Contribution to the vector analysis of the orthogonal electrocardiogram.
A method is described for characterizing the spatial directions of vectors with the aid of the angle alpha, characterizing the direction of the vector's projection upon the frontal plane, and angle beta, indicating the deflection of the spatial vector from the frontal plane. Angle alpha is expressed in the mode used with the conventional ECG system [from 0 degrees to +/- 180 degrees], and angle beta from 0 degrees to +/- 90 degrees. Calculations are made with the aid of algebraic formulae, and the results are tabulated. To facilitate the calculations of the magnitudes and directions of vectors in the space with respect to the orthogonal leads, and for better illustration, special schemes are presented.


A randomized, controlled, prospective study evaluating the effect of patellar eversion on functional outcomes in primary total knee arthroplasty.
Patellar mobilization technique during total knee arthroplasty has been debated, with some suggesting that lateral retraction, rather than eversion, of the patella may be beneficial. We hypothesized that patients with knees surgically exposed using patellar lateral retraction would have comparable outcomes with patients with knees surgically exposed using patellar eversion. After an a priori power analysis, 120 patients with degenerative arthrosis were prospectively enrolled and were randomized to one of two patellar exposure techniques during the primary total knee arthroplasty: lateral retraction or eversion. The primary outcome measure was one-year, dynamometer-measured quadriceps strength. The secondary outcome measures evaluated during hospital stay included the ability to straight-leg raise, visual analog scale in pain, walking distance, and length of stay. The secondary outcome measures that were evaluated preoperatively and through a one-year follow-up included the Short Form-36 Physical Component Summary and Mental Component Summary scores, range of motion, quadriceps strength, and radiographic rate of patella baja and tilt. A mixed-model analysis of variance showed no significant differences between the two groups in the one-year outcome measures. At one year postoperatively, quadriceps strength was not different between groups (p = 0.77), and the range of motion significantly improved (p < 0.01) from preoperative values by a mean value (and standard deviation) of 6° ± 17°, with no significant difference (p = 0.60) between groups. The Short Form-36 Physical Component Summary score and Mental Component Summary score significantly improved (p < 0.01) for both study groups from preoperatively to one year postoperatively with no significantly different effects between groups (time × group, p = 0.85 for the Physical Component Summary score and p = 0.71 for the Mental Component Summary score), and the scores were not different at one year after surgery. There were no significant differences between groups in the change in frequency of the radiographic patella baja (p = 0.99) or the radiographic patellar tilt (p = 0.77) from before surgery to one year after surgery. Lateral retraction of the patella did not lead to superior postoperative results compared with eversion of the patella during total knee arthroplasty as evaluated using our primary outcome measure of one-year, dynamometer-measured quadriceps strength or our secondary outcome measures. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report.
Essential tremor can be suppressed with chronic, bilateral deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim), the cerebellar receiving area of the motor thalamus. The goal in this study was to correlate the location of the electrodes with the clinical efficacy of DBS in a patient with essential tremor. The authors report on a woman with essential tremor in whom chronic bilateral DBS directed to the ventral thalamus produced adequate tremor suppression until her death from unrelated causes 16 months after placement of the electrodes. Neuropathological postmortem studies of the brain in this patient demonstrated that both stimulators terminated in the Vim region of the thalamus, and that chronic DBS elicited minor reactive changes confined to the immediate vicinity of the electrode tracks. Although the authors could not identify neuropathological abnormalities specific to essential tremor, they believe that suppression of essential tremor by chronic DBS correlates with bilateral termination of the stimulators in the Vim region of the thalamus.


Geology of the Crust and Mantle, Western United States: Geophysical data reveal a thin crust and anomalous upper mantle characteristic of active regions.
Seismic refraction, gravity, phase velocity, and magnetic data, coupled with the geologic record, are all approximately satisfied by the structure shown in Fig. 9. A 20-kilometer crust under the Coast Ranges and Great Valley thickens to more than 30 kilometers under the Sierra Nevada and parts of the Basin and Range province; this whole area is underlain by an anomalous upper mantle with a velocity and density about 3 percent less than normal. It is not likely that the anomalous mantle extends much deeper than 50 kilometers, and the lower boundary may be gradational. The thicker crust or "root" under the Sierran highland region (Sierra Nevada and western Basin Ranges) is not limited to the Sierra Nevada proper. The root and the voluminous plustonic rocks originated in the Mesozoic era, and they constitute the now consolidated core of the Cordilleran eugeosyncline. But it must not be supposed that the root has persisted unchanged. The great mountain-building uplifts in the Cenozoic era must have been accompanied by large changes in the root and adjacent mantle. A zone of positive gravity and magnetic anomalies extending the length of the Great Valley is associated with mafic rocks of the western Sierra greenstone belt, an element of the Cordilleran eugeosyncline. Belts of maficto-intermediate lavas, accompanied by mafic and ultramafic intrusions, are marked by similar anomalies in other ancient geosynclines. An anomalous upper mantle of plagioclase peridotite, an expanded phase of the normal mantle, could explain about 1 kilometer of the uplift that took place over much of the region in Cenozoic time. To explain all of the Cenozoic uplift in the Sierra Nevada and Basin Ranges by this means would require the hypothesis of a separation of the anomalous mantle into crust and normal mantle fractions, followed by a renewal of the anomalous mantle through the action of regional convection currents or local overturning in the upper mantle. The low-velocity zones for compressional and transverse waves in the upper mantle may be related to this problem. Whatever its origin and composition, an anomalous upper mantle characterizes many regions of present or recent tectonic activity, such as Japan and the Mid-Atlantic Ridge (39). The anomalous mantle of western North America might form a continuous belt to the south, with anomalous mantle beneath the crest of the East Pacific Rise (40). The anomalous upper mantle may thus be an essential part of the heat engine driving the tectonic activity of these regions. The Basin and Range region was broken into blocks and laterally extended during the Cenozoic uplift, so that some blocks lagged behind, or sank. Some of the intricate disruption of the upper crust may be related to shallow Cenozoic volcanism. The relatively large and rigid Sierra Nevada block may have been tilted westward during Basin-Range deformation because of the high density of greenstones on the west side and the lower density of granitic rocks to the east. Man's environment, in the longer view of geologic time, is strongly influenced by mountain-building processes originating in the earth's crust and mantle. In the scale of a few lifetimes, climate, sea level, and the shape of the land are appreciably altered. How this comes about, and whether man can hope to influence the processes, are challenging, unsolved problems. But enough has now been learned about the crust and mantle to suggest precisely what questions must be answered and what critical experiments performed. Note added in proof: Osborne (42) has directed our attention to the possibility that the granitic rocks and also the andesites and dacites were formed by fractional crystallization of basaltic magma under conditions of high oxygen pressure. This possibility in no way conflicts with the geophysical data. In fact, such direct additions to the silicic upper crust from the mantle or lower crust would simplify the perplexing problem of how the crust is replenished in areas of great erosion.


Influences on Public Perceptions of the Importance of, and Responsibility for, Supportive Care Following Cancer Diagnosis.
Comprehensive cancer services aim to provide support in all domains of care that impact distress: physical, emotional, family, practical and spiritual. The extent of provision, referral and utilisation of these services varies dramatically, suggesting a need to improve understanding of the importance of these services. The aim of this study was to assess Australian community views on the importance of supportive cancer care, the influence of individual difference variables and who is responsible for supportive care provision. An online survey of 369 members of the Australian general public measured demographic variables, experience of cancer, awareness of supportive care, attitude to psychological help seeking, health locus of control and self-efficacy for health. Supportive care importance in physical, emotional, family, practical and spiritual domains was measured on scales from 0 to 100. These were compared to perceived importance of treatment improvements. Perceptions of responsibility for the provision of care were also rated from 0 to 100. Only attitude to psychological help seeking reliably predicted perceived importance, which was uniformly lower for supportive care than treatment improvements. Survivors and their families were viewed as having a high level of responsibility for support, although those who attributed control of health to powerful others ascribed more responsibility to those within the healthcare system. Education of the general public is needed concerning what supportive care is, how it may be provided to patients and the benefits of these services.


Emergence and Control of Stacking Fault Formation during Nanoparticle Cation Exchange Reactions.
Cation exchange reactions modify the composition of a nanocrystal while retaining other features, including the crystal structure and morphology. In many cases, the anion sublattice is considered to be locked in place as cations rapidly shuttle in and out. Here we provide evidence that the anion sublattice can shift significantly during nanocrystal cation exchange reactions. When the Cu+ cations of roxbyite Cu1.8S nanorods exchange with Zn2+ to form ZnS nanorods, a high density of stacking faults emerges. During cation exchange, the stacking sequence of the close-packed anion sublattice shifts at many locations to generate a nanorod product containing a mixture of wurtzite, zincblende, and a wurtzite/zincblende polytype that contains an ordered arrangement of stacking faults. The reagent concentration and reaction temperature, which control the cation exchange rate, serve as synthetic levers that can tune the stacking fault density from high to low, which is important because once introduced, the stacking faults could not be modified through thermal annealing. This level of synthetic control through nanocrystal cation exchange is important for controlling properties that depend on the presence and density of stacking faults.


Genomic Basis of Freshwater Adaptation in the Palaemonid Prawn Genus Macrobrachium: Convergent Evolution Following Multiple Independent Colonization Events.
Adaptation to different salinity environments can enhance morphological and genomic divergence between related aquatic taxa. Species of prawns in the genus Macrobrachium naturally inhabit different osmotic niches and possess distinctive lifecycle traits associated with salinity tolerance. This study was conducted to investigate the patterns of adaptive genomic divergence during freshwater colonization in 34 Macrobrachium species collected from four continents; Australia, Asia, North and South America. Genotyping-by-sequencing (GBS) technique identified 5018 loci containing 82,636 single nucleotide polymorphisms (SNPs) that were used to reconstruct a phylogenomic tree. An additional phylogeny was reconstructed based on 43 candidate genes, previously identified as being potentially associated with freshwater adaptation. Comparison of the two phylogenetic trees revealed contrasting topologies. The GBS tree indicated multiple independent continent-specific invasions into freshwater by Macrobrachium lineages following common marine ancestry, as species with abbreviated larval development (ALD), i.e., species having a full freshwater life history, appeared reciprocally monophyletic within each continent. In contrast, the candidate gene tree showed convergent evolution for all ALD species worldwide, forming a single, well-supported clade. This latter pattern is likely the result of common evolutionary pressures selecting key mutations favored in continental freshwater habitats Results suggest that following multiple independent invasions into continental freshwaters at different evolutionary timescales, Macrobrachium taxa experienced adaptive genomic divergence, and in particular, convergence in the same genomic regions with parallel shifts in specific conserved phenotypic traits, such as evolution of larger eggs with abbreviated larval developmental.


Translational initiation frequency of atp genes from Escherichia coli: identification of an intercistronic sequence that enhances translation.
The c, b and delta subunit genes of the Escherichia coli atp operon were cloned individually in an expression vector between the tac fusion promoter and the galK gene. The relative rates of subunit synthesis directed by the cloned genes were similar in vitro and in vivo and compared favourably with the subunit stoichiometry of the assembled proton-translocating ATP synthase of E. coli in vivo. The rate of synthesis of subunit c was at least six times that of subunit b and 18 times that of subunit delta. Progressive shortening of the long intercistronic sequence lying upstream of the subunit c gene showed that maximal expression of this gene is dependent upon the presence of a sequence stretching greater than 20 bp upstream of the Shine-Dalgarno site. This sequence thus acts to enhance the rate of translational initiation. The possibility that similar sequences might perform the same function in other operons of E. coli and bacteriophage lambda is also discussed. Translation of the subunit b cistron is partially coupled to translation of the preceding subunit c cistron. In conclusion, the expression of all the atp operon genes could be adjusted to accommodate the subunit requirements of ATP synthase assembly primarily by means of mechanisms which control the efficiency of translational initiation and re-initiation at the respective cistron start codons.


Interdependence of threonine, methionine and isoleucine metabolism in plants: accumulation and transcriptional regulation under abiotic stress.
Pathways regulating threonine, methionine and isoleucine metabolism are very efficiently interconnected in plants. As both threonine and methionine serve as substrates for isoleucine synthesis, their synthesis and catabolism under different developmental and environmental conditions also influence isoleucine availability. Together, methionine gamma-lyase and threonine deaminase maintain the isoleucine equilibrium in plants under varied substrate availabilities. Isoleucine and the two other branched-chain amino acids (BCAAs) (leucine and valine) share four common enzymes in their biosynthesis pathways and thus are coordinately regulated. Induction of free amino acids as osmolytes in response to abiotic stress is thought to play a role in plant stress tolerance. In particular, the accumulation of BCAAs is induced many-fold during osmotic stress. However, unlike in the case of proline, not much research has been focused on understanding the function of the response involving BCAAs. This review describes pathways influencing branched-chain amino acid metabolism and what is known about the biological significance of their accumulation under abiotic stress. A bioinformatics approach to understanding the transcriptional regulation of the genes involved in amino acid metabolism under abiotic stress is also presented.


Travel burden associated with granulocyte colony-stimulating factor administration in a Medicare aged population: a geospatial analysis.
Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is recommended for patients receiving myelosuppressive chemotherapy regimens with a high risk of febrile neutropenia (FN). G-CSFs should be administered starting the day after chemotherapy, necessitating return trips to the oncology clinic at the end of each cycle. We examined the travel burden related to prophylactic G-CSF injections after chemotherapy in the US. We used 2012-2014 Medicare claims data to identify a national cohort of beneficiaries age 65+ with non-myeloid cancers who received both chemotherapy and prophylactic G-CSFs. Patient travel origin was based on residence ZIP code. Oncologist practice locations and hospital addresses were obtained from the Medicare Physician Compare and Hospital Compare websites and geocoded using the Google Maps Application Programming Interface (API). Driving distance and time to the care site from each patient ZIP code tabulation area (ZCTA) were calculated using Open Street Maps road networks. Geographic and socio-economic characteristics of each ZCTA from the US Census Bureau's American Community Survey were used to stratify and analyze travel estimates. The mean one-way driving distance to the G-CSF provider was 23.8 (SD 30.1) miles and the mean one-way driving time was 33.3 (SD 37.8) minutes. When stratified by population density, the mean one-way travel time varied from 12.1 (SD 10.1) minutes in Very Dense Urban areas to 76.7 (SD 72.1) minutes in Super Rural areas. About 48% of patients had one-way travel times of <20 minutes, but 19% of patients traveled ≥50 minutes one way for G-CSF prophylaxis. Patients in areas with above average concentrations of aged, poor or disabled residents were more likely to experience longer travel. Administration of G-CSF therapy after chemotherapy can present a significant travel burden for cancer patients. Technological improvements in the form and methods of drug delivery for G-CSFs might significantly reduce this travel burden.


Recent advances in biodegradable metals for medical sutures: a critical review.
Sutures that biodegrade and dissolve over a period of several weeks are in great demand to stitch wounds and surgical incisions. These new materials are receiving increased acceptance across surgical procedures whenever permanent sutures and long-term care are not needed. Unfortunately, both inflammatory responses and adverse local tissue reactions in the close-to-stitching environment are often reported for biodegradable polymeric sutures currently used by the medical community. While bioabsorbable metals are predominantly investigated and tested for vascular stent or osteosynthesis applications, they also appear to possess adequate bio-compatibility, mechanical properties, and corrosion stability to replace biodegradable polymeric sutures. In this Review, biodegradable alloys made of iron, magnesium, and zinc are critically evaluated as potential materials for the manufacturing of soft and hard tissue sutures. In the case of soft tissue closing and stitching, these metals have to compete against currently available degradable polymers. In the case of hard tissue closing and stitching, biodegradable sternal wires could replace the permanent sutures made of stainless steel or titanium alloys. This Review discusses the specific materials and degradation properties required by all suture materials, summarizes current suture testing protocols and provides a well-grounded direction for the potential future development of biodegradable metal based sutures.


Fluorescent Analogues of Human α-Calcitonin Gene-Related Peptide with Potent Vasodilator Activity.
: Human α-calcitonin gene-related peptide (h-α-CGRP) is a highly potent vasodilator peptide that belongs to the family of calcitonin peptides. There are two forms of CGRP receptors in humans and rodents: α-CGRP receptor predominately found in the cardiovascular system and β-CGRP receptor predominating in the gastrointestinal tract. The CGRP receptors are primarily localized to C and Aδ sensory fibers, where they are involved in nociceptive transmission and migraine pathophysiology. These fibers are found both peripherally and centrally, with extensive perivascular location. The CGRP receptors belong to the class B G-protein-coupled receptors, and they are primarily associated to signaling via Gα proteins. The objectives of the present work were: (i) synthesis of three single-labelled fluorescent analogues of h-α-CGRP by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis, and (ii) testing of their biological activity in isolated human, mouse, and rat arteries by using a small-vessel myograph setup. The three analogues were labelled with 5(6)-carboxyfluorescein via the spacer 6-aminohexanoic acid at the chain of Lys24 or Lys35. Circular dichroism (CD) experiments were performed to obtain information on the secondary structure of these fluorescently labelled peptides. The CD spectra indicated that the folding of all three analogues was similar to that of native α-CGRP. The three fluorescent analogues of α-CGRP were successfully prepared with a purity of >95%. In comparison to α-CGRP, the three analogues exhibited similar efficacy, but different potency in producing a vasodilator effect. The analogue labelled at the N-terminus proved to be the most readily synthesized, but it was found to possess the lowest vasodilator potency. The analogues labelled at Lys35 or Lys24 exhibited an acceptable reduction in potency (i.e., 3-5 times and 5-10 times less potent, respectively), and thus they have potential for use in further investigations of receptor internalization and neuronal reuptake.


Community cardiovascular disease risk from cross-sectional general practice clinical data: a spatial analysis.
Cardiovascular disease (CVD) continues to be a leading cause of illness and death among adults worldwide. The objective of this study was to calculate a CVD risk score from general practice (GP) clinical records and assess spatial variations of CVD risk in communities. We used GP clinical data for 4,740 men and women aged 30 to 74 years with no history of CVD. A 10-year absolute CVD risk score was calculated based on the Framingham risk equation. The individual risk scores were aggregated within each Statistical Area Level One (SA1) to predict the level of CVD risk in that area. Finally, the pattern of CVD risk was visualized to highlight communities with high and low risk of CVD. The overall 10-year risk of CVD in our sample population was 14.6% (95% confidence interval [CI], 14.3%-14.9%). Of the 4,740 patients in our study, 26.7% were at high risk, 29.8% were at moderate risk, and 43.5% were at low risk for CVD over 10 years. The proportion of patients at high risk for CVD was significantly higher in the communities of low socioeconomic status. This study illustrates methods to further explore prevalence, location, and correlates of CVD to identify communities of high levels of unmet need for cardiovascular care and to enable geographic targeting of effective interventions for enhancing early and timely detection and management of CVD in those communities.


Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.
Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.


Amplifier design for EMG recording from stimulation electrodes during functional electrical stimulation leg cycling ergometry.
Functional electrical stimulation leg cycle ergometry (FES-LCE), which is often used as exercise for people with spinal cord injury (SCI), has recently been applied in the motor rehabilitation of stroke patients. Recently completed studies show controversial results, but with a tendency to positive training effects. Current technology is identical to that used in FES-LCE for SCI, whereas the pathology of stroke differs strongly. Most stroke patients with hemiparesis are able to drive an ergometer independently. Depending on the degree of spasticity, the paretic leg will partially support or hinder movements. Electrical stimulation increases muscle force and endurance and both are prerequisites for restoring gait. However, the effect of FES-LCE on improving impaired motor coordination is unclear. To measure motor coordination during FES-LCE, an EMG-amplifier design has been investigated which suppresses stimulation artifacts and allows detection of volitional or reflex induced muscle activity. Direct measurement of EMG from stimulation electrodes between stimulation pulses is an important asset of this amplifier. Photo-MOS switches in front of the preamplifier are utilized to achieve this. The technology presented here can be used to monitor the effects of FES-LCE to adapt the stimulation strategy or to realize EMG-biofeedback training.


Communication in the third dimension: song perch height of rivals affects singing response in nightingales.
Many animals use long-range signals to compete over mates and resources. Optimal transmission can be achieved by choosing efficient signals, or by choosing adequate signalling perches and song posts. High signalling perches benefit sound transmission and reception, but may be more risky due to exposure to airborne predators. Perch height could thus reflect male quality, with individuals signalling at higher perches appearing as more threatening to rivals. Using playbacks on nightingales (Luscinia megarhynchos), we simulated rivals singing at the same height as residents, or singing three metres higher. Surprisingly, residents increased song output stronger, and, varying with future pairing success, overlapped more songs of the playback when rivals were singing at the same height than when they were singing higher. Other than expected, rivals singing at the same height may thus be experienced as more threatening than rivals singing at higher perches. Our study provides new evidence that territorial animals integrate information on signalling height and thus on vertical cues in their assessment of rivals.


Efficient kinetic macrocyclization.
In this article, the highly efficient formation of a series of recently discovered aromatic oligoamide macrocycles consisting of six meta-linked residues is first discussed. The macrocycles, with their backbones rigidified by three-center hydrogen bonds, were found to form in high yields that deviate dramatically from the theoretically allowed value obtained from kinetic simulation of a typical kinetically controlled macrocyclization reaction. The folding of the uncyclized six-residue oligomeric precursors, which belong to a class of backbone-rigidified oligoamides that have been demonstrated by us to adopt well-defined crescent conformations, plays a critical role in the observed high efficiency. Out of two possible mechanisms, one is consistent with experimental results obtained from the coupling of crescent oligoamides of different lengths, which suggests a remote steric effect that discourages the formation of oligomers having lengths longer than the backbone of the six-residue precursors. The suggested mechanism is supported by the efficient formation of very large aromatic oligoamide macrocycles consisting of alternating meta- and para-linked residues. These large macrocycles, having H-bond-rigidified backbones and large internal lumens, are formed in high (>80%) yields on the basis of one-step, multicomponent macrocyclization reactions. The condensation of monomeric meta-diamines and a para-diacid chloride leads to the efficient formation of macrocycles with 14, 16, and 18 residues, corresponding to 70-, 80-, and 90-membered rings that contain internal cavities of 2.2, 2.5, and 2.9 nm across. In addition, the condensation between trimeric or pentameric diamines and a monomeric diacid chloride had resulted in the selective formation of single macrocyclic products with 16 or 18 residues. The efficient formation of the macrocycles, along with the absence of other noncyclic oligomeric and polymeric byproducts, is in sharp contrast to the poor yields associated with most kinetically controlled macrocyclization reactions. This system represents a rare example of highly efficient kinetic macrocyclization reactions involving large numbers of reacting units, which provides very large, shape-persistent macrocycles.


Cellular and subcellular localization of paralemmin-1, a protein involved in cell shape control, in the rat brain, adrenal gland and kidney.
Paralemmin-1 is a phosphoprotein, lipid-anchored to the cytoplasmic face of membranes and implicated in plasma membrane dynamics and cell process formation. We report an immunoperoxidase histochemical analysis of the cellular and subcellular localization of paralemmin-1 in the rat tissues where its expression is highest: the brain, the adrenal gland and the kidney. Paralemmin-1 is detected throughout the brain, in neuronal perikarya, axons and dendrites including dendritic spines and also in glial processes. In the adrenal gland, paralemmin-1 is highly expressed in the medulla. The kidney displays a pattern of differential paralemmin-1 expression in various structures and cell types, with high concentrations in cells of the parietal epithelium of Bowman's capsule, intermediate tubules, distal tubules and principal cells of outer medullary collecting ducts. Mosaics of paralemmin-positive and paralemmin-negative cells are observed in proximal tubules, the parietal epithelium of Bowman's capsule and the endothelium of many blood vessels. Plasma membrane association in epithelia is often polarized: paralemmin-1 concentrates at the apical membranes of adrenal chromaffin cells, but at the basolateral plasma membranes of proximal and distal tubule cells in the kidney. Paralemmin-1 immunoreactivity exhibits a spotted pattern and can be seen both at plasma membranes and within the cytoplasm, where it is often associated with endomembranes. This discontinuous distribution and the detergent extraction properties of paralemmin-1 suggest an association with lipid microdomains. The findings are consistent with a role for paralemmin-1 in the formation and stabilization of plasma membrane elaborations, in neurons as well as in other cell types.


Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine.
Mitochondria do not exist as discrete static entities; rather, mitochondria form a network that continuously moves, divides, and fuses. The structure of this dynamic network is in part maintained by a balance of division and fusion events (Hoppins et al., 2007). The ratio of division to fusion events that defines a proper balance is not universal but varies with developmental stage, cell type, and biological circumstances. This is evident throughout the cell cycle in higher eukaryotes, where mitochondria elongate during the G1/S transition and fragment at the onset of mitosis, and when mitochondria fragment in response to certain cellular stimuli, such as increases in cytosolic calcium levels (Breckenridge et al., 2003; Cereghetti et al., 2008; Han et al., 2008; Mitra et al., 2009; Taguchi et al., 2007). The functional state and distribution of mitochondria are clearly influenced by its steady-state structure. When the normal balance of division and fusion is disrupted as a consequence of the inappropriate stimulation or inhibition of either process, problems arise at the cellular level that compromises the well-being of the organism as a whole. This is evident by the ever-increasing number of diseases in which abnormal mitochondrial dynamics have been etiologically implicated. In this context, the mitochondrial division and fusion machines are valuable and interesting targets of small molecule effectors, as inhibition or activation of these processes may be able to restore the proper dynamic balance and function. A small molecule inhibitor of mitochondrial division, mdivi-1, has already been identified and characterized (Cassidy-Stone et al., 2008). This inhibitor has provided valuable insight into the mechanism of mitochondrial division and has shown great therapeutic promise in a wide array of disease models. This review will focus on small molecule effectors of mitochondrial division, discussing their value in basic biological research as well as their therapeutic potential.


Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other leukaemias by the high potential for early haemorrhagic death. Several processes are involved, such as disseminated intravascular coagulation and hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis. TAFI can be activated by thrombin, and in its activated form potently attenuates fibrinolysis by removing C-terminal lysine and arginine residues that are important for the binding and activation of plasminogen. Activation of TAFI by the coagulation system results in a down-regulation of fibrinolytic activity and, thereby, prevents a rapid dissolution of the fibrin clot. To establish whether TAFI was involved in the severity of the bleeding complications in APL, the TAFI antigen and activity levels were determined in a group of 15 patients. The TAFI antigen concentration was normal, but the activity of TAFI was severely reduced in APL by approximately 60%. The reduction of TAFI activity was most probably caused by the action of plasmin on TAFI because in vitro experiments revealed that plasmin slightly reduced antigen levels but severely reduced TAFI activity. The acquired functional TAFI deficiency in APL may contribute to the severity of the haemorrhagic diathesis because of the impaired capacity of the coagulation system to protect the fibrin clot from fibrinolysis.


Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review.
Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist. To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them. Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included. One of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity. Despite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.


[Port visualization before intraperitoneal chemotherapy: scintigraphy or angiography?].
For assessing the functioning of intraperitoneal port-catheter systems prior to intraperitoneal chemotherapy, scintigraphy/SPECT and subtraction-angiography were compared. The patient under scrutiny had three port-catheter systems. Two of the three ports were functioning well. However, one port did not function. Via scintigraphy with 99m-Tc-nanocolloid this defective port was detected, but the cause was identified only by angiography. By the angiographic technique, a leakage near the port chamber caused by dislocation of the catheter could be verified. SPECT is a more useful method than angiography, since it shows very clearly intraperitoneal distribution by the possibility of reconstructing various slices. In conclusion, both techniques, the scintigraphic and the angiographic one, complement each other well.


Antimicrobial, antioxidant and cytotoxic activities of propolis from Melipona orbignyi (Hymenoptera, Apidae).
Propolis from stingless bees is well known for its biologic properties; however, few studies have demonstrated these effects. Therefore, this study aimed to investigate the chemical composition and antimicrobial, antioxidant and cytotoxic activities of propolis from the stingless bee Melipona orbignyi, found in Mato Grosso do Sul, Brazil. The chemical composition of the ethanol extract of propolis (EEP) indicated the presence of aromatic acids, phenolic compounds, alcohols, terpenes and sugars. The EEP was active against the bacterium Staphylococcus aureus and the fungus Candida albicans. The EEP showed antioxidant activity by scavenging free radicals and inhibiting hemolysis and lipid peroxidation in human erythrocytes incubated with an oxidizing agent. Additionally, EEP promoted cytotoxic activity and primarily necrotic death in K562 erythroleukemia cells. Taken together, these results indicate that propolis from M. orbignyi has therapeutic potential for the treatment and/or prevention of diseases related to microorganism activity, oxidative stress and tumor cell proliferation.


Clinical Outcomes and Response Predictors of Vedolizumab Induction Treatment for Korean Patients With Inflammatory Bowel Diseases Who Failed Anti-TNF Therapy: A KASID Prospective Multicenter Cohort Study.
We investigated the real-life effectiveness and safety of vedolizumab (VDZ) induction therapy among Korean patients with Crohn disease (CD) or ulcerative colitis (UC) for whom anti-tumor necrosis factor therapy previously failed. Adult patients who started VDZ induction therapy at 16 centers were prospectively enrolled in the Korean VDZ nationwide registry. The coprimary outcomes were clinical remission, defined as a Crohn's Disease Activity Index score <150 points and a partial Mayo score ≤2 points with a combined rectal bleeding and stool frequency subscore ≤1 point at week 14 and endoscopic remission defined as a Mayo endoscopic subscore ≤1 point. We also analyzed predictors of clinical remission. Between August 2017 and November 2019, a total of 158 patients (80 with CD and 78 with UC) received VDZ induction therapy. Clinical remission rates among patients with CD and patients with UC were 44.1% and 44.0%, respectively. Among patients with UC, the endoscopic remission rate was 32.4%. Clinical response and remission rates showed increasing trends during induction therapy. Multivariable analysis revealed that clinical response at week 6 was the only predictor of clinical remission at week 14 for both patients with CD and patients with UC. Among patients who experienced 1 or more adverse events (n = 71; 44.9%), disease exacerbation (n = 28; 17.7%) was the most common adverse event. Among Korean patients with CD or UC for whom anti-tumor necrosis factor therapy failed, VDZ induction therapy was effective and safe. The early clinical response was associated with clinical remission after VDZ induction therapy.


Systematic modeling study of channel waveguide fabrication by thermal silver ion exchange.
A systematic study of thermal silver ion exchange used for the fabrication of optical channel waveguides is reported in a single-alkali glass. The diffusion equilibrium and diffusion dynamics are experimentally studied, and the concentration-dependent diffusion coefficients are determined. The relationship between the fabrication conditions, i.e., time, temperature, and melt concentration, and the induced waveguide refractive index profile is established. It is demonstrated that the diffusion equation can be solved, without use of any free parameters, to predict the refractive index profiles of both planar and channel waveguides. A 1.6 cm diameter integrated optic ring resonator, with a propagation loss of 0.1 dB/cm, is fabricated in a glass by thermal silver ion exchange. The induced refractive index profile is related to the optical characteristics of the functional device.


No Racial Difference in Rehabilitation Therapy Across All Post-Acute Care Settings in the Year Following a Stroke.
Black stroke survivors experience greater poststroke disability than whites. Differences in post-acute rehabilitation may contribute to this disparity. Therefore, we estimated racial differences in rehabilitation therapy utilization, intensity, and the number of post-acute care settings in the first year after a stroke. We used national Medicare data to study 186 168 elderly black and white patients hospitalized with a primary diagnosis of stroke in 2011. We tabulated the proportion of stroke survivors receiving physical, occupational, and speech and language therapy in each post-acute care setting (inpatient rehabilitation facility, skilled nursing facility, and home health agency), minutes of therapy, and number of transitions between settings. We then used generalized linear models to determine whether racial differences in minutes of physical therapy were influenced by demographics, comorbidities, thrombolysis, and markers of stroke severity. Black stroke patients were more likely to receive each type of therapy than white stroke patients. Compared with white stroke patients, black stroke patients received more minutes of physical therapy (897.8 versus 743.4; P<0.01), occupational therapy (752.7 versus 648.9; P<0.01), and speech and language therapy (865.7 versus 658.1; P<0.01). There were no clinically significant differences in physical therapy minutes after adjustment. Blacks had more transitions (median, 3; interquartile range, 1-5) than whites (median, 2; interquartile range, 1-5; P<0.01). There are no clinically significant racial differences in rehabilitation therapy utilization or intensity after accounting for patient characteristics. It is unlikely that differences in rehabilitation utilization or intensity are important contributors to racial disparities in poststroke disability.


Immunochemical evidence for two 3-methylcholanthrene-inducible forms of cytochrome P-448 in rat liver microsomes using a double-antibody radioimmunoassay procedure.
Double-antibody radioimmunoassay (RIA) procedures were developed for the determination of two forms of cytochrome P-448 in crude liver microsomes at the picogram level. The antisera used in the RIAs were produced against two forms of cytochrome P-448 isolated from livers of rats treated with 3,4,5,3',4',5'-hexachlorobiphenyl (3,4,5-HCB) and 3-methylcholanthrene (3-MC), referred to as cytochromes P-448HCB and P-448MC, respectively. The results obtained with RIA procedures were consistent with results of radial immunodiffusion analysis, sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and estimation of aryl hydrocarbon hydroxylase (AHH) activity. Utilizing the RIAs, both forms of cytochrome P-448 were found in significant quantities in liver microsomes of rats treated with 3-MC, 3,4,5-HCB, isosafrole, and Aroclor 1254 but only in minute concentrations in untreated and phenobarbital-treated rats.


[Hormone substitution therapy in menopause and risk of breast cancer].
If the administration of an estrogen alone increases the risk of breast and endometrium cancer, the addition of a progesterone derivative does not seem to change completely the risk of breast cancer whilst it clearly decreases that of the uterine one. One must be careful in making a large extrapolation of the data on the endometrium (progestogens inhibit the mitotic action of estrogens) to that on the mammary epithelium (inhibition of the estrogen activity at the canal level but synergy with estrogens at the lobe level). The high tissue concentrations of oestradiol at the mammary gland level after menopause could partly explain the small influence of exogenous estrogens administered alone and/or in combination with progestogens on the transformation of a gland already oversaturated with estrogens.


Estrogen-induced progestin receptors in the brain and pituitary of the South African clawed frog, Xenopus laevis.
High-affinity progestin binding sites were found in the brain and pituitary of the female South African clawed frog, Xenopus laevis. Cytosol progestin receptors in the hypothalamus-preoptic area and pituitary were increased in number by estradiol treatment in ovariectomized frogs. The telencephalon also contained high-affinity binding sites, but the concentration was not affected by estrogen priming. Autoradiographic analysis of the distribution of the synthetic progestin 3H-R5020 revealed some lightly labeled cells in the anterior preoptic area and ventral infundibulum of ovariectomized animals. After estrogen priming, many heavily labeled cells were observed in the following areas: ventrolateral striatum and amygdala, anterior preoptic area, ventral infundibular nucleus, laminar nucleus of the torus semicircularis, and anterior pituitary. The areas in which dense accumulations of 3H-R5020 labeled cells were found after estrogen treatment are a subset of areas known to contain estrogen binding sites. The induction of progestin receptors by estradiol may be related to the requirement for both estrogen and progestin to elicit female sexual behavior in this species.


Treating erythroplasia of Queyrat with photodynamic therapy following circumcision and dermabrasion.
We describe a case of a patient with erythroplasia of Queyrat located on the whole glans and end of the prepuce that was successfully treated with three courses of photodynamic therapy after the completion of circumcision and dermabrasion. Skin lesions disappeared after receiving this combination of treatments and have not recurred during the past 6 months of follow-up.


[Urologic obstructions due to fungal balls].
Fungal urologic infections are unusual in children. They are associated with chronic uropathies, citostatics and antibiotic treatments and depressed immunity which allow the pathologic growth of a saprofitie organism. This infection must present special forms when the mycotic development is realized in cavities and special advantageous conditions. Then it adopt the form of fungal bezoars, and it can mobilize itself and provoke obstructions in the urinary tract. We present two cases of urinary obstructions secondary to fugal bezoars. The obstruction was localized in the uretero-vesical junction. In both of them the infection was associated with long antibiotic treatment, and with severe immunodeficiency only in one. The diagnosis was possible by echography and direct determination of candida albicans in urine. We proved also temporary ureterovesical stenosis we found before a reflux. The treatment included intravenous and local anfotericine B with dissolution of the bezoar in three and four days respectively.


Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study.
Tissue levels of n-3 fatty acids reflect dietary intake, but quantitative data about rate of incorporation and levels as a function of intake are scarce. We fed 58 men 0, 3, 6, or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters, erythrocytes, and subcutaneous fat during and after supplementation. Eicosapentaenoic acid (EPA) in cholesteryl esters plateaued after 4-8 weeks; the incorporation half-life was 4.8 days. Steady-state levels increased by 3.9 +/- 0.3 mass % points (+/- SE) for each extra gram of EPA eaten per day. Incorporation of docosahexaenoic acid (DHA) was erratic; plateau values were 1.1 +/- 0.1 mass % higher for every g/d ingested. Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days; a steady state was reached after 180 days. Each g/d increased levels by 2.1 +/- 0.1 mass %. C22:5n-3 levels increased markedly. Changes in DHA were erratic and smaller. EPA levels in adipose tissue rose also; the change after 6 months was 67% of that after 12 months in gluteal and 75% in abdominal fat. After 12 months each gram per day caused an 0.11 +/- 0.01 mass % rise in gluteal fat for EPA, 0.53 +/- 0.07 for C22:5n-3, and 0.14 +/- 0.03 for DHA. Thus, different (n-3) fatty acids were incorporated with different efficiencies, possibly because of interconversions or different affinities of the enzymatic pathways involved. EPA levels in cholesteryl esters reflect intake over the past week or two, erythrocytes over the past month or two, and adipose tissue over a period of years. These findings may help in assessing the intake of (n-3) fatty acids in epidemiological studies.


The bacterial protein YidC accelerates MPIase-dependent integration of membrane proteins.
Bacterial membrane proteins are integrated into membranes through the concerted activities of a series of integration factors, including membrane protein integrase (MPIase). However, how MPIase activity is complemented by other integration factors during membrane protein integration is incompletely understood. Here, using inverted inner-membrane vesicle and reconstituted (proteo)liposome preparations from Escherichia coli cells, along with membrane protein integration assays and the PURE system to produce membrane proteins, we found that anti-MPIase IgG inhibits the integration of both the Sec-independent substrate 3L-Pf3 coat and the Sec-dependent substrate MtlA into E. coli membrane vesicles. MPIase-depleted membrane vesicles lacked both 3L-Pf3 coat and MtlA integration, indicating that MPIase is involved in the integration of both proteins. We developed a reconstitution system in which disordered spontaneous integration was precluded, which revealed that SecYEG, YidC, or both, are not sufficient for Sec-dependent and -independent integration. Although YidC had no effect on MPIase-dependent integration of Sec-independent substrates in the conventional assay system, YidC significantly accelerated the integration when the substrate amounts were increased in our PURE system-based assay. Similar acceleration by YidC was observed for MtlA integration. YidC mutants with amino acid substitutions in the hydrophilic cavity inside the membrane were defective in the acceleration of the Sec-independent integration. Of note, MPIase was up-regulated upon YidC depletion. These results indicate that YidC accelerates the MPIase-dependent integration of membrane proteins, suggesting that MPIase and YidC function sequentially and cooperatively during the catalytic cycle of membrane protein integration.


Ethyl acetate production by the elusive alcohol acetyltransferase from yeast.
Ethyl acetate is an industrially relevant ester that is currently produced exclusively through unsustainable processes. Many yeasts are able to produce ethyl acetate, but the main responsible enzyme has remained elusive, hampering the engineering of novel production strains. Here we describe the discovery of a new enzyme (Eat1) from the yeast Wickerhamomyces anomalus that resulted in high ethyl acetate production when expressed in Saccharomyces cerevisiae and Escherichia coli. Purified Eat1 showed alcohol acetyltransferase activity with ethanol and acetyl-CoA. Homologs of eat1 are responsible for most ethyl acetate synthesis in known ethyl acetate-producing yeasts, including S. cerevisiae, and are only distantly related to known alcohol acetyltransferases. Eat1 is therefore proposed to compose a novel alcohol acetyltransferase family within the α/β hydrolase superfamily. The discovery of this novel enzyme family is a crucial step towards the development of biobased ethyl acetate production and will also help in selecting improved S. cerevisiae brewing strains.


Penetrating cardiac injuries: literature review and analysis of the forensic approach.
Penetrating cardiac injuries represent an increasingly frequent type of trauma in clinical and autopsy practice. The present study aims to review the specialist literature of the last decade (2010-2020) to assess whether the main features of these lesions have changed compared to previous years. The following characteristics were considered: sex, age, cardiac structure involved, execution or not of surgery and postoperative survival, hemodynamic stability, circumstances and mechanism of production, injury and cause of death. Furthermore, the authors propose a practical appraisal of penetrating heart injury in which death was due to a delay in rescue. In line with the data obtained from the practical case, the review showed that compared to the past, the differences concern especially the mortality rate. This paper highlights that the forensic pathologist who approaches a case of transcardiac injury must consider that the circumstances of death are not always attributable to accidental events, attacks or suicides, but may also be due to clinical malpractice or failure to rescue.


Time-varying treatment effect modification of oral analgesic effectiveness by depressive symptoms in knee osteoarthritis: an application of structural nested mean models in a prospective cohort.
Depressive symptoms are common in knee osteoarthritis (OA), exacerbate knee pain severity and may influence outcomes of oral analgesic treatments. The aim was to assess whether oral analgesic effectiveness in knee OA varies by fluctuations in depressive symptoms. The sample included Osteoarthritis Initiative (OAI) participants not treated with oral analgesics at enrolment (n = 1477), with radiographic disease at the first follow-up visit (defined as the index date). Oral analgesic treatment and depressive symptoms, assessed with the Center for Epidemiological Studies Depression [(CES-D) score ≥16] Scale, were measured over three annual visits. Knee pain severity was measured at visits adjacent to treatment and modifier using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (rescaled range = 0-100). Structural nested mean models (SNMMs) estimated causal mean differences in knee pain severity comparing treatment versus no treatment. The average causal effects of treated versus not treated for observations without depressive symptoms showed negligible differences in knee pain severity. However, causal mean differences in knee pain severity comparing treatment versus no treatment among observations with depressive symptoms increased over time from -0.10 [95% confidence interval (CI): -9.94, 9.74] to -16.67 (95% CI: -26.33, -7.01). Accordingly, the difference in average causal effects regarding oral analgesic treatment for knee pain severity between person-time with and without depressive symptoms was largest (-16.53; 95% CI: -26.75, -6.31) at the last time point. Cumulative treatment for 2 or 3 years did not yield larger causal mean differences. Knee OA patients with persistent depressive symptoms and chronic pain may derive more analgesic treatment benefit than those without depressive symptoms and less pain.


Potential underlying mechanisms of ethambutol induced optic neuropathy: Evidence from in vitro to clinical studies.
Ethambutol is an antibiotic widely used for treatment of Mycobacterium species. Although it is safe to use in patients, the ocular toxic impact, including optic neuropathy and retinopathy, can be observed in patients using ethambutol. After discontinuation of the drug, the ocular toxic effects can be reversible in some patients, but some are not. Ethambutol-induced optic neuropathy has been recognized for more than six decades and the prevalence of optic neuropathy from a standard dose of ethambutol has been reported as 0.7-1.29%. Several factors associated with ethambutol-induced optic neuropathy include dosage/duration of drug, the medical conditions of patients such as renal and hepatic dysfunction and preexisting mitochondrial mutations. Currently, there is no specific treatment and prevention of ethambutol-induced optic neuropathy. In addition, the potential underlying mechanisms of ethambutol-induced optic neuropathy is still unclear. Therefore, this review aimed to summarize and discuss evidence from clinical, in vitro, and in vivo studies in order to explore the potential pathophysiology of ethambutol-induced optic neuropathy. Any contradictory findings are also included and discussed. The insights gained from the review will facilitate the discovery of novel approaches for prevention and treatment of optic neuropathy-induced by ethambutol.


Development and preclinical evaluation of a trivalent, formalin-inactivated Shigella whole-cell vaccine.
Studies were undertaken to manufacture a multivalent Shigella inactivated whole-cell vaccine that is safe, effective, and inexpensive. By using several formalin concentrations, temperatures, and incubation periods, an optimized set of inactivation conditions was established for Shigella flexneri 2a, S. sonnei, and S. flexneri 3a to produce inactivated whole cells expressing a full repertoire of Ipa proteins and lipopolysaccharide (LPS). The inactivation conditions selected were treatment with 0.2% formalin (S. flexneri 2a and 3a) or 0.6% formalin (S. sonnei) for 48 h at 25°C. Vaccine formulations prepared under different inactivation conditions, in different doses (10E5, 10E7, and 10E9 cells), and with or without the inclusion of double-mutant heat-labile toxin (dmLT) were evaluated in mice. Two intranasal immunizations with ≥10E7 inactivated whole cells resulted in high levels of anti-Invaplex and moderate levels of LPS-specific IgG and IgA in serum and in lung and intestinal wash samples. Addition of dmLT to the vaccine formulations did not significantly enhance humoral immunogenicity. Minimal humoral responses for IpaB, IpaC, or IpaD were detected after immunization with inactivated whole Shigella cells regardless of the vaccine inactivation conditions. In guinea pigs, monovalent formulations of S. flexneri 2a of 3a or S. sonnei consisting of 10E8, 10E9, or 10E10 cells were protective in a keratoconjunctivitis assay. A trivalent formulation provided protection against all three serotypes (S. flexneri 2a, P = 0.018; S. flexneri 3a, P = 0.04; S. sonnei, P < 0.0001). The inactivated Shigella whole-cell vaccine approach incorporates an uncomplicated manufacturing process that is compatible with multivalency and the future development of a broadly protective Shigella vaccine.


PLAC1 immunization does not induce infertility in mice.
Placenta specific 1 (PLAC1) is a protein rarely expressed in normal cells, except it is important for placental development, with a possible role in the establishment of the mother-fetus interface. The gene is also highly active in a wide variety of cancers and therefore, immunization with PLAC1 peptides could possibly be part of future immunotherapeutic strategies. We investigated whether vaccination against PLAC1 could induce infertility. We inoculated female mice with PLAC1 peptides, put them in mating, measured antibody response (ELISA assay) and checked, in immunohistochemistry, binding of the induced antibodies to the native antigen. We demonstrated that mice consistently develop antibody responses. We also demonstrated that female mice, after being inoculated with the PLAC1 peptide mix, do became pregnant and can give birth to normal infants. PLAC1 antigens as a specific anti-cancer vaccine could induce anti-PLAC1 antibodies which do not necessarily cause infertility.


Unimolecular micelles of pH-responsive star-like copolymers for co-delivery of anticancer drugs and small-molecular photothermal agents: a new drug-carrier for combinational chemo/photothermal cancer therapy.
Development of stimuli-responsive drug carriers that can efficiently retain the encapsulated drug during blood circulation and selectively release the drug in disease targets under internal and/or external stimulation is important to minimize the side effects and improve the drug efficacy. Herein, we report a nanoscale polymeric carrier based on robust and pH-responsive unimolecular micelles that are able to carry multiple functional agents such as anticancer drugs and photothermal agents for improved treatment of cancer cells through combinational chemo/photothermal therapy. Specifically, we synthesized three pH-responsive amphiphilic star-like copolymers (denoted as CPDOs), which were facilely synthesized via one-step atom transfer radical polymerization (ATRP) with pH-responsive 2-(diisopropylamino) ethyl methacrylate and hydrophilic poly[(oligo ethylene glycol)methyl ether methacrylate] as co-monomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl)-β-cyclodextrin] as the initiator. Then the anticancer drug doxorubicin (DOX) and a narrow-bandgap molecule benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole-4,7-bis(9,9-dioctyl-9H-fluoren-2-yl)thiophene (denoted as BBT-2FT) as a near-infrared photothermal agent were co-encapsulated into the CPDO polymers, resulting in stable unimolecular micelles in aqueous media. The tertiary unimolecular micelles loaded with DOX and BBT-2FT showed controllable drug release kinetics and enhanced therapeutic effect against cancer cells under co-stimulation of pH change and 808 nm laser irradiation.


Towards Better Sinomenine-Type Drugs to Treat Rheumatoid Arthritis: Molecular Mechanisms and Structural Modification.
Sinomenine is the main component of the vine Sinomenium acutum. It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases. In the past few decades, significant advances have broadened our understanding of the molecular mechanisms through which sinomenine treats RA, as well as the structural modifications necessary for improved pharmacological activity. In this review, we summarize up-to-date reports on the pharmacological properties of sinomenine in RA treatment, document their underlying mechanisms, and provide an overview of promising sinomenine derivatives as potential RA drug therapies.


Glioblastoma angiogenesis and tumor cell invasiveness are differentially regulated by β8 integrin.
Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms that favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show that integrin β8 is an essential regulator of both GBM-induced angiogenesis and tumor cell invasiveness. Highly angiogenic and poorly invasive tumors expressed low levels of β8 integrin, whereas highly invasive tumors with limited neovascularization expressed high levels of β8 integrin. Manipulating β8 integrin protein levels altered the angiogenic and invasive growth properties of GBMs, in part, reflected by a diminished activation of latent TGFβs, which are extracellular matrix protein ligands for β8 integrin. Taken together, these results establish a role for β8 integrin in differential control of angiogenesis versus tumor cell invasion in GBM. Our findings suggest that inhibiting β8 integrin or TGFβ signaling may diminish tumor cell invasiveness during malignant progression and following antivascular therapies.


Electroencephalographic connectivity measures predict learning of a motor sequencing task.
Individuals vary significantly with respect to rate and degree of improvement with motor practice. While the regions that underlie motor learning have been well described, neurophysiological factors underlying differences in response to motor practice are less well understood. The present study examined both resting-state and event-related EEG coherence measures of connectivity as predictors of response to motor practice on a motor sequencing task using the dominant hand. Thirty-two healthy young right-handed participants underwent resting EEG before motor practice. Response to practice was evaluated both across the single session of motor practice and 24 h later at a retention test of short-term motor learning. Behaviorally, the group demonstrated statistically significant gains both in single-session "motor improvement" and across-session "motor learning." A resting-state measure of whole brain coherence with primary motor cortex (M1) at baseline robustly predicted subsequent motor improvement (validated R2 = 0.55) and motor learning (validated R2 = 0.68) in separate partial least-squares regression models. Specifically, greater M1 coherence with left frontal-premotor cortex (PMC) at baseline was characteristic of individuals likely to demonstrate greater gains in both motor improvement and motor learning. Analysis of event-related coherence with respect to movement found the largest changes occurring in areas implicated in planning and preparation of movement, including PMC and frontal cortices. While event-related coherence provided a stronger prediction of practice-induced motor improvement (validated R2 = 0.73), it did not predict the degree of motor learning (validated R2 = 0.16). These results indicate that connectivity in the resting state is a better predictor of consolidated learning of motor skills. NEW & NOTEWORTHY Differences in response to motor training have significant societal implications across a lifetime of motor skill practice. By evaluating both resting-state and event-related measures of brain function, our findings highlight interindividual differences in brain connectivity providing unique insights into differences in response to motor training. These findings have wide-ranging implications in settings ranging from advanced professional motor training to rehabilitation after brain injury.


Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge.
Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.


Lower Serum Androstenedione Levels in Pre-Rheumatoid Arthritis versus Normal Control Women: Correlations with Lower Serum Cortisol Levels.
Serum adrenal androgens (AAs), including androstenedione (Δ4A) and dehydroepiandrosterone sulfate (DHEAS), have been reported to be lower in female rheumatoid arthritis (RA) patients with early disease. Few data are available on hormonal status of women before the onset of clinical rheumatoid arthritis (pre-RA). A broad baseline panel of serum adrenal and sex steroids was compared in 36 female pre-RA to 144 matched cohort control (CN) subjects to determine differences in their mean values and in patterns of hormonal correlations. Study subjects having lower versus higher baseline serum cortisol levels than the total group's mean value were also analyzed separately to investigate differences in their hormonal levels and correlational patterns. In total subjects, mean (±SE) Δ4A level (nmol/L) was lower (P = 0.018) in 28 pre-RA cases (6.4 ± 0.40) versus 108 CN (7.8 ± 0.28). The significant (P = 0.013) difference was restricted to 9 pre-RA versus 53 CN subjects having lower cortisol levels (5.6 ± 0.73 versus 8.0 ± 0.42 nmol/L, resp.). In total subjects, no significant difference was found between study subjects in their bivariate correlations of the hormonal panel variables, unlike results found in the subgroups stratified by lower versus higher cortisol levels. A subgroup of pre-RA females may have relative adrenal cortical insufficiency, as reflected by lower Δ4A, especially observed among those subjects with lower cortisol levels.


Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury.
This study examined the effects of pretreatment with phencyclidine (PCP), a selective N-methyl-D-aspartate (NMDA) antagonist, on behavioral and physiologic responses of the rat to experimental traumatic brain injury (TBI). For the behavioral experiments, rats were administered either saline or PCP (1.0, 2.0, or 4.0 mg/kg, intrapentoneally [IP] 15 min before TBI. Rats were ventilated as necessary following injury. The duration of acute suppression of several reflexes (pinna, corneal, righting, and flexion) and responses (escape, head support, and spontaneous locomotion) was recorded for up to 70 min after trauma. Longer-term behavioral assessments (beam walking, beam balance, inclined plane, ambulatory activity, and body weight) were made for up to 10 days after trauma. PCP did not significantly alter the duration of acute behavioral suppression. At a dosage of 1.0 mg/kg, PCP significantly attenuated all long-term deficits except beam walking. Maximal protection against beam walking deficits was provided by the 4.0 mg/kg dosage of PCP. Sixty-three percent of saline-treated animals died within 10 days after injury. For rats pretreated with 1.0, 2.0, and 4.0 mg/kg of PCP, 40%, 23%, and 33% died, respectively. In physiologic experiments, pretreatment with 4.0 mg/kg of PCP (IP) 15 min before injury did not significantly affect systemic cardiovascular responses, plasma glucose levels, or blood gas levels observed within 30 min after injury. While the possibility of effects mediated by other neurotransmitter systems cannot be excluded, these data suggest that NMDA agonist-receptor interactions contribute to the pathophysiology of brain injury. In addition, neural mechanisms that mediate transient unconsciousness following moderate levels of head injury may differ from mechanisms that mediate more persistent neurologic deficits.


Impact of Cash Transfer programs on Food Security and Nutrition in sub-Saharan Africa: A Cross-Country Analysis.
This paper explores the extent to which government-run cash transfer programs in four sub-Saharan countries affect food security and nutritional outcomes. These programs include Ghana's Livelihood Empowerment Against Poverty, Kenya's Cash Transfer for Orphans and Vulnerable Children, Lesotho's Child Grants Program and Zambia's Child Grant model of the Social Cash Transfer program. Our cross-country analysis highlights the importance of robust program design and implementation to achieve the intended results. We find that a relatively generous and regular and predictable transfer increases the quantity and quality of food and reduces the prevalence of food insecurity. On the other hand, a smaller, lumpy and irregular transfer does not lead to impacts on food expenditures. We complement binary treatment analysis with continuous treatment analysis to understand not only the impact of being in the program but also the variability in impacts by the extent of treatment.


Evaluation of MRI-based machine learning approaches for computer-aided diagnosis of dementia in a clinical data warehouse.
A variety of algorithms have been proposed for computer-aided diagnosis of dementia from anatomical brain MRI. These approaches achieve high accuracy when applied to research data sets but their performance on real-life clinical routine data has not been evaluated yet. The aim of this work was to study the performance of such approaches on clinical routine data, based on a hospital data warehouse, and to compare the results to those obtained on a research data set. The clinical data set was extracted from the hospital data warehouse of the Greater Paris area, which includes 39 different hospitals. The research set was composed of data from the Alzheimer's Disease Neuroimaging Initiative data set. In the clinical set, the population of interest was identified by exploiting the diagnostic codes from the 10th revision of the International Classification of Diseases that are assigned to each patient. We studied how the imbalance of the training sets, in terms of contrast agent injection and image quality, may bias the results. We demonstrated that computer-aided diagnosis performance was strongly biased upwards (over 17 percent points of balanced accuracy) by the confounders of image quality and contrast agent injection, a phenomenon known as the Clever Hans effect or shortcut learning. When these biases were removed, the performance was very poor. In any case, the performance was considerably lower than on the research data set. Our study highlights that there are still considerable challenges for translating dementia computer-aided diagnosis systems to clinical routine.


Pretreatment FDG-PET metrics in stage III non-small cell lung cancer: ACRIN 6668/RTOG 0235.
ACRIN 6668/RTOG 0235 evaluated the prognostic value of positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) uptake before and after definitive, concurrent, platinum-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). In this secondary analysis, we evaluate volumetric pretreatment PET measures as predictors of clinical outcomes. Patients with stage III NSCLC underwent FDG-PET prior to treatment. A commercially available gradient-based segmentation tool was used to contour all visible hypermetabolic lesions on each scan. For each patient, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total glycolytic activity (TGA) for all contoured lesions were recorded. Cox proportional hazards regression models were used to evaluate clinical variables and PET metrics as predictors of overall survival (OS) and locoregional control (LRC). Time-dependent covariables were added to the models when necessary to address nonproportional hazards. All statistical tests were two-sided. Complete data were available for 214 patients in the OS analysis and 189 subjects in the LRC analysis. In multivariable analysis incorporating clinical and imaging data available prior to treatment, MTV was an independent predictor of OS (HR = 1.04 per 10 cm(3) increase, 95% CI = 1.03 to 1.06, P < .001). High MTV was also associated with increased risk of locoregional failure at baseline (HR = 1.16 per 10 cm(3) increase, 95% CI = 1.08 to 1.23, P < .001) and at six months (HR = 1.05 per 10 cm(3) increase, 95% CI = 1.02 to 1.07, P < .001) but not at 12 months or later time points. Pretreatment MTV is a predictor of clinical outcomes for NSCLC patients treated with chemoradiotherapy. Quantitative PET measures may serve as stratification factors in clinical trials for this patient population and may help guide novel trial designs.


Factors influencing isolation of functional pancreatic rat islets.
Yields and function of isolated islets vary considerably in spite of the introduction of new or improved methods for isolation. In most studies, these variations have been attributed to inadequacies of the applied collagenase preparations. However, when we retrospectively analyzed our rat islet isolations, we found large variations in yield and function in spite of application of identical collagenase sources. Therefore, in the present study, we determined the effect of rat donor strain, the source of inhibition of proteolytic activity (by bovine serum albumin), and the culture conditions on yield and function. AO rats showed a twofold higher islet yield than Wistar and Lewis rats. However, a higher yield was not associated with a higher response on glucose load since this response was more pronounced with Lewis islets than with Wistar and AO islets. Rats with a higher weight donate more islets but have a lower insulin secretory capacity. Islet yield and function also vary with application of different sources of bovine serum albumin during digestion. Moreover, the culture conditions influence the functional survival of isolated rat islets. CMRL1066 preserves the insulin secretory capacity of rat islets better than RPMI1640. Finally, the number of islets surviving the culture is higher when 4 instead of 12 and 24 islets were applied per square centimeter. Our observations indicate that strain and weight of the rat donor, the source of bovine serum albumin, and the culture conditions of islets are pertinent factors in efficacious isolation of islets.


Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors.
Autism spectrum disorder (ASD) is a heterogeneous group of neurobehavioral disorders characterized by the two core domains of behavioral deficits, including sociability deficits and stereotyped repetitive behaviors. It is not clear whether the core symptoms of ASD are produced by dysfunction of the overall neural network of the brain or that of a limited brain region. Recent studies reported that excessive glutamatergic or dopaminergic inputs in the dorsal striatum induced sociability deficits and repetitive behaviors. These findings suggest that the dorsal striatum plays a crucial role in autistic-like behaviors. The present study addresses whether functional deficits of well-known ASD-related genes in the dorsal striatum also produce ASD core symptoms. This study also examines whether these behavioral changes can be modulated by rebalancing glutamate and/or dopamine receptor activity in the dorsal striatum. First, we found that the siRNA-mediated inhibition of Shank3, Nlgn3, Fmr1, Mecp2, or Tsc1 in the dorsal striatum produced mild to severe behavioral changes in sociability, cognition, and/or repetitive behaviors. The knockdown effects of Mecp2 and Tsc1 on behavioral changes were the most prominent. Next, we demonstrated that behavioral changes induced by striatal inhibition of MeCP2 and TSC1 were rescued by D-cycloserine (an NMDA agonist), fenobam (an mGluR5 antagonist), SCH23390 (a D1 antagonist), and/or ecopipam (a D1 partial antagonist), pharmacological drugs that are known to regulate ASD-like symptoms in animal models. Collectively, these results suggest that the dorsal striatum is a critical brain region that, when dysfunctional, produces the core symptoms of ASD.


Regulation of Ca(2+)-signaling in cardiac myofilaments.
The contraction and relaxation of heart muscle cells is associated with a transient change in the intracellular level of free Ca2+. This transient reflects a release from the sarcoplasmic reticulum of Ca2+ ions that turn on the reaction of myosin cross-bridges of the thick filaments with actin of the thin filaments. Without this transient no contraction occurs. The first part of this paper is concerned with the molecular processes by which Ca2+ signals the actin-myosin reaction. It will show that the activation in reality involves release of the thin filaments from a prevailing inhibited state. The inhibited state depends on the activity of the troponin (TN) complex and tropomyosin (TM); disinhibition requires Ca(2+)-binding to TN. The second part of the paper describes evidence that the signaling process is itself modulated by the mechanical and chemical state of the myofilaments in the short term and by altered gene expression in the long term.


Applications of Prolamin-Based Edible Coatings in Food Preservation: A Review.
Foods are susceptible to deterioration and sour due to external environmental influences during production and storage. Coating can form a layer of physical barrier on the surface of foods to achieve the purpose of food preservation. Because of its good barrier properties and biocompatibility, prolamin-based film has been valued as a new green and environment-friendly material in the application of food preservation. Single prolamin-based film has weaknesses of poor toughness and stability, and it is necessary to select appropriate modification methods to improve the performance of film according to the application requirements. The practical application effect of film is not only affected by the raw materials and the properties of the film itself, but also affected by the selection of preparation methods and processing techniques of film-forming liquid. In this review, the properties and selection of prolamins, the forming mechanisms and processes of prolamin-based coatings, the coating techniques, and the modifications of prolamin-based coatings were systematically introduced from the perspective of food coating applications. Moreover, the defects and deficiencies in the research and development of prolamin-based coatings were also reviewed in order to provide a reference for the follow-up research on the application of prolamin-based coatings in food preservation.


Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke.
Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated. We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1(-/-) and wild-type mice. Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion, and brain atrophy in Ceacam1(-/-) mice. This translated into poor performance in neurological scoring and high poststroke-associated mortality. Elevated neutrophil influx, hyperproduction, and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1(-/-) mice were confirmed by immune fluorescence, flow cytometry, zymography, and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1(-/-) mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1(+)matrix metalloproteinase-9(+) neutrophils in the ischemic hemispheres. CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.


New Characterization Measures of Pore Shape and Connectivity Applied to Coatings used for Controlled Drug Release.
Pore geometry characterization-methods are important tools for understanding how pore structure influences properties such as transport through a porous material. Bottlenecks can have a large influence on transport and related properties. However, existing methods only catch certain types of bottleneck effects caused by variations in pore size. We here introduce a new measure, geodesic channel strength, which captures a different type of bottleneck effect caused by many paths coinciding in the same pore. We further develop new variants of pore size measures and propose a new way of visualizing 3-D characterization results using layered images. The new measures together with existing measures were used to characterize and visualize properties of 3-D FIB-SEM images of three leached ethyl-cellulose/hydroxypropyl-cellulose films. All films were shown to be anisotropic, and the strongest anisotropy was found in the film with lowest porosity. This film had very tortuous paths and strong geodesic channel-bottlenecks, while the paths through the other two films were relatively straight with well-connected pore networks. The geodesic channel strength was shown to give important new visual and quantitative insights about connectivity, and the new pore size measures provided useful information about anisotropies and inhomogeneities in the pore structures. The methods have been implemented in the freely available software MIST.


Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine.
Currently available oral second-generation antihistamines do not provide adequate symptom relief for many allergy patients. To determine the ability of azelastine nasal spray to improve rhinitis symptoms in patients with seasonal allergic rhinitis who remained symptomatic after treatment with fexofenadine. This was a multicenter, randomized, double-blind, placebo-controlled, 2-week study in patients with moderate-to-severe seasonal allergic rhinitis. The study began with a 1-week, open-label lead-in period, during which patients received fexofenadine, 60 mg twice daily. Patients who improved less than 25% to 33% with fexofenadine were randomized to treatment with (1) azelastine nasal spray, 2 sprays per nostril twice daily; (2) azelastine nasal spray, 2 sprays per nostril twice daily, plus fexofenadine, 60 mg twice daily; or (3) placebo (saline) nasal spray and placebo capsules twice daily. The primary efficacy variable was the change from baseline to day 14 in the total nasal symptom score (TNSS), consisting of runny nose, sneezing, itchy nose, and nasal congestion symptom scores. A total of 334 patients who remained symptomatic after treatment with fexofenadine were included in the efficacy analysis. After 2 weeks of treatment, azelastine nasal spray (P = .007) and azelastine nasal spray plus fexofenadine (P = .003) significantly improved the TNSS compared with placebo. Azelastine nasal spray monotherapy was as effective as the combination of azelastine nasal spray plus fexofenadine as measured by the TNSS and individual symptoms of the TNSS. Azelastine nasal spray is effective monotherapy for patients who remain symptomatic after treatment with fexofenadine and should be considered in the initial management of patients with seasonal allergic rhinitis.


Changing Behavior, Attitudes, and Beliefs About Food Safety: A Scoping Review of Interventions Across the World and Implications for Empowering Consumers.
Foodborne illnesses are a global public health issue. Responsibility to prevent foodborne disease is shared by many actors along the food supply chain, including consumers. However, consumers often lack knowledge about food safety and behaviors that can reduce risk. Consumers are often targeted for interventions to address these gaps, but a current comprehensive analysis of such interventions globally by type, geography, and outcome is lacking in the literature. In addition, there is a need to understand how individual interventions could be broadened to include the relationships between consumers and other actors in the food system, and how targeted communication strategies can affect behavior. We conducted a rigorous scoping review to assess consumer-facing food safety interventions carried out globally over the past 20 years, and categorized and analyzed them by type of intervention, methods, and outcomes to understand which interventions might be effective in changing consumer behavior, knowledge, attitudes, beliefs, and perceptions on food safety. Ninety-two interventions were reviewed, the majority of which were published in the last 10 years in North America. Most target adults, and 25% are directed at women and mothers. Health or risk communication interventions are becoming increasingly common to move beyond skill-based education and address risk perceptions of food safety that might motivate consumers. Only two studies addressed risk perception in consumers to potentially change food handlers' behavior outside of the home. This review suggests that focusing on risk perception combined with strategies that leverage emotion and trusted sources, such as respected peers or family members, might be useful strategies for interventions.


Voices from a minority: experiences of chinese male nursing students in clinical practice.
In Hong Kong, males constituted only about 10.2% of the nursing workforce in 2010. The learning experiences of male nursing students in Hong Kong during their clinical practicum have rarely been explored. If these students cannot maintain their psychological well-being and psychological health in formal education and clinical placements, then their physical health will also suffer. This ethnographic qualitative study gave male nursing students in Hong Kong a chance to voice their experiences during their clinical practicum. Selected through snowball sampling, 18 male nursing students from a local university participated in individual face-to-face semistructured interviews. The data were processed with content analysis. The findings indicated that male students not only received more support and understanding from male rather than female members of staff but endured a certain amount of oppression while working in female wards. According to the students' comments on nursing culture, the work climate of male nursing students could be improved by reorganizing the clinical placements and providing extra support to male nursing students.


The simultaneous assessment of and relations between children's sympathetic and parasympathetic psychophysiology and their reactive and proactive aggression.
The goal of the current study was to examine the link between children's psychophysiology and aggression when both constructs were assessed simultaneously in scenarios designed to provide the opportunity to aggress for either a reactive reason or a proactive reason. Both sympathetic nervous system (SNS) activity (skin conductance) and parasympathetic nervous system (PNS) activity (respiratory sinus arrhythmia or RSA), as well as their interaction, were included as physiological measures. Participants were 35 5th-grade children who were placed in two virtual-peer scenarios; one scenario provided the opportunity to aggress in response to peer provocation (i.e., reactive aggression) and the other scenario provided the opportunity to aggress for instrumental gain (i.e., proactive aggression). Both skin conductance and RSA were assessed at the time that children were given the opportunity to aggress; this simultaneous assessment of psychophysiology and aggression allowed for an examination of in-the-moment relations between the two constructs. For the reactive scenario, RSA moderated the in-the-moment relation between skin conductance and aggression such that the association was positive at low RSA but negative at high RSA. For the proactive scenario, skin conductance negatively predicted aggression in-the-moment, and RSA positively predicted aggression in-the-moment, but their interaction was not a significant predictor of aggression. Theoretical implications for reactive and proactive aggression and underlying physiological processes are discussed.


Simple statistical models can be sufficient for testing hypotheses with population time-series data.
Time-series data offer wide-ranging opportunities to test hypotheses about the physical and biological factors that influence species abundances. Although sophisticated models have been developed and applied to analyze abundance time series, they require information about species detectability that is often unavailable. We propose that in many cases, simpler models are adequate for testing hypotheses. We consider three relatively simple regression models for time series, using simulated and empirical (fish and mammal) datasets. Model A is a conventional generalized linear model of abundance, model B adds a temporal autoregressive term, and model C uses an estimate of population growth rate as a response variable, with the option of including a term for density dependence. All models can be fit using Bayesian and non-Bayesian methods. Simulation results demonstrated that model C tended to have greater support for long-lived, lower-fecundity organisms (K life-history strategists), while model A, the simplest, tended to be supported for shorter-lived, high-fecundity organisms (r life-history strategists). Analysis of real-world fish and mammal datasets found that models A, B, and C each enjoyed support for at least some species, but sometimes yielded different insights. In particular, model C indicated effects of predictor variables that were not evident in analyses with models A and B. Bayesian and frequentist models yielded similar parameter estimates and performance. We conclude that relatively simple models are useful for testing hypotheses about the factors that influence abundance in time-series data, and can be appropriate choices for datasets that lack the information needed to fit more complicated models. When feasible, we advise fitting datasets with multiple models because they can provide complementary information.