A between sex comparison of anterior-posterior knee laxity after anterior cruciate ligament reconstruction with patellar tendon or hamstrings autograft: a systematic review.
Anterior-posterior (AP) knee laxity after anterior cruciate ligament (ACL) reconstruction may differ between sexes for different graft types. Females may experience an increase in AP knee laxity following an ACL reconstruction with a hamstrings graft, which is not seen in males with a hamstrings graft or in males or females with a bone-patellar tendon-bone (BTB) graft. The hypothesis of this review is sex differences in AP knee laxity and this will be identified in patients who undergo an ACL reconstruction with a hamstrings graft, while no sex differences will be observed in patients who have an ACL reconstruction with a BTB graft. A systematic search was performed in PubMed, CINAHL and SPORTDiscus. Inclusion criteria were articles published in the English language that studied human subjects who underwent an ACL reconstruction with a BTB or hamstrings autograft, and the presence of a sex comparison on outcome measures including side-to-side difference in AP knee laxity. Methodological quality was assessed using a Modified Coleman Methodology Score. Eleven cohort studies met the inclusion criteria. Six investigated sex differences in both hamstrings and BTB grafts. Three only investigated BTB grafts and two only investigated hamstrings grafts. These studies consistently reported increases in AP knee laxity in females after an ACL reconstruction with a hamstrings graft that was not observed in the other cohorts. This systematic review indicates that female patients have greater AP knee laxity following an ACL reconstruction with a hamstrings autograft compared with males with a similar procedure, and both females and males following an ACL reconstruction with a BTB autograft. These results are derived from lower level evidence, as no randomized control trials have attempted to answer this question. Future studies need to rigorously address this clinical question to confirm the results currently in the literature.


Utility of Consumer Physical Activity Trackers as an Intervention Tool in Cardiovascular Disease Prevention and Treatment.
Consumer activity trackers have grown in popularity over the last few years. These devices are typically worn on the hip or wrist and provide the user with information about physical activity measures such as steps taken, energy expenditure, and time spent in moderate to vigorous physical activity. The consumer may also use the computer interface (e.g. device websites, smartphone applications) to monitor and track achievement of PA goals and compete with other users. This review will describe some of the most popular consumer devices and discuss the user feedback tools. We will also present the limited evidence available about the accuracy of these devices and highlight how they have been used in cardiovascular disease management. We conclude with some recommendations for future research, focusing on how consumer devices might be used to assess effectiveness of various cardiovascular treatments.


Lateral line nerve fibers do not code bulk water flow direction in turbulent flow.
The discharges of anterior and posterior lateral line nerve afferents were recorded while stimulating goldfish, Carassius auratus, with bulk water flow. With increasing flow velocity lateral line afferents increased their discharge rates. However, an increased response to flow rates occurred even if flow direction was reversed. Thus, individual lateral line afferents did not encode the direction of running water. Frequency spectra of the water motions quantified with particle image velocimetry revealed flow fluctuations that increased with increasing flow velocity. Maximal spectral amplitudes of the flow fluctuations were below 5 Hz (bulk flow velocity 4-15 cms(-1)). The frequency spectra of the firing rates of lateral line afferents also showed an increase in amplitude when fish were exposed to running water. The maximal spectral amplitudes of the recorded data were in the frequency range 3-8 Hz. This suggests that the lateral line afferents mainly responded to the higher frequency fluctuations that developed under flow conditions, but not to the direct current flow or the lower frequency fluctuations. Although individual lateral line afferents encoded neither flow velocity nor flow direction we suggest that higher order lateral line neurons can do so by monitoring flow fluctuations as they move across the surface of the fish.


New insights into the pathophysiology of coronary arteries by epicardial high frequency echocardiography.
Currently, the coronary angiogram remains the "gold standard" for the detection and quantification of coronary arterial disease. Clinical assessment of the arteriogram is usually based simply on the relative percent narrowing of the column of angiographic dye. However, such analysis oversimplifies and is not accurate for evaluating the extent and severity of coronary artery atherosclerosis. Recently a new generation of ultrasonic devices has become available for intraoperative evaluation of coronary arterial anatomy. These high frequency echocardiographic transducers use 12 MHz probes. The transducer is placed directly over the epicardium during open heart surgery to evaluate the coronary artery. With this technique, demonstration of coronary artery anatomy, including wall and cross-sectional lumen, is available in vivo. We have undertaken numerous validation studies in vitro and in vivo of animal and postmortem human heart preparations to show that this technique can be used to accurately measure luminal area, luminal diameter, and wall thickness. Subsequently in patients intraoperatively the extent of atherosclerosis using luminal diameter to wall thickness (LD/WT) ratios was compared with the routine angiographic evaluation of coronary arterial disease using percent stenosis measurements. LD/WT ratios from arterial segments with no visible angiographic disease but with angiographic lesions elsewhere in the same coronary artery showed marked variability. The majority were in the range of LD/WT ratios of those segments where high frequency echocardiography recording was made at the site of "angiographic" disease. This indicates that in vivo atherosclerosis is more widespread than the angiogram predicts and underlies the difficulties of using percent stenosis angiographically to determine the extent and severity of coronary arterial disease. In a second study we have demonstrated that there is marked variability and eccentricity in coronary plaque geometry, luminal morphology, and placement of the residual lumen with respect to the atherosclerotic plaque. This eccentricity results in some relatively "normal" coronary wall at the site of maximum atherosclerosis, theoretically preserving the ability to vasodilate and vasoconstrict. Studies with high frequency echocardiography are underway to study the capability of arteries with atherosclerosis to vasodilate. We have evaluated atherosclerotic remodeling of coronary arteries and found that remodeling occurs in an attempt by the artery to preserve its residual luminal size during encroachment on the lumen by the atherosclerotic plaque. This is the first in vivo demonstration of this process in human coronary arteries. Coronary arterial bypass grafts have been evaluated in animal models and at the time of intraoperative coronary anastomoses to evaluate the adequacy of graft anastomoses and compare vein grafts with internal mammary grafts.(ABSTRACT TRUNCATED AT 400 WORDS)


Anti-inflammatory effects of a bioavailable compound, Artepillin C, in Brazilian propolis.
Artepillin C is the major compound in the Brazilian green propolis from Baccharis dracunculifolia. Our aim in this study was to investigate the anti-inflammatory effects, absorption, and bioavailability of Artepillin C in mice. The animals used were male Swiss mice subjected to: paw oedema by carrageenan (300 microg/paw), carrageenan-induced peritonitis, and prostaglandin E(2) determination. We also measured in vitro nitric oxide production by RAW 264.7 cells and NF-kappaB activity in HEK 293 cells. Finally, we measured the absorption and bioavailability of Artepillin C in plasma from mice by means of GC-MS after a single oral dose (10 mg/kg). In vivo, Artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema. Artepillin C also decreased the number of neutrophils during peritonitis (IC(50): 0.9 (0.5-1.4) mg/kg). Treatment with Artepillin C decreased prostaglandin E(2) by 29+/-3% and 58+/-5% at 1 and 10 mg/kg, respectively, with a mean ID(50) of 8.5 (8.0-8.7) mg/kg). Similarly, in in vitro models, Artepillin C (3, 10, or 100 microM) decreased nitric oxide production by RAW 264.7 cells with a mean IC(50) of 8.5 (7.8-9.2) microM. In HEK 293 cells, Artepillin C reduced NF-kappaB activity with a mean IC(50) of 26 (22-30) mug/ml), suggesting anti-inflammatory activity, particularly during acute inflammation. Lastly, Artepillin C was absorbed after an oral dose (10 mg/kg) with maximal peaks found at 1 h (22 microg/ml). Collectively, Artepillin C showed anti-inflammatory effects mediated, at least in part, by prostaglandin E(2) and nitric oxide inhibition through NF-kappaB modulation, and exhibited bioavailability by oral administration.


Effect of tunicamycin, an inhibitor of protein glycosylation, on the high-affinity transport of acidic amino acid neurotransmitters in C6 glioma cells.
The effect of tunicamycin, an inhibitor of protein glycosylation, on the high-affinity transport of D-aspartate was investigated in C6 astrocytoma cells. A concentration of tunicamycin (1 microgram/ml) that after 24 h exposure inhibited the rate of transport by 70% and incorporation of [3H]mannose by 82-95% had only a small effect on [14C]leucine incorporation into protein and cell growth (20% reduction). Tunicamycin decreased the Vmax for transport without affecting the Km, which suggests that inhibition of glycosylation reduces the number of competent transporters on the surface of the plasma membrane. The decrease in the velocity of uptake was attenuated when C6 cells were treated with tunicamycin in the presence of protease inhibitors, indicating that the underglycosylated carriers are subject to enhanced proteolytic degradation. Incubation in drug-free medium following treatment with 1 microgram/ml of tunicamycin for 24 h resulted in recovery of D-aspartate transport within 48 h. This recovery was prevented by the presence of cycloheximide, which indicates that synthesis of new transporters is necessary for the restoration of normal rates of D-aspartate uptake. These results support our earlier postulate that the high-affinity carriers for amino acid transmitters are transmembrane glycoproteins.


Neural stem cells attacked by Zika virus.
The current outbreak of Zika virus-associated diseases in South America and its threat to spread to other parts of the world has emerged as a global health emergency. Insights from cell and animal models to understand how Zika virus causes severe birth defects may lead to treatments and prevention of these diseases.


Type of breech presentation and prognosis for delivery.
Although its role in the prognosis for delivery remains controversial, the type of breech is sometimes taken into account in the decision about mode of delivery. Objective of our study was to compare maternal and neonatal morbidity for trial of vaginal delivery according to the type of breech (complete or frank). Single-center retrospective study of women with trials of vaginal delivery of a singleton fetus in breech presentation at of after 37 weeks of gestation. Neonatal status was assessed by the composite variable of the Term Breech Trial, first considered alone, and then with the addition of a 5-min Apgar score < 7 or a neonatal arterial pH<7.0. Of the 495 trials of vaginal delivery during the study period, approximately one third of them were complete breech (35.8 %) and two thirds frank (64.2 %). The frequency of cesareans during labor was similar regardless of the type of breech (16.4 for complete vs 12.6 % for frank, p=0.24), nor did neonatal morbidity differ (1.7 for complete vs 4.1 % for frank, p=0.15). On the other hand, cord prolapse occurred almost exclusively in complete breech presentations (4.5 vs 0.3 %, p<0.01), and prognosis was good in all cases. Complete breech presentations were also associated with more frequent use of forceps to the after-coming head (16.2 vs 9.7 %, p<0.05). Finally, there were non significant difference between the two types of breech concerning severe acidosis but it seemed to have it more in frank breech (2.3 vs 1.2 %, p=0.34). Among women eligible for vaginal delivery, the type of breech presentation (complete or frank) has little influence on delivery maternal and neonatal morbidity. The type of breech need not be taken into account in deciding the route of delivery.


A colonic metastatic tumor in the hand.
Secondary tumors in the hand are very uncommon. Of the reported cases the majority arise from primary bronchial carcinoma, with multiple secondary deposits into bone. A case is reported of bony metastasis to the middle phalanx of the small finger in a patient who had a resection of a colonic adenocarcinoma 2 years previously.


The Representation of Surgery in Oncology Clinical Trials: 2001 to 2022.
Surgery is a mainstay of cancer care. Since the advancement of cancer treatment occurs through clinical trials, it is critical to investigate the degree and nature of representation of surgery in oncological clinical trials. This observational analysis used publicly available data from clinicaltrials.gov to investigate non-industry-funded oncological clinical trials in the United States between 2012 and 2022. From 2012 to 2022, 1,861 (15.7%) of the 11,843 registered oncologic clinical trials were surgical. There was a 43.2% increase in proportional surgical trials and an 18.9% increase in oncology trials over the last two decades. Surgery+diagnostic-technique trials increased from 5.14 to 12.6% (P < 0.001, 95%CI [- 0.097, - 0.052]), surgery+radiation trials increased from 5.24 to 8.1% (P = 0.004, 95%CI [- 0.047, - 0.0088]), surgery+systemic-therapy trials decreased from 34.5 to 29.2% (P = 0.003, 95%CI [0.018, 0.088]), surgery+supportive-therapy trials increased from 8.0 to 11.3% (P = 0.004, 95%CI [- 0.056, - 0.01]) and 'surgery-as-the-variable' trials decreased from 12.0 to 3.5% (P < 0.001, 95%CI[0.065, 0.1]). Systemic therapy with biologics increased from 38.1 to 53.9% (P < 0.001, 95%CI [- 0.22, - 0.091]). Surgery-vs.-no-surgery trials increased from 16.8 to 37.3% (P = 0.001, 95%CI [- 0.32, - 0.078]). Surgical oncology trials increased by 43.2% over the last 10 years. The focus of clinical trials is changing to the encouragement of innovation in more diagnostic and less invasive techniques, and targeted therapies.


Structure - membrane activity relationship in a family of peptide-based gemini amphiphiles: An insight from experimental and theoretical model systems.
A study of the interaction between five gemini amphiphilic valine-based pseudopeptides (GAPs) differing by the length of the central aliphatic spacer linking two amino acid subunits, and a model bacterial membrane lipid, 1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DMPG), is here presented. Pure DMPG, pure GAPs and mixed GAPs/DMPG monolayers were formed at the air-water interface using Langmuir technique. The properties of the Langmuir films were investigated using surface pressure measurements, polarization modulation-infrared reflection-absorption spectroscopy, and Brewster angle microscopy. The atomic level information concerning the orientation of molecules in the monolayer and hydration of the polar headgroups was obtained from molecular dynamics simulations. It was demonstrated that the length of the central spacer in the GAPs structure is important for the properties of the mixed films; the disorganization of the membrane increases with the length of the spacer. The latter point is important for developing possible antimicrobial agents based on GAPs.


Caregiver's Health Locus of Control and Medication Adherence in Sickle Cell Disease.
The authors would like to thank Dr. Morisky for giving us permission to use the Morisky Medication Adherence Scale To explore caregivers' Health Locus of Control's relationship to self-reported adherence to penicillin prophylaxis or hydroxyurea in children with sickle cell disease (SCD). A questionnaire-based study was conducted of caregivers of children with SCD who visited a comprehensive sickle cell center in an inner city hospital, who were either on penicillin prophylaxis or hydroxyurea or both. Multidimensional Health Locus of Control Scale (MHLC) and the Morisky Medication Adherence Scale (MMAS-8) questionnaires were used for the study. Caregivers of 43 children (27 on penicillin prophylaxis, 13 on hydroxyurea, and 3 on both) completed the MHLC and the MMAS-8. There was no significant difference in adherence between the penicillin and the hydroxyurea groups. The mean Powerful Others score of caregivers of the hydroxyurea only group (25.5+5.6) was higher than that of the penicillin only group (21.2+6.1, p=0.043). Regression analysis revealed an inverse relationship of Chance Locus of Control to adherence in the entire group (Beta = -0.306, R2=0.093, F[1,40]=4.12, p=0.049). Chance Locus of control may identify caregivers of children with SCD at risk for non-adherence to treatment.


[Lens Surgery: Implantation of Multifocal Intraocular Lenses].
Lens exchange surgery is the most common performed surgical ophthalmological procedure worldwide. The intraocular lens (IOL) is placed into the capsular bag. The power of the IOL decides whether afterwards the patient will be able to see objects in the far or near distance without glasses. Due to constant development of the IOL design in nowadays it is however possible to implant a lens which has multiple foci and consequently allows the patient to see in several distances. In this review article we summarize the most critical points which need to be considered when placement of a multifocal lens is planned in lens exchange surgery. Additionally, we present an overview of the currently available trifocal IOLs and IOLs with an extended depth of focus. We furthermore discuss the advantages and disadvantages of the multifocal IOLs as compared to monofocal IOLs.


Delta-sleep-inducing peptide (DSIP) stimulates the release of immunoreactive Met-enkephalin from rat lower brainstem slices in vitro.
We studied whether delta-sleep-inducing peptide (DSIP) acted on opioid receptor directly or indirectly. DSIP did not have binding activity to any subtype of opioid receptors. DSIP at doses of 1 pM-1 nM significantly stimulated the release of immunoreactive Met-enkephalin (iME) from superfused slices of the rat lower brainstem. The DSIP-induced release of iME was calcium-dependent. These results show that DSIP acts on opioid receptor indirectly by stimulating the release of iME in producing antinociceptive effects.


Constraints on the spatiotemporal accuracy of interceptive action: effects of target size on hitting a moving target.
Results of two experiments are reported that examined how people respond to rectangular targets of different sizes in simple hitting tasks. If a target moves in a straight line and a person is constrained to move along a linear track oriented perpendicular to the target's motion, then the length of the target along its direction of motion constrains the temporal accuracy and precision required to make the interception. The dimensions of the target perpendicular to its direction of motion place no constraints on performance in such a task. In contrast, if the person is not constrained to move along a straight track, the target's dimensions may constrain the spatial as well as the temporal accuracy and precision. The experiments reported here examined how people responded to targets of different vertical extent (height): the task was to strike targets that moved along a straight, horizontal path. In experiment 1 participants were constrained to move along a horizontal linear track to strike targets and so target height did not constrain performance. Target height, length and speed were co-varied. Movement time (MT) was unaffected by target height but was systematically affected by length (briefer movements to smaller targets) and speed (briefer movements to faster targets). Peak movement speed (Vmax) was influenced by all three independent variables: participants struck shorter, narrower and faster targets harder. In experiment 2, participants were constrained to move in a vertical plane normal to the target's direction of motion. In this task target height constrains the spatial accuracy required to contact the target. Three groups of eight participants struck targets of different height but of constant length and speed, hence constant temporal accuracy demand (different for each group, one group struck stationary targets = no temporal accuracy demand). On average, participants showed little or no systematic response to changes in spatial accuracy demand on any dependent measure (MT, Vmax, spatial variable error). The results are interpreted in relation to previous results on movements aimed at stationary targets in the absence of visual feedback.


Improving dose homogeneity in routine head and neck radiotherapy with custom 3-D compensation.
Anatomic contour irregularity and tissue inhomogeneity can lead to significant radiation dose variation across the complex treatment volumes found in the head and neck (H&N) region. This dose inhomogeneity can routinely create focal hot or cold spots of 10-20% despite beam shaping with blocks or beam modification with wedges. Since 1992, we have implemented the routine use of 3-D custom tissue compensators fabricated directly from CT scan contour data obtained in the treatment position in order to improve dose uniformity in patients with tumors of the H&N. Between July 1992 and January 1997, 160 patients receiving comprehensive H&N radiotherapy had 3-D custom compensators fabricated for their treatment course. Detailed dosimetric records have been analyzed for 30 cases. Dose uniformity across the treatment volume and clinically relevant maximum doses to selected anatomic sub-sites were examined with custom-compensated, uncompensated and optimally-wedged plans. The use of 3-D custom compensators resulted in an average reduction of dose variance across the treatment volume from 19+/-4% for the uncompensated plans to 5+/-2% with the use of 3-D compensators. Optimally-wedged plans were variable, but on average a 10+/-3% dose variance was noted. For comprehensive H&N treatment which encompassed the larynx within the primary field design, the peak doses delivered were reduced by 5-15% with 3-D custom compensation as compared to optimal wedging. The use of 3-D custom tissue compensation can improve dose homogeneity within the treatment volume for H&N cancer patients. Maximum doses to clinically important structures which often receive greater than 105-110% of the prescribed dose are routinely reduced with the use of 3-D custom compensators. Improved dose uniformity across the treatment volume can reduce normal tissue complication profiles and potentially allow for delivery of higher total doses in an attempt to enhance locoregional tumor control.


Nazi medical experiments on Australian prisoners of war: Commentary on the testimony of an Australian soldier.
Archival research reveals that Australian prisoners of war were exposed to non-consensual medical experiments during World War II. This article discusses the first known case of an Australian soldier exposed to German medical experiments.


First report of prenatal biochemical diagnosis of Lowe syndrome.
The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder with a severe phenotype characterized by congenital cataracts, renal tubular dysfunction and neurological deficits. The gene has been characterized and mutations have been identified in patients. Owing to the allelic heterogeneity exhibited by this gene, prenatal diagnosis by molecular analysis is limited to families in which the mutation is already known or in which linkage is informative. A more generally applicable diagnostic test would be valuable for families at risk for Lowe syndrome. Since ocrl1 is now known to encode a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ptdlns(4,5)P2 phosphatase), we assessed whether biochemical testing could be used for prenatal diagnosis. We report here the first case of prenatal diagnosis for Lowe syndrome by measuring phosphatidylinositol 4,5-bisphosphate 5-phosphatase activity in cultured amniocytes.


Body mass index and percent body fat: a meta analysis among different ethnic groups.
To study the relationship between percent body fat and body mass index (BMI) in different ethnic groups and to evaluate the validity of the BMI cut-off points for obesity. Meta analysis of literature data. Populations of American Blacks, Caucasians, Chinese, Ethiopians, Indonesians, Polynesians and Thais. Mean values of BMI, percent body fat, gender and age were adapted from original papers. The relationship between percent body fat and BMI differs in the ethnic groups studied. For the same level of body fat, age and gender, American Blacks have a 1.3 kg/m2 and Polynesians a 4.5 kg/m2 lower BMI compared to Caucasians. By contrast, in Chinese, Ethiopians, Indonesians and Thais BMIs are 1.9, 4.6, 3.2 and 2.9 kg/m2 lower compared to Caucasians, respectively. Slight differences in the relationship between percent body fat and BMI of American Caucasians and European Caucasians were also found. The differences found in the body fat/BMI relationship in different ethnic groups could be due to differences in energy balance as well as to differences in body build. The results show that the relationship between percent body fat and BMI is different among different ethnic groups. This should have public health implications for the definitions of BMI cut-off points for obesity, which would need to be population-specific.


Asymmetric synthesis of 1,3-dioxolanes by organocatalytic formal [3 + 2] cycloaddition via hemiacetal intermediates.
A novel asymmetric formal [3 + 2] cycloaddition reaction for the synthesis of 1,3-dioxolanes using cinchona-alkaloid-thiourea-based bifunctional organocatalysts is reported. The reaction proceeds via the formation of hemiacetal intermediates between γ-hydroxy-α,β-unsaturated ketones and aldehydes.


Efficient drug delivery using SiO2-layered double hydroxide nanocomposites.
MgAl-layered double hydroxide (MgAl-LDH) nanoparticles have great potentials in drug and siRNA delivery. In this work, we used a nanodot-coating strategy to prepare SiO2 dot-coated layered double hydroxide (SiO2@MgAl-LDH) nanocomposites with good dispersibility and controllable size for drug delivery. The optimal SiO2@MgAl-LDH nanocomposite was obtained by adjusting synthetic parameters including the mass ratio of MgAl-LDH to SiO2, the mixing temperature and time. The optimal SiO2@MgAl-LDH nanocomposite was shown to have SiO2 nanodots (10-15nm in diameter) evenly deposited on the surface of MgAl-LDHs (110nm in diameter) with the plate-like morphology and the average hydrodynamic diameter of 170nm. We further employed SiO2@MgAl-LDH nanocomposite as a nanocarrier to deliver methotrexate (MTX), a chemotherapy drug, to the human osteosarcoma cell (U2OS) and found that MTX delivered by SiO2@MgAl-LDH nanocomposite apparently inhibited the U2OS cell growth.


Regulation of actin filament assembly and disassembly in growth cone motility and axon guidance.
Directed outgrowth of axons is fundamental for the establishment of neuronal networks. Axon outgrowth is guided by growth cones, highly motile structures enriched in filamentous actin (F-actin) located at the axons' distal tips. Growth cones exploit F-actin-based protrusions to scan the environment for guidance cues, and they contain the sensory apparatus to translate guidance cue information into intracellular signaling cascades. These cascades act upstream of actin-binding proteins (ABP) and thereby control assembly and disassembly of F-actin. Spatiotemporally controlled F-actin dis-/assembly in growth cones steers the axon towards attractants and away from repellents, and it thereby navigates the axon through the developing nervous system. Hence, ABP that control F-actin dynamics emerged as critical regulators of neuronal network formation. In the present review article, we will summarize and discuss current knowledge of the mechanisms that control remodeling of the actin cytoskeleton in growth cones, focusing on recent progress in the field. Further, we will introduce tools and techniques that allow to study actin regulatory mechanism in growth cones.


Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program.
A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole-genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival.


[Considerations on the therapy with physiologic pacemakers].
Physiologic pacemakers offer hemodynamic benefits in comparison to conventional pacing, but demand more detailed diagnosis of the arrhythmia in need of treatment. In order to prevent endless loop tachycardias, ventriculoatrial conduction must be analyzed. Normal sinus node and atrial function should be confirmed in atrial triggered ventricular stimulation. The techniques and values of preimplantation investigations, including intracardiac electrophysiological procedures, are discussed.


Magnetic resonance studies of the spatial arrangement of glucose-6-phosphate and chromium (III)-adenosine diphosphate at the catalytic site of hexokinase.
The interaction of CrADP, an exchange-inert paramagnetic analogue of Mg-ADP, with yeast hexokinase has been studied by measuring the effects of CrADP on the longitudinal nuclear relaxation rate (1/T1) of the protons of water and the protons and phosphorus atom of enzyme-bound glucose-6-P. The paramagnetic effect of CrADP on 1/T1 of water protons is enhanced upon complexation with the enzyme. Titrations measuring this paramagnetic effect at several enzyme concentrations in the presence of glucose-6-P yielded a characteristic enhancement factor for 1/T1 of water protons and the dissociation constant of CrADP from the ternary enzyme . ADPCr . glucose-6-P complex. The latter value (2 mM) is similar to that obtained from kinetic inhibition studies (Danenberg and Cleland [1975]. Biochemistry. 14:28). The presence of glucose-6-P increased the enhancement of the water relaxation rate by enzyme-bound CrADP, suggesting the formation of an enzyme . CrADP . glucose-6-P complex. The existence of such a complex was confirmed by the observation of a paramagnetic effect of enzyme-bound CrADP on the l/T1 of the 31P-nucleus and protons of enzyme-bound glucose-6-P. From the paramagnetic effects of enzyme-bound CrADP on the relaxation rates of the 31P-nucleus and the carbon-bound protons of glucose-6-P in the enzyme . ADPCr . glucose-6-P complex, using the correlation time of approximately 0.7 ns, determined from the magnetic field-dependence of 1/T1 of water protons over the range 24.3-360 MHz, a Cr3+ to phosphorus distance of 6.6 +/- 0.7 A and Cr3+ to alpha- and beta-anomeric proton distances of 8.9 and 9.7 A were calculated. These results imply the absence of a direct coordination of the phosphoryl group of glucose-6-P by the nucleotide-bound metal on hexokinase but indicate van der Waals contact between a phosphoryl oxygen of glucose-6-P and the hydration sphere of the nucleotide-bound metal. The distances are consistent with a model that assumes molecular contact between the phosphorus of glucose-6-P and a beta-phosphoryl oxygen of ADP suggesting an associative phosphoryl transfer. Because after phosphorylation of ADP, the metal ion is coordinated to the transferred phosphoryl group, the overall migration of the phosphoryl group during the phosphoryl transfer is approximately 3.6 A toward the nucleotide-bound metal. Little or no catalysis of phosphoryl transfer from glucose-6-P to alpha, beta-bidentate or beta-monodentate CrADP ( less than or equal to 0.05% of the rate found with MgADP) occurred in the presence of hexokinase, as monitored by glucose formation in a coupled assay system using glucose oxidase and peroxidase. The ability of beta, gamma-bidentate CrATP to act as a substrate (Danenberg and Cleland [1975].


Third-trimester ultrasound dating algorithms derived from pregnancies conceived with artificial reproductive techniques.
To derive an accurate formula for ultrasound estimation of gestational age in late pregnancy. A database of 123 singleton pregnancies conceived by artificial reproductive techniques with third-trimester ultrasound measurements was studied. Biometry variables included the fetal head circumference (HC) and femur length (FL). The dataset was equally divided into a derivation sample and a target sample. To derive the equations of best fit, regression analysis was used, with true menstrual age as the dependent variable and fetal biometry measurements as independent variables. The formulae were tested on the target set and the menstrual age estimates were compared with the actual menstrual age. Clinical performance was estimated in terms of systematic and random errors, absolute errors and their 95% CI values. The menstrual ages at time of scanning ranged from 26 to 41 weeks, with a mean of 33 weeks. The best performing derived formula was a combination of HC and FL. This had a random error of 7.5 days and prediction errors within a 95% confidence limit of -13 to +17 days. With FL only, the random error was 8.2 days, whereas using the HC only yielded a random error of 9.4 days. Ultrasound estimation of gestational age in late pregnancy is better than indicated by older publications. It is more accurately estimated by combining the HC with the FL than by using the FL measurements alone.


Chemohypersensitivity and autonomic modulation of venous capacitance in the pathophysiology of acute decompensated heart failure.
Heart failure is increasing in prevalence around the world, with hospitalization and re-hospitalization as a result of acute decompensated heart failure (ADHF) presenting a huge social and economic burden. The mechanism for this decompensation is not clear. Whilst in some cases it is due to volume expansion, over half of patients with an acute admission for ADHF did not experience an increase in total body weight. This calls into question the current treatment strategy of targeting salt and water retention in ADHF. An alternative hypothesis proposed by Fallick et al. is that an endogenous fluid shift from the splanchnic bed is implicated in ADHF, rather than an exogenous fluid gain. The hypothesis states further that this shift is triggered by an increase in sympathetic tone causing vasoconstriction in the splanchnic bed, a mechanism that can translocate blood rapidly into the effective circulating volume, generating the raised venous pressure and congestion seen in ADHF. This hypothesis encourages a new clinical paradigm which focuses on the underlying mechanisms of congestion, and highlights the importance of fluid redistribution and neurohormonal activation in its pathophysiology. In this article, we consider the concept that ADHF is attributable to episodic sympathetic hyperactivity, resulting in fluid shifts from the splanchnic bed. Chemosensitivity is a pathologic autonomic mechanism associated with mortality in patients with systolic heart failure. Tonic and episodic activity of the peripheral chemoreceptors may underlie the syndrome of acute decompensation without total body salt and water expansion. We suggest in this manuscript that chemosensitivity in response to intermittent hypoxia, such as experienced in sleep disordered breathing, may explain the intermittent sympathetic hyperactivity underlying renal sodium retention and acute volume redistribution from venous storage sites. This hypothesis provides an alternative structure to guide novel diagnostic and treatment strategies for ADHF.


Highly efficient production of phosphorylated hepatitis B core particles in yeast Pichia pastoris.
Virus-like particles (VLPs) of the recombinant hepatitis B virus (HBV) core protein (HBc) are routinely used in HBV diagnostics worldwide and are of potential interest as carriers of foreign peptides (e.g., immunological epitopes and targeting addresses, and/or as vessels for packaged diagnostic and therapeutic nanomaterials). Despite numerous reports exploiting different expression systems, a rapid and comprehensive large-scale methodology for purification of HBc VLPs from yeast is still lacking. Here, we present a convenient protocol for highly efficient production and rapid purification of endotoxin-free ayw subtype HBc VLPs from the methylotrophic yeast Pichia pastoris. The HBc gene expression cassette along with the geneticin resistance gene was transferred to the P. pastoris genome via homologous recombination. A producer clone was selected among 2000 transformants for the optimal synthesis of the target protein. Fermentation conditions were established ensuring biomass accumulation of 163g/L. A simple combination of pH/heat and salt treatment followed by a single anion-exchange chromatography step resulted in a more than 90% pure preparation of HBc VLPs, with a yield of about 3.0mg per 1g of wet cells. Purification is performed within a day and may be easily scaled up if necessary. The quality of HBc VLPs was verified by electron microscopy. Mass spectrometry analysis and direct polyacrylamide gel staining revealed phosphorylation of HBc at at least two sites. To our knowledge, this is the first report of HBc phosphorylation in yeast.


Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin.
Overproduction of glucose by the liver in the face of insulin resistance is a primary cause of hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). However, mechanisms involved in control of hepatic glucose output (HGO) remain less than clear, even in normal individuals. Recent results have supported an indirect extrahepatic effect of insulin as the primary locus of insulin action to restrain HGO. One suggested extrahepatic site is the pancreatic alpha-cell. To examine whether insulin's extrahepatic site is independent of the alpha-cells, HGO suppression was examined independent of changes in glucagon secretion or insulin antagonism of glucagon action. Euglycemic glucose clamps (n = 40) with somatostatin infusion were performed in conscious dogs (n = 5). Paired experiments were conducted in which insulin was infused either portally (1.2, 3.0, 6.0 pmol.min-1.kg-1) or peripherally at half the portal infusion rate (0.6, 1.5, 3.0 pmol.min-1.kg-1). Additional zero and saturating portal-dose experiments (100 pmol.min-1.kg-1) were also performed. For the paired experiments, portal insulin infusion resulted in portal insulin concentrations approximately two to three times higher than in the corresponding peripheral insulin infusion experiments, while at the same time peripheral insulin concentrations were approximately matched. Equal peripheral insulin concentration resulted in equivalent HGO suppression irrespective of the portal concentrations. Thus, insulin affects a signal at a peripheral site, other than alpha-cell, that in turn suppresses hepatic glucose production. To investigate the nature of this signal, we measured alanine, lactate, and free fatty acids (FFAs).(ABSTRACT TRUNCATED AT 250 WORDS)


The Role of Pharmacogenomics in Anesthesia Pharmacology.
The field of pharmacogenomics seeks to identify the impact of genetic variants on drug dosing, response, metabolism, and safety outcomes. The narrow therapeutic indices for anesthesia drugs, variability of patient responses to anesthesia, and the risks associated with surgery make anesthetics and the perioperative period prime targets for pharmacogenetic research. Anesthesia providers strive to optimize anesthesia delivery and patient outcomes and to specifically reduce anesthesia-related risks and negative outcomes. Despite pharmacogenomics emerging from the field of anesthesia, the most significant advances to date in the understanding and application of genetics to pharmacology have occurred outside of anesthesiology. This chapter provides an overview of genetic concepts fundamental to understanding the pharmacogenetics of anesthesia practice and presents the current state of the science with respect to the genetic influence on the response to volatile and intravenous anesthetic agents and opioid receptor agonists commonly used in anesthesia practice. In addition, the chapter delineates U.S. Food and Drug Administration labeling tenets for pharmacogenetics, discusses clinical implications of pharmacogenomics for family members, and highlights the potential for future paradigm shifts in pharmacogenomics of anesthesia practice.


Characterization of ACTH mediated suppression of MHC class II expression by murine peritoneal macrophages.
The effect of ACTH on the expression of major histocompatibility complex (MHC) class II (I-A) glycoprotein by murine peritoneal macrophages was evaluated. ACTH suppressed the expression of I-A by macrophages in a time- and dose-dependent manner. ACTH mediated its effect by decreasing the level of I-A mRNA. ACTH suppressed the expression of I-A by macrophages from mice that are susceptible to the in vivo growth of mycobacteria but did not affect the expression of I-A by macrophages from Mycobacterium bovis strain (BCG)-resistant mice. The concentrations of ACTH required to suppress I-A expression were greater than that required for an effect on adrenal steroid production and may be related to the localized production of ACTH by lymphocytes and macrophages.


Conditional inhibition of autophagy genes in adult Drosophila impairs immunity without compromising longevity.
Immune function declines with age in Drosophila and humans, and autophagy is implicated in immune function. In addition, autophagy genes are required for life span extension caused by reduced insulin/IGF1-like signaling and dietary restriction in Caenorhabditiselegans. To test if the autophagy pathway might be limiting for immunity and/or life span in adult Drosophila, the Geneswitch system was used to cause conditional inactivation of the autophagy genes Atg5, Atg7 and Atg12 by RNAi. Conditional inhibition of Atg genes in adult flies reduced lysotracker staining of adult tissues, and reduced resistance to injected Escherichia coli, as evidenced by increased bacterial titers and reduced fly survival. However, survival of uninjected flies was unaffected by Atg gene inactivation. The data indicate that Atg gene activity is required for normal immune function in adult flies, and suggest that neither autophagy nor immune function are limiting for adult life span under typical laboratory conditions.


Synthesis and evaluation of 6-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine as a PET tracer for nicotinic acetylcholine receptors.
Both ABT-594 ((R)-2-chloro-5-(2-azetidinylmethoxy)pyridine) and A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine), novel nicotinic agonists that possess potent non-opioid analgesic properties, have high affinity for neuronal nicotinic acetylcholine receptors (nAChR) but do not elicit the pronounced toxicity of epibatidine. 6-[(18)F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[(18)F]fluoro-A-85380), a F-18 labeled analogue of these two compounds, is therefore a promising radioligand for positron emission tomography (PET) studies in humans. The use of trimethylammonium as a leaving group in nucleophilic aromatic substitution reactions has proven to be a versatile and efficient strategy, and offers several advantages over other leaving groups. Here, we report the synthetic strategy for the preparation of a precursor, as a trimethylammonium iodide salt, and its use in the radiosynthesis to 6-[(18)F]fluoro-A-85380. Preliminary compartative PET studies of 6-[(18)F]fluoro-A-85380 and 2-[(18)F]fluoro-A-85380 were carried out in baboon to examine their suitability as tracers for studying nAChR system.


Protein structural change upon ligand binding correlates with enzymatic reaction mechanism.
Overall structural changes of enzymes in response to ligand binding were investigated by database analysis of 62 non-redundant enzymes whose ligand-unbound and ligand-bound forms were available in the Protein Data Bank. The results of analysis indicate that transferases often undergo large rigid-body domain motions upon ligand binding, while other enzymes, most typically, hydrolases, change their structures to a small extent. It was also found that the solvent accessibility of the substrate molecule was low in transferases but high in hydrolases. These differences are explained by the enzymatic reaction mechanisms. The transferase reaction requires the catalytic groups to be insulated from the water environment, and thus transferases bury the ligand molecule inside the protein by closing the cleft. On the other hand, the hydrolase reaction involves the surrounding water molecules and occurs at the protein surface, requiring only a small structural change.


Pyruvate kinase activity and response to allosteric effectors in rat erythrocytes and reticulocytes fractionated by multiple partitioning in aqueous two-phase systems.
Specific activity of pyruvate kinase decreases as the age of rat erythrocytes increases in fractions obtained by counter-current distribution in dextran-polyethylene glycol biphasic systems; the enzyme is inhibited by ATP and activated by fructose-1,6-bisphosphate at low phosphoenol pyruvate concentrations. Specific activity does not change in fractions from greater than 95 per cent-rich reticulocytes (anaemic rats); the enzyme is inhibited by ATP but not activated by fructose-1,6-bisphosphate. These results can be explained on the basis of different pyruvate kinase isozymes and suggest that decrease in activity is not affecting regulatory properties during erythrocytes aging.


COVID-19 infection and vaccination uptake in men and gender-diverse people who have sex with men in the UK: analyses of a large, online community cross-sectional survey (RiiSH-COVID) undertaken November-December 2021.
Men and gender-diverse people who have sex with men are disproportionately affected by health conditions associated with increased risk of severe illness due to COVID-19 infection. An online cross-sectional survey of men and gender-diverse people who have sex with men in the UK recruited via social networking and dating applications from 22 November-12 December 2021. Eligible participants included self-identifying men, transgender women, or gender-diverse individuals assigned male at birth (AMAB), aged ≥ 16, who were UK residents, and self-reported having had sex with an individual AMAB in the last year. We calculated self-reported COVID-19 test-positivity, proportion reporting long COVID, and COVID-19 vaccination uptake anytime from pandemic start to survey completion (November/December 2021). Logistic regression was used to assess sociodemographic, clinical, and behavioural characteristics associated with SARS-CoV-2 (COVID-19) test positivity and complete vaccination (≥ 2 vaccine doses). Among 1,039 participants (88.1% white, median age 41 years [interquartile range: 31-51]), 18.6% (95% CI: 16.3%-21.1%) reported COVID-19 test positivity, 8.3% (95% CI: 6.7%-10.1%) long COVID, and 94.5% (95% CI: 93.3%-96.1%) complete COVID-19 vaccination through late 2021. In multivariable models, COVID-19 test positivity was associated with UK country of residence (aOR: 2.22 [95% CI: 1.26-3.92], England vs outside England) and employment (aOR: 1.55 [95% CI: 1.01-2.38], current employment vs not employed). Complete COVID-19 vaccination was associated with age (aOR: 1.04 [95% CI: 1.01-1.06], per increasing year), gender (aOR: 0.26 [95% CI: 0.09-0.72], gender minority vs cisgender), education (aOR: 2.11 [95% CI: 1.12-3.98], degree-level or higher vs below degree-level), employment (aOR: 2.07 [95% CI: 1.08-3.94], current employment vs not employed), relationship status (aOR: 0.50 [95% CI: 0.25-1.00], single vs in a relationship), COVID-19 infection history (aOR: 0.47 [95% CI: 0.25-0.88], test positivity or self-perceived infection vs no history), known HPV vaccination (aOR: 3.32 [95% CI: 1.43-7.75]), and low self-worth (aOR: 0.29 [95% CI: 0.15-0.54]). In this community sample, COVID-19 vaccine uptake was high overall, though lower among younger age-groups, gender minorities, and those with poorer well-being. Efforts are needed to limit COVID-19 related exacerbation of health inequalities in groups who already experience a greater burden of poor health relative to other men who have sex with men.


Lack of evidence for increased descending inhibition on the dorsal horn of the rat following periaqueductal grey morphine microinjections.
1 Recordings were made from 18 neurones in the dorsal horn of the rat, anaesthetized with halothane. All cells received A- and C-fibre inputs and responded to innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hindpaw. Transcutaneous application of suprathreshold (mean 3.2 T) 2 ms square-wave pulses to the centre of the receptive fields resulted in responses to A- and C-fibre activation being observed; a mean 32.4 +/- 6.0 C-fibre latency spikes were evoked per stimulus. 2 A high dose (20 micrograms) of morphine in 0.5 microliter sterile saline, microinjected into the periaqueductal grey matter (PAG) had no effect on the C-fibre-evoked activity of thirteen cells (72%) and facilitated 5 neurones (28%). Microinjection sites covered most of the PAG particularly the caudal medioventral zone. 3 A relatively high dose (6 mg kg-1, i.v.) of systemic morphine chloride, sufficient to elicit the direct spinal action of the opiate, inhibited all 5 cells tested. 4 We conclude that there is little evidence that the supraspinal action of morphine includes increased descending controls and depression of dorsal horn neurones in the rat.


Regulatory pathway analysis of coat color genes in Mongolian horses.
Studies on the molecular genetics of horse skin pigmentation have typically focused on very few genes and proteins. In this study, we used Illumina sequencing to determine the global gene expression profiles in horses with white-colored coats and those with black-colored coats, with the goal of identifying novel genes that could regulate horse coat color. Genes encoding ribosomal-associated proteins were highly expressed in horse skin. We found a total of 231 unigenes that were differentially expressed between horses with white coats and horses with black coats; 119 were down-regulated, and 112 were up-regulated. Many of the up-regulated genes in black horses, such as genes related to tyrosine metabolism, may directly regulate dark coat color. Keratin genes, MIA family genes, fatty acid-related genes, and melanoma-associated genes were also differentially regulated, which suggests that they may play important roles in coat color formation. These findings show that the transcription profiles from white and black horse skin provide useful information to understand the genetics underlying the control of skin melanin synthesis in horses, which may enhance our knowledge of human skin diseases, such as melanoma and albinism.


Assessment of Clinical Practices for Crushing Medication in Geriatric Units.
To assess the modification of the form of medication and evaluate staff observance of good clinical practices. One-day assessment of clinical practices. 17 geriatrics units in the 3 Teaching Hospitals of Paris-Sud (APHP), France. Elderly in-patients with difficulties swallowing capsules and tablets. Assessment of target-patient prescriptions and direct observation of nurses' medical rounds. 155/526 in-patients (29.5%) were unable to swallow tablets or capsules: 98 (40.3%) in long-term care, 46 patients (23.8%) in the rehabilitation unit and 11 (12.2%) in the acute care unit (p = .005). In thirty-nine (27.3%) of the 143 prescriptions studied all tablets were safe to crush and all capsules were safe to open. In 104 cases, at least one medication could not be safely modified, including 26 cases (18.2%) in which none of the prescribed drugs were safe to crush or open. In 48.2% of the 110 medications that were crushed, crushing was forbidden, and presented a potential threat in 12.7% of cases or a reduced efficacy in 8.2% of cases. Crushing methods were rarely appropriate: no specific protective equipment was used (81.8%), crushing equipment was shared between patients without cleaning (95.1%), medications were spilled or lost (69.9%). The method of administration was appropriate (water, jellified water) in 25% of the cases, questionable (soup, coffee, compote, juice, cream) in 55% of the cases and unacceptable (laxative) in 21% of the cases. Management of drug prescriptions in patients with swallowing difficulties is not optimal, and may even have iatrogenic effects. In this study, 12.7% of the modifications of the drug form could have been harmful. Doctors, pharmacists and nurses need to reevaluate their practices.


Comparison of Sensitivity Encoding (SENSE) and Compressed Sensing-SENSE for Contrast-Enhanced T1-Weighted Imaging in Patients With Crohn Disease Undergoing MR Enterography.
BACKGROUND. Long acquisition times for breath-hold contrast-enhanced (CE) T1-weighted imaging in MR enterography (MRE) protocols result in reduced image quality. OBJECTIVE. The purpose of this study was to compare CE T1-weighted imaging performed using sensitivity encoding (SENSE) and compressed sensing-SENSE (CS-SENSE) in terms of image quality and diagnostic performance for active inflammation in Crohn disease (CD). METHODS. This retrospective study included 41 patients (31 men, 10 women; mean age, 34 ± 12 [SD] years) who underwent MRE for known or suspected CD between June 2020 and September 2020. MRE was performed in one of two scanning rooms depending on scheduling availability. Per institutional protocol, in one room, the enteric phase was acquired using SENSE (acceleration factor, 3) and the portal phase was acquired using CS-SENSE (acceleration factor, 5); this order was reversed in the other room. Two radiologists independently assessed sequences for subjective image quality measures at the patient level and for active inflammation at the bowel-segment level. Mean image quality scores between readers were computed. Diagnostic performance for active inflammation was compared between SENSE and CS-SENSE using generalized estimating equations; a separate experienced radiologist reviewed the full MRE protocol to establish the reference standard. RESULTS. The mean acquisition time of CE T1-weighted imaging was 17.2 ± 1.1 seconds for SENSE versus 11.5 ± 0.8 seconds for CS-SENSE (p < .001). CS-SENSE scored significantly better than SENSE in overall image quality (4.2 ± 0.7 vs 3.7 ± 1.1; p = .02), motion artifacts (4.0 ± 0.8 vs 3.6 ± 1.2; p = .006), and aliasing artifacts (4.8 ± 0.4 vs 4.2 ± 0.6; p < .001). CS-SENSE scored significantly worse than SENSE in synthetic appearance (4.6 ± 0.5 vs 4.8 ± 0.4; p = .003). Contrast, sharpness, and blurring were not different between sequences (p > .05). For reader 1, CS-SENSE, compared with SENSE, showed a sensitivity of 86% versus 81% (p = .09), specificity of 88% versus 83% (p = .08), and accuracy of 87% versus 82% (p = .56). For reader 2, CS-SENSE, compared with SENSE, showed a sensitivity of 92% versus 79% (p = .006), specificity of 90% versus 98% (p = .16), and accuracy of 91% versus 86% (p = .002). CONCLUSION. Use of CS-SENSE for CE T1-weighted imaging in MRE protocols results in reduced scan times with reduced artifact and improved image quality. CLINICAL IMPACT. The benefits of CS-SENSE in MRE protocols may improve the diagnostic performance for active inflammation in CD.


Community composition and phyto-diversity assessment of ganda roba and ganda shabbo sites in Damota natural vegetation, eastern Ethiopia.
Anthropogenic activities like overexploitation of natural vegetation and plantation of exotic species in degraded areas are commonly occurring in the natural vegetation of Ethiopia. Natural forests conserve plant species and provide a number of ecosystem services to society. This study focuses on the tree species composition and regeneration possibility of Ganda Roba and Ganda Shabbo in Natural Vegetation of Damota, Eastern Ethiopia. The sample of tree species were collected from 40 plots of 20 m × 20 m, while seedlings and saplings were collected from 160 plots of 5 m × 5 m and 320 plots of 1 m × 1 m, respectively from elevations ranging from 2039-3023 m. There were 47 tree species identified, belonging to 32 genera and 21 families, with Fabacaea being the most prominent family with the most species. The mean species richness of adult trees was 39 ± 2.4, for saplings 38 ± 6.5, and for seedlings, it was 34.5 ± 5.3. The average seedling density was 21850 ± 1131.37 individuals ha-1, for saplings 17162.5 ± 972.27 individuals ha-1, and of mature trees 12450 ± 2050.61individuals ha-1. The mean basal area for trees, saplings, and seedlings were 267.65 ± 30.78 m2 ha-1, 68.6 ± 4.12 m2 ha-1, and 45.83 ± 2.86 m2 ha-1, respectively. Good regeneration was seen in 41% of total species in the Ganda Roba site while in Ganda Shabbo fair regeneration was seen in 44% of species. In Ganda Roba and Ganda Shabbo sites, 7% and 6% of species exhibited no regeneration respectively. Density-diameter distribution curve exhibited a consistent reduction in tree densities with an rise in DBH patterns. The current study provides baseline information for foresters and policymakers to better manage the forest for sustaining tree diversity and regeneration patterns and formulate better strategic conservation plans for the future.


Characterization of an immunodominant Giardia lamblia protein antigen related to alpha giardin.
The trophozoites of Giardia lamblia possess several protein antigens, predominant among them a protein of approximately 32,000 Da. In the present study, we used monospecific antibodies that recognize this protein to demonstrate its presence on a variety of G. lamblia isolates from human and animal sources. Immune electron microscopy was used to localize 32-kDa antigen on the trophozoite membrane and disk. Immunofluorescent assays employing monospecific antibodies confirmed the presence of 32-kDa antigen on the membrane and disk and its absence on flagella or nuclei. The N-terminal 17 amino acids of the 32-kDa antigen are identical to alpha-1-giardin, a protein component of microribbons on the ventral disk. These results suggest that the 32-kDa immunodominant trophozoite antigen is alpha-1-giardin.


Evaluation of a new preservation solution: Celsior in the isolated rat lung. Paris-Sud University Lung Transplatation Group.
We compared Celsior solution, a new and original extracellular preservation solution, with blood-based Wallwork's solution. In two groups of isolated rat lungs submitted to 4 hours of cold ischemia, pulmonary arterial and venous resistances, coefficient of filtration, and wet-to-dry lung weight ratio were determined at baseline and after 90 minutes of reperfusion. After ischemia-reperfusion, percentage of increases above the respective baseline coefficient of filtration values were 93% +/- 7% in the Wallwork group and 7% +/- 3% in the Celsior group (p < 0.001 versus Wallwork's solution). These results show that Celsior consistently prevented the ischemia-reperfusion-induced increase in pulmonary microvascular permeability as compared with Wallwork's solution.


Automated workflows for modelling chemical fate, kinetics and toxicity.
Automation is universal in today's society, from operating equipment such as machinery, in factory processes, to self-parking automobile systems. While these examples show the efficiency and effectiveness of automated mechanical processes, automated procedures that support the chemical risk assessment process are still in their infancy. Future human safety assessments will rely increasingly on the use of automated models, such as physiologically based kinetic (PBK) and dynamic models and the virtual cell based assay (VCBA). These biologically-based models will be coupled with chemistry-based prediction models that also automate the generation of key input parameters such as physicochemical properties. The development of automated software tools is an important step in harmonising and expediting the chemical safety assessment process. In this study, we illustrate how the KNIME Analytics Platform can be used to provide a user-friendly graphical interface for these biokinetic models, such as PBK models and VCBA, which simulates the fate of chemicals in vivo within the body and in vitro test systems respectively.


Phase II trial of SarCNU in malignant glioma: unexpected pulmonary toxicity with a novel nitrosourea: a phase II trial of the national cancer institute of canada clinical trials group.
A multi-centre phase II study of SarCNU-a novel chloroethylnitrosourea (CNU)-in patients with recurrent malignant glioma to assess response rate, survival and effects of treatment. Ten patients with histologically proven malignant glioma (seven with glioblastoma multiforme (GBM) and three with anaplastic astrocytoma) received SarCNU (860 mg/m(2)) orally on days 1, 5 and 9 on a 6 week schedule. A total of ten patients were treated on protocol before accrual was suspended for a high rate of pulmonary toxicity. Of eight evaluable patients, five demonstrated at least one grade deterioration in DLCO from baseline. This necessitated premature closure of the trial. Stable disease was seen in five of seven evaluable patients (median duration 4.8 months; range 0.8-9.2) with progressive disease in the remainder. Despite promising preclinical data, SarCNU caused pulmonary toxicity in patients with recurrent malignant glioma and we plan no further studies in this indication.


Influence of gut and intratumoral microbiota on the immune microenvironment and anti-cancer therapy.
Microbiota has been implicated in the regulation of tumor progression and therapeutic efficacy. However, the effect of microbiota on disease progression is context dependent, differing according to tumor types, therapeutic regimens, and composition of the microbiota, calling for a deeper understanding of host-microbiome interactions. Previous studies have demonstrated that gut microbiota influences disease progression by regulating local and systemic immunity. Notably, with the advent of next-generation sequencing technology, intratumoral microbiota has also been found and constitutes an important component of the tumor microenvironment. In this review, we summarize recent knowledge about the identification of intra-tumor microbiota and discuss the role of gut and intratumoral microbiota in solid tumors in the angle of immune microenvironment interaction. Furthermore, we discuss how these findings may benefit current anti-cancer approaches. Key problems to be solved in ongoing and future research are highlighted.


Differentiating Fukushima and Nagasaki plutonium from global fallout using 241Pu/239Pu atom ratios: Pu vs. Cs uptake and dose to biota.
Plutonium (Pu) has been released in Japan by two very different types of nuclear events - the 2011 Fukushima accident and the 1945 detonation of a Pu-core weapon at Nagasaki. Here we report on the use of Accelerator Mass Spectrometry (AMS) methods to distinguish the FDNPP-accident and Nagasaki-detonation Pu from worldwide fallout in soils and biota. The FDNPP-Pu was distinct in local environmental samples through the use of highly sensitive 241Pu/239Pu atom ratios. In contrast, other typically-used Pu measures (240Pu/239Pu atom ratios, activity concentrations) did not distinguish the FDNPP Pu from background in most 2016 environmental samples. Results indicate the accident contributed new Pu of ~0.4%-2% in the 0-5 cm soils, ~0.3%-3% in earthworms, and ~1%-10% in wild boar near the FDNPP. The uptake of Pu in the boar appears to be relatively uninfluenced by the glassy particle forms of fallout near the FDNPP, whereas the 134,137Cs uptake appears to be highly influenced. Near Nagasaki, the lasting legacy of Pu is greater with high percentages of Pu sourced from the 1945 detonation (~93% soils, ~88% earthworm, ~96% boar). The Pu at Nagasaki contrasts with that from the FDNPP in having proportionately higher 239Pu and was distinguished by both 240Pu/239Pu and 241Pu/239Pu atom ratios. However, compared with the contamination near the Chernobyl accident site, the Pu amounts at all study sites in Japan are orders of magnitude lower. The dose rates from Pu to organisms in the FDNPP and Nagasaki areas, as well as to human consumers of wild boar meat, have been only slightly elevated above background. Our data demonstrate the greater sensitivity of 241Pu/239Pu atom ratios in tracing Pu from nuclear releases and suggest that the Nagasaki-detonation Pu will be distinguishable in the environment for much longer than the FDNPP-accident Pu.


P-tau235: a novel biomarker for staging preclinical Alzheimer's disease.
Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.


A Multiscale Mathematical Model for Tumor Growth, Incorporating the GLUT1 Expression.
We propose a multiscale mathematical model for the avascular tumor growth. At the cellular scale, the model takes into account the biochemical environment, the different phases of the tumor cell cycle, the cells signaling, and cellular mechanics through a bioenergetics approach. A mathematical function is employed, namely, the "health function," that stands for the cells' biochemical energy in tumor's different regions, with respect to the carrying capacity of the extracellular matrix (ECM) and the metabolic processes of tumor cells. We also encounter in the model the glucose transporter GLUT1. The role that it plays in mitosis is investigated for the different kinds of tumor cell populations, as its overexpression in malignant cells is associated with the disease development. Simulations have been made, scaling up and estimating the evolution of tumor cell populations. By incorporating biochemical processes in tumor growth multiscale modeling, we aim to provide better understanding of the disease and assessment of possible targeted therapeutic strategies.


The analgesic activity of intrathecal tianeptine, an atypical antidepressant, in a rat model of inflammatory pain.
Tianeptine is an atypical antidepressant that exhibits structural similarities to the tricyclic antidepressants but has distinct neurochemical properties. We evaluated the antinociceptive activity of tianeptine and its mechanism of action regarding serotonergic and adrenergic transmission at the spinal level. The effects of intrathecally administered tianeptine and DUP-697 (a cyclooxygenase-2 inhibitor) were examined on flinching behavior evoked by intraplantar formalin injection, and their interaction was characterized using isobolographic analysis. Dihydroergocristine, prazosin, or yohimbine-which are serotonergic, α-1, and α-2 adrenergic receptor antagonists, respectively-were intrathecally administered 10 minutes before tianeptine to investigate its mechanism of action. Intrathecally administered tianeptine and DUP-697 reduced the flinching response evoked by formalin injection during phases 1 and 2 in an additive fashion. Prazosin and yohimbine attenuated the antinociceptive effect of intrathecal tianeptine during both phases of the formalin test. Dihydroergocristine reversed the antinociception of tianeptine during phase 2, but not during phase 1. Intrathecally administered tianeptine effectively relieved inflammatory pain in rats. The serotonergic system is related to the activity of tianeptine for facilitated pain at the spinal level. Adrenergic transmission is also involved in tianeptine-induced analgesia for both facilitated and acute pain. The combination of tianeptine and cyclooxygenase-2 inhibitor may provide additional benefits for the management of inflammatory pain.


Wheat cysteine proteases triticain alpha, beta and gamma exhibit mutually distinct responses to gibberellin in germinating seeds.
We cloned three novel papain-type cysteine proteases (CPs), triticain alpha, beta and gamma, from 1-d-germinating wheat seeds. Triticain alpha, beta and gamma were constituted with 461, 472 and 365 amino acid residues, respectively, and had Cys-His-Asn catalytic triads as well as signal and propeptide sequences. Triticain gamma contained a putative vacuole-sorting sequence. Phylogenetic analysis showed that these CPs were divided into mutually different clusters. Triticain alpha and gamma mRNAs were expressed in seeds at an early stage of maturation and at the stage of germination 2d after imbibition, while triticain beta mRNA appeared shortly after imbibition. The expression of mRNAs for triticain alpha and gamma was suppressed by uniconazol, a gibberellin synthesis inhibitor. All the three CP mRNAs were strongly expressed in both embryo and aleurone layers. These results suggest that triticain alpha, beta and gamma play differential roles in seed maturation as well as in digestion of storage proteins during germination.


Activation of glutaminase by phosphoribosyl-pyrophosphate and its interference with the assay of phosphoribosylpyrophosphate amidotransferase.
Phosphate-dependent glutaminase (L-glutamine amidohydrolase, EC 220.127.116.11) from rat liver was found to be strongly activated by phosphoribosylpyrophosphate (P-rib-PP), the substrate of amidophosphoribosyltransferase (EC 220.127.116.11). Since the assay of the latter is based on the P-rib-PP-dependent conversion of glutamine to glutamate, the amidotransferase activities determined in crude tissue preparations were found to be too high. The interference of glutaminase, however, could be completely eliminated by its inactivation at 50 degrees C. Amidotransferase was not affected by the heat treatment. Because of the increased rate of the glutamate formation at this temperature, the incubation time of the assay could be significantly reduced.


The Effect of Refractive Amblyopia on the Frisby Stereotest.
To identify the expected degree of stereoacuity measured by the Frisby Stereotest, in various degrees of unilateral refractive amblyopia. A prospective investigation of 22 patients, with a clinical diagnosis of unilateral refractive amblyopia. All patients were aged 4-12 years and seen between February and November 2021.All patients were recruited to the study at their first return visit with new glasses as prescribed by our physicians, following a cycloplegic refraction. All patients had a full orthoptic examination including the near Frisby Stereotest, visual acuity assessment, an induced tropia test (ITT) using a 20 base-in prism. A fixation preference qualified as amblyopia for the purpose of this study. All tests performed are part of our routine examination. Regression analysis was performed on the data to identify a correlation between variables. We compared the Frisby scores with the maximum visual acuity difference between the eyes, the amblyopic visual acuity, the non-amblyopic visual acuity, and the spherical equivalent of the patients' refractions.Analysis revealed a strong relationship between both the visual acuity difference and the Frisby score (r = 0.64, R2 = 0.41), and the amblyopic visual acuity and Frisby score (r = 0.73, R2 = 0.53). There was no relationship between the anisometropia based on spherical equivalent refractions (r = 0.03, R2 = 0.0007). Given the moderate-to-strong correlation noted between visual acuity and stereoacuity, we suggest that the Frisby Stereotest can be utilized to imply possible refractive amblyopia and allow earlier intervention which may lead to more successful outcomes.


Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia.
The finding of pyramidal cell disarray in the hippocampus of patients with schizophrenia has been disputed by several groups. Conflicting results have been attributed to differences in the subtype of patients used, staining method, the side of the hippocampus studied and the way cellular disarray has been measured. In the present study, we correct for these confounds by using a well-defined population of schizophrenic patients (n = 14) and controls (n = 10) in which Golgi impregnated material was available. Measurements were performed manually according to the method of Kovelman and Scheibel (1984). Pyramidal cell disarray for the CA1/prosubicular interface indicated significant differences between patients and controls (p = 0.0183). The findings were attributed to a bias accrued to referencing measurements in schizophrenics to the distorted circumventricular surface of the temporal horn.


Rare Occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers.
Aristolochic acids (AAs) are potent mutagens commonly found in herbal plant-based remedies widely used throughout Asian countries. To understand whether AA is involved in the tumorigenesis of the oro-gastrointestinal tract, we used whole-exome sequencing to profile 54 cases of four distinct types of oro-gastrointestinal tract cancer (OGITC) from Taiwan. A diverse landscape of mutational signatures including those from DNA mismatch repair and reactive oxygen species was observed. APOBEC mutational signatures were observed in 60% of oral squamous cell carcinomas. Only one sample harbored AA mutational signatures, contradictory to prior reports of cancers from Taiwan. The metabolism of AA in the liver and urinary tract, transient exposure time, and high cell turnover rates at OGITC sites may explain our findings. AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis.


Incorporation of Personality Typing into a Neurologic Surgery Residency Program: Utility in Systems Based Practice, Professionalism, and Self-Reflection.
In the neurosurgery residency, inherent personality traits can play a significant role in the adaptability and success of the resident physician. The Myers-Briggs Type Indicator has been used extensively in the business and administrative world. As a quality improvement effort to promote self-reflection, personal and professional improvement among both faculty and resident members of a department of neurosurgery at a tertiary care academic medical center, a group learning exercise was implemented using the Myers-Briggs Type Indicator. All residents (11/11) and 85% of faculty (11/13) participated in the exercise. INTJ ("Mastermind," "Scientist") was the most commonly represented (36.4% compared with 2.1% in the general population; P < 0.001). ENTJ ("Field Marshall," "Executive") was present in 18% compared with 1.8% of the general population (P < 0.001). Thus, the 2 most common types (_NTJ) were present in 54.4% of our department compared with 3.9% of the general population (P < 0.001). Personality typing can be used to gain valuable insight into the composition of neurosurgery residency cohorts and resolve conflicts arising from personality differences within these groups as well as within the larger hospital setting.


Reference gene selection for qRT-PCR analysis of season- and tissue-specific gene expression profiles in the honey bee Apis mellifera.
Honey bees are both important pollinators and model insects due to their highly developed sociality and colony management. To better understand the molecular mechanisms underlying honey bee colony management, it is important to investigate the expression of genes putatively involved in colony physiology. Although quantitative real-time PCR (qRT-PCR) can be used to quantify the relative expression of target genes, internal reference genes (which are stably expressed across different conditions) must first be identified to ensure accurate normalisation of target genes. To identify reliable reference genes in honey bee (Apis mellifera) colonies, therefore, we evaluated seven candidate genes (ACT, EIF, EF1, RPN2, RPS5, RPS18 and GAPDH) in samples collected from three honey bee tissue types (head, thorax and abdomen) across all four seasons using three analysis programmes (NormFinder, BestKeeper and geNorm). Subsequently, we validated various normalisation methods using each of the seven reference genes and a combination of multiple genes by calculating the expression of catalase (CAT). Although the genes ranked as the most stable gene were slightly different on conditions and analysis methods, our results suggest that RPS5, RPS18 and GAPDH represent optimal honey bee reference genes for target gene normalisation in qRT-PCR analysis of various honey bee tissue samples collected across seasons.


Pharmacological effects of isopolar phosphonate analogues of ATP on P2-purinoceptors in guinea-pig taenia coli and urinary bladder.
Isopolar methylene phosphonate analogues of adenosine triphosphate (ATP) were synthesized and tested on the guinea-pig isolated taenia coli (where ATP causes relaxation) and urinary bladder (where ATP causes contraction), to see if restoration of the electronegativity of the methylene linkage would enhance pharmacological potency. The compounds used were the dichloromethylene and difluoromethylene analogues of adenosine 5'-(beta,gamma-methylene)triphosphonate (AMP-PCP), L-adenosine 5'-(beta,gamma-methylene)triphosphonate (L-AMP-PCP) and 2-methylthioadenosine 5'-(beta,gamma-methylene)-triphosphonate (2-methylthio-AMP-PCP). The order of potency of the analogues depended on the tissue, and was independent of the nature of the purine or ribose moieties. None of the analogues was degraded by ectonucleotidases on either tissue. In the taenia coli the order of potency for relaxation was difluoromethylene greater than or equal to dichloromethylene greater than methylene, and this reflected the order of electronegativity of the analogues. The isopolar analogues of L-AMP-PCP were inactive in the taenia coli. In the bladder the order of potency for contraction was difluoromethylene greater than or equal to methylene greater than dichloromethylene, suggesting that electronegativity is of lesser importance here. The isopolar analogues of L-AMP-PCP were active in this tissue. The differences between the two tissues in the order of potency for these non-degradable analogues supports suggestions that P2-purinoceptors in the taenia coli (P2Y) are different from those in the bladder (P2X). The isopolar analogues of L-AMP-PCP, like L-AMP-PCP itself, were selective agonists at the P2X-purinoceptor.


Blood-brain barrier permeability to leucine-enkephalin, D-alanine2-D-leucine5-enkephalin and their N-terminal amino acid (tyrosine).
The permeability of the blood-brain barrier to [tyrosyl-3,5-3H]enkephalin-(5-L-leucine) (abbreviated to Leu-Enk) and of its synthetic analogue D-alanine2-[tyrosyl-3,5-3H]enkephalin-(5-D-leucine) (abbreviated to D-Ala2-D-Leu5-Enk) was studied, in the adult rat, by means of Oldendorf's27 intracarotid injection technique. The brain uptake index (BUI) corrected for residual vascular radioactivity was about the same for both peptides, indicating a low extraction from the blood during a 5- or 15-s period of exposure to the peptides. Transport of Leu-Enk was not saturated by unlabelled Enk at a concentration as high as 5 mM but was completely abolished by 5mM tyrosine and by the inhibitor of aminopeptidase activity, bacitracin (2 mM). Also the typical L-transport system substrate, 2-aminobicyclo(2,2,1)heptane-2 carboxylic acid (BCH)9 at 10 mM concentration markedly reduced (by 80%) Leu-Enk uptake by the brain. In contrast, brain uptake of D-Ala2-D-Leu5-Enk was reduced only to about one-half of its control value by bacitracin or by 25% by BCH. Brain uptake for L-tyrosine was typically large and markedly inhibited by BCH but not inhibited by 5 mM unlabelled Leu-Enk. These results show that the measurable but low first-pass extractions for enkephalins are not representative of the uptake of these peptides into the brain, but rather reflect their extreme sensitivity to enzymatic degradation with a release of the N-terminal tyrosine residue. The results also suggest that small amounts of D-Ala2-D-Leu5-Enk might cross the blood-brain barrier in an intact form.(ABSTRACT TRUNCATED AT 250 WORDS)


Assessment of radiopharmaceutical retention for vascular access ports using positron emission tomography imaging.
The purpose of this study was to resolve the issue of whether various generations of CR Bard peripheral vascular access ports and catheters are prone to retain PET radiopharmaceuticals. The study evaluates the residual radioactivity remaining following injection for two PET radiopharmaceuticals currently used extensively in the clinic, FDG and Na18 F. FDG was purchased from a local cyclotron facility and Na18 F was prepared in-house. Three generations of currently marketed vascular access ports were tested. A total of five (n = 5) of each model was tested. Radiopharmaceutical of 2-3 mCi of each was injected into each port and flushed with 10, 30, 60, and 120 ml of saline. MicroPET scans were performed after each flush to detect the residual radioactivity on each port. A dose calibrator was used to detect the retention of radioactivity after each flush. Radioactivity retention for all vascular port models measured by microPET imaging was similar for both FDG and Na18 F, with less than 1% residual activity following a 10 ml saline flush. Based on the microPET images, all the subsequent flushes of 30, 60, and 120 ml were also considered. Dose calibrator activity measurements validated microPET measurements as negligible for all the ports, even with the first 10 ml flush. MicroPET imaging was more sensitive than the dose calibrator in determining the radioactivity retention of the vascular access ports from CR Bard. These ports may be used for the injection of FDG and Na18 F to track glucose metabolism and bone uptake with PET imaging. It is recommended to apply at least a 10 ml flush after radiopharmaceutical administration, to reduce residual activity to baseline levels.


Ambipolar inverters with natural origin organic materials as gate dielectric and semiconducting layer.
Thin film electronics fabricated with non-toxic and abundant materials are enabling for emerging bioelectronic technologies. Herein complementary-like inverters comprising transistors using 6,6'-dichloroindigo as the semiconductor and trimethylsilyl-cellulose (TMSC) films on anodized aluminum as bilayer dielectric layer are demonstrated. The inverters operate both in the first and third quadrant, exhibiting a maximum static gain of 22 and a noise margin of 58% at a supply voltage of 14 V. (© 2015 WILEY-VCH Verlag GmbH &Co. KGaA, Weinheim).


Serum gonadotropins and estradiol levels in Turkish pubertal girls.
Serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) levels were measured by radioimmunoassay in the sera of 37 healthy Turkish pubertal girls. The data show that FSH levels significantly increased from stage 2 to 3, and tented to plateau during stages 3,4 and 5, and LH and estradiol levels constantly rises with advances in sexual development and significantly correlates with pubertal stages. When the serum FSH level was compared in pre and postmenarcheal girls of the same age the level was almost identical. Adversely, LH and estradiol levels were higher in postmenarcheal girls than in premenarcheal girls.


Association of Muscle Mass, Area, and Strength With Incident Diabetes in Older Adults: The Health ABC Study.
Skeletal muscle plays a key role in glucose regulation, yet the association between muscle quantity or quality and the risk of developing type 2 diabetes has not been explored. The objective of the study was to assess the association between muscle quantity and strength and incident diabetes and to explore whether this association differs by body mass index (BMI) category. Participants were 2166 older adults in the Health, Aging, and Body Composition Study who were free of diabetes at baseline (1997–1998). Computed tomography and dual-energy x-ray absorptiometry were used to measure abdominal and thigh muscle area and total body lean mass, respectively. Strength was quantified by grip and knee extensions. Incident diabetes, defined as fasting glucose of 126 mg/dL or greater, a physician's diagnosis, and/or the use of hypoglycemic medication were measured. After a median 11.3 years of follow-up, there were 265 incident diabetes cases (12.2%). In fully adjusted models, no association was found between muscle or strength measures and incident diabetes (for all, P > .05). For women, there was a significant interaction with BMI category for both abdominal and thigh muscle, such that greater muscle predicted lower risk of incident diabetes for normal-weight women (hazard ratio 0.37 [0.17–0.83] and 0.58 [0.27–1.27] per SD, respectively) and a greater risk for overweight and obese women (hazard ratio 1.23 [0.98–1.54] and 1.28 [1.00–1.64], respectively). No significant interactions by BMI category existed for strength measures or any measures for men (for all, P > .05). Greater muscle area is associated with a lower risk of incident diabetes for older normal-weight women but not for men or overweight women.


Six years of wearer experience in children participating in a myopia control study of MiSight® 1 day.
To evaluate the experience of children wearing soft contact lenses (CLs) during a trial of MiSight® 1 day (omafilcon A, CooperVision, Inc.), a dual-focus myopia-control daily disposable CL. A 3-year, double-masked, randomised trial (Part 1) comparing experiences with MiSight 1 day and a single-vision control (Proclear® 1 day, omafilcon A, CooperVision, Inc.) of neophyte, myopic children (ages 8-12). Treatment (n = 65) and control (n = 70) participants received lenses at sites in Canada, Portugal, Singapore, and the UK. Successful participants completing Part 1 were invited to continue for a further 3 years wearing the dual-focus CL (Part 2), and 85 participants completed the 6-year study. Children and parent questionnaires were conducted at baseline, 1 week, 1 month, and every 6 months until the 60-month visit, with children only also completing questionnaires at 66 and 72 months. Throughout the study, children reported high satisfaction with handling (≥89% top 2 box [T2B]), comfort (≥94% T2B), vision (≥93% T2B for various activities), and overall satisfaction (≥97% T2B). Ratings for comfort and vision were not significantly different between lens groups, visits, or study parts and did not change when children switched to dual-focus CLs. Ratings for 'really easy' or 'kind of easy' application improved from the outset for the neophytes (57% at 1-week follow-up and 85% at 1-month follow-up) and remained high throughout the study (visit: P = 0.007; part: P = 0.0004). Overall satisfaction improved in Part 2 (P = 0.04). Wearing times increased in Part 2 (14 vs. 13 hrs/weekday; 13 vs. 12 hrs/day on weekends; P < 0.001); there were no differences between groups. Children adapted rapidly to full-time wear, rated lenses highly, and rarely reported issues. The dual-focus optics included in the MiSight® 1 day lenses successfully achieved myopia control without lowering subjective ratings when fitted to neophytes or children refitted from single-vision CLs.


Reducing Stress and Promoting Social Integration of International Medical Students through a Tandem Program: Results of a Prospective-Program Evaluation.
Medical students, and especially international medical students (IMS), have been shown to experience more psychological distress than the general student population in Germany. In order to address these issues, a structured Tandem Program (TP) to reduce stress and foster social integration of IMS has been introduced at the Medical Faculty of Tuebingen. The Tandem Program was evaluated prospectively with perceived stress (PSQ-20) as the main outcome. Secondary outcomes were 'motives to participate' in the TP, 'specific stressors', and 'experiences made' during the program. Stress levels of IMS at the beginning of the program (t₀) (M = 48.14, SD = 11.95) were higher than those of German participants (M = 39.33, SD = 8.31) (t (67) = -3.66, p < 0.001). At the end of the TP (t₁), stress levels of international students were significantly lower than at t₀. "Improved ability to work in a team" was seen as one of the most beneficial factors. The results indicate that tandem programs at medical faculties may be a promising curricular intervention towards reducing stress levels, improving integration of international students, and to enhance intercultural and team-oriented competencies in both international and national medical students.


Graphene-embedded oblique V-shaped silver nanoarrays for hydrophobic pollutants pre-concentration and high-sensitivity SERS detection.
A surface enhanced Raman scattering (SERS) substrate of silver nanorod modified with graphene and silver nanorod (AgNR@Graphene@AgNR) has been fabricated to improve the sensitivity of SERS detection of hydrophobic pollutants, in which, graphene is an interlayer and AgNR is arranged on both sides of the graphene. The embedded graphene could help the oblique V-shaped AgNR structure to improve the sensitivity of SERS detection with a significant electric field enhancement effect. The annealing treatment of the substrate, shortening the nanometer gap between the graphene and AgNR, is benefit for producing a large number of "hot spots" at the fold, which has been verified by the finite difference time domain (FDTD) simulation. The enhancement factor (EF) of AgNR@Graphene@AgNR could reach up to 1.6 × 108 with a good reproducibility. The substrate could achieve high-sensitivity detection of 4-chlorobiphenyl (PCB-3) and 3, 3', 4, 4'-tetrachlorobiphenyl (PCB-77) with the limit of detections (LODs) of 1.72 × 10-10 M and 2.11 × 10-8 M, and the effective identification of PCBs mixture has been realized through principal component analysis (PCA), which means that the AgNR@Graphene@AgNR substrate has a potential significance for the detection and analysis of hydrophobic pollutant mixtures in the environment.


Exploring the healing power of singing bowls: An overview of key findings and potential benefits.
Singing bowl sound meditation is an ancient practice that has been used for centuries in Tibetan and Buddhist cultures as a form of healing and relaxation. The practice involves the use of singing bowls, which produce a soothing sound believed to have a powerful effect on the body's energy system, helping to balance the chakras and promote healing. Over the years, several studies have been conducted to explore the effects of singing bowl sound meditation on mood, tension, and well-being. The reasons behind the positive effects of singing bowl sound healings are not fully understood. Possible explanations include alterations in brain waves, binaural beats, and the vibrations of singing bowls interacting with the energy field surrounding the human body, known as the biofield. Studies have shown that singing bowl sound meditation can produce physiological and psychological responses, reducing negative affect and increasing positive affect, as well as improving blood pressure, heart rate, and respiratory rate. Singing bowl sound meditation may be an effective low-cost and low-technology intervention for reducing feelings of tension, anxiety, and depression while promoting spiritual well-being. However, further research is needed to determine the long-term effects of singing bowl sound meditation on physiological and psychological well-being, as well as its potential clinical applications.


Design and synthesis of azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities.
The 5,10-dihydro-2-thioxo-pyrimido[4,5-b]quinolines (2a-c) and its oxidized form 3 were prepared and used as key intermediates for the synthesis of thiazolo[3',2':1,2]pyrimido[4,5-b]-quinolines (5a-c), isoxazolo[5'',4'':4',5']thiazolo[3',2':1,2]pyrimido[4,5-b]quinolines (6a-c), 4-chloro-2-methylthio-pyrimido[4,5-b]quinoline, its amino derivatives (19-21) and 10,11,12,13-tetrahydro-5H-quino[2',3':4,5]pyrimido[6,1-b]quinazoline (22). The newly synthesized compounds were characterized by IR, NMR (1H, 13C) and mass spectral studies. Representative of the synthesized compounds was tested and evaluated for anti-oxidant, anti-inflammatory and analgesic activities. Compounds 2a-c showed the highest inhibitory anti-oxidant activity either using erythrocyte hemolysis or ABTS methods. Compounds 2a, 10b, 16, and 17a manifested the best protective effect against DNA damage induced by bleomycin. Compounds 2c, 5a, 20a, 2a, and 2b exhibited a potent anti-inflammatory activity using carrageenan-induced paw edema test in rats.


"So hard not to feel blamed!": Assessment of implementation of Benin's Maternal and Perinatal Death Surveillance and Response strategy from 2016-2018.
To assess the implementation of the Maternal and Perinatal Death Surveillance and Response (MPDSR) strategy institutionalized in Benin in 2013 to address the alarmingly high maternal and neonatal death rates. A retrospective, mixed-methods study was performed. We used all maternal and neonatal death notifications and reviews from 2016 to 2018, reviewed the reports of 63 MPDSR working groups, and held two online group discussions. Descriptive quantitative analysis was performed, and content analysis was applied to qualitative data. Deaths were under-notified, with estimated notification rates at 46%-48% for maternal and 16%-21% for neonatal deaths over the 3 years. Review completion rates were low, corresponding to 50%-56% of maternal and 8%-17% of neonatal deaths. Causes of undernotification included very low notification of community-based and private health facility deaths, and fear of blame. Low review completion rates were due to heavy workload, staffing shortages, fear of blame, and weak leadership. Moreover, reviews were of poor quality and the response was weak. Maternal and Perinatal Death Surveillance and Response is operational in Benin. However, this assessment highlights the need to strengthen the notification strategy, continuously build MPDSR committee members' capacities, engage decision-makers for an effective response, and create a better blame-free, accountable, and learning culture.


Imaging local acoustic pressure in microchannels.
A method for determining the spatially resolved acoustic field inside a water-filled microchannel is presented. The acoustic field, both amplitude and phase, is determined by measuring the change of the index of refraction of the water due to local pressure using stroboscopic illumination. Pressure distributions are measured for the fundamental pressure resonance in the water and two higher harmonic modes. By combining measurement at a range of excitation frequencies, a frequency map of modes is made, from which the spectral line width and Q-factor of individual resonances can be obtained.


Gender differences in pharmacological response.
Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions. Is the increased risk due to sex differences in pharmacokinetics, in pharmacodynamics, or did females receive more medications and higher mg/kg doses than males? Recent studies suggest that all of the above may play a role. Generally, males weigh more than females, yet few drugs are dosed based on body weight. Drug concentrations are dependent on the volume of distribution (Vd) and clearance (Cl). Both parameters are dependent on body weight for most drugs independent of sex differences. Females have a higher percent body fat than males which can affect the Vd of certain drugs. Renal clearance of unchanged drug is decreased in females due to a lower glomerular filtration. Sex differences in activity of the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes and renal excretion will result in differences in Cl. There is evidence for females having lower activity of CYP1A2, CYP2E1, and UGT; higher activity of CYP3A4, CYP2A6, and CYP2B6; and no differences in CPY2C9 and CYP2D6 activity. Pharmacodynamic changes can affect both the desired therapeutic effect of a drug as well as its adverse effect profile. The most widely reported sex difference is the higher risk in females for drug-induced long QT syndrome, with two-thirds of all cases of drug-induced torsades occurring in females. Females also have a higher incidence of drug-induced liver toxicity, gastrointestinal adverse events due to NSAIDs, and allergic skin rashes. In conclusion, at the minimum, it is important to take into account size and age as well as co-morbidities in determining the appropriate drug regiment for females, as well as males. There are still large gaps in our knowledge of sex differences in clinical pharmacology and significantly more research is needed.