Role of Dimensionality in Predicting the Spontaneous Behavior of the Brain Using the Classical Ising Model and the Ising Model Implemented on a Structural Connectome.
There is accumulating evidence that spontaneous fluctuations of the brain are sustained by a structural architecture of axonal fiber bundles. Various models have been used to investigate this structure-function relationship. In this work, we implemented the Ising model using the number of fibers between each pair of brain regions as input. The output of the Ising model simulations on a structural connectome was then compared with empirical functional connectivity data. A simpler two-dimensional classical Ising model was used as the baseline model for comparison purpose. Thermodynamic properties, such as the magnetic susceptibility and the specific heat, illustrated a phase transition from an ordered phase to a disordered phase at the critical temperature. Despite the differences between the two models, the lattice Ising model and the Ising model implemented on a structural connectome (the generalized Ising model) exhibited similar patterns of global properties. To study the behavior of the generalized Ising model around criticality, calculation of the dimensionality and critical exponents was performed for the first time, by introducing a new concept of distance based on structural connectivity. Same value inside the fitting error was found for the dimensionality in both models suggesting similar behavior of the models around criticality.


Band structure of Si/Ge core-shell nanowires along the [110] direction modulated by external uniaxial strain.
Strain modulated electronic properties of Si/Ge core-shell nanowires along the [110] direction were reported, on the basis of first principles density-functional theory calculations. In particular, the energy dispersion relationship of the conduction/valence band was explored in detail. At the Γ point, the energy levels of both bands are significantly altered by applied uniaxial strain, which results in an evident change of the band gap. In contrast, for the K vectors far away from Γ, the variation of the conduction/valence band with strain is much reduced. In addition, with a sufficient tensile strain (∼1%), the valence band edge shifts away from Γ, which indicates that the band gap of the Si/Ge core-shell nanowires experiences a transition from direct to indirect. Our studies further showed that effective masses of charge carriers can also be tuned using the external uniaxial strain. The effective mass of the hole increases dramatically with tensile strain, while strain shows a minimal effect on tuning the effective mass of the electron. Finally, the relation between strain and the conduction/valence band edge is discussed thoroughly in terms of site-projected wavefunction characters.


Application of intraoperative indocyanine green videoangiography to brain tumor surgery.
Videoangiography using indocyanine green (ICG) has been used in the ophthalmologic field for a long time. It was introduced to the neurosurgical field several years ago but has been limited to vascular surgeries. We applied ICG videoangiography to brain tumor surgery and evaluated the usefulness. Twenty-three patients with a brain tumor who underwent microsurgical resection were analyzed. The pathological diagnosis was meningioma in 15 patients, metastasis in three, glioma in three, and hemangioblastoma in two. A microscope with a special filter and infrared excitation light to illuminate the operating field was used in this study. The intravascular fluorescence was imaged with a video camera attached to the microscope. ICG was injected intravenously with the dose of 5-25 mg, and overall, ICG was injected intraoperatively 32 times. ICG videoangiography allowed for an excellent evaluation of blood flow in the tumoral and peri-tumoral vessels both before and after the resection in all cases. ICG videoangiography is a useful method for monitoring blood flow in the exposed vessels during microsurgery for a brain tumor. This noninvasive method is simple, safe, cost-effective, and easily repeatable. Before resection, it provides information on the tumoral and peri-tumoral circulation including sequential visualization of vessels or direction of the blood flow. After resection, it checks the patency of the peri-tumoral vessels and is especially useful for the vein. This ICG videoangiography can be an alternative tool to intraoperative angiography or Doppler ultrasonography in selective cases.


Feasibility Study on Neurally Adjusted Ventilatory Assist in Noninvasive Ventilation After Cardiac Surgery in Infants.
Our objective was to evaluate the feasibility, the quality of synchronization, and the influence on respiratory parameters of the noninvasive neurally adjusted ventilatory assist (NIV-NAVA) mode in infants after cardiac bypass surgery. We conducted a prospective, randomized cross-over study in infants undergoing noninvasive ventilation (NIV) after cardiac surgery. Subjects were 10 infants < 5 kg. After extubation, subjects underwent 2 consecutive ventilatory modes after randomization into groups. In the CPAP first group, the subjects were ventilated first in nasal CPAP-1 and then in NIV-NAVA-2 for 30 min in each mode. In the NIV-NAVA first group, periods were reversed. All children were ventilated using the same interface. The analysis of curves showed a synchronization rate of 99.3% for all respiratory cycles. The rate of pneumatic inspiratory trigger was 3.4%. Asynchronies were infrequent. Some typical respiratory patterns (continuous effort and discontinuous inspiration) were found at rates of 10.9% and 31.1%, respectively. The respiratory trends showed a lower maximum diaphragmatic electrical activity (EAdi(max)) in NIV-NAVA periods compared with CPAP periods (P < .001 in the beginning of periods). The breathing frequency decreased significantly during the nasal CPAP-2 and NIV-NAVA-1 periods (P < .05). The inspiratory pressure increased significantly during the NIV-NAVA-1 and NIV-NAVA-2 periods (P < .05), but there was no significant difference for each parameter when comparing Δ values between the beginning and the end of each period. The EAdi signal was easy to obtain in all subjects, and no major side effects were associated with the use of NIV-NAVA. NIV-NAVA allows good synchronization in bi-level NIV in infant cardiac subjects weighing < 5 kg. The analysis of respiratory parameters shows that NIV NAVA decreases the work of breathing more effectively than nasal CPAP. The study shows some typical respiratory patterns in infants. (ClinicalTrials.gov registration NCT01570933.).


Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.
Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic beta cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of beta cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating beta cells. Hence, disruption of the frataxin gene in pancreatic beta cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of beta cell function observed in different subtypes of diabetes in humans.


Early life adiposity and telomere length across the life course: a systematic review and meta-analysis.
Background: The relationship between adiposity at birth and in childhood, and telomere length is yet to be determined. We aimed to systematically review and meta-analyse the results of studies assessing associations between neonatal and childhood adiposity, and telomere length. Methods: We searched Medline, EMBASE and PubMed for studies reporting associations between adiposity measured in the neonatal period or childhood, and leucocyte telomere length, measured at any age via quantitative polymerase chain reaction, or terminal restriction fragment analysis, either cross-sectionally, or longitudinally. Papers published before April 2017 were included. Results: Out of 230 abstracts assessed, 23 papers (32 estimates) were retained, from which 19 estimates were meta-analysed (15 cross-sectional, four longitudinal). Of the 15 cross-sectional estimates, seven reported on neonates: four used binary exposures of small-for-gestational-age vs. appropriate-for-gestational age (or appropriate- and large-for-gestational age), and three studied birth weight continuously. Eight estimates reported on childhood measures; five estimates were from studies of binary exposures (overweight/obese vs. non-obese children), and three studies used continuous measures of body mass index. All four longitudinal estimates were of neonatal adiposity, with two estimates for small-for-gestational-age vs. appropriate-for-gestational age neonates, and two estimates of birth weight studied continuously, in relation to adult telomere (49-61 years). There was no strong evidence of an association between neonatal or childhood adiposity, and telomere length. However, between study heterogeneity was high, and there were few combinable studies. Conclusions: Our systematic review and meta-analysis found no strong evidence of an association between neonatal or childhood adiposity and telomere length.


Community water fluoridation support and opposition in Australia.
To estimate the level of support for water fluoridation across Australia and examine the association between water fluoridation stance and demographic and socioeconomic characteristics, commitment to the stance, and opinions, beliefs and knowledge regarding water fluoridation. Cross-sectional questionnaire data were obtained from 510 Australian adults (response rate = 34%) in 2008. Data were weighted by age, gender and state and territory estimated resident population. Participants were asked to rate the strength of their support for or opposition to water fluoridation on a 7-point scale. Approximately 70% of survey respondents supported water fluoridation, 15.4% were opposed, and 14.5% were neutral. Those strongly opposed were most resistant to altering their opinion on the basis of new information or research. However, approximately 90% of people who were neutral, slightly supportive or moderately supportive would "maybe" or "definitely" change their stance. Fluoridation opposition was associated with lower income and educational attainment, more self-rated knowledge, and with beliefs about reduced benefits and greater harms. Opinions about who should be responsible for the introduction of water fluoridation and sources of information on fluoridation varied significantly by water fluoridation opinion. While this survey lends further weight to the evidence confirming extensive support for water fluoridation in Australia, a large percentage of the public may be open to changing their stance if presented with new information or research. To maintain the widespread acceptance of water fluoridation, it is important that the public are provided with unbiased and accurate interpretations of the continual stream of research related to fluorides and water fluoridation.


Phylogenetic position of the giant anuran trypanosomes Trypanosoma chattoni, Trypanosoma fallisi, Trypanosoma mega, Trypanosoma neveulemairei, and Trypanosoma ranarum inferred from 18S rRNA gene sequences.
Phylogenetic relationships within the kinetoplastid flagellates were inferred from comparisons of small-subunit ribosomal RNA gene sequences. These included 5 new gene sequences, Trypanosoma fallisi (2,239 bp), Trypanosoma chattoni (2,180 bp), Trypanosoma mega (2,211 bp), Trypanosoma neveulemairei (2,197 bp), and Trypanosoma ranarum (2,203 bp). Trees produced using maximum-parsimony and distance-matrix methods (least-squares, neighbor-joining, and maximum-likelihood), supported by strong bootstrap and quartet-puzzle analyses, indicated that the trypanosomes are a monophyletic group that divides into 2 major lineages, the salivarian trypanosomes and the nonsalivarian trypanosomes. The nonsalivarian trypanosomes further divide into 2 lineages, 1 containing trypanosomes of birds, mammals, and reptiles and the other containing trypanosomes of fish, reptiles, and anurans. Among the giant trypanosomes, T. chattoni is clearly shown to be distantly related to all the other anuran trypanosome species. Trypanosoma mega is closely associated with T. fallisi and T. ranarum, whereas T. neveulemairei and Trypanosoma rotatorium are sister taxa. The branching order of the anuran trypanosomes suggests that some toad trypanosomes may have evolved by host switching from frogs to toads.


Is the frequency of Robinow syndrome relatively high in Turkey? Four more case reports.
We describe the clinical features of Robinow syndrome in the children of four Turkish couples. All the patients had cardinal features of this condition, such as short stature, frontal bossing, hypertelorism, short upturned nose with anteverted nares, micrognathia, mesomelic shortening of the forearms, vertebral and costal anomalies and hypoplastic genitalia. In contrast to reports in the literature, one patient showed extensive webbing of the toes and epigastric hernia. Parental consanguinity was present in two of the four cases. To our knowledge, at least 80 cases have been reported in the literature to date, including 19 cases born to Turkish couples in addition to our four cases. The evidence suggests that the frequency of Robinow syndrome is relatively higher in Turkey than in other areas of the world.


Essential oils, phenolics, and antioxidant activities of different parts of cumin (Cuminum cyminum L.).
Cuminum cyminum L. roots, stems and leaves, and flowers were investigated for their essential oils, total phenolics, flavonoids, and tannins contents, individual phenolic compounds, and antioxidant activities. The essential oil was investigated by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS), whereas identification and quantification of individual target polyphenolic compounds was performed by reversed-phase high-performance liquid chromatography (RP-HPLC). Essential oil yields were 0.03% in roots, 0.1% in stem and leaves, and 1.7% in flowers. Major components of the oils were bornyl acetate (23%), α-terpinene (34%), and γ-terpinene (51%) in roots, stems and leaves, and flowers, respectively. In all C. cyminum organs, total phenolics content ranged from 11.8 to 19.2 mg of gallic acid equivalents per gram of dry weight (mg of GAE/g of DW). Among the polyphenols studied, 13 were identified in roots, 17 in stem and leaves, and 15 in flowers. The major phenolic compound in the roots was quercetin (26%), whereas in the stems and leaves, p-coumaric, rosmarinic, trans-2-dihydrocinnamic acids and resorcinol were predominant. In the flowers, vanillic acid was the main compound (51%). The antioxidant activities of C. cyminum essential oils and acetone extracts obtained from the three organs were assessed using four tests [1,1-diphenyl-2-picrylhydrazyl (DPPH), β-carotene/linoleic acid, reducing power, and chelating power assays]. The acetone extract of flowers was strongly effective as a DPPH radical scavenger, lipid peroxidation inhibitor, and reducing agent, with IC(50) values of 4, 32, and 8 μg/mL, respectively. Moreover, the acetone extract of stems and leaves showed the highest chelating power. However, the essential oils exhibited moderate activities in the different tests.


Development of indinavir submicron lipid emulsions loaded with lipoamino acids-in vivo pharmacokinetics and brain-specific delivery.
The aim of our present work was to develop indinavir O/W submicron lipid emulsions (SLEs) loaded with lipoamino acids for specific delivery to brain. Tetradecyl aspartic acid (A) and decyl glutamic acid (G) loaded stable SLEs of indinavir having a mean size range of 210-220 nm and average zeta potential of -23.54±1.2 mV were developed using homogenization and ultrasonication. The cumulative % drug release from different SLEs varied in between 26% and 85%. The formulations, SLE, SLE-A3, and SLE-G3 were stable to the centrifugal stress, dilution stress, and storage at RT. The total drug content and entrapment efficiency were determined by HPLC method. During pharmacokinetic studies in male Wistar rats there was no significant difference in the serum levels of indinavir for SLE, SLE-A3 and SLE-G3 formulations at all time points. In tissue distribution studies, the therapeutic availability (TA) of indinavir in brain and kidneys for SLE-A3 were 4.27- and 2.66-fold whereas for SLE-G3 were 2.94 and 2.12 times, respectively, higher than that of indinavir solution. But when compared with that of SLE, in brain tissue the levels of indinavir from SLE-G3 and SLE-A3 varied in between 2.5- and 3.38-fold. While in case of the kidney, it was between 1.23- and 1.54-fold only. However, the TA is not significantly different in tissues like the heart, liver, and spleen. Thus, brain-specific delivery of indinavir was improved by including tetradecyl aspartic acid and decyl glutamic acid in submicron lipid emulsions.


How should careproviders respond to patients' requests that may be refused?
Some requests made to careproviders by patients may be of great personal importance to patients. Careproviders may assign proportionally greater weight to these exceptional requests, and may choose to take exceptional measures to assist. A strong trust relationship may be formed with patients as a result.


[A Three Band Chlorophyll-a Concentration Estimation Model Based on GOCI Imagery].
A GOCI-based three band model is proposed for chlorophyll-a concentration estimation based on the classical three band model. The model was built based on 289 in-situ measured chlorophyll-a concentration and hyperspectral spectrums-simulated GOCI spectrums, and was compared with MERIS-based three band model and GOCI band ratio model. At last, the model was validated using several GOCI images and an independent in-situ sampling dataset. The results showed that: (1) For the current dataset, the ratio of aph (680) and aph (660) was relatively stable. (2) The GOCI-based three band algorithm had a similar performance with MERIS-based three band algorithm in the modeling dataset. The R2 value of the GOCI-based three band model was 0. 809, which was a little lower than that of the MERIS-based three band model (R2 = 0. 820), but was obviously higher than that of GOCI band ratio model (R2 = 0. 450). (3) The performance of GOCI-based three band model in the validation dataset was similar with that in the modeling dataset, which was close to that of the MERIS-based three band model, and significantly better than that of GOCI band ratio model. (4) The GOCI image data validation indicated that GOCI band ratio model would clearly underestimate chlorophyll-a concentration in Taihu Lake. The spatial difference of chlorophyll-a concentration that yielded by the band ratio model was not clear. Compared with the widely used band ratio algorithm, the GOCI-based three band algorithm has higher stability, better accuracy, and stronger potential in application.


Perceptual-motor coupling in the development of grasp.
The purpose of this study was to investigate the effect of haptic attributes of objects on infants' grasping patterns and evaluate whether this effect is influenced by the infant's age (i.e., phase of motor development). Grasping patterns of 180 infants who were typically developing were measured by the Posture and Fine Motor Assessment of Infants (PFMAI); the PFMAI-I was administered to infants 2 months to 6 months of age (n = 60), and the PFMAI-II was administered to infants 6 months to 12 months of age (n = 120). Grasping patterns were compared for ages by month and for three objects, each with differing haptic features. The interaction between age and object was analyzed. Grasping patterns were significantly different when scores by age in months were compared. In addition, grasping patterns differed depending on the object and its haptic features and were influenced by the interaction between object held and age. Certain haptic features were associated with primitive grasp at younger ages and precision grasp at older ages. More mature skills were observed when the objects' haptic features appeared to match an infant's perceptual-motor skill. The haptic features of objects influence an infant's grasping patterns, and this influence changes with the infant's age. These results suggest that therapists attempt to match the haptic features of objects to the infant's perceptual-motor skill in intervention in order to enhance grasping patterns.


Pressure phosphene self-tonometry: a comparison with goldmann tonometry in glaucoma patients.
To evaluate whether the pressure phosphene tonometer (PPT) is suitable for self-tonometry in patients with glaucoma or ocular hypertension. This was a prospective comparative study of 102 eyes of 102 patients with chronic glaucoma or ocular hypertension. Intraocular pressure (IOP) measurements by the Goldmann tonometer (GT) were compared with self-measured readings with the PPT. Patients evaluated the ease of home use of the PPT. The last 15 patients were asked to stop their glaucoma medications, and the ability of the PPT to detect an elevated IOP during self-tonometry was studied. The mean +/- SD difference between PPT and GT readings was -0.24 +/- 1.57 mm Hg. Comparing the PPT with the GT, 86% of the readings were within +/- 2.0 mm Hg, and 91% were within +/- 3.0 mm Hg. Spearman's correlation coefficient was 0.91. A Bland-Altman plot showed that the 95% limits of agreement between the two methods lay between 2.90 and -3.38 mm Hg. Within-subject coefficients of variation for the GT and the PPT were 4.4% and 7.3%, respectively. In detecting an elevated IOP of more than 21 mm Hg, the sensitivity and the specificity of the PPT were 92.3% and 98.6% respectively. The mean satisfaction score for home use of the PPT was 87.4 +/- 16.3 (maximum 100). With proper training and technique, self-tonometry with the PPT appears to be accurate up to at least 25 mm Hg and is reproducible. The PPT was sensitive and specific in detecting an elevated IOP of more than 21 mm Hg. As patients were expected to seek ophthalmic care before the self-measured IOP reaches 25 mm Hg, the PPT may have a value for self-monitoring. Patients rated the PPT as satisfactory for home use. Because the PPT is portable and relatively inexpensive and requires no topical anesthesia or direct contact with the eyeball, it may have potential as an instrument for home self-tonometry.


Which potential harms and benefits of using ginger in the management of nausea and vomiting of pregnancy should be addressed? a consensual study among pregnant women and gynecologists.
Nausea and vomiting of pregnancy (NVP) affect approximately 80-90% of the pregnant women. Ginger (Zingiber officinale Roscoe) is the most widely used herbal therapy in the management of NVP. Like conventional therapies, herbal therapies have potential harms and benefits that patients need to be informed about in order to develop their therapy preferences. The aim of this study was to achieve consensus among women who suffered NVP and physicians often consulted by pregnant women on a core list of potential harms and benefits of using ginger to manage NVP to be addressed during clinical consultations. In this study, the Delphi technique was used to achieve consensus on a core list of important harms and benefits of using ginger in the management of NVP to be addressed during the clinical consultation. A Delphi process was followed in two panels in parallel sessions. One panel was composed of 50 gynecologists and other physicians who are often consulted by pregnant women suffering NVP and the other panel was composed of 50 women who suffered NVP. Consensus was achieved on 21 (75%) of the 28 potential harms presented to the panelists. Panelists agreed that potential harms of the anticoagulant effects of ginger, risk with other co-morbidities, and risk of potential allergic reactions are important to address during the clinical consultation. Of the 14 potential benefits presented to the panelists in both panels, consensus was achieved on 13 (92.9%). Partial consensus on 7 potential harms and 1 potential benefit was achieved in both panels. Addressing important potential harms and benefits of using ginger for the management of NVP during the clinical consultations is important in promoting congruence and reducing patient dissatisfaction in clinical practice. Consensus was achieved on a core list of important harms and benefits of using ginger for the management of NVP to be addressed during the clinical consultations by a panel of women and a panel of physicians. Further studies are still needed to investigate what is being addressed during clinical consultations.


Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection.
The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether P. aeruginosa influences the susceptibility of S. aureus to frontline antibiotics used to treat CF lung infections. Using our in vitro coculture model, we observed that addition of P. aeruginosa supernatants to S. aureus biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of S. aureus to vancomycin. Mutant analyses showed that 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), a component of the P. aeruginosa Pseudomonas quinolone signal (PQS) system, protects S. aureus from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of P. aeruginosa to protect S. aureus from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO, P. aeruginosa supernatant, and growth under anoxia decreased S. aureus growth, likely explaining why this cell wall-targeting antibiotic is less effective. P. aeruginosa supernatant did not confer additional protection to slow-growing S. aureus small colony variants. Importantly, P. aeruginosa supernatant protects S. aureus from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby P. aeruginosa causes S. aureus to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in S. aureus growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis.IMPORTANCE Cystic fibrosis (CF) lung infections are chronic and difficult to eradicate. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients and are associated with poor patient outcomes. Both organisms adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these infections. Here, we show that P. aeruginosa exoproducts decrease the sensitivity of S. aureus biofilm and planktonic populations to vancomycin, a frontline antibiotic used to treat methicillin-resistant S. aureus in CF patients. P. aeruginosa also protects S. aureus from other cell wall-active antibiotics as well as various classes of protein synthesis inhibitors. Thus, interspecies interactions can have dramatic and unexpected consequences on antibiotic sensitivity. This study underscores the potential impact of interspecies interactions on antibiotic efficacy in the context of complex, polymicrobial infections.


Exposure of endothelial cells to cyclic strain induces elevations of cytosolic Ca2+ concentration through mobilization of intracellular and extracellular pools.
We have previously reported that exposure of endothelial cells to cyclic strain elicited a rapid but transient generation of inositol 1,4,5-trisphosphate (IP3), which reached a peak 10 s after the initiation of cyclic deformation. To address the effect of cyclic strain on intracellular Ca2+ concentration ([Ca2+]i) and its temporal relationship to IP3 generation, confluent bovine aortic endothelial cells were grown on flexible membranes, loaded with aequorin and the membranes placed in a custom-designed flow-through chamber. The chamber was housed inside a photomultiplier tube, and vacuum was utilized to deform the membranes. Our results indicate that the initiation of 10% average strain induced a rapid increase in [Ca2+]i which contained two distinct components: a large initial peak 12 s after the initiation of stretch which closely followed the IP3 peak, and a subsequent lower but sustained phase. Pretreatment with 5 microM GdCl3 for 10 min or nominally Ca2+-free medium (CFM) for 3 min reduced the magnitude of the initial rise and abolished the sustained phase. Repetitive 10% average strain at a frequency of 60 cycles/min also elicited a single IP3 peak at 10 s. However, there was also a large initial [Ca2+]i peak followed by multiple smaller transient [Ca2+]i elevations. Preincubation with 5 microM GdCl3 or CFM diminished the initial [Ca2+]i transient and markedly inhibited the late-phase component. Preincubation with 25 microM 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ) attenuated the initial [Ca2+]i transient. Cyclic-strain-mediated IP3 formation in confluent endothelial cells at 10 s, however, was not modified by pretreatment with 25 microM BHQ, 500 microM NiCl2, 10 nM charybdotoxin, 5 microM GdCl3 or CFM. We conclude that in endothelial cells exposed to cyclic strain, Ca2+ enters the cytosol from intracellular and extracellular pools but IP3 formation is not dependent on Ca2+ entry via the plasma membrane.


Anticonvulsant effect of Uncaria rhynchophylla (Miq) Jack. in rats with kainic acid-induced epileptic seizure.
This study investigated the anticonvulsant effect of Uncaria rhynchophylla (UR) and the physiological mechanisms of its action in rats. A total of 70 male Sprague-Dawley (SD) rats were selected for study. Thirty four of these rats were divided into 5 groups as follows: 1) CONTROL GROUP (n = 6): received intraperitoneal injection (i.p.) of kainic acid (KA, 12 mg/kg); 2) UR1000 group (n = 10), 3) UR500 group (n = 6) 4) UR250 group, received UR 1000, 500, 250 mg/kg i.p. 30 min prior to KA administration, respectively; 5) Contrast group: received carbamazepine 20 mg/kg i.p. 30 min prior to KA administration. Behavior and EEG were monitored from 15 min prior to drug administration to 3 hours after KA administration. The number of wet dog shakes were counted at 10 min intervals throughout the experimental course. The remaining 36 rats were used to measure the lipid peroxide level in the cerebral cortex one hour after KA administration. These rats were divided into 6 groups of 6 rats as follows: 1) Normal group: no treatment was given; 2) CONTROL GROUP: received KA (12 mg/kg) i.p.; 3) UR1000 group, 4) UR500 group, 5) UR250 group, received UR 1000, 500, 250 mg/kg i.p. 30 min prior to KA administration, respectively; 6) Contrast group: received carbamazepine 20 mg/kg i.p. 30 min prior to KA administration. Our results indicated that both UR 1000 and 500 mg/kg decreased the incidence of KA-induced wet dog shakes, no similar effect was observed in the UR 250 mg/kg and carbamazepine 20 mg/kg group. Treatment with UR 1000 mg/kg, 500 mg/kg, or 250 mg/kg and carbamazepine 20 mg/kg decreased KA-induced lipid peroxide level in the cerebral cortex and was dose-dependent. These findings suggest that the anticonvulsant effect of UR possibly results from its suppressive effect on lipid peroxidation in the brain.


The history of spinal deformity.
Spinal deformity is the oldest disease known to humankind. The first record of correction of spinal deformity was documented in an Indian religious mythological book written between 3500 BC and 1800 BC. Initially, all spinal deformities were treated with the use of braces, traction, or casts. Hippocrates was the first physician to treat spinal deformities by using axial traction combined with direct pressure. Galen specifically described the anatomy of the spine and spinal nerves. The treatment of spinal deformity was greatly improved by the development of radiographic imaging by Roentgen. After x-rays became available, spinal fusions began to be used to treat scoliotic curves. Hibbs described the first spinal fusion to stabilize a deformed tuberculous spine. Soon enough, other investigators began to report on a variety of surgical techniques used to treat spinal deformity. Surgical approaches from both the posterior and anterior directions were developed and modified in an attempt to achieve durable curve corrections. Harrington's distraction rod system was a major innovation in providing a method to improve coronal plane deformity. Luque introduced segmental instrumentation, which opened up the era of modern surgical techniques for spinal deformity. This concept allowed surgeons to begin to achieve three-dimensional corrections by respecting both the sagittal and coronal curves simultaneously. The introduction of pedicle screws, throughout the thoracolumbar spine, has increased the ability of surgeons to achieve greater degrees of curve correction than had previously been possible. The history of spinal deformity is still maturing as newer procedures continue to be performed on a daily basis.


Enzymatically cross-linked injectable alginate-g-pyrrole hydrogels for neovascularization.
Microparticles capable of releasing protein drugs are often incorporated into injectable hydrogels to minimize their displacement at an implantation site, reduce initial drug burst, and further control drug release rates over a broader range. However, there is still a need to develop methods for releasing drug molecules over extended periods of time, in order to sustain the bioactivity of drug molecules at an implantation site. In this study, we hypothesized that a hydrogel formed through the cross-linking of pyrrole units linked to a hydrophilic polymer would release protein drugs in a more sustained manner, because of an enhanced association between cross-linked pyrrole groups and the drug molecules. To examine this hypothesis, we prepared hydrogels of alginate substituted with pyrrole groups, alginate-g-pyrrole, through a horse-radish peroxidase (HRP)-activated cross-linking of the pyrrole groups. The hydrogels were encapsulated with poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with vascular endothelial growth factor (VEGF). The resulting hydrogel system released VEGF in a more sustained manner than Ca(2+) alginate or Ca(2+) alginate-g-pyrrole gel systems. Finally, implantations of the VEGF-releasing HRP-activated alginate-g-pyrrole hydrogel system on chicken chorioallantoic membranes resulted in the formation of blood vessels in higher densities and with larger diameters, compared to other control conditions. Overall, the drug releasing system developed in this study will be broadly useful for regulating release rates of a wide array of protein drugs, and further enhance the quality of protein drug-based therapies.


Biofunctional Hyaluronic Acid/κ-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing.
The in situ injectable hydrogel system offers a widespread range of biomedical applications in prompt chronic wound treatment and management, as it provides self-healing, maintains a moist wound microenvironment, and offers good antibacterial properties. This study aimed to develop and evaluate biopolymer-based thermoreversible injectable hydrogels for effective wound-healing applications and the controlled drug delivery of meropenem. The injectable hydrogel was developed using the solvent casting method and evaluated for structural changes using proton nuclear magnetic resonance, Fourier transforms infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the self-assembly of hyaluronic acid and kappa-carrageenan and the thermal stability of the fabricated injectable hydrogel with tunable gelation properties. The viscosity assessment indicated the in-situ gelling ability and injectability of the hydrogels at various temperatures. The fabricated hydrogel was loaded with meropenem, and the drug release from the hydrogel in phosphate buffer saline (PBS) with a pH of 7.4 was 96.12%, and the simulated wound fluid with a pH of 6.8 was observed to be at 94.73% at 24 h, which corresponds to the sustained delivery of meropenem. Antibacterial studies on P. aeruginosa, S. aureus, and E. coli with meropenem-laden hydrogel showed higher zones of inhibition. The in vivo studies in Sprague Dawley (SD) rats presented accelerated healing with the drug-loaded injectable hydrogel, while 90% wound closure with the unloaded injectable hydrogel, 70% in the positive control group (SC drug), and 60% in the negative control group was observed (normal saline) after fourteen days. In vivo wound closure analysis confirmed that the developed polymeric hydrogel has synergistic wound-healing potential.


Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study.
Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. We compared 2269 subjects with psychotic features in DSM-IV-TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders.


Human extraocular muscles: unique pattern of myosin heavy chain expression during myotube formation.
To study the myosin heavy chain composition of the human extraocular muscles (EOMs) during development. EOMs from human fetuses of 8 to 22 weeks of gestation were studied with immunocytochemistry and gel electrophoresis. Antibodies specific against nine isoforms of myosin heavy chain (MyHC) were used in serial frozen sections. The developing EOMs had a delayed time course of myotube formation and a unique composition and distribution of MyHCs compared with human limb skeletal muscle. The primary myotubes coexpressed two developmental isoforms of MyHCI from the earliest stages. The third developmental MyHCI delineated the future orbital layer at 10 to 12 weeks of gestation. MyHC-slow tonic also appeared early, whereas MyHC alpha-cardiac and MyHC-extraocular, important components of adult EOM, were never detected at the gestational ages studied. The developmental features of the EOMs differed significantly from those reported for limb muscles of the corresponding ages. It is clear that the knowledge of limb muscle development does not fully apply to more specialized muscles, such as the eye muscles. The extreme complexity displayed by the EOMs probably reflects their distinct embryonic origin, innervation, and regulatory program of myogenesis.


Patient-centered clinical success after lower extremity revascularization for complex diabetic foot wounds treated in a multidisciplinary setting.
Physician-oriented outcomes, such as patency and amputation-free survival (AFS), have traditionally been markers of success after lower extremity revascularization. Previous studies have defined clinical success based on a composite of patient-centered outcomes and have shown this outcome to be achieved in less than 50% of patients, far lower than standard physician-oriented outcomes. The purpose of this study is to evaluate clinical success after lower extremity bypass (LEB) or peripheral vascular intervention (PVI) for tissue loss in diabetic patients treated in a multidisciplinary setting to better understand what factors are associated with success from a patient's perspective. All patients presenting to our multidisciplinary diabetic limb preservation service from July 2012 to January 2020 were enrolled in a prospective database. Patients who underwent either LEB or PVI for ulcer or gangrene were included in the analysis. Clinical success was defined as the composite outcome of secondary patency to the point of wound healing, limb salvage for 1 year, maintenance of ambulatory status for 1 year, and survival for 6 months. Secondary outcomes included 1-year wound healing, patency, and AFS. A total of 134 revascularizations were performed in 131 patients, including 91 (68%) PVI and 43 (32%) LEB. Patients were more frequently male (64%) and black (61%), and 16% were dialysis-dependent. All patients had tissue loss (53% ulcer, 47% gangrene). There were 5 (3.7%) wound, ischemia, and foot infection stage 1, 6 (6.0%) stage 2, 29 (22%) stage 3, and 92 (69%) stage 4 limbs at the time of revascularization. Overall, 76.9% of patients preserved secondary patency to the point of wound healing, 92.5% had limb salvage for 1 year, 90.3% had maintenance of ambulatory status for 1 year, and 96.3% survived for 6 months. The clinical success composite outcome was achieved in 71.6% of patients and was not statistically different between those undergoing PVI vs LEB (69.2% vs 76.7%, P = .37). Secondary patency, limb salvage, and AFS at 1 year were 80.8% ± 3.6%, 91.8% ± 2.3%, and 83.3% ± 3.1%, respectively. Wound healing at 1 year was 84.3% ± 3.4%. The only covariate associated with clinical failure on multivariable analysis was increased age (odds ratio, 0.95; 95% confidence interval, 0.91-0.99; P = .008). Among diabetic patients presenting with tissue loss, the composite outcome of patient-centered clinical success is lower than traditional physician-centered outcomes after lower extremity revascularization, mostly due to low rates of secondary patency to the point of wound healing. In the current study, clinical failure was only associated with older age and was no different after PVI compared with LEB.


Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor.
Hemophilia A and B are caused by deficiencies in coagulation factor VIII (FVIII) and factor IX, respectively, resulting in deficient blood coagulation via the intrinsic pathway. The extrinsic coagulation pathway, mediated by factor VIIa and tissue factor (TF), remains intact but is negatively regulated by tissue factor pathway inhibitor (TFPI), which inhibits both factor VIIa and its product, factor Xa. This inhibition limits clot initiation via the extrinsic pathway, whereas factor deficiency in hemophilia limits clot propagation via the intrinsic pathway. ARC19499 is an aptamer that inhibits TFPI, thereby enabling clot initiation and propagation via the extrinsic pathway. The core aptamer binds tightly and specifically to TFPI. ARC19499 blocks TFPI inhibition of both factor Xa and the TF/factor VIIa complex. ARC19499 corrects thrombin generation in hemophilia A and B plasma and restores clotting in FVIII-neutralized whole blood. In the present study, using a monkey model of hemophilia, FVIII neutralization resulted in prolonged clotting times as measured by thromboelastography and prolonged saphenous-vein bleeding times, which are consistent with FVIII deficiency. ARC19499 restored thromboelastography clotting times to baseline levels and corrected bleeding times. These results demonstrate that ARC19499 inhibition of TFPI may be an effective alternative to current treatments of bleeding associated with hemophilia.


Drying-off dairy cows without antibiotic therapy and orally supplemented with lyophilized Aloe arborescens: effects on rumen activity, immunometabolic profile, and milk yield.
The drying-off is a stressful stage of the lactation cycle of dairy cows that deeply affects cows' metabolism, inflammatory status, and immune system. The promising effects observed during the transition period resulting from supplementation with Aloe arborescens Mill. suggest its potential utility during this phase. A group of 23 Holstein dairy cows with somatic cell count (SCC) less than 200 × 103 cells/ml and without intramammary infections were enroled in the study. Cows were divided into two groups: one orally receiving 10 g/day of A. arborescens Mill. lyophilized powder (AL; 11 cows) between -7 and 7 days from dry-off (DFD), and a control group (CTR; 12 cows). From -14 to 7 DFD and 7 and 28 days from calving, the body condition score and rectal temperature were determined, and rumen fluid, feces, milk, and blood samples were collected. Daily rumination times and milk yield were recorded. Data were analyzed through repeated measures mixed models. Compared to the CTR group, AL cows tended to show reduced production of volatile fatty acids in the rumen with acetate proportion that tended to be higher and valerate proportion that was lower. Moreover, Aloe supplementation caused a reduction in fecal dry matter. At the end of drying-off, AL cows presented better liver function, as suggested by higher paraoxonase plasma concentrations at 7 DFD, higher glucose, and lower urea, but showed increased reactive oxygen metabolites. Aloe supplementation at dry-off ameliorated inflammatory status after calving (lower haptoglobin and ceruloplasmin levels), and improved milk yield in the first weeks of subsequent lactation, without influencing milk composition, SCC, and incidence of intramammary infections. These results confirmed the positive effects of Aloe administration on liver function in dairy cows but indicate the need for further studies investigating the effects of Aloe on rumen fermentation profile and oxidative status.


Implementation of an Advanced Access Scheduling System in Primary Healthcare: One Clinic's Experience.
Advanced access scheduling is a system designed to allow patients to be seen same day or next day or in the future according to their preference. The scheduling system has been associated with patients being seen earlier in the course of illness and patients being hospitalized less often. The advanced access system focuses on timely access to primary healthcare, ideally within 48 hours. A group of Ontario primary healthcare nurse practitioners recently implemented the system at a newly established nurse practitioner-led clinic. The team's experiences with the implementation of the advanced access scheduling system are reviewed. The team's experiences are then compared and contrasted with what has been published on the scheduling system to date. The article approaches the subject matter from the perspectives of primary healthcare providers, clerical staff and administrators. Advanced access has become a timely subject in primary care, given the chronic shortages of service and funding constraints and the need for enhanced effectiveness.


A subgroup-specific antigenic site in the G protein of respiratory syncytial virus forms a disulfide-bonded loop.
An antigenic site (represented by 15 amino acids, residues 174 to 188, designated peptide 12) of the large glycoprotein G of respiratory syncytial virus was demonstrated to be subgroup specific in peptide enzyme-linked immunosorbent assay tests with murine monoclonal antibodies and human postinfection sera. The role of individual amino acids in this subgroup-specific site was determined by use of single-amino-acid-deletion sets of peptides. When monoclonal antibodies were reacted with the deletion sets, a broad amino acid dependence of 11 or 12 residues, Cys-176 (Ile-175 in subgroup B) to Cys-186, was found. Human postinfection sera exhibited a narrower reaction profile (for subgroup A, Cys-182 to Trp-183; for subgroup B, Cys-176 to Lys-183). Reduction of peptides on microtiter plates by treatment with dithiothreitol completely destroyed their antigenic activity in tests with monoclonal antibodies and human postinfection sera of subgroup B. A variant of peptide 12 containing all four cysteines of the G protein (represented by 16 amino acids, residues 172 to 187, designated peptide 12var) also was subgroup specific. We concluded that the activity of the antigenic site in tests with monoclonal antibodies for subgroups A and B appears to depend on intrapeptide disulfide bonds. Reactions with postinfection sera of subgroup B also may depend on a disulfide bond. In contrast, postinfection sera of subgroup A appeared to have the capacity to identify a subgroup-specific site in a linear form of the selected 15-amino-acid-long peptide. Treatment of peptides with dithiothreitol had no effect on their antigenic activity in tests with human postinfection sera of subgroup A. These findings have relevance for molecular engineering of peptide antigens for use in respiratory syncytial virus subgroup-specific site-directed serology.


Regulation of IL-1 receptor-associated kinases by lipopolysaccharide.
IL-1R-associated kinase (IRAK) plays a pivotal role in IL-1R/Toll-like receptor (TLR)-mediated signaling and NF-kappaB activation. IRAK from leukocytes undergoes rapid activation and inactivation/degradation following IL-1 or LPS stimulation. The rapid degradation of IRAK may serve as a negative feedback mechanism of down-regulating IL-1R/TLR-mediated signaling and cytokine gene transcription. Although IL-1/IL-1R-triggered IRAK degradation has been studied in detail, the mechanism of LPS-induced IRAK activation and degradation is not clearly defined. In this study, we demonstrate that the IRAK N-terminal 186-aa region is required for LPS-induced degradation. The N-terminally truncated IRAK protein expressed in human monocytic THP-1 cells remains stable upon LPS challenge. In comparison, IRAK as well as the IRAK mutant with C-terminal truncation undergo degradation with LPS stimulation. We demonstrate that pretreatment with protein kinase C inhibitor calphostin inhibits LPS-induced IRAK degradation. Furthermore, we observe coimmunoprecipitation of endogenous IRAK and protein kinase C-zeta protein. We show that functional TLR4 is required for LPS-mediated IRAK degradation. IRAK protein in the murine GG2EE cells harboring a mutated TLR4 gene does not undergo degradation upon LPS treatment. In sharp contrast, we observe that the IRAK homolog, IRAK2, does not undergo degradation upon prolonged LPS treatment, suggesting complex regulation of the innate immunity network upon microbial challenge.


[Management of attention to emergency rooms and the federal role].
Attention to the emergency care has been criticized, and since 2002 the Brazilian State has assumed the efforts to standardize the level of attention. It was proposed the analysis of documents and acts based on the Structuration Theory that considers the mobilization of allocative and authoritarian resources as dimensions of structure in interaction, which would justify the legitimacy exercised since the establishment of regulations. The National Emergency Plan (PNAU) had as guides: the federal funding, regionalization, professional education, management by urgency committees, and the expansion of the network. It was identified the density of the documental proposals as the facilitator trend of the structural resource, innovative due to the regionalization and responsibilization proposals presented by the several actors and by the alleged centrality of the user. The financing of SUS, despite its persistent state of embarrassment, had no coercive action on the technology investment. Under the current administration there was a vigorous expansion and structuring of the network, which was made by a strong inflow of federal funds. The management by committees should be investigated and points out how fragile the management of labor is.


Tempol protection of spinal cord mitochondria from peroxynitrite-induced oxidative damage.
Peroxynitrite (PN)-mediated mitochondrial dysfunction has been implicated in the secondary injury process after traumatic spinal cord injury (SCI). This study investigated the detrimental effects of the PN donor SIN-1 (3-morpholinosydnonimine) on isolated healthy spinal cord mitochondria and the protective effects of tempol, a catalytic scavenger of PN-derived radicals. A 5 min exposure of the mitochondria to SIN-1 caused a dose-dependent decrease in the respiratory control ratio (RCR) that was accompanied by significant increases in complex I-driven states II and IV respiration rates and decreases in states III and V. These impairments occurred together with an increase in mitochondrial protein 3-nitrotyrosine (3-NT), but not in lipid peroxidation (LP)-related 4-hydroxynonenal (4-HNE). Tempol significantly antagonized the respiratory effects of SIN-1 in parallel with an attenuation of 3-NT levels. These results show that the exogenous PN donor, SIN-1, rapidly causes mitochondrial oxidative damage and complex I dysfunction identical to traumatic spinal cord mitochondrial impairment and that this is mainly due to tyrosine nitration. Consistent with that, the protection of mitochondrial respiratory function by tempol is associated with a decrease in 3-NT levels in mitochondrial proteins also similar to the previously reported antioxidant actions of tempol in traumatically-injured spinal cord mitochondria.


Longitudinal Associations between Maternal Work Stress, Negative Work-Family Spillover, and Depressive Symptoms.
The current study examined associations over an 18-month period between maternal work stressors, negative work-family spillover, and depressive symptoms in a sample of 414 employed mothers with young children living in six predominantly nonmetropolitan counties in the Eastern United States. Results from a one-group mediation model revealed that a less flexible work environment and greater work pressure predicted higher levels of depressive symptoms, and further, that these associations were mediated by perceptions of negative work-family spillover. Additionally, results from a two-group mediation model suggested that work pressure predicted greater perceptions of spillover only for mothers employed full-time. Findings suggest the need for policies that reduce levels of work stress and help mothers manage their work and family responsibilities.


A model of collaboration between nursing education institutions in the North West Province of South Africa.
Professional nursing in South Africa is obtained through a 4-year diploma offered at nursing colleges, or a 4-year degree in universities, and the South African Nursing Council (SANC) registered both for professional nursing. New SANC legislation now requires a bachelor's degree for registration as professional nurse. The aim of the study was to explore and describe perceptions of nurse educators and stakeholders to develop a model of collaboration for joint education and training of nursing professionals by colleges and universities through a bachelor's degree. A mixed methods approach was used to explore perceptions of nurse educators utilising a questionnaire, and perceptions of other nurse training stakeholders through interviews, about a model of collaboration between the college and the university. Themes that emerged from the interviews included identifying collaboration goals, establishing a conducive environment, maximising exchange of resources, role clarification and perceived challenges. Quantitative results showed high agreement percentages (84.13%-100%) on most basic concepts and themes. A model of collaboration was developed indicating a framework, agents, recipients, procedure, dynamics, and terminus. A model of collaboration was acceptable to the majority of nurse education stakeholders. Other implications are that there was a need for the improvement of scholarship among nurse educators and clinical mentors, sharing rare skills, and addressing perceived challenges.


Effectiveness of community-based family-focused interventions on family functioning among families of children with chronic health conditions: A systematic review and meta-analysis.
Community-based family-focused interventions can offer support to families of children with chronic health conditions. This review aimed to evaluate the effectiveness of community-based family-focused interventions in improving family functioning, disease knowledge, and child health outcomes among families of children with chronic health conditions. Eight electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, Scopus, Web of Science, and ProQuest Dissertations & Theses Global) and one trial registry (ClinicalTrials.gov) were searched from their dates of inception to October 2022. Meta-analysis was performed under the random-effect model when appropriate otherwise, findings were narratively synthesized. I2 statistics and Cochran's Q chi-squared test were used to determine heterogeneity. Quality appraisal was conducted by the Cochrane risk of bias tool and the Grades of Recommendation, Assessment, Development, and Evaluation approach at the study and outcome level, respectively. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines guided this review. Eight studies were included in this review. Community-based family-focused interventions were viable methods that could support families of children with chronic health conditions. Family-focused interventions that incorporate guided role-playing exercises for parents and children, psychoeducational components, and elements from relationship-focused interventions could support families more effectively. However, current findings are mostly limited to interventions conducted in patients' homes, and the long-term effect of these interventions cannot be determined. Overall, community-based family-focused interventions have the potential to offer valuable support to families of children with chronic health conditions, and future research could seek to improve the effectiveness of these interventions.


Positive-More than unbiased-Self-perceptions increase subjective authenticity.
Authenticity is often described using terms like "real," "genuine," and "true" suggesting that unbiased and objective self-perception is a core component of the construct. However, people tend to view themselves in an overly positive way. Therefore, we propose that experiencing a positive self-versus an unbiased self-will increase authenticity. We find support for this in seven studies (Ntotal = 1,795) with two operationalizations of self-rated authenticity: attributed and state authenticity. We find that authenticity emerges from positive self-beliefs (Study 1), positive personality assessments (Study 2), and positive self-expressions (Study 3a and b). Further, we find that these effects are not driven only by positivity, but positive selves (Study 4), and mediated by the identity centrality (Study 5). Finally, Study 6 finds that this positivity bias does not extend to other-rated authenticity: People who present an overly positive self seem less authentic to others relative to a mixed or negative self-presentation. Taken together, these findings suggest that being "unreal" through positive self-illusions can, paradoxically, make one feel more real. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Virgin rice bran oil alleviates hypertension through the upregulation of eNOS and reduction of oxidative stress and inflammation in L-NAME-induced hypertensive rats.
Endothelial dysfunction associated with reduction in nitric oxide (NO) bioavailability plays an important role in development of hypertension. Consumption of a diet rich in antioxidants appears to lower the risk for hypertension. Virgin rice bran oil (VRBO) possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to our knowledge, the antihypertensive effect of VRBO has not been investigated. The aim of this study was to examine the antihypertensive effect of VRBO in Nω-nitro-l-arginine methyl ester (L-NAME)-induced hypertensive rats and its underlying mechanisms. Hypertension was induced in rats by administration of L-NAME, after which VRBO, lisinopril (Lis), or VRBO + Lis was administered. Studies were then conducted on the hemodynamics of vascular responses to vasoactive substances, plasma angiotensin-converting enzyme (ACE), plasma nitrate/nitrite, oxidative stress, and inflammatory markers. L-NAME administration induced hemodynamic changes including elevation of blood pressure, increased peripheral vascular resistance, and endothelial dysfunction. Reduction in plasma nitrate/nitrite, overproduction of vascular superoxide, and increases in plasma ACE, malondialdehyde, protein carbonyl, and plasma tumor necrosis factor-α were observed in L-NAME hypertensive rats. The changes were associated with a marked decrease in endothelial NO synthase expression, increased expression of gp91phoxand vascular cell adhesion molecule-1, and activation of nuclear factor-κB in aortic tissues. Administration of either VRBO or Lis significantly mitigated all of these deleterious effects. The combination of VRBO and Lis was more effective than either treatment alone. The antihypertensive effect of VRBO may be mediated by restoration of hemodynamics, increased NO bioavailability, and alleviation of oxidative stress and inflammation. VRBO has an additive effect on antihypertensive medication.


Childhood vitiligo: response to methylprednisolone oral minipulse therapy and topical fluticasone combination.
Childhood vitiligo is always a challenge to treat, especially when the disease is progressing rapidly in such a patient. Oral minipulse with betamethasone has been tried in childhood vitiligo and also in some other immune mediated skin disorders with good results. The aim of the present study was to see the overall efficacy of methylprednisolone oral minipulse therapy in combination with topical fluticasone in progressive childhood vitiligo. The combination was tried to achieve a significant amount of repigmentation of vitiligo lesions already present at the initial visit. Four hundred children with progressive vitiligo were enrolled for this study and were prescribed oral methylprednisolone on two consecutive days every week in a minipulse form for a period of six months. In addition, the patients were instructed to apply fluticasone ointment topically once a day on their vitiligo lesions. The patients were assessed for the remission achieved as well as the extent of repigmentation of their already existent lesions. More than 90% of patients went into complete remission after the start of the therapy. Moreover, about 65% (two-thirds) of patients achieved good to excellent repigmentation of lesions at the end of six months of therapy. The therapy was also well tolerated and the side effects seen were almost negligible. Oral minipulse treatment with methylprednisolone is an effective treatment option for controlling the disease spread in childhood vitiligo and with the addition of topical fluticasone the extent of repigmentation achieved is also quite significant.


Ameliorating effects of auricular electroacupuncture on rectal distention-induced gastric dysrhythmias in rats.
Gastric slow waves (GSW) are known to regulate gastric motility and are impaired with rectal distention (RD). Electroacupuncture (EA) at body acupoints, such as ST 36, has been shown to improve gastric dysrhythmias; however, little is known about the possible effects of auricular electroacupuncture (AEA) on GSW. To study effects and possible mechanisms of AEA on RD-induced gastric dysrhythmias in rats, ten male Sprague-Dawley (SD) rats implanted with gastric serosal electrodes were studied in two different experiments in fed state. Four sessions were performed in experiment 1 as follows: control (RD, no stimulation), RD+AEA, RD+EA at body points and RD+sham AEA. Two sessions were included in experiment 2 to study mechanisms of AEA: RD + atropine and RD + atropine + AEA. It was found that 1) RD significantly decreased the percentage of normal GSW from 89.8 ± 3.5% to 76.0 ± 3.3% (P<0.05); 2) AEA increased the percentage of normal GSW during RD to 94.0 ± 2.1% (P<0.05 vs. RD) via a reduction in the percentages of tachygastria and arrhythmia (P<0.05 vs. RD); 3) atropine blocked the ameliorating effect of AEA on RD-induced gastric dysrhythmias. Our results demonstrated that RD induces gastric dysrhythmias in fed state in rats. AEA improves RD-induced gastric dysrhythmias via the vagal pathway. AEA may have a therapeutic potential in treating gastric dysrhythmias.


Low-dose Gentamicin for Uncomplicated Enterococcus faecalis Bacteremia May be Nephrotoxic in Children.
Uncertainty exists regarding the role of synergistic gentamicin for uncomplicated Enterococcus faecalis bacteremia in children. We conducted a retrospective, observational study comparing clinical outcomes of children with E. faecalis bacteremia without endocarditis receiving ampicillin monotherapy with those receiving ampicillin along with low-dose gentamicin therapy. To account for nonrandom assignment of combination therapy, propensity score weighting was combined with multivariable regression to estimate the effect of combination therapy on duration of bacteremia, bacteremic relapse, and acute kidney injury (AKI). One hundred sixty-three (52%) patients received ampicillin with low-dose gentamicin, and 150 (48%) patients received ampicillin monotherapy. Incorporating propensity-score weighting with additional adjustment for source control measures, patients receiving combination therapy experienced bacterial clearance 10 hours faster than children receiving ampicillin monotherapy (adjusted mean difference 0.42; confidence interval (CI), .02 to .82; P = .04). Bacteremic relapse was similar between the two groups (17% vs 18%); adjusted hazards ratio (aHR) 1.12; 95% CI, .65 to 1.92. Children receiving low-dose gentamicin had approximately twice the risk of developing AKI compared to children not receiving this agent, adjusting for the receipt of additional nephrotoxins (aHR 1.94; 95% CI, 1.48-2.97). Our study suggests that for children with uncomplicated E. faecalis bacteremia, the addition of low-dose gentamicin may decrease the time to bacterial clearance by 10 hours but without any impact on recurrent bacteremia. However, with this potential benefit comes the increased likelihood of AKI. Low-dose gentamicin for the treatment of uncomplicated enterococcal bacteremia may pose harm to children with limited benefit.


Cooperative Effects between Hydrophilic Pores and Solvents: Catalytic Consequences of Hydrogen Bonding on Alkene Epoxidation in Zeolites.
Hydrophobic voids within titanium silicates have long been considered necessary to achieve high rates and selectivities for alkene epoxidations with H2O2. The catalytic consequences of silanol groups and their stabilization of hydrogen-bonded networks of water (H2O), however, have not been demonstrated in ways that lead to a clear understanding of their importance. We compare turnover rates for 1-octene epoxidation and H2O2 decomposition over a series of Ti-substituted zeolite *BEA (Ti-BEA) that encompasses a wide range of densities of silanol nests ((SiOH)4). The most hydrophilic Ti-BEA gives epoxidation turnover rates that are 100 times larger than those in defect-free Ti-BEA, yet rates of H2O2 decomposition are similar for all (SiOH)4 densities. These differences cause the most hydrophilic Ti-BEA to also give the highest selectivities, which defies conventional wisdom. Spectroscopic, thermodynamic, and kinetic evidence indicate that these catalytic differences are not due to changes in the electronic affinity of the active site, the electronic structure of Ti-OOH intermediates, or the mechanism for epoxidation. Comparisons of apparent activation enthalpies and entropies show that differences in epoxidation rates and selectivities reflect favorable entropy gains produced when epoxidation transition states disrupt hydrogen-bonded H2O clusters anchored to (SiOH)4 near active sites. Transition states for H2O2 decomposition hydrogen bond with H2O in ways similar to Ti-OOH reactive species, such that decomposition becomes insensitive to the presence of (SiOH)4. Collectively, these findings clarify how molecular interactions between reactive species, hydrogen-bonded solvent networks, and polar surfaces can influence rates and selectivities for epoxidation (and other reactions) in zeolite catalysts.


Lipopeptides activate Gi-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells.
Synthetic lipopeptides activate superoxide-anion (O2-) formation in human neutrophils in a pertussis-toxin (PTX)-sensitive manner, suggesting the involvement of G-proteins of the Gi family in the signal-transduction pathway. We compared G-protein activation by lipopeptides and the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) in dibutyryl-cyclic-AMP-differentiated HL-60 cells. The lipopeptide (2S)-2-palmitoylamino-6-palmitoyloxymethyl-7-palmitoyloxy heptanoyl-SK4 (Pam3AhhSK4) and fMLP activated high-affinity GTPase, i.e. the enzymic activity of G-protein alpha-subunits, in HL-60 membranes in a time- and protein-dependent manner, but they had no effect on Mg(2+)-ATPase and Na+/K(+)-ATPase. Pam3AhhSK4 and fMLP increased Vmax. of GTP hydrolysis. Pam3AhhSK4 activated GTP hydrolysis with half-maximal and maximal effects at about 2 microM and 10 microM respectively. Other lipopeptides activated GTP hydrolysis as well. Lipopeptides were less effective than fMLP to activate GTPase. In membranes from PTX-treated cells, the stimulatory effects of lipopeptides and fMLP on GTPase were abolished. In N-ethylmaleimide-treated membranes, the relative stimulatory effect of Pam3AhhSK4 on GTP hydrolysis was enhanced, whereas that of fMLP was diminished. fMLP and Pam3AhhSK4 activated GTPase in an over-additive manner in N-ethylmaleimide-treated membranes. Unlike fMLP, Pam3AhhSK4 did not enhance incorporation of GTP azidoanilide into, and cholera-toxin-catalysed ADP-ribosylation of Gi-protein alpha-subunits in, HL-60 membranes and did not induce rises in cytosolic Ca2+ concentration. Pam3AhhSK4 and fMLP stimulated phosphatidic acid formation in a PTX-sensitive manner. Pam3AhhSK4 itself did not activate O2- formation, but potentiated the stimulatory effects of fMLP. Our data suggest that (i) lipopeptides activate the GTPase of Gi-proteins, (ii) lipopeptides and fMLP activate Gi-proteins differently, (iii) lipopeptides stimulate phospholipase D via Gi-proteins, and (iv) phosphatidic acid formation is not sufficient for activation of O2- formation.


Vocal Parameters of Elderly Female Choir Singers.
Introduction Due to increased life expectancy among the population, studying the vocal parameters of the elderly is key to promoting vocal health in old age. Objective This study aims to analyze the profile of the extension of speech of elderly female choristers, according to age group. Method The study counted on the participation of 25 elderly female choristers from the Choir of Messianic Church of São Paulo, with ages varying between 63 and 82 years, and an average of 71 years (standard deviation of 5.22). The elders were divided into two groups: G1 aged 63 to 71 years and G2 aged 72 to 82. We asked that each participant count from 20 to 30 in weak, medium, strong, and very strong intensities. Their speech was registered by the software Vocalgrama that allows the evaluation of the profile of speech range. We then submitted the parameters of frequency and intensity to descriptive analysis, both in minimum and maximum levels, and range of spoken voice. Results The average of minimum and maximum frequencies were respectively 134.82-349.96 Hz for G1 and 137.28-348.59 Hz for G2; the average for minimum and maximum intensities were respectively 40.28-95.50 dB for G1 and 40.63-94.35 dB for G2; the vocal range used in speech was 215.14 Hz for G1 and 211.30 Hz for G2. Conclusion The minimum and maximum frequencies, maximum intensity, and vocal range presented differences in favor of the younger elder group.


Different Modes of Action of Genetic and Chemical Downregulation of Histone Deacetylases with Respect to Plant Development and Histone Modifications.
A high degree of developmental plasticity enables plants to adapt to continuous, often unfavorable and unpredictable changes in their environment. At the molecular level, adaptive advantages for plants are primarily provided by epigenetic machinery including DNA methylation, histone modifications, and the activity of noncoding RNA molecules. Using a mass spectrometry-based proteomic approach, we examined the levels of acetylated histone peptide forms in Arabidopsis plants with a loss of function of histone deacetylase 6 (HDA6), and in plants germinated in the presence of HDA inhibitors trichostatin A (TSA) and sodium butyrate (NaB). Our analyses revealed particular lysine sites at histone sequences targeted by the HDA6 enzyme, and by TSA- and NaB-sensitive HDAs. Compared with plants exposed to drugs, more dramatic changes in the overall profiles of histone post-translational modifications were identified in hda6 mutants. However, loss of HDA6 was not sufficient by itself to induce hyperacetylation to the maximum degree, implying complementary activities of other HDAs. In contrast to hda6 mutants that did not exhibit any obvious phenotypic defects, the phenotypes of seedlings exposed to HDA inhibitors were markedly affected, showing that the effect of these drugs on early plant development is not limited to the modulation of histone acetylation levels.


Microbial in situ degradation of aromatic hydrocarbons in a contaminated aquifer monitored by carbon isotope fractionation.
We present an approach for characterizing in situ microbial degradation using the 13C/12C isotope fractionation of contaminants as an indicator of biodegradation. The 13C/12C isotope fractionation of aromatic hydrocarbons was studied in anoxic laboratory soil percolation columns with toluene or o-xylene as the sole carbon and electron source, and sulfate as electron acceptor. After approximately 2 months' of incubation, the soil microbial community degraded 32 mg toluene l(-1) and 44 mg o-xylene l(-1) to less than 0.05 mg l(-1), generating a stable concentration gradient in the column. The 13C/12C isotope ratio in the residual non-degraded fraction of toluene and o-xylene increased significantly, corresponding to isotope fractionation factors (alphaC) of 1.0015 and 1.0011, respectively. When the extent of biodegradation in the soil column was calculated based on the measured isotope ratios (R(t)) and an isotope fractionation factor (alphaC=1.0017) obtained from a sulfate-reducing batch culture the theoretical residual substrate concentrations (C(t)) matched the measured toluene concentrations in the column. This indicated that a calculation of biodegradation based on isotope fractionation could work in systems like soil columns. In a field study, a polluted, anoxic aquifer was analyzed for BTEX and PAH contaminants. These compounds were found to exhibit a significant concentration gradient along an 800-m groundwater flow path downstream of the source of contamination. A distinct increase in the carbon isotope ratio (delta13C) was observed for the residual non-degraded toluene (7.2 per thousand ), o-xylene (8.1 per thousand ) and naphthalene fractions (1.2 per thousand ). Based on the isotope values and the laboratory-derived isotope fractionation factors for toluene and o-xylene, the extent to which the residual substrate fraction in the monitoring wells had been degraded by microorganisms was calculated. The results revealed significant biodegradation along the groundwater flow path. In the wells at the end of the plume, the bioavailable toluene and o-xylene fractions had been almost completely reduced by in situ microbial degradation. Although indane and indene showed decreasing concentrations downstream of the groundwater flow path, suggesting microbial degradation, their carbon isotope ratios remained constant. As the physical properties of these compounds are similar to those of BTEX compounds, the constant isotope values of indane and indene indicated that microbial degradation did not lead to isotope fractionation of all aromatic hydrocarbons. In addition, physical interaction with the aquifer material during the groundwater passage did not significantly alter the carbon isotope composition of aromatic hydrocarbons.


Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.
Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.


Measurement of surface roughness changes of unpolished and polished enamel following erosion.
To determine if Sa roughness data from measuring one central location of unpolished and polished enamel were representative of the overall surfaces before and after erosion. Twenty human enamel sections (4x4 mm) were embedded in bis-acryl composite and randomised to either a native or polishing enamel preparation protocol. Enamel samples were subjected to an acid challenge (15 minutes 100 mL orange juice, pH 3.2, titratable acidity 41.3mmol OH/L, 62.5 rpm agitation, repeated for three cycles). Median (IQR) surface roughness [Sa] was measured at baseline and after erosion from both a centralised cluster and four peripheral clusters. Within each cluster, five smaller areas (0.04 mm2) provided the Sa roughness data. For both unpolished and polished enamel samples there were no significant differences between measuring one central cluster or four peripheral clusters, before and after erosion. For unpolished enamel the single central cluster had a median (IQR) Sa roughness of 1.45 (2.58) μm and the four peripheral clusters had a median (IQR) of 1.32 (4.86) μm before erosion; after erosion there were statistically significant reductions to 0.38 (0.35) μm and 0.34 (0.49) μm respectively (p<0.0001). Polished enamel had a median (IQR) Sa roughness 0.04 (0.17) μm for the single central cluster and 0.05 (0.15) μm for the four peripheral clusters which statistically significantly increased after erosion to 0.27 (0.08) μm for both (p<0.0001). Measuring one central cluster of unpolished and polished enamel was representative of the overall enamel surface roughness, before and after erosion.


The escape of cancer from T lymphocytes: immunoselection of MHC class I loss variants harboring structural-irreversible "hard" lesions.
The discovery of tumor antigens recognized by T lymphocytes has stimulated the development of a variety of cancer treatment protocols aimed at enhancing antitumor-specific T cell responses and tumor rejection. However, immunotherapy-mediated regression of established tumors and clearly positive clinical response to such treatment has not been achieved yet despite the induction of T cells directed against tumor antigens. The failure of the modern immunotherapy protocols can be explained by different tumor escape mechanisms that have been defined in various types of malignancy. The loss or downregulation of MHC class I antigens in tumor cells is one of the best analyzed mechanisms. In this review, we show experimental evidence obtained in our laboratory on human tumors and in a mouse cancer model suggesting that the molecular mechanism responsible for the MHC class I alteration in tumor cells might have a crucial impact on tumor recovery of normal H-2/HLA expression during the natural history of tumor development or after immunotherapy. When the preexisting molecular lesion underlying tumor MHC class I alteration is reversible (regulatory or soft), class I expression can be recovered leading to regression of tumor lesion. In contrast, if the HLA class I alteration is irreversible in nature (structural or hard), the lesion will progress killing the host. This is a new vision of the role of MHC class I alteration in tumors that can explain the failure of immunotherapy in a variety of different clinical protocols.


Brazil's policy on healthcare for government workers: players, paths and challenges.
This article aims to analyze the extent to which Brazil's public sector has made progress in institutionalizing an integral and participative model for the healthcare of government workers, based on the principles of universality, integrality and workers' participation. Based on documents produced by the Rio de Janeiro Permanent Forum on Workers' Health, the paper analyses the process of implantation of the Integrated Public Workers' Healthcare Sub-System (SIASS) in the municipality of Rio de Janeiro over the period 2009-2016, based on the historical institutionalism. Although it was conceived as an integrated system referenced to the principles of workers' health, as from 2013 an inflexion was observed in this Subsystem, in the direction of a conservative model of occupational health, such as had been traditional and hegemonic in labor relations in Brazil. One factor that emerges is the loss of the universal character of the system due to the flexibility of employment relations in the public sector. There are various challenges: the need to expand the dialogue, and integration of the Policies on health, employment relations and management of the public administration, in such a way as to guarantee the principles of workers' health and the universality of the system, evolving from the concept of the 'public servant' to that of the 'public employee'.


Therapeutic effect of thalidomide combined with temozolomide and three-dimensional conformal radiotherapy for patients with high-grade gliomas after operation.
To explore the efficacy and safety of 125 I radioactive seed implantation combined with intermittent hormonal therapy (IHT) in the clinical treatment of moderate- and high-risk non-metastatic prostate cancer. A total of 136 patients were divided into the observation group (n=68) and the control group (n=68). In the observation group, 125I radioactive seed implantation was performed, bicalutamide capsules were taken orally immediately after operation, and leuprorelin was injected from 1 week after operation. In the control group, IHT alone was administered. The level of serum prostate specific antigen (PSA), maximum urine flow rate (Q max ) and international prostate symptom scale (IPSS) score were compared between the two groups before and after treatment. Moreover, the overall survival (OS), tumor-specific survival (TSS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) of patients were recorded. There were no statistically significant differences in the PSA level, Q max and IPSS score between the two groups before treatment (p>0.05). At 6, 12 and 24 months after treatment, the level of PSA in the observation group was significantly lower than in the control group (p=0.005, p<0.001, p<0.001). At 24 months after treatment, Q max in the observation group was significantly higher than in the control group (p=0.025). At 12 and 24 months after treatment, the IPSS score in the observation group was significantly lower than that in the control group (p=0.013, p=0.002). During the follow-up period, the intermission time of hormonal therapy and PFS time in the observation group were obviously longer than those in control group (p<0.001). In the two groups, OS was 97.1% and 94.1%, TSS was 95.6% and 92.6%, DMFS was 82.4% and 66.2%, and PFS was 72.1% and 51.5%, respectively. It can be seen that OS and TSS had no statistically significant differences between the two groups (p=0.405, p=0.496), while DMFS and PFS in the observation group were remarkably superior to those in the control group (p=0.037, p=0.022). 125 I seed implantation combined with IHT is safe and effective in the clinical treatment of patients with moderate- and high-risk non-metastatic prostate cancer. Compared with the IHT alone, the combination therapy can significantly prolong the intermission time of hormonal therapy and effectively control the progression of disease.


Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.
Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD. This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status. A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.


Phosphatidylcholine synthesis is required for optimal function of Legionella pneumophila virulence determinants.
The function of phosphatidylcholine (PC) in the bacterial cell envelope remains cryptic. We show here that productive interaction of the respiratory pathogen Legionella pneumophila with host cells requires bacterial PC. Synthesis of the lipid in L. pneumophila was shown to occur via either phospholipid N-methyltransferase (PmtA) or phosphatidylcholine synthase (PcsA), but the latter pathway was demonstrated to be of predominant importance. Loss of PC from the cell envelope caused lowered yields of L. pneumophila within macrophages as well as loss of high multiplicity cytotoxicity, while mutants defective in PC synthesis could be complemented either by reintroduction of PcsA or by overproduction of PmtA. The lowered yields and reduced cytotoxicity in mutants with defective PC biosynthesis were due to three related defects. First, there was a poorly functioning Dot/Icm apparatus, which delivers substrates required for intracellular growth into the cytosol of infected cells. Second, there was reduced bacterial binding to macrophages, possibly due to loss of PC or a PC derivative on the bacterium that is recognized by the host cell. Finally, strains lacking PC had low steady-state levels of flagellin protein, a deficit that had been previously associated with the phenotypes of lowered cytotoxicity and poor cellular adhesion.


Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase.
Barrier to autointegration factor (BAF/BANF1) is a cellular DNA-binding protein found in the nucleus and cytoplasm. Cytoplasmic BAF binds to foreign DNA and can act as a defense against vaccinia DNA replication. To evade BAF, vaccinia expresses the B1 kinase, which phosphorylates BAF and blocks its ability to bind DNA. Interestingly, B1 is also needed for viral intermediate gene expression via an unknown mechanism. Therefore, we evaluated the impact of B1-BAF signaling on vaccinia transcription. Strikingly, the decrease in vaccinia transcription caused by loss of B1 can be rescued by depletion of BAF. The repressive action of BAF is greatest on a viral promoter, and is more modest when non-vaccinia promoters are employed, which suggests BAF acts in a gene specific manner. These studies expand our understanding of the role of the B1 kinase during infection and provide the first evidence that BAF is a defense against viral gene expression.


Near-field Raman imaging using optically trapped dielectric microsphere.
The stumbling block of employing Raman imaging in nanoscience and nanotechnology is the diffraction-limited spatial resolution. Several approaches have been employed to improve the spatial resolution, among which aperture and apertureless near-field Raman techniques are the most frequently used. In this letter, we report a new approach in doing near-field Raman imaging with spatial resolution of about 80 nm, by trapping and scanning a polystyrene microsphere over the sample surface in water. We have used this technique to resolve PMOS transistors with SiGe source drain stressors with poly-Si gates, as well as gold nanopatterns with excellent reproducibility.


[Recollections and ideas in tobacco dependence].
++Clinico-psychopathological and patho-psychological methods were employed to study statically and over time the main types of reproducing recollections, ideas and correlations to the motivation and formation of tobacco dependence in 480 smokers and non-smokers. Three basic types of reproducing recollections and ideas, namely mental, image-bearing, and mental and image-bearing were distinguished. The main space and time constitutional forms of the types of the development of recollections and ideas are presented. In patients with tobacco dependence, the characteristic features of the explored types of recollections and ideas are viewed as one of the risk factors of the onset of tobacco dependence. The data are presented about their implication in the formation of pathological craving for tobacco smoking.


Intracellular antibodies and cancer: new technologies offer therapeutic opportunities.
Since the realisation that the antigen-binding regions of antibodies, the variable (V) regions, can be uncoupled from the rest of the molecule to create fragments that recognise and abrogate particular protein functions in cells, the use of antibody fragments inside cells has become an important tool in bioscience. Diverse libraries of antibody fragments plus in vivo screening can be used to isolate single chain variable fragments comprising VH and VL segments or single V-region domains. Some of these are interfering antibody fragments that compete with protein-protein interactions, providing lead molecules for drug interactions that until now have been considered difficult or undruggable. It may be possible to deliver or express antibody fragments in target cells as macrodrugs per se. In future incarnations of intracellular antibodies, however, the structural information of the interaction interface of target and antibody fragment should facilitate development of binding site mimics as small drug-like molecules. This is a new dawn for intracellular antibody fragments both as macrodrugs and as precursors of drugs to treat human diseases and should finally lead to the removal of the epithet of the 'undruggable' protein-protein interactions.


Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients.
40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics and the safety of RAD were also evaluated. Twenty-six de novo liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single-dose RAD coadministration. RAD capsules administered in single doses of 7.5 mg were well tolerated and safe.


Membranous Budd-Chiari syndrome in a well-anticoagulated patient.
We describe an unusual case of a 54-year-old woman who was diagnosed with a subacute Budd-Chiari syndrome due to membranous venous obstruction in the inferior vena cava. The unusual feature of this case was that she had been diagnosed with pulmonary emboli a few years earlier and was on lifelong warfarin with a therapeutic international normalised ratio. She was effectively treated by venoplasty.