Immunogenicity of COVID-19 vaccines in patients with hematologic malignancies: a systematic review and meta-analysis.
The objectives of this study were to assess the immunogenicity and safety of COVID-19 vaccines in patients with hematologic malignancies. A systematic review and meta-analysis of clinical studies of immune responses to COVID-19 vaccination stratified by underlying malignancy and published from January 1, 2021, to August 31, 2021, was conducted using MEDLINE, EMBASE, and Cochrane CENTRAL. Primary outcome was the rate of seropositivity after 2 doses of COVID-19 vaccine with rates of seropositivity after 1 dose, rates of positive neutralizing antibodies, cellular responses, and adverse events as secondary outcomes. Rates were pooled from single-arm studies while rates of seropositivity were compared against the rate in healthy controls for comparator studies using a random effects model and expressed as a pooled odds ratios with 95% confidence intervals. Forty-four studies (16 mixed group, 28 disease specific) with 7064 patients were included in the analysis (2331 after first dose, 4733 after second dose). Overall seropositivity rates were 62% to 66% after 2 doses of COVID-19 vaccine and 37% to 51% after 1 dose. The lowest seropositivity rate was 51% in patients with chronic lymphocytic leukemia and was highest in patients with acute leukemia (93%). After 2 doses, neutralizing antibody response rates were 57% to 60%, and cellular response rates were 40% to 75%. Active treatment, ongoing or recent treatment with targeted and CD-20 monoclonal antibody therapies within 12 months were associated with poor immune responses to COVID-19 vaccine. New approaches to prevention are urgently required to reduce COVID-19 infection morbidity and mortality in high-risk patient groups that respond poorly to COVID-19 vaccination.


Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).
Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was 233.5 ± 177.8 GBq/μmol (n = 4). The radiochemical yield of [(18)F]3 was 16.4 ± 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.


A practical technique for rapid characterisation of ent-kaurane diterpenoids in Isodon serra (Maxim.) Hara by UHPLC-Q-TOF-MS/MS.
The diterpenoids are the most important active constituents that contribute to the pharmacological efficacy of Isodon serra (Maxim.) Hara. Clinical studies have revealed that diterpenoids possess multiple features, e.g. antitumour, antitubercular and anti-ischemic activities. Therefore, the identification and detection of diterpenoids may be equally important for understanding the pharmacological basis of diterpenoids and enhancing the product quality control of I. serra. The purpose of this study was to develop a practical analysis approach of rapid characterisation using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) for the structure characterisation of the ent-kaurane diterpenoids from I. serra. The analytical strategy was as follows: first, ent-kaurane diterpenoids were detected by a novel on-line data acquisition approach, i.e. sequential window acquisition of all theoretical fragment-ion spectra (SWATH). Second, the MS of eight ent-kaurane diterpenoids was explored, and their mass spectrum cleavage pathways were summarised and determined. Finally, the methanol extract of I. serra was studied using SWATH and identified by extracted ion chromatography (XIC). Compared to the traditional information-dependent acquisition (IDA) method, SWATH significantly improved the hit rate of ent-kaurane diterpenoids. With support from UHPLC separation and specific detection by tandem mass spectrometry (MS/MS), 48 ent-kaurane diterpenoids were successfully characterised and classified as ent-kaurane diterpenoids from a complex matrix. These combined qualitative methods were used to provide a potential approach for the characterisation of traditional Chinese medicine (TCM) and its preparations. Meanwhile, the SWATH provided a novel and reliable method for the structural characterisation of ent-kaurane diterpenoids from other complicated TCMs.


Escherichia coli bacteriocins: antimicrobial efficacy and prevalence among isolates from patients with bacteraemia.
Bacteriocins are antimicrobial peptides generally active against bacteria closely related to the producer. Escherichia coli produces two types of bacteriocins, colicins and microcins. The in vitro efficacy of isolated colicins E1, E6, E7, K and M, was assessed against Escherichia coli strains from patients with bacteraemia of urinary tract origin. Colicin E7 was most effective, as only 13% of the tested strains were resistant. On the other hand, 32%, 33%, 43% and 53% of the tested strains exhibited resistance to colicins E6, K, M and E1. Moreover, the inhibitory activity of individual colicins E1, E6, E7, K and M and combinations of colicins K, M, E7 and E1, E6, E7, K, M were followed in liquid broth for 24 hours. Resistance against individual colicins developed after 9 hours of treatment. On the contrary, resistance development against the combined action of 5 colicins was not observed. One hundred and five E. coli strains from patients with bacteraemia were screened by PCR for the presence of 5 colicins and 7 microcins. Sixty-six percent of the strains encoded at least one bacteriocin, 43% one or more colicins, and 54% one or more microcins. Microcins were found to co-occur with toxins, siderophores, adhesins and with the Toll/Interleukin-1 receptor domain-containing protein involved in suppression of innate immunity, and were significantly more prevalent among strains from non-immunocompromised patients. In addition, microcins were highly prevalent among non-multidrug-resistant strains compared to multidrug-resistant strains. Our results indicate that microcins contribute to virulence of E. coli instigating bacteraemia of urinary tract origin.


Elastic properties of the lung and the chest wall in young and adult healthy pigs.
Understanding of the elastic pressure/volume (Pel/V) curve is still limited in health and disease. The aim of the present study was to elucidate the Pel/V curve and elastance of the respiratory system (ERS) lung (EL) and chest wall (ECW) in healthy pigs. Six young (20.8 kg) and seven adult (58.9 kg), anaesthetized, paralysed and ventilated pigs were studied. Pel/V curves were recorded at zero end-expiratory pressure (ZEEP) and at positive end-expiratory pressure (PEEP) up to 40 cmH2O with a computer controlled ventilator during an insufflation at a low, constant flow. Pel/V curves of the respiratory system showed a complex pattern in both young and adult pigs. During the insufflation, ERS decreased, increased, fell, and increased again. A second Pel/V curve recorded immediately after the first one showed lower elastance and only one early fall in ERS. ECW fell over the initial segment and was then nearly stable. Difference between 1st and 2nd curves reflected changes in EL caused by recruitment during the 1st insufflation. At PEEP, such signs of collapse and recruitment were reduced. A strong tendency to lung collapse contributes to a complex pattern of elastic pressure/volume curves. At low volumes and distending pressures the chest wall contributes significantly to changes in respiratory system elastance.


[Morphological studies of the adrenal zona glomerulosa cells and the thyroid and pituitary glands in streptozocin-induced experimental diabetic rats].
Changes in pathological morphology in the adrenal glomerulosa, the thyroid and pituitary glands in streptozotocin-induced experimental diabetic rats were studied by histologic, ultrastructural examination and morphometry. Experimental diabetes provoked atrophy and retrograde degeneration of organelles in the adrenal zona glomerulosa cells and the thyroid follicular epithelium. In the pituitary of diabetic rats, organelles in thyrotrophs were the same as the controls in morphometry, but TSH release was impaired. These studies indicate that pathological changes in the zone glomerulsa cells and the thyroid of diabetic rats appear to be responsible for the impaired function of these two glands. Moreover, reduced TSH release in the pituitary glands is also associated with impaired function of the thyroid gland.


Platelet activation, and antiplatelet targets and agents: current and novel strategies.
Platelets play a key role in thrombosis and haemostasis, which can be either beneficial or deleterious depending on the circumstances. Multiple factors, such as genetic polymorphisms, pathological state and lifestyle, are thought to be associated with platelet hyperreactivity. Platelet activation occurs through the complex process of transmembrane signalling, with a cascade of biochemical interactions leading to platelet activation. Transmembrane signalling involves many different molecules with different enzymatic activity and/or function. Based on the signalling pathways involved in platelet activation, there are four possible targets of antiplatelet drugs: (i) inhibition of agonist generation; (ii) receptor inhibition; (iii) G-protein inhibition; and (iv) inhibition of enzymatic cascades. However, both established and novel antiplatelet drugs have their own advantages and disadvantages. Because of the problems associated with the use of current antiplatelet drugs, such as resistance, optimal dosage and safety, future strategies for the development of new antiplatelet drugs and new treatment regimens may include consideration of the following: (i) a shift from single targets within the signalling cascade to multiple targets; (ii) a shift from therapy with a single drug to combination therapy; and (iii) investigating drugs in current clinical use for novel antiplatelet properties.


Use of ruthenium dyes for subnanosecond detector fidelity testing in real time transient absorption.
Transient absorption spectroscopy is a powerful tool for the study of photoreactions on time scales from femtoseconds to seconds. Typically, reactions slower than approximately 1 ns are recorded by the "classical" technique; the reaction is triggered by an excitation flash, and absorption changes accompanying the reaction are recorded in real time using a continuous monitoring light beam and a detection system with sufficiently fast response. The pico- and femtosecond region can be accessed by the more recent "pump-probe" technique, which circumvents the difficulties of real time detection on a subnanosecond time scale. This is paid for by accumulation of an excessively large number of shots to sample the reaction kinetics. Hence, it is of interest to extend the classical real time technique as far as possible to the subnanosecond range. In order to identify and minimize detection artifacts common on a subnanosecond scale, like overshoot, ringing, and signal reflections, rigorous testing is required of how the detection system responds to fast changes of the monitoring light intensity. Here, we introduce a novel method to create standard signals for detector fidelity testing on a time scale from a few picoseconds to tens of nanoseconds. The signals result from polarized measurements of absorption changes upon excitation of ruthenium complexes {[Ru(bpy)(3)](2+) and a less symmetric derivative} by a short laser flash. Two types of signals can be created depending on the polarization of the monitoring light with respect to that of the excitation flash: a fast steplike bleaching at magic angle and a monoexponentially decaying bleaching for parallel polarizations. The lifetime of the decay can be easily varied via temperature and viscosity of the solvent. The method is applied to test the performance of a newly developed real time transient absorption setup with 300 ps time resolution and high sensitivity.


Candida tropicalis prompted effectively simultaneous removal of carbon, nitrogen and phosphorus in activated sludge reactor: Microbial community succession and functional characteristics.
A new Candida tropicalis that simultaneously remove nitrogen and phosphorus, and degrade organic matters was isolated. Three continuous stirred tank reactors inoculated with C. tropicalis, activated sludge, and their co-existing system in aerobic condition were operated for 150 days. Results demonstrated that the inoculation of C. tropicalis in the co-existing system remarkably improved the carbon, nitrogen, and phosphorus removal efficiencies. The co-existing system had increased carbon, nitrogen, and phosphorus removal efficiencies (92%, 73%, and 63%, respectively); decreased biomass (reduced from 1200 mg/L to 500 mg/L); and C. tropicalis as the dominant strain. The relative abundance of traditional nitrogen- and phosphorus-removing microorganisms, such as Mycobacterium, Flavonifactor, and Devsia, increased in the co-existing system. Metagenomic analysis showed that the presence of the PCYT2, EPT1, and phnPP genes and more complexed metabolism pathways in the co-existing system might be responsible for the more activated metabolism process.


Photosynthesis of Grass Species Differing in Carbon Dioxide Fixation Pathways: IV. ANALYSIS OF REDUCED OXYGEN RESPONSE IN PANICUM MILIOIDES AND PANICUM SCHENCKII.
Reduced photorespiration has been reported in Panicum milioides on the basis of lower CO(2) compensation concentrations than in C(3) species, lower CO(2) evolution in the light, and less response of apparent photosynthesis to O(2) concentration. The lower response to O(2) in P. milioides could be due to reduced O(2) competition with CO(2) for reaction with ribulose 1,5-bisphosphate, to a reduced loss of CO(2), or to an initial fixation of CO(2) by phosphoenolpyruvate carboxylase. Experiments were carried out with Panicum maximum Jacq., a C(4) species having no apparent photorespiration; tall fescue (Festuca arundinacea Schreb.), a C(3) species; P. milioides Nees ex Trin.; and Panicum schenckii Hack. The latter two species are closely related and have low photorespiration rates. CO(2) exchange was measured at five CO(2) concentrations ranging from 0 to 260 microliters per liter at both 2 and 21% O(2). Mesophyll conductance or carboxylation efficiency was estimated by plotting substomatal CO(2) concentrations against apparent photosynthesis. In the C(4) species P. maximum, mesophyll conductance was 0.96 centimeters per second and was unaffected by O(2) concentration. At 21% O(2) mesophyll conductance of tall fescue was decreased 32% below the value at 2% O(2). Decreases in mesophyll conductance at 21% O(2) for P. milioides and P. schenckii were similar to that for tall fescue. On the other hand, loss of CO(2) in CO(2)-free air, estimated by extrapolating the CO(2) response curve to zero CO(2), was increased from 1.8 to 6.5 milligrams per square decimeter per hour in tall fescue as O(2) was raised from 2-21%. Loss of CO(2) was less than 1 milligram per square decimeter per hour for P. milioides and P. schenckii and was unaffected by O(2). The results suggest that the reduced O(2) response in P. milioides and P. schenckii is due to a lower loss of CO(2) in the light rather than less inhibition of carboxylation by O(2), since the decrease in carboxylation efficiency at 21% O(2) was similar for P. milioides, P. schenckii, and tall fescue. The inhibition of apparent photosynthesis by 21% O(2) in these three species at low light intensities was similar at 31 to 36% which also indicates similar O(2) effects on carboxylation. Apparent photosynthesis at high light intensity was inhibited less by 21% O(2) in P. milioides (16.8%) and P. schenckii (23.8%) than in tall fescue (28.4%). This lower inhibition in the Panicum species may have been due to a higher degree of recycling of photorespired CO(2) in these species than in tall fescue.


Alternative tertiary care pathways for a rural Department of Veterans Affairs Medical Center.
This study addresses the cost of rural health care delivery where veterans do not have ready access to tertiary Department of Veterans Affairs Medical Centers (VAMCs) but where local community health care is available. The study sample was 209 patients referred for tertiary care to a VAMC 50 miles distant from the referring rural VAMC. The cost of tertiary referral VAMC care was retrospectively compared with the cost had the patients received the tertiary care in the local community hospital located in the immediate vicinity. In addition, the cost of travel resulting from the remote access was also computed. Findings indicate that a savings of +309,293 could have been obtained had a local community hospital provided the tertiary care utilizing the Health Care Financing Administration Medicare rate. Data generated by the methodology of this study are expected to provide a baseline for policy decisions relating to alternative pathways for tertiary care in the Department of Veterans Affairs.


Pyogenic lumbar facet joint arthritis with intradural extension: a case report.
There have been 40 previously reported cases of lumbar facet joint pyogenic infection. These have been well characterized earlier. Intradural pyogenic extension has never been reported from a facet joint origin. This case demonstrates an elderly diabetic man with acute onset of nontraumatic back pain with no other source of infectious pathology. Surgical exploration identified a purulent left L4-L5 facet joint with epidural and intradural extension. Minimal spinal fluid leak was present. Wound cultures were positive for Group B beta Full resolution occurred with appropriate intravenous vancomycin antibiotic therapy.


Spectral response of large-area luminescent solar concentrators.
Measuring the spectral response (SR) of large-area (>100cm2) luminescent solar concentrators (LSCs) has proven difficult because common laboratory photovoltaic (PV) instruments that offer monochromatic incidence measure devices with limited sizes (typically <50cm2). This report addresses this issue through a method called regional measurements. In this method, large-area LSCs are configured to small surface and edge regions, which are sequentially illuminated and measured, respectively. The measured SRs of large-area LSCs are consistent with those from the conventional method and the Monte Carlo ray-tracing simulation. This method is also applied to analyze scattering effects in the LSCs, showing the relationships of the scattering-induced power gain and power loss to the surface root-mean-squared roughness (Rq) of the devices. The results explain why the PV performance of the LSCs can be improved through proper surface scattering treatment.


A [3]Rotaxane Host Selects Between Stereoisomers.
What has it got in its pockets? A new approach to the selective binding and reporting of stereoisomers using mechanical bonding to produce a well-defined three-dimensional binding pocket was recently reported by Beer and co-workers. The highly stereoselective binding of stereoisomers by the reported [3]rotaxane suggest that the use of the mechanical bond to engineer a binding pocket has great potential for the development of stereoselective hosts.


The surveillance of communicable disease in Vermont: who reports?
The Vermont Department of Health reviewed 2,035 reports of selected notifiable diseases received from January 1, 1986, through December 31, 1987. Laboratories provided 1,160, or 71 percent, of the initial reports on 1,636 confirmed cases. This demonstrates that laboratories, when required by law and when part of active surveillance, can make a significant contribution to surveillance of infectious disease. A survey of primary care physicians indicated that 18 percent always reported notifiable diseases. The most frequently mentioned reason for lack of reporting was an assumption that the laboratory would report the cases.


Theoretical insights on the catalytic activity and mechanism for oxygen reduction reaction at Fe and P codoped graphene.
The non-precious metal graphene catalyst doped with Fe-Px are recently proposed as a promising candidate in substituting Pt for catalyzing oxygen reduction reaction (ORR) in fuel cells. Systematic DFT calculations are performed to investigate the catalytic activity and the ORR mechanism on the Fe-Px (x = 1-4) system in acid medium in this work. Our results indicated that the configuration with one Fe and two P atoms codoped at zigzag edge site (Fe-P2-zig-G) is the most stable, in excellent agreement with the experimental observation that the ratio of Fe and P is nearly 1 : 2. The four-electron reduction mechanism for ORR on the Fe-P2-zig-G is via the competing OOH hydrogenation pathways (to form either OH + OH or O + H2O). The rate determining step is the O2 hydrogenation with an energy barrier of 0.43 eV, much smaller that of calculated 0.80 eV for pure Pt. In addition, the highest energy barrier of the studied ORR mechanism is the O2 dissociation with an energy barrier of 0.70 eV, a value also smaller than that of pure Pt. This demonstrated that the zigzag edge site of the Fe-P2 codoped graphene should be active for the ORR.


Gait parameters in four strains of turkeys and correlations with bone strength.
Locomotion problems in meat poultry have multifactorial etiology. A better understanding of normal gait and its influences on biomechanical aspects of leg bones among turkey genetic lines is important to prevent skeletal disorders and locomotion issues. The objective of this experiment was to determine the possible differences in gait kinetic and kinematic parameters of turkey strains and their effects on bone biomechanical properties. Four genetic lines, named A, B, C, and D, were obtained and raised in 48 floor pens with new pine shavings. Leg health issues were classified at 16 and 33 d of age. Fifteen turkeys from each strain with apparent normal legs and gait at 33 d of age were selected for gait analysis. These 15 turkeys were trained to walk on a pressure sensitive walkway and video was recorded to calculate articulation movements. These data also were analyzed to obtain kinetic and kinematic parameters of the gait cycle collected at 47, 84, 107, and 145 d of age. At 20 wk all turkeys were sacrificed, and legs were collected and frozen for analysis. Weights and morphologic measurements of the femur, tibia, and shank were recorded. Bone mineral density (BMD) and content (BMC) were obtained using DEXA. Femur and tibia strength were evaluated by a 4-point bending test and torsion test, respectively. Gait parameters changed as toms aged and some differences were observed among lines. Genetic lines differed on BMD, but not on BMC. Strain D had a higher BMD and smaller diaphyseal angle than strain C, characteristics that were correlated with stronger bones. Strain D also had the lowest incidence of leg problems while strain C had the highest. Furthermore, the D strain had a smaller vertical motion of the toe than strains C and B at 47 d and strain A at 145 d, indicating that the D strain had a more efficient gait. In summary, genetic strains differ significantly on gait parameters, which in turn impacts bone biomechanics.


Involvement of a Formally Copper(III) Nitrite Complex in Proton-Coupled Electron Transfer and Nitration of Phenols.
A unique high-valent copper nitrite species, LCuNO2, was accessed via the reversible one-electron oxidation of [M][LCuNO2] (M = NBu4+ or PPN+). The complex LCuNO2 reacts with 2,4,6-tri-tert-butylphenol via a typical proton-coupled electron transfer (PCET) to yield LCuTHF and the 2,4,6-tri-tert-butylphenoxyl radical. The reaction between LCuNO2 and 2,4-di-tert-butylphenol was more complicated. It yielded two products: the coupled bisphenol product expected from a H-atom abstraction and 2,4-di-tert-butyl-6-nitrophenol, the product of an unusual anaerobic nitration. Various mechanisms for the latter transformation were considered.


Evaluation of Ischemia-Modified Albumin in Patients with Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is considered a chronic gastrointestinal inflammatory disease with unknown etiology. Oxidative stress has been demonstrated to play a critical role in the pathophysiology of IBD. We aimed to investigate the effect of the ischemia-modified albumin (IMA) and CRP levels on the pathophysiology and activities of IBD and its subgroups. The study included 39 patients with Crohn's disease (CD) and 41 patients with ulcerative colitis (UC). Thirty-three healthy volunteers participated in the study as the control group. The IMA concentrations were determined by colorimetric method. IMA levels were significantly higher in IBD than in the controls (p = 0.02). In the subgroups of IBD, IMA levels were significantly lower in the control group and CD group than in UC (p < 0.001 and p < 0.001, respectively) while IMA levels were significant higher in the UC when compared with the CD group (p < 0.001). C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels were significantly higher in the CD group compared to the control group (p < 0.01 and p < 0.02, respectively). Higher IMA level, which is a marker of oxidative stress in diseases with inflammation, indicates that inflammation and oxidative stress are related in the pathogenesis of IBD.


Imaging techniques in the evaluation of pulmonary parenchymal neoplasms.
Conventional PA and lateral chest radiographs continue to be the initial examination of choice to evaluate patients who are suspected of having a pulmonary parenchymal neoplasm. A lung lesion can be characterized as probably benign or malignant based on its radiographic appearance (size, shape, margins, presence of calcification, cavitation or air bronchograms, growth rate). A spiculated or lobulated lesion greater than 3 cm in size that is noncalcified is highly suspicious for malignancy. A lung lesion less than 3 cm in size with smooth borders that appears noncalcified on conventional radiographs should be examined by CT, including densitometry to detect calcification or fat, which indicates benignity. In patients with known lung cancer, CT can help to stage the tumor by indicating hilar or mediastinal involvement, or distant metastases. Currently, MR imaging has a limited role, but can be used as a "problem solving" modality for selected cases in evaluating pulmonary parenchymal neoplasms.


Characterization of a regulatory network that controls sigma B expression in Bacillus subtilis.
The sigB operon of Bacillus subtilis encodes sigma B and three additional open reading frames (orfV, orfW, and orfX). Having previously mapped several mutations that alter the induction pattern of a sigma B-dependent promoter (ctc) to regions of cloned B. subtilis DNA which contain these three open reading frames, we directly tested the regulatory potential of orfV, orfW, and orfX by creating null alleles of each of these genes and examining the effects of the mutations, either singly or in pairs, on transcription of ctc and the sigB operon. Using lacZ reporter gene fusions and Northern (RNA) blot analyses, we have determined that all three genes modulate the activation of the sigma B-dependent promoters at both the sigB operon and ctc. Our data are consistent with the three gene products participating in a single pathway of negative control. orfW and orfX single-mutant strains have high levels of sigB and ctc transcription. sigB and ctc transcription in an orfV strain is similar to that found in mutant strains which lack sigma B itself. The orfV mutation is dominant to orfX but recessive to orfW. These results suggest that OrfW is the primary inhibitor of sigma B-dependent transcription and that OrfV is capable of counteracting the negative control of OrfW but is prevented from doing this by the orfX gene product.


Early intervention in 208 Swedish preschoolers with autism spectrum disorder. A prospective naturalistic study.
Early intervention has been reported to improve outcome in children with autism spectrum disorders (ASDs). Several studies in the field have been randomized controlled trials (RCTs). The aim of this study was to assess ASD outcome in a large naturalistic study. Two hundred and eight children, aged 20-54 months, with a clinical diagnosis of ASD were given intervention and monitored prospectively in a naturalistic fashion over a period of 2 years. The toddlers were considered representative of all but the most severely multiple disabled preschool children with ASD in Stockholm county. They fell into three cognitive subgroups: one with learning disability, one with developmental delay, and one with normal intellectual functioning. Data on intervention type and intensity were gathered prospectively in a systematic fashion. Intervention was classified into intensive applied behaviour analysis (ABA) and non-intensive, targeted interventions, also based on ABA principles. Children were comprehensively assessed by a research team before the onset of intervention, and then, again, 2 years later. Change in Vineland adaptive behaviour scales composite scores from intake (T1) to leaving the study (T2) was set as the primary outcome variable. The research team remained blind to the type and intensity of interventions provided. One hundred and ninety-eight (95%) of the original samples stayed in the study throughout the whole 2-year period and 192 children had a complete Vineland composite score results both at T1 and T2. Vineland composite scores increased over the 2-year period. This increase was accounted for by the subgroup with normal cognitive functioning. There was no significant difference between the intensive and non-intensive groups. Individual variation was considerable, but no child in the study was "problem-free" at follow-up. Our data do not support that children with ASD generally benefit more from the most intensive ABA intervention programs than from less intensive interventions or targeted interventions based on ABA.


Best practices for measuring and reporting ground reaction forces in dogs.
Kinetic gait analysis and ground reaction forces (GRFs) have been used in hundreds of scientific manuscripts. Specific methodology, interpretation of results, and translation to clinical veterinary medicine have been inconsistent. This impedes the advance of veterinary medicine and poses a risk to patients. The objective of this report was to address methodological variations and share our consensus on a recommended approach with viable alternatives to data collection methods, analysis, reporting, and interpretation for GRFs in the dog. Investigators with experience performing kinetic gait analysis reviewed the literature and discussed the topics that most influenced GRF data collection, reporting, and interpretation. Methodological variations were reported and a consensus from the group was devised. There are several reasonable alternatives to collect, report, and interpret GRFs in dogs appropriately. Attention to detail is required in several areas to collect and report them. This review and consensus report should assist future investigations and interpretations of studies, optimize comparison between publications, minimize use of animals, and limit the investment in cost and time.


Bridging the gulf between science and action: the "new fuzzies" of neopragmatism.
Rather than a philosophy, pragmatism is a way of doing philosophy that has major implications for solving disputes involving nursing science, theory, and practice that may otherwise be interminable. Pragmatism weaves together theory and action so that one modifies the other continuously, but both maintain their mutual relevance. Pragmatism emphasizes pluralism and diversity, and depends on an ethical base for determination of what is reasonable. Recently repopularized by the philosopher Richard Rorty and others, pragmatic ideals seem inherent to nursing. We propose that a better understanding of the history and utility of pragmatism will enhance both clinically relevant nursing theory and theoretically relevant nursing practice.


Mechanism of TGFbeta receptor inhibition by FKBP12.
Transforming growth factor-beta (TGFbeta) signaling requires phosphorylation of the type I receptor TbetaR-I by TbetaR-II. Although TGFbeta promotes the association of TbetaR-I with TbetaR-II, these receptor components have affinity for each other which can lead to their ligand-independent activation. The immunophilin FKBP12 binds to TbetaR-I and inhibits its signaling function. We investigated the mechanism and functional significance of this effect. FKBP12 binding to TbetaR-I involves the rapamycin/Leu-Pro binding pocket of FKBP12 and a Leu-Pro sequence located next to the activating phosphorylation sites in TbetaR-I. Mutations in the binding sites of FKBP12 or TbetaR-I abolish the interaction between these proteins, leading to receptor activation in the absence of added ligand. FKBP12 does not inhibit TbetaR-I association with TbetaR-II, but inhibits TbetaR-I phosphorylation by TbetaR-II. Rapamycin, which blocks FKBP12 binding to TbetaR-I, reverses the inhibitory effect of FKBP12 on TbetaR-I phosphorylation. By impeding the activation of TGFbeta receptor complexes formed in the absence of ligand, FKBP12 may provide a safeguard against leaky signaling resulting from the innate tendency of TbetaR-I and TbetaR-II to interact with each other.


Contemporary strategies for managing cardiometabolic risk factors.
To review the metabolic syndrome as defined by the 2001 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) and its modifiable risk factors and to review currently available treatment modalities. Metabolic syndrome, although still controversial, is a growing concern. Most definitions include elevated blood pressure, smoking, inflammation, insulin resistance, abdominal adiposity, elevated blood glucose, and atherogenic dyslipidemia as modifiable risk factors. Some researchers believe that additional signs of inflammation such as plasminogen activator inhibitor-1 and C-reactive protein should be added to this list. Current treatment options include lifestyle changes (diet and exercise), pharmacotherapy, and bariatric surgery. The endocannabinoid system appears to play a key role in metabolism and weight gain. The investigational agent rimonabant is a cannabinoid receptor type 1 blocker that has been employed in numerous trials involving more than 6,500 patients. It has led to significant weight loss, reduced central fat, and improved glycemic and lipid profiles.


Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis.
Allogeneic hematopoieteic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis (MF), but it is still associated with significant risks and complications. One of these complications is poor graft function, but incidence and risk factors have not been studied yet. We retrospectively studied a cohort of 100 patients with primary MF or post-ET/PV MF who received a reduced-intensity HSCT in our center. The cumulative incidence of primary leukocyte engraftment was 98%. The cumulative incidence of poor graft function was 17% and all of the cases occurred before day 100 after HSCT at a median of 49 days (range 24-99 days). In the univariate analysis, age as continuous parameter (P=0.05; hazard ratio 1042) and persistence of significant splenomegaly (defined as palpable splenomegaly of ⩾10 cm under costal margin) at d+30 after HSCT (33% vs 12%; P=0.05) showed an increased cumulative incidence of poor graft function. In conclusion, the incidence of poor graft function after HSCT for MF is rather high, but did not influence survival. Persistence of splenomegaly after transplantation is a significant factor for poor graft function in myelofibrosis patients. Whether therapeutic reduction of splenomegaly before HSCT would result in a lower incidence of poor graft function should be investigated in future studies.


Trunk muscle activities during abdominal bracing: comparison among muscles and exercises.
Abdominal bracing is often adopted in fitness and sports conditioning programs. However, there is little information on how muscular activities during the task differ among the muscle groups located in the trunk and from those during other trunk exercises. The present study aimed to quantify muscular activity levels during abdominal bracing with respect to muscle- and exercise-related differences. Ten healthy young adult men performed five static (abdominal bracing, abdominal hollowing, prone, side, and supine plank) and five dynamic (V- sits, curl-ups, sit-ups, and back extensions on the floor and on a bench) exercises. Surface electromyogram (EMG) activities of the rectus abdominis (RA), external oblique (EO), internal oblique (IO), and erector spinae (ES) muscles were recorded in each of the exercises. The EMG data were normalized to those obtained during maximal voluntary contraction of each muscle (% EMGmax). The % EMGmax value during abdominal bracing was significantly higher in IO (60%) than in the other muscles (RA: 18%, EO: 27%, ES: 19%). The % EMGmax values for RA, EO, and ES were significantly lower in the abdominal bracing than in some of the other exercises such as V-sits and sit-ups for RA and EO and back extensions for ES muscle. However, the % EMGmax value for IO during the abdominal bracing was significantly higher than those in most of the other exercises including dynamic ones such as curl-ups and sit-ups. These results suggest that abdominal bracing is one of the most effective techniques for inducing a higher activation in deep abdominal muscles, such as IO muscle, even compared to dynamic exercises involving trunk flexion/extension movements. Key PointsTrunk muscle activities during abdominal bracing was examined with regard to muscle- and exercise-related differences.Abdominal bracing preferentially activates internal oblique muscles even compared to dynamic exercises involving trunk flexion/extension movements.Abdominal bracing should be included in exercise programs when the goal is to improve spine stability.


Randomized, double-blind, placebo-controlled study to investigate the pharmacodynamic interaction of 5-HT3 antagonist ondansetron and paracetamol in postoperative patients operated in an ENT department under local anesthesia.
The preclinical incision pain models and clinical studies in healthy volunteers have demonstrated the central serotonergic analgesic mechanism, paracetamol analgesia. This has been evidenced by raised serotonin concentrations in the brain following paracetamol administration in a few studies. The inhibition of paracetamol analgesia by 5-HT3 antagonists suggests that this analgesia is 5-HT3 mediated. However, in a few studies, 5-HT3 antagonists themselves exhibited an analgesic action. Various studies in this context stated intricate results. The present study was intended to understand the pharmacodynamic interaction between paracetamol and ondansetron in postoperative patients. This randomized clinical trial included 32 postoperative cases of either sex, ages between 18 and 70 years. The patients were randomly allocated into the placebo and test groups and received respective treatment at the end of surgery. The pain score was recorded using Visual Analogue Scale (VAS) and Face, Legs, Activity, Cry, Consolability (FLACC) behavioral scale at awakening and every 30 min for the next 3 h. The postoperative rescue analgesic consumption for 24 h was recorded. The data were analyzed using OpenEpi and SciStatCalc statistical software. A significantly higher pain score was observed in the placebo group postoperatively for 60 min on VAS (p<0.05 and p<0.01), whereas the FLACC behavior scale score was significantly higher at 120 and 150 min (p<0.05). The test group patients were more comfortable throughout the study, and the postoperative analgesic requirement was significantly lesser (p<0.05). The pharmacodynamic interaction between paracetamol and ondansetron coadministration does not block but instead increase paracetamol analgesia, reduce the postoperative analgesic requirement, and improve the postoperative comfort level.


Endocarditis in critically ill patients: a review.
To summarize the advances in literature that support the best current practices regarding infective endocarditis (IE) in critically ill patients. IE due to rheumatic diseases has decreased significantly, and in fact, the majority of cases are associated with degenerative valvopathies, prosthetic valves, and cardiovascular implantable electronic devices. The Duke criteria were recently updated, addressing the increasing incidence of new risk factors for IE, such as IE associated with the use of endovascular cardiac implantable electronic devices and transcatheter implant valves. The presence of organ dysfunction, renal replacement therapies, or extracorporeal membrane oxygenation should be considered in the choice of drug and dosage in critically ill patients with suspected or confirmed IE. As highlighted for other severe infections, monitoring of therapeutic antibiotic levels is a promising technique to improve outcomes in critically ill patients with organ dysfunction. The diagnostic investigation of IE must consider the current epidemiological criteria and the diagnostic particularities that these circumstances require. A careful evaluation of these issues is necessary for the prompt clinical or surgical management of this infection.


Comparative study on the toxic effects of red tide flagellates Heterocapsa circularisquama and Chattonella marina on the short-necked clam (Ruditapes philippinarum).
Heterocapsa circularisquama showed much higher toxic effects on short-necked clams than Chattonella marina. Clams exposed to H. circularisquama exhibited morphological changes concomitant with an accumulation of mucus-like substances in the gills, a profound reduction in filtration activity, and lysosomal destabilization in hemocytes. Chattonella marina was less effective than H. circularisquama, and Heterocapsa triquetra was almost harmless in all these criteria. These results suggest that H. circularisquama exerted its lethal effect on short-necked clams through gill tissue damage and subsequent induction of physiological stress.


The Healer's Art (HART): Veterinary Students Connecting with Self, Peers, and the Profession.
This case study sought to understand veterinary students' perceptions and experiences of the Healer's Art (HART) elective to support well-being and resilience. Students' "mindful attention" was assessed using the MAAS-State scale. Course evaluations and written materials for course exercises (artifacts) across the 2012-2015 cohorts of Colorado State University's HART veterinary students (n=99) were analyzed for themes using a grounded theory approach, followed by thematic comparison with analyses of HART medical student participants. HART veterinary students described identity/self-expression and spontaneity/freedom as being unwelcome in the veterinary curriculum, whereas HART medical students described spirituality as unwelcome. HART veterinary students identified issues of "competition" and "having no time," which were at odds with their descriptions of not competing and having the time to connect with self and peers within their HART small groups. HART veterinary students shared that the course practices of nonjudgment, generous listening, and presence (i.e., mindfulness practices) helped them build relationships with peers. Although not statistically significant, MAAS pre-/post-scores trended in the positive direction. HART provides opportunities for students to connect with self and foster bonds with peers and the profession, factors that are positively associated with resilience and wellness.


[The 'Guideline for OSAS in children'].
The obstructive sleep apnoea syndrome is a sleep-related disorder characterised by repetitive upper airway obstructions during sleep. In children this sleep-related disorder is associated with medical and developmentrelated disorders such as failure to thrive, cardiovascular complications and neurocognitive problems. Recently, the Dutch multidisciplinary guidelines for diagnosis and treatment of sleep apnoea syndrome in children were developed. In these guidelines adenotonsillectomy is considered to be the first-line treatment. Distraction surgery can be considered for children with severe sleep apnoea syndrome as a result of midfacial hypoplasia or micrognathia. The guidelines define a limited role for orthodontic treatment of dysgnathia. With mandibular repositioning appliances and rapid maxillary expansion, an increase of the upper airway volume can be produced. According to the new guidelines, orthodontic therapy may be considered as one of the secondary treatment options for sleep apnoea syndrome in children with specific disturbed jaw relations in selected cases.


Characteristics of ADHD Symptom Response/Remission in a Clinical Trial of Methylphenidate Extended Release.
Clinical trials in attention-deficit/hyperactivity disorder (ADHD) have typically measured outcome using clinician ratings on the Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Remission has been defined as an endpoint score of less than or equal to 18 on the ADHD-RS-IV (or a mean score of 1). Responders have been defined as patients who achieve a CGI-I score of much or very much improved (1 or 2). There is a lack of agreement in the literature on what percent change in symptoms on the ADHD-RS-IV should be used to define improvement or remission. This study uses data from a clinical trial of a methylphenidate extended release (MPH-MLR; Aptensio XR®) phase III clinical trial to attempt to determine the percent change of symptoms that best corresponds with improvement and remission. Symptom remission at endpoint (ADHD-RS-IV total score ≤18) was most closely aligned with a ≥46% reduction in ADHD-RS-IV total score. Clinical improvement was most closely aligned with a ≥40% reduction in ADHD-RS-IV total score. The three different measures of outcome were strongly aligned during double blind and open label treatment, and were independent of subtype status. Our data suggest that at least 40% improvement in symptoms is needed to achieve a robust response at endpoint.


[MESA (microsurgical epididymal sperm aspiration) and IVF (in vitro fertilization). A therapy concept in treatment of male infertility].
Microsurgical epididymal sperm aspiration (MESA), or sperm microaspiration retrieval technique (SMART), in conjunction with in vitro fertilization is a successful therapy in male infertility. From November 1991 to March 1994 a total of 29 attempts at MESA with subsequent IVF were made. Of 48 aspirations, 37 were successful and 13 attempts at IVF were possible, 6 of which were successful with 10 subsequent embryo transfers. In all, 3 pregnancies were achieved and 1 boy was born. In conclusion, microsurgical spermaspiration in conjunction with in vitro fertilization is a way of treating male infertility with a chance of achieving paternity with the partner's own sperm; the chances are probably better with intracytoplasmatic sperm injection.


Assessing an intensive school-based assistance program to enroll uninsured children.
Children eligible but not enrolled in subsidized health insurance programs, such as Medicaid and S-CHIP, received considerable outreach activity in recent years. Schools in low-income and middle-income communities often are cited as excellent places to find and reach parents. This study assessed the cost and effectiveness of contacting parents through schools, educating them about health insurance programs and preventive care, and assisting them with insurance applications. The accumulative cost per enrolled child was $75, and schools were able to locate and assist large numbers of uninsured children who had failed other outreach methods. School-based application assistance and parent education succeeded in improving child access to care and utilization of services.


Synthesis of 8-(hydroxymethyl)-3,N(4)-etheno-2'-deoxycytidine, a potential carcinogenic glycidaldehyde adduct, and its site-specific incorporation into DNA oligonucleotides.
The previously unreported glycidaldehyde adduct, 8-(hydroxymethyl)-3, N(4)-etheno-2'-deoxycytidine (8-HM-epsilondC), has been synthesized for the first time by reaction of 2'-deoxycytidine with bromoacetaldehyde at pH 4.5, followed by reduction with sodium borohydride. The adduct was characterized by UV, MS, and NMR. The compound was stable to neutral and acidic conditions but not in alkaline solution. The corresponding phosphoramidite was synthesized in good yield from the intermediate, 3, N(4)-ethenocarbaldehyde-2'-deoxycytidine, using the standard methodology and site-specifically incorporated in both 15- and 25-mer oligonucleotides, for studies on biochemical and biophysical properties. The resulting oligonucleotides were purified using HPLC, and the base composition was verified by HPLC after enzymatic digestion.


Intracellular calcium signals in response to bradykinin in individual neuroblastoma cells.
The Ca indicator fura 2 was used to study the modulation of cytoplasmic Ca by bradykinin (Bk) in single N1E-115 murine neuroblastoma cells. Increases in cytoplasmic Ca in response to Bk were mediated by the B2 receptor subtype. Responses to high concentrations of Bk (1-100 nM) were homogeneous and characterized by a rapidly rising transient that decayed to baseline in the continued presence of agonist, with a half-time of 15 s. Responses to low concentrations of Bk (100-500 pM) were more heterogeneous, with longer latencies and often with oscillations. Pretreatment with thapsigargin for 20 min prevented the Ca response, showing that the Ca change results from intracellular Ca release. Removal of external Ca had little effect on the response to Bk, indicating that the agonist does not activate Ca influx. The extent of Ca release and refilling after Bk was tested with ionomycin. A saturating dose of Bk (20 nM) mobilizes > 90% of stored Ca within 30 s, and this is replaced slowly. Replacement of external Na by N-methyl-D-glucamine to block Na/Ca exchange affected the Ca response, causing decreases in latency and in the period of Ca oscillations and increases in overall duration and peak amplitude of the response.


Efficient RMSD measures for the comparison of two molecular ensembles. Root-mean-square deviation.
Quantitative measures are presented for comparing the conformations of two molecular ensembles. The measures are based on Kabsch's formula for the root-mean-square deviation (RMSD) and the covariance matrix of atomic positions of isotropically distributed ensembles (IDE). By using a Taylor series expansion, it is shown that the RMSD can be expressed solely in terms of the IDE matrices. A fast approximate method is introduced for the pairwise RMSD determination whose computational cost scales linearly with the number of structures. A similarity measure for two structural ensembles that is based on the trace metric of the differences of powers of the IDE matrices is presented. The measures are illustrated for conformational ensembles generated by a molecular dynamics computer simulation of a partially folded A-state analog of ubiquitin.


Hypovalent titanium and Ti(II)-Ti(III) interconversions.
Treatment of pink titanium(iii) triflate (0.045 M) with HF in triflic acid (CH(3)SO(3)H) converts Ti(iii) rapidly to a 1 : 1 mixture of Ti(IV) and green Ti(II): (2 Ti(III) + 4 HF --> TiF(4) + Ti(II) + 4 H(+)). This disproportionation is half complete when [HF] added is 0.027 M. Substituted 1,4-benzoquinones are reduced rapidly by Ti(iii) in the absence of fluoride, yielding straightforward logarithmic curves, but reactions of the same quinones with Ti(ii) in fluoride media exhibit more complex profiles, the major portions of which are zero order in oxidant. These reactions are strongly catalyzed by added Ti(iv). Analyses of complex curves are consistent with a reaction sequence initiated by Ti(ii)-Ti(iv) disproportionation, forming Ti(iii), which reacts with the quinone, yielding the quinhydrone, QH . The latter is rapidly reduced by Ti(ii). Values of rate constants obtained from these analyses are in agreement with those for reductions of quinones by Ti(iii), in the absence of fluoride.


Art box deliveries: The experiences of people with dementia and their carers during the Covid 19 lockdown.
Art workshops have been looked at before in terms of impact for people with dementia but never those conducted remotely during a pandemic lockdown. Two artists, working with local museums, provided Art workshops for people with dementia and their caregivers. Due to the first Covid 19 lockdown in the UK, the artists set up a weekly delivery service of Home Art Boxes to thirty-three people with dementia and their caregivers over a period spanning 11 months. The artists received funding from local organisations and the Community Lottery Fund. Thematic analysis of the feedback from the participants regarding the project and the artists themselves provided the data for this evaluation of the project. Seven main themes were identified: organisation of the project; community and connections; supporting the caregivers; enjoyment and enrichment; well-being and cognitive benefits of the projects; equipment and instructions; and drawbacks within the project. The participants' feedback enabled the artists to improve the contents and instructions given each week so that they were able to adjust the activities for those people with dementia whose condition was declining. Implications are that remote Art workshops are possible during lockdown restrictions, but that personal communication is equally important.


Protolimonoids and norlimonoids from the stem bark of Toona ciliata var. pubescens.
Six new tirucallane protolimonoids, toonapubesins A-F (1-6), one new rearranged tirucallane protolimonoid, toonapubesin G (7), and two new 21,22,23-trinorapotirucallane limonoids, toonapubesic acids A (8) and B (9), possessing an unprecedented carbon skeleton, along with five known tirucallane protolimonoids (10-14) and one known apotirucallane limonoid (15), were isolated from the stem bark of Toona ciliata var. pubescens. Their structures and relative configurations were determined by detailed spectroscopic analysis and by chemical methods. The proposed structures of 8 and 11 were confirmed by X-ray diffraction analysis of their respective derivatives (8a and 11a). The absolute configuration of 8 was determined by a novel solid-state TDDFT ECD approach on its derivative 8a while the absolute configuration of 10 was determined by the modified Mosher's method. In addition, the structures of dyvariabilin H (10c) proposed by Sticher et al. and cneorin-NP(36) (11b) by Mondon et al. were corrected as 10 and 11, respectively. Toonapubesin G (7) showed promising inhibitory activity against CDC25B with an IC(50) value of 2.1 μM, while compound 8a showed significant cell protecting activity against H(2)O(2)-induced SH-SY5Y cell damage with 11.5% increase in cell viability.


Ultrasound Phantoms to Protect Patients from Novices.
With the growing use of ultrasound for pain management, we are interested in how to teach and practice ultrasound-guided procedures. Ethically, we should not insert a needle in a patient until after much practice on a phantom. Several types of phantoms have been introduced for ultrasound training, including water, agar/gelatin, elastomeric rubber, and meat phantoms and cadavers. The ideal phantom is similar to human tissue, is readily available and inexpensive, can be used repeatedly, provides tactile feedback, will hold a needle in place, does not generate needle tracks, and is not a health hazard. Several studies have shown the effectiveness of phantoms for improving the proficiency of novices. We hope that the application of phantoms in education leads to improved proficiency and increased patient safety.


Structural and functional characterization of the Clostridium perfringens N-acetylmannosamine-6-phosphate 2-epimerase essential for the sialic acid salvage pathway.
Pathogenic bacteria are endowed with an arsenal of specialized enzymes to convert nutrient compounds from their cell hosts. The essential N-acetylmannosamine-6-phosphate 2-epimerase (NanE) belongs to a convergent glycolytic pathway for utilization of the three amino sugars, GlcNAc, ManNAc, and sialic acid. The crystal structure of ligand-free NanE from Clostridium perfringens reveals a modified triose-phosphate isomerase (β/α)8 barrel in which a stable dimer is formed by exchanging the C-terminal helix. By retaining catalytic activity in the crystalline state, the structure of the enzyme bound to the GlcNAc-6P product identifies the topology of the active site pocket and points to invariant residues Lys(66) as a putative single catalyst, supported by the structure of the catalytically inactive K66A mutant in complex with substrate ManNAc-6P. (1)H NMR-based time course assays of native NanE and mutated variants demonstrate the essential role of Lys(66) for the epimerization reaction with participation of neighboring Arg(43), Asp(126), and Glu(180) residues. These findings unveil a one-base catalytic mechanism of C2 deprotonation/reprotonation via an enolate intermediate and provide the structural basis for the development of new antimicrobial agents against this family of bacterial 2-epimerases.


Towards a Better Molecular Diagnosis of FMR1-Related Disorders-A Multiyear Experience from a Reference Lab.
The article summarizes over 20 years of experience of a reference lab in fragile X mental retardation 1 gene (FMR1) molecular analysis in the molecular diagnosis of fragile X spectrum disorders. This includes fragile X syndrome (FXS), fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which are three different clinical conditions with the same molecular background. They are all associated with an expansion of CGG repeats in the 5'UTR of FMR1 gene. Until 2016, the FMR1 gene was tested in 9185 individuals with the pre-screening PCR, supplemented with Southern blot analysis and/or Triplet Repeat Primed PCR based method. This approach allowed us to confirm the diagnosis of FXS, FXPOI FXTAS in 636/9131 (6.96%), 4/43 (9.3%) and 3/11 (27.3%) of the studied cases, respectively. Moreover, the FXS carrier status was established in 389 individuals. The technical aspect of the molecular analysis is very important in diagnosis of FXS-related disorders. The new methods were subsequently implemented in our laboratory. This allowed the significance of the Southern blot technique to be decreased until its complete withdrawal. Our experience points out the necessity of implementation of the GeneScan based methods to simplify the testing procedure as well as to obtain more information for the patient, especially if TP-PCR based methods are used.


Relative pre- and postjunctional roles of noradrenaline and adenosine 5'-triphosphate as neurotransmitters of the sympathetic nerves of guinea-pig and mouse vas deferens.
Experiments were designed to examine the relative roles of noradrenaline and adenosine 5'-triphosphate (ATP) as mediators of the contractile responses of the guinea-pig and the mouse vas deferens to electrical nerve stimulation. To study possible prejunctional actions of the agents used, in some experiments their effects on the secretion of [3H]noradrenaline were determined. The contractile responses were recorded with force displacement transducers. Pharmacological techniques were employed to examine the pre- and/or postjunctional effects mediated by noradrenaline and ATP, respectively. Noradrenaline-mediated components were "removed" by depleting the neuronal stores of noradrenaline (by pretreatment with reserpine), or by addition of adrenoceptor-blocking agents. ATP-mediated components were "removed" by desensitizing ATP receptors (with the stable analogue alpha, beta-methylene ATP). The results permit three major conclusions: (1) In both species noradrenaline and ATP "auto-inhibit" mechanisms responsible for transmitter secretion; the prejunctional effects of ATP are less marked in the mouse vas deferens, and in both species much weaker than those mediated by noradrenaline, acting via alpha 2-adrenoceptors. (2) In these species, both noradrenaline and ATP participate in the generation of both phases of the contractile responses to nerve stimulation. The relative roles of each vary with the frequency and train length of stimulation, and also with the species. The main transmitter of "phase I" contractions in guinea-pig vas deferens is ATP, and in the mouse vas deferens, noradrenaline. "Phase II" contractions are triggered mainly by noradrenaline, in both species. Sympathetic neuroeffector transmission in these tissues can be accounted for almost entirely in terms of dynamic interplay between pre- and postjunctional actions of noradrenaline and ATP. (3) The results are compatible with the hypothesis that ATP is a co-transmitter with noradrenaline in these sympathetic nerves.


In Silico prediction and experimental evaluation of furanoheliangolide sesquiterpene lactones as potent agents against Trypanosoma brucei rhodesiense.
As a continuation of our earlier study on the in vitro antiprotozoal activity of 40 natural sesquiterpene lactones (STLs), we extended the set of tested compounds from our laboratories to 59. On the basis of this extended data set, further enriched by literature data for 10 compounds tested under the same conditions, our quantitative structure-activity relationship (QSAR) analyses for activity against T. brucei rhodesiense (etiologic agent of human African trypanosomiasis, or sleeping sickness) were continued, and the QSAR model thus obtained with 69 structures was used to predict the activity of a virtual library of 1,750 STL structures. As a major result from these calculations, furanoheliangolide-type compounds, a subclass of STLs hitherto untested against T. brucei rhodesiense, were predicted to have an exceptionally high level of in vitro activity. Four representative compounds of this type, goyazensolide, 4,5-dihydro-2',3'-epoxy-15-deoxygoyazensolide, budlein A, and 4,15-isoatriplicolide tiglate, were therefore tested. They displayed 50% inhibitory concentrations (IC50s) of 0.07, 0.20, 0.07, and 0.015 μM, respectively, so that the in silico prediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL against T. b. rhodesiense found. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more detailed investigations.


Mitigating Financial Burden of Tuberculosis through Active Case Finding Targeting Household and Neighbourhood Contacts in Cambodia.
Despite free TB services available in public health facilities, TB patients often face severe financial burden due to TB. WHO set a new global target that no TB-affected families experience catastrophic costs due to TB. To monitor the progress and strategize the optimal approach to achieve the target, there is a great need to assess baseline cost data, explore potential proxy indicators for catastrophic costs, and understand what intervention mitigates financial burden. In Cambodia, nationwide active case finding (ACF) targeting household and neighbourhood contacts was implemented alongside routine passive case finding (PCF). We analyzed household cost data from ACF and PCF to determine the financial benefit of ACF, update the baseline cost data, and explore whether any dissaving patterns can be a proxy for catastrophic costs in Cambodia. In this cross-sectional comparative study, structured interviews were carried out with 108 ACF patients and 100 PCF patients. Direct and indirect costs, costs before and during treatment, costs as percentage of annual household income and dissaving patterns were compared between the two groups. The median total costs were lower by 17% in ACF than in PCF ($240.7 [IQR 65.5-594.6] vs $290.5 [IQR 113.6-813.4], p = 0.104). The median costs before treatment were significantly lower in ACF than in PCF ($5.1 [IQR 1.5-25.8] vs $22.4 [IQR 4.4-70.8], p<0.001). Indirect costs constituted the largest portion of total costs (72.3% in ACF and 61.5% in PCF). Total costs were equivalent to 11.3% and 18.6% of annual household income in ACF and PCF, respectively. ACF patients were less likely to dissave to afford TB-related expenses. Costs as percentage of annual household income were significantly associated with an occurrence of selling property (p = 0.02 for ACF, p = 0.005 for PCF). TB-affected households face severe financial hardship in Cambodia. ACF has the great potential to mitigate the costs incurred particularly before treatment. Social protection schemes that can replace lost income are critically needed to compensate for the most devastating costs in TB. An occurrence of selling household property can be a useful proxy for catastrophic cost in Cambodia.


[Two case reports: chronic obstructive pulmonary disease developed in long term survived patients after acute paraquat poisoning].
Patients with acute paraquat poisoning mostly die of respiratory failure, and the surviving ones may live with pulmonary fibrosis, but the long-term changes in lung function are still un-clear. Two patients with acute paraquat poisoning survived for more than 7 years were followed up in Northern Jiangsu People's Hospital to evaluate the imaging and spirometric changes. Eight years after poisoning, 1 patient's chest computerized tomography (CT) revealed interstitial pneumonia, chronic bronchitis, emphysema, accompanied by bronchiectasis. Spirometric test showed very severe obstructive ventilatory dysfunction [percentage of vital capacity (VC) to predicted values was 63.7%, percentage of forced expiratory volume in one second (FEV1) to predicted values was 33.2%, percentage of forced vital capacity (FVC) to predicted values was 64.7%, forced expiratory volume in one second to forced vital capacity (FEV1/FVC) was 52.5%, percentage of maximal mid-expiratory flow (MMEF) to predicted values was 9.9%, percentage of diffusion capacity for carbon monoxide in single breath (DLCO-SB) to predicted values was 49.3%]. The radiography of the other patient who survived over 7 years after poisoning also discovered chronic bronchitis, emphysema and bullae, along with pleural effusion. Spirometry identified severe mixed ventilatory dysfunction, mainly obstructive ventilatory disorder (percentage of VC to predicted values was 47.8%, percentage of FEV1 to predicted values was 35.6%, percentage of FVC to predicted values was 49.3%, FEV1/FVC was 74.1%, percentage of MMEF to predicted values was 17.1%, percentage of DLCO-SB to predicted values was 21.8%). These 2 cases indicate that acute paraquat poisoning had long-term effects on lung structure and pulmonary function, which may be manifested as chronic obstructive pulmonary disease.


Neuroleptics and migraine.
Many dopamine antagonists are proven acute migraine treatments. Genetic studies also imply that polymorphisms in dopamine genes (DRD2 receptors) in persons with migraine may create dopamine hypersensitivity. However, treatment is limited by the adverse event profiles of conventional neuroleptics including extrapyramidal symptoms, anticholinergic and antihistaminergic effects, hyperprolactinemia, and prolonged cardiac QT interval. Atypical neuroleptics cause less extrapyramial symptoms and some atypical neuroleptics, including olanzapine and quetiapine, may be beneficial as both acute and preventive migraine treatment. The combination of prochlorperazine, indomethacin, and caffeine is effective in the treatment of the acute migraine attack. The mechanism of action by which neuroleptics relieve headache is probably related to dopamine D2 receptor antagonist. Other actions via serotonin (5HT) receptor antagonists may also be important, particularly for migraine prevention. Additional studies to clarify the mechanism of action of neuroleptics in migraine could lead to new drugs and better management of migraine.


Acute opioid pretreatment potentiates naltrexone-induced drinking suppression in water-deprived rats.
Pretreatment with morphine-like agonists potentiates the behavioral effects of opioid antagonists, possibly reflecting a state of acute physical dependence. Several studies have used operant behavior to quantify these effects. However, little research has been done using unconditioned behavior. One objective of this study was to determine whether opioid agonist pretreatment (e.g., morphine, fentanyl, and meperidine) potentiated naltrexone-induced suppression of water consumption following deprivation. Another objective was to determine whether the agonist pretreatment interval was functionally related to efficacy for the manifestation of acute dependence. Finally, we compared temporally the effects of the three agonists. Adult male Sprague-Dawley rats were water deprived for 18, 20, or 22 h and given an injection (s.c.) of an agonist or saline. After 1.75, 3.75, or 5.75 h, animals received a single dose (s.c.) of naltrexone (0.01-30 mg/kg) or saline. Fifteen minutes later, subjects had access to water for 30 min. A time course of antinociception was constructed after agonist administration, using the tail-flick procedure. All three agonists dose dependently potentiated naltrexone-induced drinking suppression, decreasing the ED50 of naltrexone by as much as 150-fold. There was no clear relationship between agonist efficacy and pretreatment interval. Sensitization to naltrexone was seen up to 6 h after agonist administration, occurring in the apparent absence of an antinociceptive effect. These data extend the range of behavioral effects of opioid antagonists potentiated by opioid agonist pretreatment to suppression of drinking and show that such potentiation can occur in the absence of a prototypical agonist effect.


In vitro antibacterial activity of some systemic and topical antihistaminic preparations.
In vitro antibacterial activity of topical and systemic antihistaminic preparations containing different active substrates against the standard strains of two bacteria was evaluated. Four topical and 3 systemic preparations containing pheniramine maleate, chlorophenoxamine hydrochloride, and diphenhydramine hydrochloride were studied. The antibacterial activities of these preparations against strains of S. aureus (American Type Culture Collection, ATCC 29213) and S. epidermidis (ATCC 25212) were tested using the disc diffusion method. In addition, the Minimal Innhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) of parenteral preparations for these two bacteria were determined. Pheniramine maleate-topical and pheniramine maleate-systemic had no activity against bacteria, but the others showed various rates of activity. Chlorophenoxamine hydrochloride-topical and chlorophenoxamine hydrochloride-systemic were the most effective (P < 0.05). Despite the same active substrate content, diphenhydramine hydrochloride-topical-1 and diphenhydramine hydrochloride-topical-2 yielded different results when they were compared with each other or with the other preparations. Diphenhydramine hydrochloride-topical-2 had a relatively higher rate of activity than diphenhydramine hydrochloride-topical-1. Inhibition zone diameters were 16.9+/-1.5 mm 12.3+/-0.5 mm for S .aureus, 17.4+/-1.0 mm 0 mm for S .epidermidis respectively (P < 0.05). MIC values of parenteral preparations were equal to or above 125 ?g/ml. MIC values of parenteral preparations were higher than their blood levels in clinical use. Thus, effects of parenteral preparations may not have been reflected in routine clinical practice. However, topical forms have antibacterial activity due to additive substrates and the use of high concentration levels at the site of application. Therefore, in selection of topical forms for appropriate cases, these effects should also be taken into consideration. The antibacterial activity of topical antihistaminic preparations may be useful in certain dermatological pathology.


Analogies between granular jamming and the liquid-glass transition.
Based on large-scale, three-dimensional chute flow simulations of granular systems, we uncover strong analogies between the jamming of the grains and the liquid-glass transition. The angle of inclination theta in the former transition appears as an analog of temperature T in the latter. The transition is manifested in the development of a plateau in the contact normal force distribution P(f) at small forces, the splitting of the second peak in the pair-correlation function g(r), and increased fluctuations of the system energy. The static state also exhibits history dependence, akin to the quench-rate dependence of structural properties of glasses, due to the hyperstaticity of the contact network.


Assignment of the gene for acid beta-glucosidase to human chromosome 1.
The structural gene for human acid beta-glucosidase (GBA) has been assigned to chromosome 1 using somatic cell hybridization techniques for gene mapping. The human enzyme was detected in mouse RAG cell-human fibroblast cell hybrids by a sensitive double antibody immunoprecipitation assay using a mouse antihuman GBA antibody. No cross-reactivity between mouse beta-glucosidase and human GBA or neutral beta-glucosidase (GBN) was observed. Fifty-two primary, secondary, and tertiary manmouse hybrid lines, derived from three separate fusion experiments, were analyzed for human GBA and enzyme markers for the human chromosomes. Without exception, the presence of human GBA in these hybrid clones was correlated with the presence of human chromosome 1 or its enzymatic markers, phosphoglucomutase 1 (PGM1), and fumarate hydratase (FH). All other human chromosomes were eliminated by the independent segregation of GBA and their respective enzyme markers and/or chromosomes. Using a RAG X human fibroblast line with a mouse-human rearrangement of human chromosome 1, the locus for GBA was limited to the region 1p11 to 1qter.


Spondylodiscitis (Andersson lesion) in psoriatic spondyloarthritis: a rare event successfully treated with an anti-TNF therapy.
Spondylodiscitis (Andersson lesion) is an infrequent and late complication of advanced ankilosing arthritis. Scanty data on the efficacy of anti-TNF therapy for these lesions are available. To our knowledge, only few cases of spondylodiscitis occurring in patients with psoriatic arthritis were reported in literature. We describe the case of a patient with psoriatic arthritis who early developed Andersson lesions successfully treated with infliximab plus methotrexate therapy.


Carnosine research in relation to aging brain and neurodegeneration: A blessing for geriatrics and their neuronal disorders.
Carnosine, an endogenous dipeptide (β-Ala-l-His), is enriched in prefrontal cortex and olfactory bulb of the brain, blood and also in muscle. It has mainly antioxidant and antiglycating properties which makes this molecule unique. Its content reduces during aging and aging-induced neurodegenerative diseases. Aging is a progressive biological process that leads to develop the risk factors of diseases and death. During aging the morphological, biochemical, cellular and molecular changes occur in brain and blood including other tissues. The objective of this review is to combine the updated information from the existing literature about the aging-induced neurodegeneration and carnosine research to meet the lacuna of mechanism of carnosine. The grey matter and white matter loses its normal ratio in aging, and hence the brain volume and weight. Different aging related neurodegenerative disorders arise due to loss of neurons, and synapses as a result of proteinopathies in some cases. Carnosine, being an endogenous biomolecule and having antioxidant, antiglycating properties has shown its potency to counteract erroneous protein biosynthesis, stress, activated microglial and astrocyte activity, and different neurodegenerative disorders. It (carnosine) can also inhibit the metal ion-induced degeneration by acting as a metal chelator. In this review the trends in carnosine research in relation to aging brain and neurodegeneration have been discussed with a view to its (carnosine) eligibility (including its mechanism of action) to be used as a promising neurotherapeutic for the betterment of elderly populations of our society at the national and international levels in near future.


Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation.
The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c-derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid-specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.


Efficacy of Temozolomide-Conjugated Gold Nanoparticle Photothermal Therapy of Drug-Resistant Glioblastoma and Its Mechanism Study.
Temozolomide (TMZ) is a standard-of-care chemotherapeutic drug for the treatment of glioblastoma (GBM), but TMZ-acquired resistance limits its therapeutic effect. In this study, TMZ-loaded gold nanoparticles (TMZ@GNPs) with anti-EphA3 modification on the surface (anti-EphA3-TMZ@GNPs) were synthesized for chemical and auxiliary plasma photothermal treatment (GNPs-PPTT), aiming to overcome the problem of glioma resistance to TMZ and improve the therapeutic effects of GBM. The prepared anti-EphA3-TMZ@GNPs were spherical with a particle size of 45.88 ± 1.9 nm, and the drug loading was 7.31 ± 0.38%. In vitro, cell-culture-based experiments showed that anti-EphA3 increased the cellular uptake of GNPs in T98G cells. Upon laser irradiation, the cytotoxicity and apoptosis rate in the anti-EphA3-TMZ@GNPs-treated group were significantly higher than those in the GNPs and nonphotothermal groups (p < 0.001). The Western blot analysis showed that the GNPs-PPTT-mediated killing of tumor cells induced apoptosis by regulating the apoptotic signaling molecules and cell cycle inhibitors; the expression of MGMT significantly decreased upon p53 induction, thereby reversing drug resistance. After photothermal treatment, the survival time of the subcutaneous GBM model of nude mice in the anti-EphA3-TMZ@GNPs group was prolonged to 46 days, 1.64-fold longer as compared to that in the TMZ group. Based on H&E and TUNEL staining, GNPs-PPTT could elevate apoptosis in T98G cells. In vivo thermal imaging results showed that GNPs could enter the brain via intranasal administration and be eliminated in 2 days, indicating that GNPs are safe for brain. In conclusion, GNPs-PPTT could effectively induce apoptosis in glioma cells and reverse TMZ resistance, thereby, indicative of a promising treatment strategy for GBM.


Electrokinesis is a microbial behavior that requires extracellular electron transport.
We report a previously undescribed bacterial behavior termed electrokinesis. This behavior was initially observed as a dramatic increase in cell swimming speed during reduction of solid MnO(2) particles by the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1. The same behavioral response was observed when cells were exposed to small positive applied potentials at the working electrode of a microelectrochemical cell and could be tuned by adjusting the potential on the working electrode. Electrokinesis was found to be different from both chemotaxis and galvanotaxis but was absent in mutants defective in electron transport to solid metal oxides. Using in situ video microscopy and cell tracking algorithms, we have quantified the response for different strains of Shewanella and shown that the response correlates with current-generating capacity in microbial fuel cells. The electrokinetic response was only exhibited by a subpopulation of cells closest to the MnO(2) particles or electrodes. In contrast, the addition of 1 mM 9,10-anthraquinone-2,6-disulfonic acid, a soluble electron shuttle, led to increases in motility in the entire population. Electrokinesis is defined as a behavioral response that requires functional extracellular electron transport and that is observed as an increase in cell swimming speeds and lengthened paths of motion that occur in the proximity of a redox active mineral surface or the working electrode of an electrochemical cell.


Piezoelectric internal sinus elevation (PISE) technique: a new method for internal sinus elevation.
This article reports the surgical procedure of a transalveolar approach for sinus floor elevation using piezoelectric surgery without a mallet, called piezoelectric internal sinus elevation (PISE) technique. PISE is the modified technique of the osteotome-mediated sinus floor elevation. Osteotome-mediated sinus floor elevation uses a mallet to break the sinus floor and to push sinus membrane up. Using this technique might possibly bring positional vertigo to the patient. PISE technique does not use a mallet during the procedure to break the sinus floor and to elevate the sinus membrane; therefore, it can reduce the possibility of postoperative positional vertigo.


Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse.
The purpose of the present study was to examine the role of mitochondria in the aging process by determining whether the activities of various electron transport chain oxidoreductases are deleteriously affected during aging and whether the hypothesized age-related alterations in different tissues follow a common pattern. Activities of respiratory complexes I, II, III, and IV were measured in mitochondria isolated from brain, heart, skeletal muscle, liver, and kidney of young (3.5 months), adult (12-14 months), and old (28-30 months) C57BL/6 mice. Activities of some individual complexes were decreased in old animals, but no common pattern can be discerned among various tissues. In general, activities of the complexes were more adversely affected in tissues such as brain, heart, and skeletal muscle, whose parenchyma is composed of postmitotic cells, than those in the liver and kidney, which are composed of slowly dividing cells. The main feature of age-related potentially dysfunctional alterations in tissues was the development of a shift in activity ratios among different complexes, such that it would tend to hinder the ability of mitochondria to effectively transfer electrons down the respiratory chain and thus adversely affect oxidative phosphorylation and/or autooxidizability of the respiratory components.


New fluorinated 1,2,4-benzothiadiazine 1,1-dioxides: discovery of an orally active cognitive enhancer acting through potentiation of the 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors.
In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro-substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability.


Somatostatinoma of the pancreas associated with von Hippel-Lindau disease.
A 39-year-old man was admitted because of lumbago, vomiting and massive gastrointestinal bleeding. Oliguria developed a few days later, which was followed by hyperkalemia and cardiac arrest. Autopsy disclosed multiple renal cell carcinomas with diffuse metastasis to the liver, adrenal gland, psoas muscle and vertebrae. In addition, a somatostatinoma was found in the pancreas. From these findings and past history of cerebellar hemangioblastoma and spinal hemangioma he was diagnosed to have von Hippel-Lindau disease. Von Hippel-Lindau disease with islet cell tumor is very rare and is reported here with a review of literature.


Excitation energy transfer studies on the proximity between SH1 and the adenosinetriphosphatase site in myosin subfragment 1.
Excitation energy transfer studies were carried out to determine the distance between the adenosinetriphosphatase (ATPase) site and a unique "fast-reacting" sulfhydryl (referred to as SH1) in myosin subfragment 1. The fluorescent moiety of the probe N-(iodoacetyl)-N'-(5-sulfo-1-naphthyl)ethylene-diamine was used as the donor attached at SH1. The chromophoric nucleotide analogue 2'(3')-0-(2,4,6-trinitrophenyl)adenosine 5'-diphosphate was used as the acceptor noncovalently bound at the ATPase site. The energy transfer efficiency was found to be 56% by measuring the decrease in donor fluorescence lifetime. The critical transfer distance, R0(2/3), was determined to be 40.3 A. Since both donor and acceptor are likely to be rigidly attached, a statistical interpretation of the data was applied (Hillel, Z., & Wu, C.-W. (1976) Biochemistry 15, 2105] to determine distances. The method yielded the following conclusions: most probable distance = 38.7 A; maximum possible distance = 52 A; 10% probability for the distance to be less than 20 A; 3% probability to be less than 15 A. It may be concluded that despite the great influence that the two sites exert on each other, it is not likely that SH1 interacts directly with the ATPase site in myosin subfragment 1. This conclusion is in agreement with the findings of Wiedner et al. [Wiedner, H., Wetzel, R., & Eckstein, F. (1978) J. Biol. Chem. 253, 2763] and Botts et al. [Botts, J., Ue., K., Hozumi, T., & Samet, J. (1979) Biochemistry 18, 5157].


The Ratio Serum Creatinine/Serum Cystatin C (a Surrogate Marker of Muscle Mass) as a Predictor of Hospitalization in Chronic Obstructive Pulmonary Disease Outpatients.
In chronic obstructive pulmonary disease (COPD), low muscle mass has been associated with several clinical outcomes such as low exercise capacity, hospital admission, and mortality. The Sarcopenia Index (SI) is a novel way to estimate muscle mass based on the ratio of serum creatinine (produced exclusively by muscle)/cystatin C (produced by all nucleated body cells). This study aims to assess the SI in stable COPD outpatients, as compared with a healthy control group, to quantify its relationship with several important clinical features in COPD, and to study its potential usefulness to predict COPD exacerbations and hospital admissions. The SI was calculated in 18 healthy control subjects and 65 stable COPD outpatients were included in the study. Patients were prospectively followed for 1 year after being enrolled in the study. COPD patients had a lower SI than controls, that is lower muscle mass. Furthermore, patients with a modified Medical Research Council dyspnea score ≥2, patients with a COPD Assessment Test score ≥10, and patients with a high risk of exacerbation had lower levels of SI compared with patients without these characteristics. SI correlated with FEV1 (r = 0.491, p < 0.001), the 6-min walking test (r = 0.560, p = 0.001), and the Fat-Free Mass Index (r = 0.431, p = 0.017). Univariate and multivariate Cox proportional risk analysis showed that a low SI is an independent predictor of hospital admission in COPD outpatients followed for 1 year (HR 5.16, p = 0.025). The ratio serum creatinine/serum cystatin C correlates with several COPD characteristics, and it can be used to predict COPD hospitalization.


Home mechanical ventilation in South Korea.
To survey the use of invasive and noninvasive home mechanical ventilation (HMV) methods in South Korea from the perspective of physical medicine and rehabilitation (PM&R). For 413 users of HMV, retrospective reviews of PM&R interventions and survey of HMV methods employed from Mar 2000 to Dec 2009. Of the 413 users, the majority of whom with progressive neuromuscular disorders (NMDs) (n=358), 284 patients initially used noninvasive mechanical ventilation (NIV), while 63 others who were using tracheostomy mechanical ventilation switched to NIV as part of their rehabilitation. The NMD patients began HMV at an earlier age (34.9±20.3 yrs), and used for longer (14.7±7.5) hours than patients with non-neuromuscular causes of respiratory impairment. Noninvasive management was preferred over invasive ones, and transition to the former was a result of PM&R interventions.


Recent progress and advanced technology in carbohydrate-based drug development.
Carbohydrates, one of the most abundant and widespread biomolecules in nature, play indispensable roles in diverse biological functions, and represent a treasure trove of untapped potential for pharmaceutical applications. Here, we provide a brief overview of carbohydrate-based drug development (CBDD) over the past two decades. More importantly, advanced techniques and methodologies related to CBDD are emerging, including enzymatic synthesis, metabolic engineering, site-specific glycoconjugation, carbohydrate libraries and microarrays as well as carbohydrate-gut microbiome evaluation. These technologies have dramatically accelerated the speed of CBDD. The recently approved drugs and emerging techniques summarized herein will inspire new sights into potential opportunities to discover novel carbohydrate drugs.


Neuroimaging of pediatric posterior fossa tumors including review of the literature.
Conventional, anatomical MRI is an essential tool for diagnosis and evaluation of location, quality, and extent of posterior fossa tumors, but offers limited information regarding tumor grade and type. Advanced MRI techniques such as diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) may improve the specific diagnosis of brain tumors in the posterior fossa in children. In this review the conventional neuroimaging findings, as well as the DWI, and DTI characteristics of common pediatric posterior fossa tumors are discussed and summarized.


Coronary angioplasty. Statewide experience in California.
This report describes the in-hospital experience with percutaneous transluminal coronary angioplasty (PTCA) for the state of California in 1989. Data are derived from the statewide hospital discharge abstracts. A total of 24,883 PTCAs were performed; most patients (70%) were men and most procedures were single vessel (87%). About one fifth (19%) of patients had a principal diagnosis of acute myocardial infarction (AMI). Overall mortality was 1.4% and was higher in the AMI group (4.2%) versus the non-AMI group (0.8%, P = .0001). Mortality was higher for AMI patients having PTCA on the day of or day after admission (5.5%) versus those treated later (2.6%, P = .0001). Five percent of patients had coronary artery bypass surgery (CABG) after PTCA; CABG was performed on the same day as PTCA in 61.7% of cases. Patients presenting with AMI were more likely to have CABG (7.1%) than non-AMI patients (4.5%, P = .0001). Mortality associated with CABG was 7.3% and was higher in the AMI group (12.0%) than in the non-AMI group (5.5%, P = .0001). Factors predictive of increased mortality by bivariate analysis included age > 63 years (2.1% mortality versus 0.8% < or = 63, P = .01), female sex (1.9% versus 1.2% for men, P < .01), and the presence of diabetes (1.9% versus 1.3% for nondiabetics, P < .05). Multiple logistic regression showed that timings of PTCA with respect to admission (P = .004) and age (P = .05) were predictors of mortality, but female sex was predictive only in the non-AMI group (P = .03). Mean hospital charges were $19,597 (+/- SD, $18,213). Forty-two percent of the 110 hospitals performed more than the recommended minimum of 200 cases per year. The requirement for CABG during the same admission or the combined adverse outcome of CABG and/or death was increased in the lower-volume centers for both AMI and non-AMI patients (P < .001), although mortality alone was not. The mortality and need for CABG surgery in the statewide California PTCA experience is higher than that generally reported in the literature. In patients with an admitting diagnosis of AMI, the overall mortality was higher, as was the need for CABG and the associated CABG mortality. Most hospitals performed fewer than 200 PTCAs per year. Rates of CABG surgery and the combination of CABG and/or mortality, adjusted only for the presence or absence of AMI, were increased at the low-volume institutions.


Value of vaginal cervical position in estimating uterine anatomy.
The anatomy of the uterus is defined with the angles of the vagina, cervix and uterine corpus. Hereunder there are angles of version and flexion. The cervical position observed during the vaginal speculum examination, may give information about the uterine anatomy. In this study, we investigated the place of the cervical position in the estimation of the uterine anatomy observed during the cervical examination. We enrolled 240 patients in our study, who applied to our routine gynecology outpatient clinic with various complaints. We divided these patients into two groups according to the cervical position (anterior cervical position and posterior cervical position) observed during the speculum examination. We recorded the uterine anatomy also with the transvaginal ultrasonography. During the speculum examination, we determined that 90% of the cases with posterior fornix position were anteverted and 10% retroverted; 64.2% of the cases with anterior fornix position were anteverted and 35.8% retroverted. According to these findings, cervical position observed during the speculum examination might be useful in the estimation of the uterine anatomy regarding the angles of the version. However, the ultrasonographic examination is essential for a definitive determination of the uterine anatomy. Clin. Anat. 30:404-408, 2017. © 2017 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.