[Actomyosin from a low-differentiation skeletal muscle tumor].
Actin and subunits of myosin were identified in actomyosin preparations isolated from a low-differentiated rhabdomyosarcoma. Determination was made of Ca2+-ATPase activity and of the ratio of concentrations of tumor myosin light chains. Aggregates were obtained bearing similarity with synthetic filaments. The tumor myosin has all the light chains characteristic of the myosin of definitive fast skeletal muscles, and does not have light chains corresponding to any other myosin isoforms. Quantitative peculiarities of light chain composition of tumor myosin may be explained by peculiarities of cell composition of the tumor. The data obtained indicate that the mechanism coordinating myosin gene expression is extremely resistant to tumoral discoordinating factors. Peculiarities of coordination of the expression of genes coding tissue-specific polypeptides are discussed.


Evidence for active maintenance of phylotranscriptomic hourglass patterns in animal and plant embryogenesis.
The developmental hourglass model has been used to describe the morphological transitions of related species throughout embryogenesis. Recently, quantifiable approaches combining transcriptomic and evolutionary information provided novel evidence for the presence of a phylotranscriptomic hourglass pattern across kingdoms. As its biological function is unknown it remains speculative whether this pattern is functional or merely represents a nonfunctional evolutionary relic. The latter would seriously hamper future experimental approaches designed to test hypotheses regarding its function. Here, we address this question by generating transcriptome divergence index (TDI) profiles across embryogenesis of Danio rerio, Drosophila melanogaster, and Arabidopsis thaliana. To enable meaningful evaluation of the resulting patterns, we develop a statistical test that specifically assesses potential hourglass patterns. Based on this objective measure we find that two of these profiles follow a statistically significant hourglass pattern with the most conserved transcriptomes in the phylotypic periods. As the TDI considers only recent evolutionary signals, this indicates that the phylotranscriptomic hourglass pattern is not a rudiment but possibly actively maintained, implicating the existence of some linked biological function associated with embryogenesis in extant species.


Biophysics of α-synuclein induced membrane remodelling.
α-Synuclein is an intrinsically disordered protein whose aggregation is a hallmark of Parkinson's disease. In neurons, α-synuclein is thought to play important roles in mediating both endo- and exocytosis of synaptic vesicles through interactions with either the lipid bilayer or other proteins. Upon membrane binding, the N-terminus of α-synuclein forms a helical structure and inserts into the hydrophobic region of the outer membrane leaflet. However, membrane structural changes induced by α-synuclein are still largely unclear. Here we report a substantial membrane area expansion induced by the binding of α-synuclein monomers. This measurement is accomplished by observing the increase of membrane area during the binding of α-synuclein to pipette-aspirated giant vesicles. The extent of membrane area expansion correlates linearly with the density of α-synuclein on the membrane, revealing a constant area increase induced by the binding per α-synuclein molecule. The area expansion per synuclein is found to exhibit a strong dependence on lipid composition, but is independent of membrane tension and vesicle size. Fragmentation or tubulation of the membrane follows the membrane expansion process. However, contrary to BAR domain proteins, no distinct tubulation-transition density can apparently be identified for α-synuclein, suggesting a more complex membrane curvature generation mechanism. Consideration of α-synuclein's membrane binding free energy and biophysical properties of the lipid bilayer leads us to conclude that membrane expansion by α-synuclein results in thinning of the bilayer. These membrane thinning and tubulation effects may underlie α-synuclein's role in mediating cell trafficking processes such as endo- and exocytosis.


Autocrine/paracrine mechanisms in human hematopoiesis.
Autocrine/paracrine regulatory mechanisms are believed to play a role in the pathophysiology of several hematologic malignancies. Evidence is accumulating that various growth factors, cytokines, and chemokines are expressed and secreted by normal early and differentiated hematopoietic cells and thus could also regulate normal hematopoiesis in an autocrine/paracrine manner. In this review we summarize recent advances in identification and understanding of the role of autocrine/paracrine axes in the growth of both malignant and normal human hematopoietic cells. Better understanding of intercellular crosstalk operating in normal and pathological states and the mechanisms regulating synthesis of these endogenously produced factors (potential targets for various pharmacological approaches) may allow us to improve antileukemia treatments, undertake more efficient ex vivo stem cell expansion, and develop other therapeutic strategies.


Nocturnal desaturation in patients with stable heart failure.
To determine the prevalence of sleep disordered breathing within a United Kingdom heart failure population. 104 patients and 21 matched normal volunteers. Overnight home pulse oximetry with simultaneous ECG recording in the patient group; daytime sleepiness was assessed using the Epworth sleepiness scale (ESS); 41 patients underwent polysomnography to assess the validity of oximetry as a screening test for Cheyne-Stokes respiration. Home oximetry was a good screening test for Cheyne-Stokes respiration (specificity 81%, sensitivity 87%). Patients with poorer New York Heart Association (NYHA) classes had higher sleepiness scores (p < 0.005). Twenty three patients had "abnormal" patterns of nocturnal desaturation suggestive of Cheyne-Stokes respiration. The mean (SEM) frequency of dips in Sao2 exceeding 4% was 10.3 (0.9) per hour in the patients and 4.8 (0.6) in normal controls (p < 0.005). Ejection fraction correlated negatively with dip frequency (r = -0.5, p < 0.005). The patient subgroup with > or = 15 dips/hour had a higher mean (SEM) NYHA class (3.0 (0.2) v 2.3 (0.1), p < 0.05), and experienced more ventricular ectopy (220 (76) v 78 (21) beats/hour, p < 0.05). There was no excess of serious arrhythmia. Nocturnal desaturation is common in patients with treated heart failure. Low ejection fraction was related to dip frequency. Lack of correlation between dips and ESS suggests that arousal from sleep is more important than hypoxia in the aetiology of daytime sleepiness in heart failure. Overnight oximetry is a useful screening test for Cheyne-Stokes respiration in patients with known heart failure.


Visual localization in patients with unilateral brain disease.
The accuracy of localization of briefly exposed single dots and pairs of dots was assessed in patients with lesions of the left and right hemispheres and in control patients without history or evidence of brain disease. A remarkably high frequency of impaired performance was found in the patients with right hemisphere lesions. The performance of the patients with left hemisphere lesions was comparable with that of the control patients. Visual field defect was associated with defective localization in the right hemisphere group but not in the left hemisphere group. Aphasic disorder and age were not related to performance level. The relationship of the findings to those of previous studies of visual localization in patients with unilateral brain disease is discussed.


Preliminary evaluation of biplane correlation (BCI) stereographic imaging for lung nodule detection.
A biplane correlation (BCI) imaging system obtains images that can be viewed in stereo, thereby minimizing overlapping structures. This study investigated whether using stereoscopic visualization provides superior lung nodule detection compared to standard postero-anterior (PA) image display. Images were acquired at two oblique views of ±3° as well as at a standard PA position from 60 patients. Images were processed using optimal parameters and displayed on a stereoscopic display. The PA image was viewed in the standard format, while the oblique views were paired to provide a stereoscopic view of the subject. A preliminary observer study was performed with four radiologists who viewed and scored the PA image then viewed and scored the BCI stereoscopic image. The BCI stereoscopic viewing of lung nodules resulted in 71 % sensitivity and 0.31 positive predictive value (PPV) index compared to PA results of 86 % sensitivity and 0.26 PPV index. The sensitivity for lung nodule detection with the BCI stereoscopic system was reduced by 15 %; however, the total number of false positives reported was reduced by 35 % resulting in an improved PPV index of 20 %. The preliminary results indicate observer dependency in terms of relative advantage of either system in the detection of lung nodules, but overall equivalency of the two methods with promising potential for BCI as an adjunct diagnostic technique.


The labeling problem in aphasia: an illustrative case.
Twenty-five "experts" on neurogenic motor speech disorders participated in a tutorial exercise. Each was given information on M, a patient who had communication difficulties as the result of stroke, and asked to complete a questionnaire about his problem. The information included a detailed case description, an audiotape of M's speech obtained at 4, 9, 13, and 17 days post-stroke, and test results from the Western Aphasia Battery, the Token Test, and a battery for apraxia of speech. The experts were in excellent agreement on M's primary problem, although it was called by seven different names. The experts were in poor agreement on his secondary problem(s), e.g., the presence and type of aphasia and dysarthria. The results suggest that labeling is difficult, even for "experts." Furthermore, the practicing clinician needs to be sensitive to the likelihood of more than one coexisting problem.


Bispectral index changes following etomidate induction of general anaesthesia and orotracheal intubation.
Etomidate-associated hypnosis has only been studied using standard clinical criteria and raw EEG variables. We conducted a BIS-based investigation of etomidate induction of general anaesthesia. Thirty hydroxyzine-premedicated ASA I patients were randomly allocated to receive etomidate 0.2, 0.3, or 0.4 mg kg(-1) intravenously over 30 s. The BIS was continuously recorded. A tourniquet was placed on a lower limb to record purposeful movements and myoclonia. Tracheal intubation was facilitated using rocuronium 0.6 mg kg(-1) when the BIS value was 50. The times to disappearance of the eyelash reflex, to a decrease in the BIS to 50, and to tracheal intubation were compared. The BIS values 30 s following tracheal intubation, and mean arterial pressure (MAP) and heart rate (HR) at all time points were also recorded. The BIS value decreased to 50 for tracheal intubation with no purposeful movement in all but one patient in the 0.2 mg kg(-1) group. There was no difference between the etomidate groups (0.2, 0.3, and 0.4 mg kg(-1)) in regards to time to loss of the eyelash reflex (103 (67), 65 (34), 116 (86) s, P=0.2), or to a decrease in BIS to 50 (135 (81), 82 (36), 150 (84) s, P=0.1). Also, the BIS value 30 s after intubation (41 (10), 37 (4), 37 (4), P=0.4), and plasma etomidate concentrations (161 [29-998], 308 [111-730], 310 [90-869] ng ml(-1), P=0.2) did not differ between groups. The time to loss of the eyelash reflex was 12-140 s shorter than the time to a decrease in BIS to 50 in three patients in each group who received etomidate 0.2 and 0.4 mg kg(-1), and in four patients who received 0.3 mg kg(-1). No awareness was recorded. MAP and HR increases following tracheal intubation were comparable between groups. Etomidate induction doses do not predict the time for BIS to decrease to 50 as this variable varies markedly following three etomidate dose regimen.


Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response.
Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 (NLR, nucleotide oligomerization domain-like receptor) inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we used an established nanotechnology capable of generating/releasing NO over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, although human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, tumor necrosis factor-α (TNF-α), IL-8, and IL-6 from human monocytes, and IL-8 and IL-6 from human keratinocytes, respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α nor IL-6 secretion, nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1β secretion was through inhibition of caspase-1 and IL-1β gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response.


Comparison of Control-IQ and open-source AndroidAPS automated insulin delivery systems in adults with type 1 diabetes: The CODIAC study.
To compare open-source AndroidAPS (AAPS) and commercially available Control-IQ (CIQ) automated insulin delivery (AID) systems in a prospective, open-label, single-arm clinical trial. Adults with type 1 diabetes who had been using AAPS by their own decision entered the first 3-month AAPS phase then were switched to CIQ for 3 months. The results of this treatment were compared with those after the 3-month AAPS phase. The primary endpoint was the change in time in range (% TIR; 70-80 mg/dL). Twenty-five people with diabetes (mean age 34.32 ± 11.07 years; HbA1c 6.4% ± 3%) participated in this study. CIQ was comparable with AAPS in achieving TIR (85.72% ± 7.64% vs. 84.24% ± 8.46%; P = .12). Similarly, there were no differences in percentage time above range (> 180 and > 250 mg/dL), mean sensor glucose (130.3 ± 13.9 vs. 128.3 ± 16.9 mg/dL; P = .21) or HbA1c (6.3% ± 2.1% vs. 6.4% ± 3.1%; P = .59). Percentage time below range (< 70 and < 54 mg/dL) was significantly lower using CIQ than AAPS. Even although participants were mostly satisfied with CIQ (63.6% mostly agreed, 9.1% strongly agreed), they did not plan to switch to CIQ. The CODIAC study is the first prospective study investigating the switch between open-source and commercially available AID systems. CIQ and AAPS were comparable in achieving TIR. However, hypoglycaemia was significantly lower with CIQ.


Spatial and temporal analysis of China's healthcare resource allocation measurements based on provincial data: 2010-2021.
With the development of society, industrialization, urbanization, aging, lifestyle and social transformation, environmental degradation, global warming and other factors have had a great impact on the health of the population, and there is an urgent need to take a series of practical actions to promote the improvement of national health. Among them, healthcare resource allocation plays a key role in advancing the level of national health, treatment of chronic diseases, and leisure and healthcare. This article collected panel data on healthcare resource allocation in all provinces of China from 2010 to 2021, and comprehensively applied Analytic Hierarchy Process, comprehensive scoring method, regional difference analysis and spatial autocorrelation analysis to reveal regional differences, spatial-temporal patterns and development characteristics of healthcare resource allocation in China. In terms of regional differences, intra-regional differences in healthcare resource allocation tend to narrow and inter-regional differences tend to widen. In terms of spatial pattern, the western provinces on the left side of the Hu Huanyong line generally have higher scores, while the central and eastern provinces on the right side of the Hu Huanyong line have lower scores, and healthcare resource allocation in the provinces on the left side of the Hu Huanyong line, such as Tibet, Xinjiang, Qinghai, Ningxia, Gansu, Inner Mongolia, Sichuan, have the spatial characteristics of HH clusters in terms of geographic location, while the southeast coastal provinces, such as Zhejiang, Fujian, Guangdong, Hainan, have the spatial characteristics of LL clusters in terms of geographic location. From the quadrant analysis, the 2010-2021 healthcare resource allocation in the first quadrant concentrates most of the provinces in the western and northeastern regions, while the third quadrant concentrates most of the provinces in the eastern region. The allocation of healthcare resources in China's four major zones has undergone a process of change from "unbalanced quantity to relatively balanced quantity," but high-quality healthcare resources are highly concentrated in the eastern part of the country, and the problem of contradiction between people and doctors is prominent. It is recommended that Internet plus healthcare technology be used to reshape the regional allocation of high-quality healthcare resources.


Infectious Bronchitis Virus Types Affecting European Countries-A Review.
Since its first detection in Europe in the 1940s, infectious bronchitis virus has continued to be one of the major respiratory pathogens affecting the European poultry industry. The development of effective and widely used vaccines for both broilers (live attenuated) and breeders and layers (live attenuated and inactivated) helped improve the health and welfare of poultry but never eliminated the problem. The main reason is the continual emergence of new infectious bronchitis variants (serotypes or genotypes). This review discusses the most prevalent genotypes of the last few decades in Europe. Some of these genotypes seem to be local European types; others have an origin outside Europe.


Characterising the prevalence of overweight and obese status among adults with sickle cell disease.
Individuals with sickle cell disease (SCD) have historically been considered underweight. Despite increasing body mass index (BMI) in the general population, the prevalence of overweight and obese status remains unclear in the adult SCD population. Our primary aim was to determine the prevalence of overweight and obese status and to identify associations between BMI, demographic, and clinical characteristics. We conducted an analysis of abstracted electronic health record data and patient-reported outcomes from the Sickle Cell Disease Implementation Consortium registry; individuals aged 20-45 years were included. The median (interquartile range) BMI for the 1664 adults in this analysis was 23.9 (21.1-28) kg/m2 . In this cohort, 42.9% had a BMI of >25 kg/m2 (Centers for Disease Control and Prevention definition of overweight/obese). In multivariable analysis, higher odds of being overweight or obese were associated with female gender, older age, college education, private insurance, and hypertension diagnosis. Higher odds of a BMI of >25 kg/m2 were observed in individuals with HbSC or HbSβ+ thalassaemia regardless of hydroxycarbamide (hydroxyurea) exposure (odds ratio [OR] 3.4, p < 0.0001) and HbSS or HbSβ0 thalassaemia exposed to hydroxycarbamide (OR 1.6, p = 0.0003) compared to those with HbSS or HbSβ0 thalassaemia with no hydroxycarbamide exposure. These data highlight the importance of early identification, prevention, and intervention for increasing BMI to reduce obesity-related complications that may impact SCD-related complications.


saltPAD: A New Analytical Tool for Monitoring Salt Iodization in Low Resource Settings.
We created a paper test card that measures a common iodizing agent, iodate, in salt. To test the analytical metrics, usability, and robustness of the paper test card when it is used in low resource settings, the South African Medical Research Council and GroundWork performed independent validation studies of the device. The accuracy and precision metrics from both studies were comparable. In the SAMRC study, more than 90% of the test results (n=1704) were correctly classified as corresponding to adequately or inadequately iodized salt. The cards are suitable for market and household surveys to determine whether salt is adequately iodized. Further development of the cards will improve their utility for monitoring salt iodization during production.


MR of the submandibular gland: normal and pathologic states.
To evaluate the MR appearance of normal and pathologic states of the submandibular gland. MR images of 22 healthy subjects and 21 patients with histopathologically confirmed disorders of the submandibular gland (five pleomorphic adenomas, two hemangiomas, two malignant lymphomas, one adenoid cystic carcinoma, one squamous cell carcinoma, and 10 cases of sialadenitis) were reviewed. All normal submandibular glands showed higher signal intensity than surrounding muscle but lower intensity than fat on T1-weighted and T2-weighted images. Postcontrast images showed moderate enhancement of the gland. All the tumors had lower signal intensity than the normal submandibular gland on T1-weighted images and had intermediate to high (n = 8) or high (n = 3) signal intensity relative to the normal submandibular gland on T2-weighted images. Six of seven benign tumors were well defined, and three of four malignant tumors were poorly defined. In all cases of sialadenitis, the submandibular gland showed diffusely different signal intensities from the normal gland on both T1-weighted and T2-weighted images. Eight cases of chronic sialadenitis showed lower T2-weighted signal intensities than the normal gland, and this can be explained histopathologically by marked fibrosis and cellular infiltration. MR imaging can show the presence, extent, margins, and signal intensity changes of pathologic conditions of the submandibular gland.


Injectable scaffolds for bone regeneration.
Clinical treatments of significant bone defects involve invasive procedures such as the application of auto- and allografts. These procedures present many limitations including the potential for infection and rejection. There is therefore a need to develop novel therapeutic strategies able to exploit the natural regenerative potential of bone and that can be delivered in a less invasive manner. Among the materials studied for the development of novel scaffolds, stimuli-responsive gels containing hydroxyapatite and carbon nanotubes as nanofillers have generated great interest. In the present work, chitosan gels containing chitosan grafted CNTs and chitosan-hydroxyapatite complex have been formed by cross-linking with glycerol phosphate. The addition of the nanofillers afforded hydrogels with a faster sol/gel transition at 37 °C and enhanced mechanical properties. The thermosensitive composite gels also showed a good bioactivity profile associated with potential for the prolonged delivery of protein drugs. The inclusion of chemically cross-linked CNTs and HA in thermosensitive gels afforded injectable composite materials with enhanced properties, including reduction of gelation time, improved mechanical properties, good bioactivity, and prolonged drug release.


Mechanism for the Extremely Efficient Sensitization of Yb3+Luminescence in CsPbCl3 Nanocrystals.
Rare earth ion (RE3+)-doped inorganic CsPbX3 (X = Cl or Cl/Br) nanocrystals have been presented as promising materials for applications in solar-energy-conversion technology. An extremely efficient sensitization of Yb3+ luminescence in CsPbCl3 nanoparticles (NCs) was very recently demonstrated where quantum cutting is responsible for the performance of photoluminescence quantum yields over 100% ( T. J. Milstein, et al. Nano Letters 2018 , 18 , 3792 ). In the present work, based on the cubic phase of inorganic perovskite, we seek to obtain atom-level insight into the basic mechanisms behind these observations in order to boost the further development of RE3+-doped CsPbX3 NCs for optoelectronics. In our calculations of cubic crystal structure, we do not find any energy level formed in the middle of the band gap, which disfavors a mechanism of stepwise energy transfer from the perovskite host to two Yb3+ ions. Our work indicates that the configuration with "right-angle" Yb3+-VPb-Yb3+ couple is most likely to form in Yb3+-doped CsPbCl3. Associated with this "right-angle" couple, the "right-angle" Pb atom with trapped excited states would localize the photogenerated electrons and act as the energy donor in a quantum cutting process, which achieves simultaneous sensitization of two neighboring Yb3+ ions.


Novel simple insulin delivery device reduces barriers to insulin therapy in type 2 diabetes: results from a pilot study.
The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. This single-center, open-label, single-arm study comprised three 2-week periods: baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Validated questionnaires were administered during the baseline and PaQ treatment periods: Barriers to Insulin Treatment questionnaire (BIT), Insulin Treatment Appraisal Scale (ITAS), and Problem Areas in Diabetes scale (PAID). Eighteen patients (age 59 ± 5 years, diabetes duration 15 ± 7 years, 21% female, HbA1c 7.7 ± 0.7%) completed the questionnaires. There was a strong, significant effect of PaQ use in mean BIT total scores (difference [D] = -5.4 ± 0.7.7, P = .01, effect size [d] = 0.70). Patients perceived less stigmatization by insulin injection (D = -2.2 ± 6.2, P = .18, d = 0.35), increased positive outcome (D = 1.9 ± 6.6, P = .17, d = 0.29), and less fear of injections (1.3 ± 4.8, P = .55, d = 0.28). Mean change in ITAS scores after PaQ device use showed a nonsignificant improvement of 1.71 ± 5.63 but moderate effect size (d = 0.30, P = .14). No increase in PAID scores was seen. The results and moderate to large effects sizes suggest that PaQ device use has beneficial and clinically relevant effects to overcoming barriers to and negative appraisal of insulin treatment, without increasing other diabetes-related distress.


Protective role of protocatechuic acid in sevoflurane-induced neuron apoptosis, inflammation and oxidative stress in mice.
In neonatal mice, sevoflurane, inspired through the nasal cavity to act as anesthesia, triggers neuronal apoptosis, inflammation and oxidative injury that can hamper cognitive functions in the growth of the central nervous system in the later stages of life. Our study aimed to explore the potential neuroprotective effects of protocatechuic acid (PCA) to ameliorate neonatal sevoflurane-induced neurotoxicity. Male mice were pretreated with PCA (10 or 20 mg/kg) for half an hour before continuous treatment for 6 h with 3 % sevoflurane. TUNEL staining was performed to examine the apoptotic cells to record their count. ELISA was performed to evaluate the expressions of the proteins - IL-1β, IL-18 and TNF-α. Analysis of the Western blot and test of the Morris maze was determined and the results analyzed. TUNEL findings assay showed a significant reduction with sevoflurane in neuronal apoptosis treated with PCA at 20 mg/kg. The expression of protein Caspase-3 showed significant changes in the group SEV + PCA (20 mg/kg). ELISA analysis showed that the levels of IL-18 and TNF-α were significantly reduced in the SEV + PCA (20 mg/kg) group as compared to SEV + PCA (10 mg/kg) group. MDA, ROS and SOD levels were noted to decrease significantly only in the SEV + PCA group (20 mg/kg) while IL-1β levels decreased in both SEV + PCA groups (10 or 20 mg/kg) respectively. Our findings imply that apoptosis, inflammation, and oxidative stress in the hippocampal region of neonatal mouse brain were significantly reduced by pre-treatment with PCA before sevoflurane exposure. Therefore, suggesting a role for PCA as a novel therapeutic agent in the treatment of sevoflurane anesthesia-induced neurobehavioral dysfunction.


Intrinsic and synaptic mechanisms determining the timing of neuron population activity during hippocampal theta oscillation.
Hippocampal theta (3-8 Hz) is a major electrophysiological activity in rodents, which can be found in primates and humans as well. During theta activity, pyramidal cells and different classes of interneurons were shown to discharge at different phases of the extracellular theta. A recent in vitro study has shown that theta-frequency oscillation can be elicited in a hippocampal CA1 slice by the activation of metabotropic glutamate receptors with similar pharmacological and physiological profile that was found in vivo. We constructed a conductance based three-population network model of the hippocampal CA1 region to study the specific roles of neuron types in the generation of the in vitro theta oscillation and the emergent network properties. Interactions between pairs of neuron populations were studied systematically to assess synchronization and delay properties. We showed that the circuitry consisting of pyramidal cells and two types of hippocampal interneurons [basket and oriens lacunosum-moleculare (O-LM) neurons] was able to generate coherent theta-frequency population oscillation. Furthermore, we found that hyperpolarization-activated nonspecific cation current in pyramidal cells, but not in O-LM neurons, plays an important role in the timing of spike generation, and thus synchronization of pyramidal cells. The model was shown to exhibit the same phase differences between neuron population activities found in vivo, supporting the idea that these patterns of activity are determined internal to the hippocampus.


Co-assembly of GABA rho subunits with the GABA(A) receptor gamma(2) subunit cloned from white perch retina.
Although it is well established that GABA(C) receptors are comprised in part of GABA rho subunits, the exact subunit composition of neuronal GABA(C) receptors is yet to be determined. A detailed comparison of GABA(C)-mediated neuronal responses elicited from retinal neurons with those obtained from receptors formed by GABA rho subunits revealed a number of significant differences both in the kinetics and the pharmacology of the responses. Our previous studies indicated that the human GABA(A) receptor gamma(2) subunit could co-assemble with one (rho(1B)) of the white perch GABA rho subunits to form a heterooligomeric receptor with properties that resembled those of the GABA(C) receptors on white perch bipolar cells. In this study, we cloned the white perch gamma(2) subunit, and investigated its co-assembly with four white perch GABA rho subunits. When expressed in Xenopus oocytes, perch gamma(2) and rho(1B) subunits form heterooligomeric receptors with distinct properties: the GABA-elicited responses have fast kinetics and are sensitive to pentobarbital modulation. The enhancement of GABA-elicited responses by pentobarbital on the heterooligomeric receptors could be eliminated by a single mutation in the third transmembrane domain of the gamma(2) subunit, indicating that pentobarbital sensitivity is mediated by the incorporated gamma(2) subunit. On the other hand, co-expression of the perch gamma(2) subunit with the other perch GABA rho subunits produced no detectable changes in the kinetics of GABA-elicited response or the sensitivity to pentobarbital modulation. These results suggest that the gamma(2) subunit can co-assemble only with one (rho(1B)), but not with other white perch GABA rho subunits.


Identification of glutathione conjugates of acetylene-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.
A recent medicinal chemistry campaign to identify positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) led to the discovery of potent compounds featuring an oxazolidinone structural core flanked by biaryl acetylene and haloaryl moieties. However, biotransformation studies of some of these mGluR5 PAMs demonstrated the formation of glutathione (GSH) conjugates. The conjugates in question were formed independently of NADPH as the main products in liver microsomes and liver cytosol (rat and human) and exhibited masses that were 307 u greater than their respective substrates, indicating the involvement of a reductive step in the formation of these metabolites. To further characterize the relevant metabolic sequences, GSH conjugates of (4R,5R)-5-(3-fluorophenyl)-4-(5-(pyrazin-2-ylethynyl)pyridin-3-yl)oxazolidin-2-one and (4R,5R)-5-(4-fluorophenyl)-4-(6-((3-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)oxazolidin-2-one were biosynthesized and isolated. Subsequent analysis by NMR showed that GSH had reacted with the acetylene carbon atoms of these mGluR5 PAMs, suggesting a conjugate addition mechanism and implicating cytosolic and microsomal GSH S-transferases (GSTs) in catalysis. Interestingly, five closely related mGluR5 PAMs were not similarly prone to the formation of GSH conjugates in vitro. These compounds also featured acetylenes, but were flanked by either phenyl or cyclohexyl rings, which indicated that the formation of GSH conjugates was influenced by proximal functional groups that modulated the electron density of the triple bond and/or differences in enzyme-substrate specificity. These results informed an ongoing drug-discovery effort to identify mGluR5 PAMs with drug-like properties and a low risk of reactivity with endogenous thiols.


Restudy of shoulder motion in the theropod dinosaur Mononykus olecranus (Alvarezsauridae).
Range of motion in the forelimb of the Upper Cretaceous theropod dinosaur Mononykus olecranus, a member of the family Alvarezsauridae, has previously been investigated. However, the method used to investigate range of motion at the shoulder in M. olecranus did not follow the standardized procedure used in subsequent studies. The latter procedure yields more reliable results, and its standardization provides that its results are directly comparable to the results of similar studies in other species. I therefore reinvestigated the range of motion at the shoulder in M. olecranus, using the latter procedure. Casts of the left scapula and coracoid of M. olecranus were posed on a horizontal surface, supported from beneath with modeling clay, with the medial surface of the scapula facing toward the horizontal surface. A cast of the left humerus was posed at the limits of motion through the transverse and parasagittal planes. Photos of the poses in orthal views were superimposed and used to measure range of motion, which was measured as the angle between lines drawn down the long axis of the humerus in each position. Through the transverse plane, the humerus of M. olecranus could be elevated to a subhorizontal position and depressed to a subvertical position. It could move through the parasagittal plane from a subvertical position at full protraction to a position above the horizontal at full retraction. These results correct the previous mischaracterization of shoulder motion in M. olecranus as restricted to a small arc with the arms held in a permanent sprawl. The range of humeral motion in M. olecranus is much greater than that found by the previous method and allowed the animal to tuck its arms in at the sides, in addition to allowing them to sprawl so as to orient the palm downward. The wide range of humeral motion allowed M. olecranus to forage for insects by employing hook-and-pull digging at surfaces with a wider range of orientations than the previous study showed to be possible.


[Preoperative 2-stage UHF-hyperthermia in combination with single-stage irradiation in breast cancer].
The authors described a method of two-stage UHF-hyperthermia combined with single irradiation of the breast prior to operation. At the 1st stage the temperature was 39 degrees C, duration of exposure 30 min directly before irradiation, irradiation at a dose of 13 Gy. The 2nd stage followed 2 h after irradiation, the temperature was 42 degrees C, duration 90 min. The above therapy did not deteriorate the conditions of surgical intervention, nor did it complicate a postoperative course. Local and general reactions were of transient nature. No recurrences were noted after 1 year of follow-up. A study of tumor pathomorphosis showed injuries of I degree in 30.8%, II degree in 46.2%, III degree in 5.6%, in single irradiation in 18, 8.4 and 2.8%, respectively.


Exploring trauma and wellbeing of people who use drugs after witnessing overdose: A qualitative study.
The national overdose crisis is often quantified by overdose deaths, but understanding the traumatic impact for those who witness and respond to overdoses can help elucidate mental health needs and opportunities for intervention for this population. Many who respond to overdoses are people who use drugs. This study adds to the literature on how people who use drugs qualitatively experience trauma resulting from witnessing and responding to overdose, through the lens of the Trauma-Informed Theory of Individual Health Behavior. We conducted 60-min semi-structured, in-depth phone interviews. Participants were recruited from six states and Washington, DC in March-April 2022. Participants included 17 individuals who witnessed overdose(s) during the COVID-19 pandemic. The interview guide was shaped by theories of trauma. The codebook was developed using a priori codes from the interview guide; inductive codes were added during content analysis. Transcripts were coded using ATLAS.ti. A vast majority reported trauma from witnessing overdoses. Participants reported that the severity of trauma varied by contextual factors such as the closeness of the relationship to the person overdosing or whether the event was their first experience witnessing an overdose. Participants often described symptoms of trauma including rumination, guilt, and hypervigilance. Some reported normalization of witnessing overdoses due to how common overdoses were, while some acknowledged overdoses will never be "normal." The impacts of witnessing overdose on drug use behaviors varied from riskier substance use to increased motivation for treatment and safer drug use practices. Recognizing the traumatic impact of witnessed overdoses is key to effectively addressing the full range of sequelae of the overdose crisis. Trauma-informed approaches should be central for service providers when they approach this subject with clients, with awareness of how normalization can reduce help-seeking behaviors and the need for psychological aftercare. We found increased motivation for behavior change after witnessing, which presents opportunity for intervention.


Type-specific antibodies to purified streptococcal M proteins from potentially rheumatogenic M-types in patients with rheumatic fever and rheumatic heart disease.
This study was designed to identify the predominant serotypes of group A streptococci (GAS) responsible for rheumatic fever (RF) and rheumatic heart disease (RHD) in India. RF and RHD sera were screened for antibodies to M proteins retrospectively against known rheumatogenic M types and M types isolated from patients with acute RF. All GAS strains isolated from four patients with acute RF in a short outbreak of RF, were identical - serum opacity factor (SOF) negative, T-pattern 3/13 B3264 and M-non-typable. Because of this, M protein was isolated from only one of these four M-non-typable strain (S-399). This was done by limited pepsin digestion and purification by ion-exchange chromatography on DEAE-Sephadex, followed by gel filtration. Purified M protein was found to be homologous on SDS-PAGE (mol.wt 20 kDa), immunogenic in rabbits and to retain its antigenic structure. This purified M protein from an M-non-typable strain (pep-MNT) was used as an antigen to screen RF and RHD sera retrospectively by ELISA for the prevalence of the M-non-typable GAS strain. The prevalence of the M-non-typable strain was compared with that of the known rheumatogenic M types. Results suggest that the M-non-typable strain could be a provisional new rheumatogenic M type in India and could be a candidate for a multivalent M-protein vaccine to control RF and RHD.


Impact of N-terminal myristoylation on the Ca2+-dependent conformational transition in recoverin.
Recoverin is a Ca2+-regulated signal transduction modulator found in vertebrate retina that has been shown to undergo dramatic conformational changes upon Ca2+ binding to its two functional EF-hand motifs. To elucidate the differential impact of the N-terminal myristoylation as well as occupation of the two Ca2+ binding sites on recoverin structure and function, we have investigated a non-myristoylated E85Q mutant exhibiting virtually no Ca2+ binding to EF-2. Crystal structures of the mutant protein as well as the non-myristoylated wild-type have been determined. Although the non-myristoylated E85Q mutant does not display any functional activity, its three-dimensional structure in the presence of Ca2+ resembles the myristoylated wild-type with two Ca2+ but is quite dissimilar from the myristoylated E85Q mutant. We conclude that the N-terminal myristoyl modification significantly stabilizes the conformation of the Ca2+-free protein (i.e. the T conformation) during the stepwise transition toward the fully Ca2+-occupied state. On the basis of these observations, a refined model for the role of the myristoyl group as an intrinsic allosteric modulator is proposed.


Effect of ketanserin in the treatment of patients with intermittent claudication: results from 13 placebo-controlled parallel group studies.
The effect of ketanserin on intermittent claudication was assessed in 13 placebo-controlled parallel group studies following basically the same protocol. After a single-blind placebo run-in period of 1-2 months, the patients randomly received either ketanserin (n = 152) or placebo (n = 158) for 3-6 months. Data on walking distance, assessed on the treadmill, were available in 12 centers (239 patients). Walking distance significantly increased in seven centers with ketanserin and in two centers with placebo. In two centers, the intergroup comparison between ketanserin and placebo was significantly in favor of ketanserin; in one center, it was in favor of placebo. A pooled analysis of all data on walking distance showed that ketanserin significantly increased walking distance by 65%, whereas placebo significantly increased it by 25%. However, the intergroup comparison does not show significant differences. Comparison of individual responses, on the other hand, showed that more patients experienced a doubling of walking distance on ketanserin than on placebo (25 versus 13%), and fewer patients deteriorated on ketanserin than on placebo (23 versus 32%); this difference in response rate is significant (p less than 0.05). In these studies there was a striking difference in drop-out rate between ketanserin and placebo. In total, 25 patients dropped out during placebo treatment versus 14 during ketanserin treatment. Nine of the 25 dropouts on placebo suffered severe "cardiovascular events," whereas no such events were observed in the ketanserin group. This difference is highly significant and suggests that ketanserin may have a vascular protective effect in patients with intermittent claudication. This possibility is being investigated in a prospective trial (PACK trial).


Adhesion of Microdroplets on Water-Repellent Surfaces toward the Prevention of Surface Fouling and Pathogen Spreading by Respiratory Droplets.
Biofouling caused by the adhesion of respiratory microdroplets generated in sneezing and coughing plays an important role in the spread of many infectious diseases. Although water-repellent surfaces are widely used for the long-term repellency of aqueous solutions, their repellency to pathogen-containing microdroplets is elusive. In this work, microdroplets from picoliter to nanoliter were successfully generated in a controlled manner to mimic the exhaled microdroplets in sneezing and coughing, which allowed us to evaluate the adhesion of microdroplets on both superhydrophobic and lubricant-infused "slippery" surfaces for the first time. The impact and retention of water microdroplets on the two water-repellent surfaces are compared and investigated. Microdroplet-mediated surface biofouling and pathogen transmission were also demonstrated. Our results suggested that the adhesion of microdroplets should be duly considered in the design and application of water-repellent surfaces on biofouling prevention.


Diagnosis and management of diabetic retinopathy.
More frequent testing may sometimes be required, but annual comprehensive eye examinations generally seem best for uncovering early diabetic retinopathy and initiating treatment. Prevention and stabilization may be aided by tightly controlled diabetes.


The Dirichlet Dual Response Model: An Item Response Model for Continuous Bounded Interval Responses.
Standard response formats such as rating or visual analogue scales require respondents to condense distributions of latent states or behaviors into a single value. Whereas this is suitable to measure central tendency, it neglects the variance of distributions. As a remedy, variability may be measured using interval-response formats, more specifically the dual-range slider (RS2). Given the lack of an appropriate item response model for the RS2, we develop the Dirichlet dual response model (DDRM), an extension of the beta response model (BRM; Noel & Dauvier in Appl Psychol Meas, 31:47-73, 2007). We evaluate the DDRM's performance by assessing parameter recovery in a simulation study. Results indicate overall good parameter recovery, although parameters concerning interval width (which reflect variability in behavior or states) perform worse than parameters concerning central tendency. We also test the model empirically by jointly fitting the BRM and the DDRM to single-range slider (RS1) and RS2 responses for two Extraversion scales. While the DDRM has an acceptable fit, it shows some misfit regarding the RS2 interval widths. Nonetheless, the model indicates substantial differences between respondents concerning variability in behavior. High correlations between person parameters of the BRM and DDRM suggest convergent validity between the RS1 and the RS2 interval location. Both the simulation and the empirical study demonstrate that the latent parameter space of the DDRM addresses an important issue of the RS2 response format, namely, the scale-inherent interdependence of interval location and interval width (i.e., intervals at the boundaries are necessarily smaller).


Expression of the EGFR-RAS Inhibitory Proteins DOK1 and MTMR7 and its Significance in Colorectal Adenoma and Adenoma Recurrence.
Colorectal adenomas are precursor lesions for colorectal cancer (CRC), a major cause of cancer-related death. Despite all molecular insights, there are still unknown variables in the development of CRC as well as uncertainties regarding adenoma recurrence after resection. We aimed to characterize the expression of docking protein 1 (DOK1) and myotubularin-related protein 7 (MTMR7), which share inhibiting functions on EGFR-RAS-signalling, a major oncogenic driver in CRC, and their association with clinical variables and adenoma recurrence. This observational study is based on clinical data obtained from patients who underwent routine endoscopy and consecutive follow-up examinations. Immunohistochemistry was conducted both in dysplastic tissue and adjacent non-dysplastic mucosa followed by microscopical assessment. Recurrence was differentiated between local, segmental and distant relapse. A total of 56 patients (23 females) gathering 96 adenomas/polyps were included. 36 patients experienced a metachronous lesion, 23 patients had simultaneous lesions in their index endoscopy. Female patients showed lower levels of MTMR7 in adenomas (p=0.0318). Adenomas of young patients showed lower DOK1 than those of older patients (p=0.0469). Big adenomas showed a higher expression of DOK1 than small lesions (p=0.0044). In serrated lesions, DOK1 was reduced (p=0.0026) and correlated with the quantity of lesions (p < 0.001). MTMR7 was significantly reduced in distant (p=0.05) and local segmental recurrence (p=0.0362), while DOK1 showed higher expression in recurrence (p=0.0291). We found ambivalent results regarding the role of the markers as potential tumor suppressors, implying a context-dependent function of these molecules which might change in the course of time. DOK1 may play an inhibiting role in the serrated pathway. Remarkably, molecular markers have the potential to predict recurrence, since a combined expression analysis of high DOK1 and low MTMR7 correlated with the likelihood of segmental adenoma recurrence.


Collagenase-3 (MMP-13) is expressed in periapical lesions: an immunohistochemical study.
To determine whether or not matrix metalloproteinase 13 (MMP-13) is present in periapical granulomas with and without epithelium. Seventeen open periapical granulomas of pulpal origin (seven lesions without epithelium and 10 with proliferating epithelium) were fixed in formalin and then embedded in paraffin prior to being processed for immunohistochemical analysis. A monoclonal antibody against human MMP-13 was used to evaluate MMP-13 expression. Immunocomplexes were subsequently treated with the secondary antibody and then detected by means of streptavidin peroxidase. Immunoreactivity was visualized by development with 3,3'-diaminobenzidine. An immunopositive cytoplasmatic reaction for MMP-13 was observed in all the specimens, although the immunostaining by anti-MMP-13 antibody was heterogeneous and its levels varied according to histopathological findings. In periapical lesions without epithelium MMP-13 immunolabelling was detected in a few fibroblast-like cells, and in some plasma cells within the granulomatous tissue. A clear upregulation of MMP-13 expression was detected in periapical lesions with epithelium, especially in small island and thin strands of epithelium. The expression pattern of MMP-13 demonstrates that it is involved in the conversion of a periapical granuloma with epithelium into a radicular cyst. This property is related to the ability of MMP-13 to influence not only the migration of epithelial cell but also the invasion of granulomatous tissue.


Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2.
Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate the clinical management, even lead to death. Silibinin is a flavonoid antioxidant and wildly used for its antihepatotoxic properties and recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of silibinin. In this study, we first observed that silibinin exerted a dose- and time-dependent inhibitory effect on the invasion and motility, but hardly on the adhesion, of highly metastatic A549 cells in the absence of cytotoxicity. To look at the precise involvement of silibinin in cancer metastasis, A549 cells were treated with silibinin at various concentrations, up to 100 microM, for a defined period and then subjected to gelatin zymography, casein zymography and Western blot to investigate the impacts of silibinin on metalloproteinase-2 (MMP-2), urokinase plasminogen activator (u-PA), and tissue inhibitor of metalloproteinase-2 (TIMP-2), respectively. The results showed that a silibinin treatment may decrease the expressions of MMP-2 and u-PA in a concentration- and time-dependent manner and enhance the expression of TIMP-2. Further analysis with semi-quantitative RT-PCR showed that silibinin may regulate the expressions of MMP-2 and u-PA on the transcriptional level while on the translational or post-translational level for TIMP-2.


Synthetic MRI for Clinical Neuroimaging: Results of the Magnetic Resonance Image Compilation (MAGiC) Prospective, Multicenter, Multireader Trial.
Synthetic MR imaging enables reconstruction of various image contrasts from 1 scan, reducing scan times and potentially providing novel information. This study is the first large, prospective comparison of synthetic-versus-conventional MR imaging for routine neuroimaging. A prospective multireader, multicase noninferiority trial of 1526 images read by 7 blinded neuroradiologists was performed with prospectively acquired synthetic and conventional brain MR imaging case-control pairs from 109 subjects (mean, 53.0 ± 18.5 years of age; range, 19-89 years of age) with neuroimaging indications. Each case included conventional T1- and T2-weighted, T1 and T2 FLAIR, and STIR and/or proton density and synthetic reconstructions from multiple-dynamic multiple-echo imaging. Images were randomized and independently assessed for diagnostic quality, morphologic legibility, radiologic findings indicative of diagnosis, and artifacts. Clinical MR imaging studies revealed 46 healthy and 63 pathologic cases. Overall diagnostic quality of synthetic MR images was noninferior to conventional imaging on a 5-level Likert scale (P < .001; mean synthetic-conventional, -0.335 ± 0.352; Δ = 0.5; lower limit of the 95% CI, -0.402). Legibility of synthetic and conventional morphology agreed in >95%, except in the posterior limb of the internal capsule for T1, T1 FLAIR, and proton-density views (all, >80%). Synthetic T2 FLAIR had more pronounced artifacts, including +24.1% of cases with flow artifacts and +17.6% cases with white noise artifacts. Overall synthetic MR imaging quality was similar to that of conventional proton-density, STIR, and T1- and T2-weighted contrast views across neurologic conditions. While artifacts were more common in synthetic T2 FLAIR, these were readily recognizable and did not mimic pathology but could necessitate additional conventional T2 FLAIR to confirm the diagnosis.


Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis: the AMBITION study.
Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo. Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration. C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01). Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points. ClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.


Bioavailability of Isothiocyanates From Broccoli Sprouts in Protein, Lipid, and Fiber Gels.
Optimization of bioavailability of dietary bioactive health-beneficial compounds is as important as increasing their concentration in foods. The aim of this study is to explore the change in bioavailability of isothiocyanates (ITCs) in broccoli sprouts incorporated in protein, fiber, and lipid gels. Five participants took part in a cross-over study and collected timed urine samples up to 24 h after consumption of proteins, dietary fibers, and lipid gels containing broccoli sprouts powder. Sulforaphane and iberin metabolites were determined in the urine samples. Samples in which sulforaphane and iberin were preformed by myrosinase led to a higher bioavailability of those compounds. Compared to the control broccoli sprout, incorporation of sprouts in gels led to lower bioavailability for preformed sulforaphane and iberin (although for sulforaphane the lower bioavailability was not significantly different) whereas for the gels rich in their precursors, glucoraphanin and glucoiberin, the opposite trend was observed (although not significantly different). This explorative study suggests that ITCs bioavailability can be modulated by food structure and composition and further and deeper investigations are needed to develop food products that lead to an optimized ITCs bioavailability.


Growth factors in critical illness: regulation and therapeutic aspects.
The erosion of lean body mass observed during catabolic illness is still a major cause of morbidity and mortality. The known anabolic actions of growth hormone and insulin-like growth factor-I have stimulated interest in the use of these agents to mitigate the loss of muscle protein after injury. This review summarizes advances in our understanding of how nutrition, hormones and proinflammatory cytokines regulate the somatotropic axis in health and disease, and recent studies involving the use of growth hormone or insulin-like growth factor-I in the treatment of critically ill patients.


Melatonin: a pleiotropic molecule regulating inflammation.
Melatonin is a neurohormone produced by the pineal gland that regulates sleep and circadian functions. Melatonin also regulates inflammatory and immune processes acting as both an activator and inhibitor of these responses. Melatonin demonstrates endocrine, but also paracrine and autocrine effects in the leukocyte compartment: on one side, leukocytes respond to melatonin in a circadian fashion; on the other side, leukocytes are able to synthesize melatonin by themselves. With its endocrine and paracrine effects, melatonin differentially modulates pro-inflammatory enzymes, controls production of inflammatory mediators such as cytokines and leukotrienes and regulates the lifespan of leukocytes by interfering with apoptotic processes. Moreover, its potent antioxidant ability allows scavenging of oxidative stress in the inflamed tissues. The interesting timing of pro- and anti-inflammatory effects, such as those affecting lipoxygenase activity, suggests that melatonin might promote early phases of inflammation on one hand and contribute to its attenuation on the other hand, in order to avoid complications of chronic inflammation. This review aims at giving a comprehensive overview of the various inflammatory pathways regulated by this pleiotropic hormone.


Articulatory constraints on spontaneous entrainment between speech and manual gesture.
The present study examined the extent to which speech and manual gestures spontaneously entrain in a non-communicative task. Participants had to repeatedly utter nonsense /CV/ syllables while continuously moving the right index finger in flexion/extension. No instructions to coordinate were given. We manipulated the type of syllable uttered (/ba/ vs. /sa/), and vocalization (phonated vs. silent speech). Assuming principles of coordination dynamics, a stronger entrainment between the fingers oscillations and the jaw motion was predicted (1) for /ba/, due to expected larger amplitude of jaw motion and (2) in phonated speech, due to the auditory feedback. Fifteen out of twenty participants showed simple ratios of speech to finger cycles (1:1, 1:2 or 2:1). In contrast with our predictions, speech-gesture entrainment was stronger when vocalizing /sa/ than /ba/, also more widely distributed on an in-phase mode. Furthermore, results revealed a spatial anchoring and an increased temporal variability in jaw motion when producing /sa/. We suggested that this indicates a greater control of the speech articulators for /sa/, making the speech performance more receptive to environmental forces, resulting in the greater entrainment observed to gesture oscillations. The speech-gesture coordination was maintained in silent speech, suggesting a somatosensory basis for their endogenous coupling.


Focusing on surgery results in infertile patients with deep endometriosis.
Infertility is a common problem in patients with endometriosis and the involved mechanisms are still not completely known. The management of infertility in endometriosis patients includes surgery as well as assisted reproductive technology. Laparoscopic surgery has shown better results in infertility patients with endometriosis in comparison to laparotomy procedures. Laparoscopic surgery has proposed benefits in both minimal to moderate diseases. However, while there may be some benefits with severe diseases, there is still not enough evidence to recommend laparoscopic surgery as the recommended surgery when the main goal is to obtain fertility. We performed a MEDLINE search for articles on fertility in women with deep infiltrating endometriosis (DIE) published between 1990 and April 2015 using the following keywords: "endometriosis", "deep infiltrative endometriosis", "infertility", "fertility after surgery", "laparoscopy surgery", "laparotomy", "pregnancy", "fertility outcome", "bladder endometriosis", and "ureteral endometriosis". The aim of this review was to analyze the results of available clinical studies (randomized controlled or not controlled studies; retrospective cohort studies; or case-control and prospective studies) and guidelines on surgical treatment of infertile endometriosis patients, and pregnancy outcomes after surgery.


Assessment of a new Goldmann applanation tonometer.
The classic Goldmann applanation tonometer (GAT) has been further developed by Haag-Streit International. The applanation principle has been retained, while the internal force transmission and the pressure gauging have been optimised, the display of results digitised. The authors compared the GAT standard with the new GAT digital. Four fixed tonometer pairs were used. The protocol included: non-contact pachymetry, slit-lamp examination, three consecutive measurements with each tonometer with a 5 min interval in between, check for side effects in 15 min. Three groups (intraocular pressure (IOP) levels) were defined: (1) IOP ≤ 16; (2) IOP>16 and <23; (3) IOP ≥ 23 mm Hg. 125 Patients (250 eyes) were evaluated. IOP (mm Hg), GAT standard versus GAT digital, for the rights eyes was: Group 1: 12.94 ± 0.55 versus 13.11 ± 0.53, p=0.71. Group 2: 18.26 ± 0.59 versus 18.03 ± 0.52, p=0.53; Group 3: 30.28 ± 0.48 versus 30.42 ± 0.41, p=0.97; all right eyes: 17.48 ± 7.48 versus 17.73 ± 7.4, p=0.99. For the left eyes, there was no significant difference, either. The correlation was very good and was not influenced by the IOP level. The Pearson coefficient for the right eye was 0.985, and for the left eye 0.994. In the Bland-Altman analysis, although there were two single readings that differed by as much as 5 mm Hg, GAT digital measures showed almost no skew, and the mean difference was 0.03 ± 1.23 mm Hg (n=250). A multiple regression analysis showed no influence of order of measurement, eyeside or pachymetry. The new GAT digital is as reliable and safe as GAT standard. IOP values correlate well. It offers a digitised display and a wireless transfer of data. The display of values up to the first decimal digit is not necessarily associated with a more precise measurement, but may offer an additional comfort compared with the 2 mm Hg scale of the classic GAT.


Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12).
To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: -8.59 [95% CI -10.20; -7.00]). Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. NCT01959529 (ClinicalTrials.gov).


Preexisting hypertension and pregnancy-induced hypertension reveal molecular differences in placental proteome in rodents.
Preexisting or new onset of hypertension affects pregnancy and is one of the leading causes of maternal and fetal morbidity and mortality. In certain cases, it also leads to long-term maternal cardiovascular complications. The placenta is a key player in the pathogenesis of complicated hypertensive pregnancies, however the pathomechanisms leading to an abnormal placenta are poorly understood. In this study, we compared the placental proteome of two pregnant hypertensive models with their corresponding normotensive controls: a preexisting hypertension pregnancy model (stroke-prone spontaneously hypertensive rats; SHRSP) versus Wistar-Kyoto and the transgenic RAS activated gestational hypertension model (transgenic for human angiotensinogen Sprague-Dawley rats; SD-PE) versus Sprague-Dawley rats, respectively. Label-free proteomics using nano LC-MS/MS was performed for identification and quantification of proteins. Between the two models, we found widespread differences in the expression of placental proteins including those related to hypertension, inflammation, and trophoblast invasion, whereas pathways such as regulation of serine endopeptidase activity, tissue injury response, coagulation, and complement activation were enriched in both models. We present for the first time the placental proteome of SHRSP and SD-PE and provide insight into the molecular make-up of models of hypertensive pregnancy. Our study informs future research into specific preeclampsia and chronic hypertension pregnancy mechanisms and translation of rodent data to the clinic.


Genetic polymorphisms in TLR1, TLR2, TLR4, and TLR10 of Helicobacter pylori-associated gastritis: a prospective cross-sectional study in Thailand.
The toll-like receptors (TLRs) mediate the recognition of Helicobacter pylori and initiate the innate immune response to infection. We hypothesized those genetic polymorphisms in the TLR1, TLR2, TLR4, and TLR10 influence bacterial infection, affecting susceptibility H. pylori to disease outcomes. Genomic DNA was extracted and genotypes of TLR1 (rs4833095), TLR2 (rs3804099 and rs3804100), TLR4 (rs10759932), and TLR10 (rs10004195) polymorphism were detected by the TagMan single-nucleotide epolymorphisms genotyping assay using the real-time PCR hybridization probe method. The TLR1 (rs4833095), C allele and the TLR10 (rs10004195), A allele frequency was significantly increased risk in the H. pylori infection group (odds ratio=1.76, 95% confidence interval=1.84-2.15, P=0.01 and odds ratio=1.81, 95% confidence interval=1.18-3.26, P=0.04, respectively). The TLR1 (rs4833095), C allele and TLR10 (rs10004195), A allele are susceptible TLRs polymorphisms in the Thai population. These findings suggest that TLR1 rs4833095 and TLR10 rs10004195 may play crucial roles in H. pylori susceptibility and gastric pathogenesis.


Engineering Probiotic E. coli Nissle 1917 for Release of Therapeutic Nanobodies.
Bioengineered probiotics enable new opportunities to improve cancer treatment strategies due to their tumor-colonizing capabilities. Here, we will describe the development of a probiotic E. coli Nissle 1917 platform encoding a synchronized lysis mechanism for the localized and sustained release of blocking nanobodies against immune checkpoint molecules like programmed cell death protein-ligand 1 and cytotoxic T lymphocyte-associated protein-4. Specifically, we will detail the experimental protocols needed to (1) encode and validate binding of recombinantly produced checkpoint blockade nanobodies, (2) evaluate the therapeutic efficacy and safety of the probiotic platform in syngeneic tumor-bearing mice, and (3) analyze the immunophenotype of the tumor microenvironment.


Astrocyte Responses Influence Local Effects of Whole-Brain Magnetic Stimulation in Parkinsonian Rats.
Excessive glutamatergic transmission in the striatum is implicated in Parkinson's disease (PD) progression. Astrocytes maintain glutamate homeostasis, protecting from excitotoxicity through the glutamate-aspartate transporter (GLAST), whose alterations have been reported in PD. Noninvasive brain stimulation using intermittent theta-burst stimulation (iTBS) acts on striatal neurons and glia, inducing neuromodulatory effects and functional recovery in experimental parkinsonism. Because PD is associated with altered astrocyte function, we hypothesized that acute iTBS, known to rescue striatal glutamatergic transmission, exerts regional- and cell-specific effects through modulation of glial functions. 6-Hydroxydopamine-lesioned rats were exposed to acute iTBS, and the areas predicted to be more responsive by a biophysical, hyper-realistic computational model that faithfully reconstructs the experimental setting were analyzed. The effects of iTBS on glial cells and motor behavior were evaluated by molecular and morphological analyses, and CatWalk and Stepping test, respectively. As predicted by the model, the hippocampus, cerebellum, and striatum displayed a marked c-FOS activation after iTBS, with the striatum showing specific morphological and molecular changes in the astrocytes, decreased phospho-CREB levels, and recovery of GLAST. Striatal-dependent motor performances were also significantly improved. These data uncover an unknown iTBS effect on astrocytes, advancing the understanding of the complex mechanisms involved in TMS-mediated functional recovery. Data on numerical dosimetry, obtained with a degree of anatomical details never before considered and validated by the biological findings, provide a framework to predict the electric-field induced in different specific brain areas and associate it with functional and molecular changes. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Sludge, stones and sickle cell anaemia.
A total of ninety-seven paediatric and adult patients with sickle cell anaemia and fourty-eight control subjects were investigated with the aim of determining the content of the gallbladder. The patients and control subjects were categorised according to the presence or otherwise of gallbladder stones, and, or sludge. The age last birthday, PCV and number of crises per year were recorded in order to determine their influence on the development of gallbladder stones and sludge. The gallbladder contents were examined using ultrasonographic technique. The age and number of crises per year was determined from the clinical record files and direct questioning of patients. Seventy patients had normal gallbladder content while eighteen had sludge, six had stones, and three had a combination of sludge and stones. None of the control subjects had sludge or stone. The age of patients increased from progressively from those with normal content through those with sludge to those with stones. The PCV and number of crises per year only differentiated between normal and abnormal gallbladder contents. While the prevalence of gallbladder stones in this study falls within the range in previous studies, a high prevalence of sludge was observed. The association between the occurrence of sludge and stones with age, PVC and number of crises per year suggests the need for a larger series and that they may identify a group of patients requiring closer monitoring.


Incidence and clinical characteristics of hepatitis B virus reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for rheumatoid arthritis.
To analyse the incidence, clinical characteristics, and prognosis of patients with rheumatoid arthritis (RA) and hepatitis B virus (HBV) surface antigen negative/core antibody positive serostatus (HBsAg-/HBcAb+), who underwent rituximab therapy and developed HBV reactivation. Medical records of RA patients with different HBV serostatus who received rituximab from January 2000 through January 2015 were reviewed. Case notes of four HBsAg-/HBcAb+ patients with RA who had HBV reactivation during treatment with rituximab were excerpted and summarised. We also searched the Medline (PubMed) database to identify published reports of other HBsAg-/HBcAb+ RA patients who likewise developed HBV reactivation during rituximab treatment. The study cohort comprised 54 RA patients who received rituximab, of whom 44 (81.5%) were HBsAg-/HBcAb+ whilst receiving rituximab. Four HBsAg-/HBcAb+ patients had HBV reactivations during rituximab therapy; thus, the incidence of HBV reactivation in the HBsAg-/HBcAb+ group was 9.1%. The literature search discovered another three cases, making a total of at least seven known rituximab-treated HBsAg-/HBcAb+ RA patients who have developed HBV reactivation. The mean duration from the first rituximab infusion to HBV reactivation was 25.4±4.6 months; no fatalities occurred. Approximately 9% of Taiwanese RA patients with HBsAg-/HBcAb+ serostatus had HBV reactivation around 2 years after starting regular rituximab therapy; they all had a relatively good prognosis.


Anti-Biofilm Activity of Cocultimycin A against Candida albicans.
Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory effect on planktonic C. albicans cells. This study aimed to evaluate the anti-biofilm activity of cocultimycin A against C. albicans and explore its underlying mechanism. Crystal violet staining showed that cocultimycin A remarkably inhibited biofilm formation in a dose-dependent manner and disrupted mature biofilms at higher concentrations. However, the metabolic activity of mature biofilms treated with lower concentrations of cocultimycin A significantly decreased when using the XTT reduction method. Cocultimycin A could inhibit yeast-to-hypha transition and mycelium formation of C. albicans colonies, which was observed through the use of a light microscope. Scanning electron microscopy revealed that biofilms treated with cocultimycin A were disrupted, yeast cells increased, and hypha cells decreased and significantly shortened. The adhesive ability of C. albicans cells treated with cocultimycin A to the medium and HOEC cells significantly decreased. Through the use of a qRT-PCR assay, the expression of multiple genes related to adhesion, hyphal formation and cell membrane changes in relation to biofilm cells treated with cocultimycin A. All these results suggested that cocultimycin A may be considered a potential novel molecule for treating and preventing biofilm-related C. albicans infections.


Mechanism of cooperative behaviour in systems of slow and fast molecular motors.
Two recent theoretical advances have described cargo transport by multiple identical motors and by multiple oppositely directed, but otherwise identical motors [M. J. Muller, S. Klumpp and R. Lipowsky, Proc. Natl. Acad. Sci. U. S. A., 2008, 105(12), 4609-4614; S. Klumpp and R. Lipowsky, Proc. Natl. Acad. Sci. U. S. A., 2005, 102(48), 17284-17289]. Here, we combine a similar theoretical approach with a simple experiment to describe the behaviour of a system comprised of slow and fast molecular motors having the same directionality. We observed the movement of microtubules by mixtures of slow and fast kinesin motors attached to a glass coverslip in a classic sliding filament assay. The motors are identical, except that the slow ones contain five point mutations that collectively reduce their velocity approximately 15-fold without compromising maximal ATPase activity. Our results indicate that a small fraction of fast motors are able to accelerate the dissociation of slow motors from microtubules. Because of this, a sharp, highly cooperative transition occurs from slow to fast microtubule movement as the relative number of fast motors in the assay is increased. Microtubules move at half-maximal velocity when only 15% of the motors in the assay are fast. Our model indicates that this behaviour depends primarily on the relative motor velocities and the asymmetry between their forward and backward dissociation forces. It weakly depends on the number of motors and their processivity. We predict that movement of cargoes bound to two types of motors having very different velocities will be dominated by one or the other motor. Therefore, cargoes can potentially undergo abrupt changes in movement in response to regulatory mechanisms acting on only a small fraction of motors.


Efficacy of a flexible quit date versus an a priori quit date approach to smoking cessation: a cross-study analysis.
Most treatment guidelines recommend that smokers should set a target quit date (TQD) at treatment onset because making a public commitment to quit on a given date should increase motivation. On the other hand, allowing smokers the flexibility to choose when to stop after starting treatment might allow smokers to better tailor their quit date and might improve the acceptability of treatment among smokers not willing to set a TQD. In a recent placebo-controlled study, we found varenicline effective when smokers were not required to set a quit date a priori; i.e., with a "flexible quit date" (FQD) approach. The current analysis compares the effect sizes and quit rates in this FQD study with those of nine prior varenicline randomized controlled trials (RCTs) that used a TQD approach. The odds ratio for varenicline versus placebo in the FQD study was the 4th highest of the 10 trials and the incidence of continuous abstinence for varenicline was 5th highest. These results suggest that a FQD approach can produce quit rates similar to a TQD approach. Cross-study comparisons can have hidden bias; thus, a RCT of fixed versus flexible quit dates would provide a more valid test. Also, a study of whether different subpopulations of smokers may be more interested in or especially benefit from, one or the other approach to quitting is indicated.


Translation, Adaptation, and Validation of Revised Colorectal Cancer Perception and Screening Instrument among First-Degree Relatives of People with Colorectal Cancer in China.
The purpose of the study was to translate and validate the psychometric properties of the Revised Colorectal Cancer Perception and Screening (RCRCPS) instrument for the first-degree relatives (FDRs) of people with colorectal cancer (CRC) in China. The translation, adaptation, and validation guideline developed by Sousa and Rojjanasrirat was used to guide this study. All items from the Colorectal Cancer Perception and Screening (CRCPS) instrument and three items from the Perceived Barriers Questionnaire were combined and further adapted for a colonoscopy test, resulting in RCRCPS. The resultant RCRCPS was translated from English to Chinese through forward- and backward-translation methods, and a panel review was conducted to examine its content validity. The RCRCPS (simplified Chinese version) was then tested with a convenience sample of 197 Chinese FDRs of patients with CRC. Validity was tested through confirmatory factor analysis (CFA) and discriminative validity, and reliability was assessed using Cronbach's α and test-retest reliability. The content validity index (CVI) of the RCRCPS (simplified Chinese version) was satisfactory (item CVI = 0.80-1 and scale CVI = 0.92). The results demonstrated acceptable internal consistency (Cronbach's α = 0.74-0.87) and test-retest reliability in a 4-week interval (intraclass coefficient = 0.53-0.84). CFA revealed that the RCRCPS (simplified Chinese version) conformed to the four-factor model suggested by the original version (Chi-square/degree of freedom = 1.326, root-mean-square error of approximation = 0.041, comparative fit index = 0.904, Tucker-Lewis index = 0.896, and standardized root mean square residual = 0.684). The 38-item simplified Chinese version of RCRCPS demonstrated acceptable reliability and validity. Healthcare professionals may use this instrument in the development and evaluation of interventions to promote colonoscopy screening among people at an increased risk of developing CRC.


Evaluation of the effects of diazepam and an experimental anti-anxiety drug on regional cerebral blood flow.
In the normal brain, cerebral blood flow (CBF) and function are closely coupled. Thus, changes in brain function associated with drug-induced anxiety reduction should be accompanied by parallel CBF changes. Benzodiazepines such as diazepam have been reported to reduce CBF. It is unclear, however, if this CBF decrease is specifically a function of the anti-anxiety property of the drug. To examine the relationship between drug-induced anxiety reduction and CBF changes more closely, i.v. injections of an established anxiolytic agent and an experimental anti-anxiety drug were given to patients with generalized anxiety disorder. CBF and anxiety levels were measured before and 30 min after i.v. administration of diazepam (0.12 mg/kg), ondansetron (0.24 mg/kg), and normal saline during separate visits to the laboratory. The order of drug administration was randomized, and the injections were given under double-blind conditions. Diazepam but not ondansetron or saline reduced anxiety. Global CBF reduction was seen after diazepam, but no changes were found following the other two experimental conditions. The CBF values were adjusted for test-retest changes in carbon dioxide levels. Postdiazepam decreases in CBF and anxiety levels did not correlate.


Gene Expression Pathways in Prostate Tissue Associated with Vigorous Physical Activity in Prostate Cancer.
Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR <0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.


Fabrication and cellular biocompatibility of porous carbonated biphasic calcium phosphate ceramics with a nanostructure.
Microwave heating was applied to fabricate interconnective porous structured bodies by foaming as-synthesized calcium-deficient hydroxyapatite (Ca-deficient HA) precipitate containing H(2)O(2). The porous bodies were sintered by a microwave process with activated carbon as the embedding material to prepare nano- and submicron-structured ceramics. By comparison, conventional sintering was used to produce microstructured ceramics. The precursor particles and bulk ceramics were characterized by transmission electron microscopy (TEM), dynamic light scattering, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transformed infrared spectroscopy (FTIR) and mechanical testing. TEM micrographs and assessment of the size distribution showed that the needle-like precursor particles are on the nanoscale. SEM observation indicated that the ceramics formed by microwave sintering presented a structure of interconnective pores, with average grain sizes of approximately 86 and approximately 167nm. XRD patterns and FTIR spectra confirmed the presence of carbonated biphasic calcium phosphate (BCP), and the mechanical tests showed that the ceramics formed by microwave sintering had a compressive strength comparable to that obtained by conventional methods. Rat osteoblasts were cultured on the three kinds of BCP ceramics to evaluate their biocompatibility. Compared with the microscale group formed by conventional sintering, MTT assay and ALP assay showed that nanophase scaffolds promoted cell proliferation and differentiation respectively, and SEM observation showed that the nanoscale group clearly promoted cell adhesion. The results from this study suggest that porous carbonated biphasic calcium phosphate ceramics with a nanostructure promote osteoblast adhesion, proliferation and differentiation. In conclusion, porous carbonated BCP ceramics with a nanostructure are simple and quick to prepare using microwaves and compared with those produced by conventional sintering, may be better bone graft materials.


Where to refer employees for treatment of drinking problems. The limited lessons from empirical research.
Although employee assistance programs appear to be spreading rapidly, much remains to be discovered about how they should proceed. A critical review of the literature undergirding these programs reveals wide gaps in knowledge about the relative efficacy of a variety of alternative strategies. In particular, empirical data on the question of where to refer employees for treatment of drinking problems are urgently needed. As medical scientists with ties to industry, occupational health professionals can play a decisive role in the articulation of central research questions and in the design and implementation of key studies that will begin to yield the blueprint for an efficient and effective system of care for alcohol problems.


Indigenous community care -- documented depression in patients with diabetes.
This article reports on documented levels of depression among people with diabetes attending indigenous primary care centres. Between 2005 and 2009, clinical audits of diabetes care were conducted in 62 indigenous community health centres from four Australian states and territories. The overall prevalence of documented depression among people with diabetes was 8.8%. Fourteen (23%) of the 62 health centres had no record of either diagnosed depression or prescription of selective serotonin reuptake inhibitors among people with diabetes. For the remaining 48 centres, 3.3-36.7% of people with diabetes had documented depression. The results of this study are inconsistent with the evidence showing high prevalence of mental distress among indigenous people. A more thorough investigation into the capacity, methods and barriers involved in diagnosing and managing depression in indigenous primary care is needed.


Incidence of histoplasmosis in patients receiving TNF-alpha inhibitors: A systematic review and meta-analysis.
Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy. This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate. We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies. The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.


Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound.
Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication. Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ΔF. Measurements were repeated after inhalation of salbutamol. We found significant differences in ΔF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably. We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD. ClinicalTrials.gov: NCT01080924.


Rewarding Replications: A Sure and Simple Way to Improve Psychological Science.
Although replications are vital to scientific progress, psychologists rarely engage in systematic replication efforts. In this article, we consider psychologists' narrative approach to scientific publications as an underlying reason for this neglect and propose an incentive structure for replications within psychology. First, researchers need accessible outlets for publishing replications. To accomplish this, psychology journals could publish replication reports in files that are electronically linked to reports of the original research. Second, replications should get cited. This can be achieved by cociting replications along with original research reports. Third, replications should become a valued collaborative effort. This can be realized by incorporating replications in teaching programs and by stimulating adversarial collaborations. The proposed incentive structure for replications can be developed in a relatively simple and cost-effective manner. By promoting replications, this incentive structure may greatly enhance the dependability of psychology's knowledge base.


Deoxyguanosine enhancement of cytarabine nucleotide accumulation in human leukemia cells.
We studied the effect of deoxyguanosine (dGuo) on cellular cytarabine (ara-C) nucleotide accumulation of the human leukemia cell line K562 and of bone marrow blast cells derived from patients with acute nonlymphocytic leukemia. Exposure of cells in culture to dGuo increased ara-C nucleotide accumulation measured in cell lysate, with an average increase of 386% (range, 242%-537%) of control in the presence of 500 microM dGuo. Maximal elevation occurred after 8 hours of exposure and remained constant through 48 hours. dGuo also enhanced deoxycytidine nucleotide accumulation, but dGuo enhancement favored accumulation of ara-C nucleotides over dCyd nucleotides. In cell cycle kinetic studies using flow cytometry, dGuo slowed accumulation of cells with apparent S-phase DNA content in a concentration-dependent fashion. However, neither the rate nor the magnitude of this effect correlated with the increase in ara-C nucleotide accumulation. Since the increase in ara-C nucleotide accumulation caused by dGuo could be prevented by 5 micrograms/ml of cycloheximide, this process appears to require new protein synthesis. Although these data suggest that the elevation of ara-C nucleotide accumulation caused by dGuo may represent induction of enzyme synthesis, other possibilities are discussed. Exposure of bone marrow blast cells obtained from patients with acute nonlymphocytic leukemia to dGuo for 16 hours in liquid culture also increased ara-C nucleotide accumulation. In six of seven studies, exposure to dGuo in concentrations from 50 to 500 microM increased ara-C nucleotide accumulation from 160% to 3400%. These data suggest that dGuo may alter ara-C metabolism in a clinically useful fashion.


Diamino-diamido tetrathiafulvalene for the sensing of anions and cations: a view in electrochemistry and structure.
A new cation- and anion-sensitive system based on a TTF derivative with a diamino-diamido moiety (H(2)L) has been studied. The results of cyclic voltammetry indicated that the redox potentials of the protonated H(2)L (H(4)L(2+)) selectively respond to later transition metal cations and some oxo anions. Solid-state structures of the cation-anion compounds formed by H(4)L(2+) and oxo anions were characterized crystallographically, which is helpful to understand the matter of the sensitivity for the anion. There are two types of hydrogen bonds in these compounds, one is with an amino group and the other is with an amido group. The shift of the redox potential is obviously related to formation of hydrogen bonding with the amido group. The packing structures of these cation-anion compounds are arranged to layered sandwiched structures assembled by an oxo-anion layer and two TTF layers through hydrogen bonding.


Spontaneous septic arthritis complicating rheumatoid arthritis.
Thirteen cases (in twelve patients) of septic arthritis complicating rheumatoid arthritis are reported. One ankle, one metacarpopophalangeal joint, one shoulder, and ten knees were involved. Staphylococcus aureus was cultured from twelve joints and Escherichia coli, from one. Treatment consisted of repeated needle aspirations in two patients, arthrotomy with Penrose drainage in six, and arthrotomy with through-and-through irrigation in four. Needle aspiration was the least effective therapy. The authors recommend as the treatment of choice: systemic antibiotic therapy and immediate arthrotomy followed by through-and-through irrigation with fluid containing the appropriate antibiotics.