospective quasi-experimental design with intervention (n=33) and control (n=23) groups. This 2-year pilot intervention study was implemented in 14 health centres and 4 hospitals in northern Finland. The material was gathered via self-reported questionnaires from the health care staff at baseline and 1 follow-up. The intervention was composed of regional networking, self-ruling teamwork, staff education and guidance for the multiprofessional teams consisting of participants from primary and special health care units. The objective of these teams was to construct and disseminate regional models of patient education for the service process of 6 patient groups: cardiovascular, COPD, total joint replacement, cerebral infarction, cancer and chronic ulcer patients. The network development intervention had positive effects on attitudes towards work concerning organizational commitment, occupational commitment and growth satisfaction. The positive effects were also found in well-being at work, measured by absorption. The results are encouraging, although the study failed to demonstrate statistically significant improvements in other attitude and well-being outcomes that were measured. Network development intervention particularly improved positive attitudes towards work among health care staff. Although randomized controlled trials are needed, regional network development between health centres and hospitals is recommended when the goal is positive attitudes towards work and well-being at work in sparsely populated and rural areas.


Synthesis in Escherichia coli and immunological characterization of a polypeptide containing the cleavage sites associated with trypsin enhancement of rotavirus SA11 infectivity.
About 45% of the rotavirus SA11 VP3 gene was inserted into a thermoinducible expression plasmid under the control of phage lambda PL promoter. The primary translation product predicted on the basis of the plasmid construction was a hybrid protein in which the 98 amino-terminal amino acids of phage MS2 polymerase were followed by amino acids 42 to 387 of the VP3 protein, which included the region containing the cleavage sites associated with trypsin enhancement of infectivity. On induction, a polypeptide that had the expected mol. wt. and contained VP3-related amino acid sequences as judged by immunological criteria, was synthesized to a level representing about 15% of the total bacterial protein. When a bacterial lysate enriched for the fusion polypeptide was injected into mice, it induced antibodies which inhibited haemagglutination and neutralized SA11 rotavirus infectivity.


Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis.
Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.


Self-efficacy and exercise participation in sedentary adult females.
This study examined the importance of selected psychosocial and biometric variables in the prediction of exercise behavior in sedentary adult females. Specifically, the relationships among exercise behavior and instructor influence, self-efficacy cognitions, self-motivation, and body composition and their ability to predict exercise participation were evaluated. Fifty-eight females volunteered to participate in an eight-week aerobic exercise program. Biometric and psychosocial variables were assessed prior to and following the program. Attendance data and activity logs provided participation data. Subjects were also contacted three months after program termination to assess their activity patterns at that time. Multivariate analyses of variance indicated that subjects categorized as high or low in either program or overall exercise participation differed significantly on body weight, efficacy cognitions, and post-program perceptions. Multiple regression analyses indicated that instructor influence (R2 = .116) and self-efficacy cognitions (R2 = .093) contributed to the variance in subjects' program attendance. However, only self-efficacy was a significant predictor of overall exercise levels (R2 = .125). Correlational analyses revealed a modest but significant difference between self-efficacy and regularity of exercise (r = .28) and duration of activity (r = .32) at follow-up. The findings are discussed in relation to the role that efficacy might play in exercise behavior.


Cutting edge: a role for CD1 in the pathogenesis of lupus in NZB/NZW mice.
Since anti-CD1 TCR transgenic T cells can activate syngeneic B cells via CD1 to secrete IgM and IgG and induce lupus in BALB/c mice, we studied the role of CD1 in the pathogenesis of lupus in NZB/NZW mice. Approximately 20% of B cells from the spleens of NZB/NZW mice expressed high levels of CD1 (CD1high B cells). The latter subset spontaneously produced large amounts of IgM anti-dsDNA Abs in vitro that was up to 25-fold higher than that of residual CD1int/low B cells. T cells in the NZB/NZW spleen proliferated vigorously to the CD1-transfected A20 B cell line, but not to the parent line. Treatment of NZB/NZW mice with anti-CD1 mAbs ameliorated the development of lupus. These results suggest that the CD1high B cells and their progeny are a major source of autoantibody production, and activation of B cells via CD1 may play an important role in the pathogenesis of lupus.


[The intermittent and constant pain score (ICOAP) - a questionnaire to assess pain in patients with gonarthritis].
The purpose of this investigation was to test the German version of the intermittent and constant osteoarthritis pain score (ICOAP) in patients with advanced knee osteoarthritis. The ICOAP measures pain with 12 items divided in the two subscales "pain which comes and goes" and "permanent pain". The reliability, the validity, the sensitivity to change, the practicability and the acceptance of this questionnaire were investigated in 120 patients with advanced knee osteoarthritis necessitating a total knee replacement. Retest reliability was determined in a subsample of 29 patients prior to hospital admission. Convergent construct validity was assessed by comparing the results of the ICOAP subscales and the overall score to the pain scales of the Western Ontario and McMasters University osteoarthrosis score (WOMAC) and the knee-injury and osteoarthrosis outcome score (KOOS). Sensitivity to change was determined by comparing the results of the ICOAP prior to admission with those assessed at discharge from hospital as well as 3 months after knee replacement surgery. To quantify the strength of associations between the ICOAP scales and the measures of validity as well as to test its reliability the Spearman correlation coefficient was calculated with an absolute value of "r" indicating the strength of a relationship. Sensitivity to change was assessed with an analysis of variance of the score results at the three different times of assessment. A p value of < 0.5 was regarded to be significant. The reliability of this questionnaire was high, retest reliability ranged between r = 0.57-0.67, for the overall score as well as for the subscales. As a further criterion of reliability the internal consistency of the questionnaire was high as well, with r = 0.81-0.9. In comparison to the WOMAC pain scale, there was a concordance with r = 0.67 (overall score) and r = 0.68 (subscales). The pain scale of the KOOS correlated highly to the ICOAP scales. It ranged between r = 0.64 and r = 0.91. The review of sensitivity to change of this questionnaire showed a significant (p < 0.5) decrease of pain within three months after implantation of a total knee arthroplasty for the overall score as well as for both subscales. The median significantly decreased from 30.37 to 12.93 % for the overall score and from 16.77 to 7.07 or, respectively, 13.59 to 5.86 for the subscales. Practicability is given and the acceptancy in patients was high, with no drop-outs during this study. With the validated German version of the ICOAP a questionnaire is available now which accurately measures pain in patients with advanced knee osteoarthritis.


Are parents accurate in their assessment of fluid volumes?
Ingestions constitute a common problem in pediatric emergency medicine. Management decisions are frequently based on parental assessments of the amount of the ingested material. The purpose of this study was to examine the accuracy of parental estimates of fluid volumes. One hundred parents of children seen in an outpatient clinic and emergency department were asked to estimate fluid volumes in four containers. There were no significant differences (P greater than 0.05) in the accuracy of fluid volume assessment between younger and older parents, between participants with and without high school education, or between parents with one or more children. While most parents are accurate in their fluid volume estimates, 14.5% of the assessments were overestimates of over 300% of the actual volume. In view of our findings, caution should be used when management decisions are being based on parental fluid volume estimates.


The DEAD box protein eIF4A. 2. A cycle of nucleotide and RNA-dependent conformational changes.
Limited proteolysis experiments have been carried out with the DEAD box protein eIF4A. The results suggest that there is a substantial conformational change in eIF4A upon binding single-stranded RNA. Binding of ADP induces conformational changes in the free enzyme and the enzyme.RNA complex, and binding of the ATP analogue AMP-PNP induces a conformational change in the enzyme.RNA complex. The presence or absence of the gamma-phosphate on the bound nucleotide acts as a switch, presumably via the Walker motifs, that mediates changes in protein conformation and, as described in the preceding paper in this issue, also mediates changes in RNA affinity. Thus, these results suggest that there is a series of changes in conformation and substrate affinity throughout the ATP hydrolysis reaction cycle. A model is proposed in which eIF4A and the eIF4A-like domains of the DEAD box proteins act as ATP-driven conformational switches or motors that produce movements or structural rearrangements of attached protein domains or associated proteins. These movements could then be used to rearrange RNA structures or RNA.protein complexes.


Genotoxic effects of catmint (Nepeta meyeri Benth.) essential oils on some weed and crop plants.
This study investigates the genotoxicity of the essential oils extracted from the aerial parts of catmint (Nepeta meyeri Benth.) against two weeds (Bromus danthoniae and Lactuca serriola) and two crop plants (Brassica napus and Zea mays). The essential oils of N. meyeri analyzed by gas chromatography-mass spectrometry contained 14 compounds, with 4aα, 7α, 7aβ-nepetalactone (83.4%), 4aα, 7α, and 7aα-nepetalactone (8.83%) as the major components. The oils were diluted (25, 50, 100, and 150 ppm) and the solutions were applied to seeds or leaves of these plants. The study compared the germination percentage and random amplified polymorphic DNA (RAPD) results with the control group. The results showed that the oils had a strong inhibitory activity and caused a change in RAPD profiles in terms of variation in band intensity, loss of bands, and appearance of new bands compared with the control group. The results suggested that RAPD analysis could be applied as a suitable biomarker assay for the detection of genotoxic effects of plant allelochemicals. This study indicates the genotoxical potential of N. meyeri essential oils on weed and crop plants.


Treatment of Ph1-positive chronic myelogenous leukemia in children: comparison between allogeneic bone marrow transplantation and conventional chemotherapy. Spanish Working Party for BMT in Children (GETMON).
To compare the estimated survival and disease-free survival between children with Ph1-positive chronic myeloid leukemia treated with allogeneic bone marrow transplantation or conventional chemotherapy. In this retrospective study we compared the results obtained in a group of 14 children who received allogeneic bone marrow transplantation (BMT) between 1983 and 1993, and another group of 27 children treated with busulfan, hydroxyurea or alpha-interferon during the same time period. Patients were transplanted at a median of 7 months from diagnosis and all except one were in their first chronic phase. Conditioning consisted in total body irradiation and cyclophosphamide in 12 cases, and busulfan was added in two. Of the 14 patients treated with BMT, two died of transplant-related complications and two relapsed 18 and 48 months after the BMT. Ten children remain alive and disease free at a median follow up of 60 months. The probability of DFS at 5 years is 70%. Of the 27 patients treated with chemotherapy, 22 have died at a median of 36 months from diagnosis. The probability of survival at 5 years is 5% versus 83% for the BMT group (p = 0.001). Allogeneic BMT is a safe and very effective treatment for Ph-positive CML in children. Patients who have an HLA-identical sibling donor must receive a transplant as soon as possible after being diagnosed.


Deletion of p75NTR enhances the cholinergic innervation pattern of the visual cortex.
The cholinergic system is involved in cortical plasticity, attention, and learning. Within the visual cortex the cholinergic system seems to play a role in visual perception. The cholinergic neurons which project into the visual cortex are located in the basal forebrain. It has been shown that mice deficient for the low-affinity neurotrophin receptor p75NTR display increased numbers of cholinergic neurons in the basal forebrain and a denser cholinergic innervation of the hippocampus. This prompted us to analyze whether the cholinergic system is altered in adult p75NTR deficient mice. By analyzing the densities of cholinergic fibers within layer IV as well as within layer V of the visual cortex, we found that adult p75NTR deficient mice display increased cholinergic fiber densities. However, this increase was not accompanied by an increase in the density of local cholinergic neurons within the visual cortex. This indicates that the enhanced cholinergic innervation of the visual cortex is due to alteration of the cholinergic neurons located in the basal forebrain, projecting to the visual cortex. The increased cholinergic innervation of the visual cortex makes the p75NTR deficient mice an attractive model to study the necessity of the cholinergic system for the visual cortex.


Laser-induced acoustic desorption/atmospheric pressure chemical ionization mass spectrometry.
Laser-induced acoustic desorption (LIAD) was successfully coupled to a conventional atmospheric pressure chemical ionization (APCI) source in a commercial linear quadrupole ion trap mass spectrometer (LQIT). Model compounds representing a wide variety of different types, including basic nitrogen and oxygen compounds, aromatic and aliphatic compounds, as well as unsaturated and saturated hydrocarbons, were tested separately and as a mixture. These model compounds were successfully evaporated into the gas phase by using LIAD and then ionized by using APCI with different reagents. From the four APCI reagent systems tested, neat carbon disulfide provided the best results. The mixture of methanol and water produced primarily protonated molecules, as expected. However, only the most basic compounds yielded ions under these conditions. In sharp contrast, using APCI with either neat benzene or neat carbon disulfide as the reagent resulted in the ionization of all the analytes studied to predominantly yield stable molecular ions. Benzene yielded a larger fraction of protonated molecules than carbon disulfide, which is a disadvantage. A similar but minor amount of fragmentation was observed for these two reagents. When the experiment was performed without a liquid reagent (nitrogen gas was the reagent), more fragmentation was observed. Analysis of a known mixture as well as a petroleum cut was also carried out. In summary, the new experiment presented here allows the evaporation of thermally labile compounds, both polar and nonpolar, without dissociation or aggregation, and their ionization to predominantly form stable molecular ions.


Glucose-mediated protein glycation: Contribution of methanolic extract of Ceratonia siliqua L. in protection and in vitro potential inhibition of acetylcholinesterase.
Chronic hyperglycemia presents the major etiology of diabetes mellitus and related complications mainly Alzheimer's disease, via the protein glycation and toxic products generated. In the current study, we investigated the eventual protective effect of the methanolic extract of Ceratonia siliqua L. (CsME) against glucose-mediated glycation in serum bovine albumin. The multi-stage glycation markers, namely fructosamines and advanced glycation end products (AGEs) levels were monitored along with measurement of thiol groups; moreover, the in vitro acetylcholinesterase (AChE) inhibition potential was carried out. HPLC was also assessed. Rutin was the main phenolic compound found in CsME. CsME showed a good capacity to inhibit AGEs, fructosamines and protected thiol groups against glycation. CsME exhibited a great AChE inhibition activity. In the present study, CsME prevented glucose-induced protein glycation, it also exhibited a good inhibition of AChE, suggesting its DM complications such as memory troubles related to AD. PRACTICAL APPLICATIONS: Neurodegenerative disorders ranging from memory troubles to Alzheimer's disease present the most diabetes mellitus complications and mainly attributed to protein glycation process. Currently, there is a strong trend to search for efficient natural sources of glycation and acetylcholinesterase inhibitors to replace the synthetic ones, whose secondary effects were shown. The present article tries to justify scientifically the wide use of Ceratonia siliqua L. in Moroccan folk medicine, demonstrating that the methanolic extract of leaves from this species presents a promising source of new natural compounds inhibiting acetylcholinesterase and acting in vitro against glycation generated compounds. Furthermore, for the first time, Rutin was the main phenolic compound found in this extract, these encouraging results should be coupled with further studies to integrate it in pharmaceutical formulations. As such, this paper should be of interest to a broad readership, including those interested in Biochemistry, Phytochemistry, pharmacology, and neurosciences.


Energy storage and fecundity explain deviations from ecological stoichiometry predictions under global warming and size-selective predation.
A key challenge for ecologists is to predict how single and joint effects of global warming and predation risk translate from the individual level up to ecosystem functions. Recently, stoichiometric theory linked these levels through changes in body stoichiometry, predicting that both higher temperatures and predation risk induce shifts in energy storage (increases in C-rich carbohydrates and reductions in N-rich proteins) and body stoichiometry (increases in C : N and C : P). This promising theory, however, is rarely tested and assumes that prey will divert energy away from reproduction under predation risk, while under size-selective predation, prey instead increase fecundity. We exposed the water flea Daphnia magna to 4 °C warming and fish predation risk to test whether C-rich carbohydrates increase and N-rich proteins decrease, and as a result, C : N and C : P increase under warming and predation risk. Unexpectedly, warming decreased body C : N, which was driven by reductions in C-rich fat and sugar contents while the protein content did not change. This reflected a trade-off where the accelerated intrinsic growth rate under warming occurred at the cost of a reduced energy storage. Warming reduced C : N less and only increased C : P and N : P in the fish-period Daphnia. These evolved stoichiometric responses to warming were largely driven by stronger warming-induced reductions in P than in C and N and could be explained by the better ability to deal with warming in the fish-period Daphnia. In contrast to theory predictions, body C : N decreased under predation risk due to a strong increase in the N-rich protein content that offsets the increase in C-rich fat content. The higher investment in fecundity (more N-rich eggs) under predation risk contributed to this stronger increase in protein content. Similarly, the lower body C : N of pre-fish Daphnia also matched their higher fecundity. Warming and predation risk independently shaped body stoichiometry, largely by changing levels of energy storage molecules. Our results highlight that two widespread patterns, the trade-off between rapid development and energy storage and the increased investment in reproduction under size-selective predation, cause predictable deviations from current ecological stoichiometry theory.


Environmental adaptation contributes to gene polymorphism across the Arabidopsis thaliana genome.
The level of within-species polymorphism differs greatly among genes in a genome. Many genomic studies have investigated the relationship between gene polymorphism and factors such as recombination rate or expression pattern. However, the polymorphism of a gene is affected not only by its physical properties or functional constraints but also by natural selection on organisms in their environments. Specifically, if functionally divergent alleles enable adaptation to different environments, locus-specific polymorphism may be maintained by spatially heterogeneous natural selection. To test this hypothesis and estimate the extent to which environmental selection shapes the pattern of genome-wide polymorphism, we define the "environmental relevance" of a gene as the proportion of genetic variation explained by environmental factors, after controlling for population structure. We found substantial effects of environmental relevance on patterns of polymorphism among genes. In addition, the correlation between environmental relevance and gene polymorphism is positive, consistent with the expectation that balancing selection among heterogeneous environments maintains genetic variation at ecologically important genes. Comparison of the gene ontology annotations shows that genes with high environmental relevance are enriched in unknown function categories. These results suggest an important role for environmental factors in shaping genome-wide patterns of polymorphism and indicate another direction of genomic study.


Indirect White Matter Pathways Are Associated With Treated Naming Improvement in Aphasia.
White matter disconnection of language-specific brain regions associates with worse aphasia recovery. Despite a loss of direct connections, many stroke survivors may maintain indirect connections between brain regions. To determine (1) whether preserved direct connections between language-specific brain regions relate to better poststroke naming treatment outcomes compared to no direct connections and (2) whether for individuals with a loss of direct connections, preserved indirect connections are associated with better treatment outcomes compared to individuals with no connections. We computed structural whole-brain connectomes from 69 individuals with chronic left-hemisphere stroke and aphasia who completed a 3-week-long language treatment that was supplemented by either anodal transcranial direct current stimulation (A-tDCS) or sham stimulation (S-tDCS). We determined differences in naming improvement between individuals with direct, indirect, and no connections using 1-way analyses of covariance and multivariable linear regressions. Independently of tDCS modality, direct or indirect connections between the inferior frontal gyrus pars opercularis and angular gyrus were both associated with a greater increase in correct naming compared to no connections (P = .027 and P = .039, respectively). Participants with direct connections between the inferior frontal gyrus pars opercularis and middle temporal gyrus who received S-tDCS and participants with indirect connections who received A-tDCS significantly improved in naming accuracy. Poststroke preservation of indirect white matter connections is associated with better treated naming improvement in aphasia even when direct connections are damaged. This mechanistic information can be used to stratify and predict treated naming recovery in individuals with aphasia.


Genome-wide identification of coding and non-coding conserved sequence tags in human and mouse genomes.
The accurate detection of genes and the identification of functional regions is still an open issue in the annotation of genomic sequences. This problem affects new genomes but also those of very well studied organisms such as human and mouse where, despite the great efforts, the inventory of genes and regulatory regions is far from complete. Comparative genomics is an effective approach to address this problem. Unfortunately it is limited by the computational requirements needed to perform genome-wide comparisons and by the problem of discriminating between conserved coding and non-coding sequences. This discrimination is often based (thus dependent) on the availability of annotated proteins. In this paper we present the results of a comprehensive comparison of human and mouse genomes performed with a new high throughput grid-based system which allows the rapid detection of conserved sequences and accurate assessment of their coding potential. By detecting clusters of coding conserved sequences the system is also suitable to accurately identify potential gene loci. Following this analysis we created a collection of human-mouse conserved sequence tags and carefully compared our results to reliable annotations in order to benchmark the reliability of our classifications. Strikingly we were able to detect several potential gene loci supported by EST sequences but not corresponding to as yet annotated genes. Here we present a new system which allows comprehensive comparison of genomes to detect conserved coding and non-coding sequences and the identification of potential gene loci. Our system does not require the availability of any annotated sequence thus is suitable for the analysis of new or poorly annotated genomes.


Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains.
Alzheimer's disease (AD) is characterized by dysfunction in cognitive and noncognitive domains with clinical diagnosis based on multiple neuropsychological tests. Here, we evaluated cognitive and noncognitive behaviors in 2 age cohorts (8 and 14 months at the start of the study) of APPSwe/PS1dE9 transgenic mice that model AD-like amyloidosis. We used a battery of tests that included fear-conditioned context and tone memories, swimming activity, and orientation to a proximal cue in a visible platform water maze test and burrowing and nest building activity. To compare the performance of mice across all tests, we used z-score normalization of data. The analyses revealed that the behavior of the transgenic mice was significantly compromised in cognitive as well as in noncognitive domains. Combining scores across multiple behavioral tests produced an integrated index characterizing the overall phenotypic abnormality in this model of AD-like amyloidosis. Assessing multiple behavioral domains provides a broader view of the breadth of impairments in multiple behavioral systems. Greater implementation of such approaches could enable reliable and clinically predictive evaluation of therapeutics in mouse models of amyloidosis.


Current Trends in Orthopaedics and Trauma in Germany.
During the Guest Nation Symposium (cobranded with the Deutsche Gesellschaft für Orthopädie und Unfallchirurgie, Deutsche Gesellschaft für Orthopädie und Orthopädische Chirurgie, and Deutsche Gesellschaft für Unfallchirurgie) at the 2023 American Academy of Orthopaedic Surgeons Congress in Las Vegas, the goal was to compile nationally important content from German orthopaedics and trauma surgery. This resulted in a mix of content on the latest developments in trauma care, knee arthroplasty, spinopelvic importance for hip arthroplasty, stemless shoulder endoprostheses, joint preservation for ankle osteoarthritis, trauma education, and research. Of course, this is only a small selection of the important issues that are being driven forward in Germany.


Combination Therapy with Ciprofloxacin and Pentamidine against Multidrug-Resistant Pseudomonas aeruginosa: Assessment of In Vitro and In Vivo Efficacy and the Role of Resistance-Nodulation-Division (RND) Efflux Pumps.
The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against Galleria mellonella larvae infected with an MDR strain of P. aeruginosa and (ii) determine if pentamidine acts as an efflux-pump inhibitor. Resistant clinical isolates, mutant strains overexpressing one of three RND efflux pumps (MexAB-OprM, MexCD-OprJ, and MexEF-OprN), and a strain with the same three pumps deleted were used. MIC assays confirmed that the clinical isolates and the mutants overexpressing efflux pumps were resistant to ciprofloxacin and pentamidine. The deletion of the three efflux pumps induced sensitivity to both compounds. Exposure to pentamidine and ciprofloxacin in combination resulted in the synergistic inhibition of all resistant strains in vitro, but no synergy was observed versus the efflux-pump deletion strain. The treatment of infected G. mellonella larvae with the combination of pentamidine and ciprofloxacin resulted in enhanced efficacy compared with the monotherapies and significantly reduced the number of proliferating bacteria. Our measurement of efflux activity from cells revealed that pentamidine had a specific inhibitory effect on the MexCD-OprJ and MexEF-OprN efflux pumps. However, the efflux activity and membrane permeability assays revealed that pentamidine also disrupted the membrane of all cells. In conclusion, pentamidine does possess some efflux-pump inhibitory activity, in addition to a more general disruptive effect on membrane integrity that accounts for its ability to potentiate ciprofloxacin activity. Notably, the enhanced efficacy of combination therapy with pentamidine and ciprofloxacin versus MDR P. aeruginosa strains in vivo merits further investigation into its potential to treat infections via this pathogen in patients.


A wave energy driven high-performance self-powered oil spill positioner.
The oil spill positioner is capable of real-time monitoring oil films on the sea surface. However, the lack of high-performance power supply methods greatly restricts the application of oil spill positioner. In this research, we design a high-performance self-powered oil spill positioner based on a Soft-Contact-Triboelectric-Nanogenerator (SC-TENG).This device achieves soft-contact by attaching rabbit fur to the rotor, which can effectively reduce frictional resistance, quickly transfer charge to the electrode, and improve the durability of the parts. First, we calculate the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of PTFE and PVDF molecules through first-principles simulations, and compared the ease of electron excitation between the two materials. The results show that the performance of SC-TENG with polyvinylidene fluoride (PVDF) as dielectric material is significantly better than that of polytetrafluoroethylene (PTFE). At the same time, this phenomenon has been confirmed by experiments. On the basis of experimental and simulate research on two types of power management circuits, a bridge rectifier circuit with the function of converting alternating current to direct current is selected to realize the self-power supply of the oil spill positioner. Additionally, by optimizing the structure of the SC-TENG and employing a bridge rectifier circuit, the SC-TENG can achieve a maximum open-circuit voltage of 1400V and a short-circuit current of 3.49 μA, which are enough to light up 200 light-emitting diodes (LEDs) and power the oil spill positioner. Finally, we simulate the open-circuit voltage and short-circuit current of the SC-TENG on a six-degree-of-freedom (6-DOF) platform and test its durability under real-world ocean wave conditions, all of which show excellent performance. This work develops an efficient wave energy conversion mechanism and successfully realizes the high-performance self-powering of the oil spill positioner, making oil spill monitoring more flexible and reliable.


[Design of a multicenter registry to evaluate rhythm versus rate control in atrial fibrillation: Atrial Fibrillation Mexican Registry (ReMeFA)].
Atrial fibrillation is the most common arrhythmia, predominantly affecting individuals older than 70 years of age. There is little information about its management in Mexico, for this purpose the Mexican Registry of Atrial Fibrillation (ReMeFa) was designed. ReMeFA is a prospective multicentric, observational registry concerning the treatment of atrial fibrillation in Mexico. It includes patients 18 years and older, from both genders, with documented atrial fibrillation. Patients with secondary atrial fibrillation from a reversible cause, previous treatment with pulmonary vein ablation (percutaneous or surgical), pacemakers or defibrillators, and with a life expectancy of less than one year, physically or mentally impaired for completing the protocol were excluded. Clinical and demographic data were collected at enrollment and in two scheduled visits at 6 and 12 months. Information about pharmacologic treatment for rhythm or rate control was particularly obtained. Between December 2008 to July 2009, 1201 patients from 79 centers were enrolled. This registry will provide valuable information about the strategy chosen by physicians in Mexico for the treatment of atrial fibrillation.


Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation.
Appreciation of the molecular and cellular processes of atherosclerosis, thrombosis, and vascular inflammation has identified new targets for imaging. The common goals of molecular imaging approaches are to accelerate and refine diagnosis, provide insights that reveal disease diversity, guide specific therapies, and monitor the effects of those therapies. Here we undertake a comparative analysis of imaging modalities that have been used in this disease area. We consider the elements of contrast agents, emphasizing how an understanding of the biology of atherosclerosis and its complications can inform optimal design. We address the potential and limitations of current contrast approaches in respect of translation to clinically usable agents and speculate on future applications.


Targeting of short TRPM8 isoforms induces 4TM-TRPM8-dependent apoptosis in prostate cancer cells.
Since its cloning a decade ago, TRPM8 channel has emerged as a promising prognostic marker and a putative therapeutic target in prostate cancer (PCa). However, recent studies have brought to light the complexity of TRPM8 isoforms in PCa. Consequently, the respective role of each TRPM8 isoform needs to be deciphered prior to considering TRPM8 as an attractive therapeutic target. Full-length (6 transmembrane (TM)-domain) TRPM8 channel is overexpressed in early PCa and repressed in advanced prostate tumors whereas the localization of the truncated, 4TM-TRPM8 channel (4 transmembrane (TM)-domain), in the membranes of endoplasmic reticulum (ER) is independent of the pathogenic status of epithelial cells. In the same line, expression of non-channel cytoplasmic small TRPM8 isoforms (namely sM8) is conserved in cancer cells. In this study, we identify sM8s as putative regulator of PCa cell death. Indeed, suppression of sM8 isoforms was found to induce concomitantly ER stress, oxidative stress, p21 expression and apoptosis in human epithelial prostate cancer cells. We furthermore demonstrate that induction of such mechanisms required the activity of 4TM-TRPM8 channels at the ER-mitochondria junction. Our study thus suggests that targeting sM8 could be an appropriate strategy to fight prostate cancer.


Aggravation of Allergic Airway Inflammation by Cigarette Smoke in Mice Is CD44-Dependent.
Although epidemiological studies reveal that cigarette smoke (CS) facilitates the development and exacerbation of allergic asthma, these studies offer limited information on the mechanisms involved. The transmembrane glycoprotein CD44 is involved in cell adhesion and acts as a receptor for hyaluronic acid and osteopontin. We aimed to investigate the role of CD44 in a murine model of CS-facilitated allergic airway inflammation. Wild type (WT) and CD44 knock-out (KO) mice were exposed simultaneously to house dust mite (HDM) extract and CS. Inflammatory cells, hyaluronic acid (HA) and osteopontin (OPN) levels were measured in bronchoalveolar lavage fluid (BALF). Proinflammatory mediators, goblet cell metaplasia and peribronchial eosinophilia were assessed in lung tissue. T-helper (Th) 1, Th2 and Th17 cytokine production was evaluated in mediastinal lymph node cultures. In WT mice, combined HDM/CS exposure increased the number of inflammatory cells and the levels of HA and OPN in BALF and Th2 cytokine production in mediastinal lymph nodes compared to control groups exposed to phosphate buffered saline (PBS)/CS, HDM/Air or PBS/Air. Furthermore, HDM/CS exposure significantly increased goblet cell metaplasia, peribronchial eosinophilia and inflammatory mediators in the lung. CD44 KO mice exposed to HDM/CS had significantly fewer inflammatory cells in BALF, an attenuated Th2 cytokine production, as well as decreased goblet cells and peribronchial eosinophils compared to WT mice. In contrast, the levels of inflammatory mediators were similar or higher than in WT mice. We demonstrate for the first time that the aggravation of pulmonary inflammation upon combined exposure to allergen and an environmental pollutant is CD44-dependent. Data from this murine model of concomitant exposure to CS and HDM might be of importance for smoking allergic asthmatics.


Localization of damage in the human leg muscles induced by downhill running.
We investigated localization of damage within the knee extensors (KEs) and plantar flexors (PFs) induced by downhill running (DR) by using transverse relaxation time (T2)-weighted magnetic resonance imaging (MRI). Fourteen young adults performed 45-min DR (-15% slope) at their maximal tolerable velocity. At pre- and 24, 48, and 72 h post-exercise, T2-MRI was scanned and T2 values for each muscle composing KEs and PFs at proximal, middle, and distal sites were calculated. Maximal isometric torque and rate of torque development (RTD: 0-30, 0-50, 0-100, 0-200 ms) were also measured. Maximal torque significantly decreased in KEs (14-17%) and PFs (6-8%) at 24-48 h post-exercise, with greater reductions for KEs. RTD in all phases, except for 0-200 ms in PFs, significantly decreased in KEs (11-42%) and PFs (13-23%) at least at one time point post-exercise. T2 significantly increased at several sites (3-5%) in both muscle groups at 24 and/or 48 h post-exercise. Among the T2-increased sites, the peak effect size (Cohen's d) regarding T2 change was pronounced at proximal (1.05) and middle (1.64) vastus intermedius compared to the other sites (0.72-0.77). These results suggest that DR induces damage in both KEs and PFs, and especially affects proximal-middle sites of the vastus intermedius.


Silencing of BCR/ABL Chimeric Gene in Human Chronic Myelogenous Leukemia Cell Line K562 by siRNA-Nuclear Export Signal Peptide Conjugates.
Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8.3% at 200 nM and 11.6% at 50 nM, and siRNA-HIV-1REV NES conjugate suppressed to 4.0% at 200 nM and 6.3% at 50 nM, whereas native siRNA suppressed to 36.3% at 200 nM and 30.2% at 50 nM. We could also show complex of siRNA-NES conjugate and designed amphiphilic peptide peptideβ7 could be taken up into cells with no cytotoxicity and showed excellent silencing efficiency. We believe that the complex siRNA-NES conjugate and peptideβ7 is a promising candidate for in vivo use and therapeutic applications.


On-chip spectro-detection for fully integrated coherent beam combiners.
This paper presents how photonics associated with new arising detection technologies is able to provide fully integrated instrument for coherent beam combination applied to astrophysical interferometry. The feasibility and operation of on-chip coherent beam combiners has been already demonstrated using various interferometric combination schemes. More recently we proposed a new detection principle aimed at directly sampling and extracting the spectral information of an input signal together with its flux level measurement. The so-called SWIFTS demonstrated concept that stands for Stationary-Wave Integrated Fourier Transform Spectrometer, provides full spectral and spatial information recorded simultaneously thanks to a motionless detecting device. Due to some newly available detection principles considered for the implementation of the SWIFTS concept, some technologies can even provide photo-counting operation that brought a significant extension of the interferometry domain of investigation in astrophysics. The proposed concept is applicable to most of the interferometric instrumental modes including fringe tracking, fast and sensitive detection, Fourier spectral reconstruction and also to manage a large number of incoming beams. The paper presents three practical implementations, two dealing with pair-wise integrated optics beam combinations and the third one with an all-in-one 8 beam combination. In all cases the principles turned into a pair wise baseline coding after proper data processing.


Death Acceptance in Vietnamese Cancer Patients: A Phenomenological Study.
To date, death acceptance is not well investigated in the Vietnamese population. Cultural influences may affect death acceptance. The purpose of this phenomenological study is to describe Vietnamese cancer patients' lived experience with death acceptance. Eleven Vietnamese patients with various cancer diagnoses participated in the study. Data were analyzed using the Giorgian method of data analysis. Themes of death acceptance found were (1) accepting destiny, (2) knowing and sacrificing the self, (3) believing in living persons and handing over responsibilities, (4) accepting death while continuing to fight for life, and (5) looking for a "role model death." Death acceptance is a contextually bound concept, which needs further investigation. To help patients with their death acceptance, nurses should include spiritual support and the involvement of loved ones in patients' care plans.