Comparison of the efficacy of two interventions in ameliorating abdominal thickness and sitting function in children with diplegia.
The abdominal muscles are extremely important in stabilizing the trunk and maximizing postural stability. The presence of apparent stiffness in children with spastic diplegia is associated with unsteadiness, impaired walking, and pelvic malrotation. The aim of this study was to compare the efficacy of hippotherapy and whole-body vibration in ameliorating abdominal muscle thickness and sitting function in children with diplegia. A total of 60 children with spastic diplegia were selected from the Faculty of Physical Therapy's outpatient clinic, Cairo University, and randomly allocated into two groups. Group A received conventional physical therapy for 1 h in addition to whole-body vibration, whereas group B received hippotherapy for 40 min. The same designed physical therapy program was administered for 12 weeks, three times per week, in both groups. Ultrasonography was used to measure abdominal thickness, and Gross Motor Function Measurement-88 was used to measure functional ability. A significant improvement in abdominal muscle thickness and sitting function (p < 0.05) was observed in both groups, and greater improvements were observed in group B. Whole-body vibration and hippotherapy training may be recommended to facilitate sitting function and ameliorate abdominal thickness in children with diplegia. Hippotherapy is more effective than whole-body vibration in improving sitting function and abdominal muscle thickness.


Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex.
Recent progress in psychiatric research has accumulated many mouse models relevant to developmental neuropsychiatric disorders using numerous genetic and environmental manipulations. Since the prefrontal cortex (PFC) is essential for cognitive functions whose impairments are central symptoms associated with the disorders in humans, it has become crucial to clarify altered developmental processes of PFC circuits in these mice. To that end, we aimed to understand a sequence of molecular events during normal mouse PFC development. Expression profiles for representative genes covering diverse biological processes showed that while there were little changes in genes for neuroreceptors and synaptic molecules during postnatal period, there were dramatic increases in expression of myelin-related genes and parvalbumin gene, peaking at postnatal day (P) 21 and P35, respectively. The timing of the peaks is different from one observed in the striatum. Furthermore, evaluation of the circuitry maturation by measuring extracellular glutamate in PFC revealed that sensitivity to an NMDA antagonist became adult-like pattern at P56, suggesting that some of maturation processes continue till P56. The trajectory of molecular events in the PFC maturation described here should help us to characterize how the processes are affected in model mice, an important first step for translational research.


Temporal hollowing and other adverse effects after lateral orbital wall decompression.
To evaluate the outcome and late postoperative complications after lateral orbital wall decompression in a series of patients with thyroid eye disease (TED). One hundred and three patients operated in the period 1999-2013 were invited to participate in the study, and 84 were included after a median (range) follow-up time of 124 (13-188) months. The patients were interviewed, and preoperative and postoperative data were collected from hospital records. Photographs ('selfies') were obtained from 64 patients. Wilcoxon signed-rank test was used to evaluate the change in pre- and postoperative data. On average, visual acuity was unchanged with a median value (range) of 1.0 (0.4-1.25) before to 1.0 (0-1.25) after surgery (p = 0.5). Intraocular pressure (IOP) was reduced from a median value (range) of 17 (9-26) to 15 (8-23) mmHg (p < 0.001). Median (range) Hertel values were 23 (15-30) mm preoperatively and 20 (12-26) mm postoperatively (p < 0.001) respectively. Mean (SD) reduction in proptosis was 3.6 (±2.1) mm. Oscillopsia was reported in 24 patients (29%), 42 (50%) experienced a change in temporal sensation, and four (5%) had new-onset diplopia. In 47 patients (56%), some degree of temporal hollowing was reported. Among 64 photographed patients, 38 (59%) had noticeable hollowing on examination of postoperative pictures. There was agreement of the patient's perception of temporal hollowing and the appearance in photographs in 26 of 37 patients (70%). Lateral orbital wall decompression has been considered a safe and effective procedure for treatment of TED. Serious side-effects are infrequent, but in rare circumstances, even blindness may occur. Less serious side-effects are relatively common. Among others, a significant number of the patients developed temporal hollowing after the procedure. The patients must be informed about the possible complications before surgery.


Global effects of identity and aging on the human sperm methylome.
As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man's age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals. We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions. We uncovered epigenetic signatures that reflect a stable process which begins in early adulthood, progressing steadily through most of the male lifespan, and warrants consideration in any future study of the aging sperm epigenome.


The effect of fasting on the interactions between human low density lipoproteins and calcium, heparin and chondroitin sulfate.
Fasting modified the in vitro interactions between low density lipoproteins (LDL) and glycosaminoglycans. Calcium had a potentiating effect on these interactions. LDL-calcium-heparin interaction was dependent on the presence of sialic acid whereas LDL-calcium-chondroitin sulfate interaction was inversely correlated with cholesterol content.


Fear expression is suppressed by tyrosine administration.
Animal studies have demonstrated that catecholamines regulate several aspects of fear conditioning. In humans, however, pharmacological manipulations of the catecholaminergic system have been scarce, and their primary focus has been to interfering with catecholaminergic activity after fear acquisition or expression had taken place, using L-Dopa, primarily, as catecholaminergic precursor. Here, we sought to determine if putative increases in presynaptic dopamine and norepinephrine by tyrosine administered before conditioning could affect fear expression. Electrodermal activity (EDA) of 46 healthy participants (24 placebo, 22 tyrosine) was measured in an instructed fear task. Results showed that tyrosine abolished fear expression compared to placebo. Importantly, tyrosine did not affect EDA responses to the aversive stimulus (UCS) or alter participants' mood. Therefore, the effect of tyrosine on fear expression cannot be attributed to these factors. Taken together, these findings provide evidence that the catecholaminergic system influences fear expression in humans.


GABAA receptor cysteinyl mutants and the ginkgo terpenoid lactones bilobalide and ginkgolides.
The terpenoid lactones from Ginkgo biloba, bilobalide and ginkgolides, have been shown to act as negative modulators at α1β2γ2L GABAA receptors. They have structural features similar to those of the chloride channel blocker picrotoxinin. Unlike picrotoxinin, however they are not known to produce convulsant effects. Using two-electrode voltage clamp electrophysiology, this study compared the effect of mutation of 2', 6' and 15' pore facing M2 domain residues to cysteine on the action of picrotoxinin, bilobalide and ginkgolides at α1β2γ2L GABAA receptors expressed in Xenopus oocytes. Picrotoxinin was affected by mutation differently from the ginkgo terpenoid lactones. Although some of these compounds were affected by the mutation at same position and/or subunit, the changes in their potency were found to be dissimilar. The results suggest that the intracellular pore binding site for picrotoxinin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C is comprised of 2'β-6'β6'γ, 2'α2'β-6'α6'β, 2'α2'β2'γ-6'β6'γ, 2'α, 2'β2'γ-6'β and 2'α2'β, respectively. Unlike bilobalide and ginkgolides, the inhibitory action of picrotoxinin was not affected by mutations at 15' position. It is proposed that 15'α15'β, 15'β, 15'α15'β and 15'α15'β15'γ forms an extracellular pore binding site for bilobalide, ginkgolide A, ginkgolide B and ginkgolide C, respectively. The lack of convulsant effects of bilobalide, and ginkgolide A and B may be associated in part with their different binding locations within the chloride channel.


Stent-Related Adverse Events as Related to Dual Antiplatelet Therapy in First- vs Second-Generation Drug-Eluting Stents.
There are limited data on the long-term stent-related adverse events as related to the duration of dual antiplatelet therapy (DAPT) in second-generation (G2) drug-eluting stents (DES) compared with first-generation (G1) DES. This study sought to compare the long-term stent-related outcomes of G2-DES with those of G1-DES. The study group consisted of 15,009 patients who underwent their first coronary revascularization with DES from the CREDO-Kyoto PCI/CABG (Coronary Revascularization Demonstrating Outcome Study in Kyoto Percutaneous Coronary Intervention/Coronary Artery Bypass Grafting) Registry Cohort-2 (first-generation drug-eluting stent [G1-DES] period; n = 5,382) and Cohort-3 (second-generation drug eluting stent [G2-DES] period; n = 9,627). The primary outcome measures were definite stent thrombosis (ST) and target vessel revascularization (TVR). The cumulative 5-year incidences of definite ST and TVR were significantly lower in the G2-DES group than in the G1-DES group (0.7% vs 1.4%; P < 0.001; and 16.2% vs 22.1%; P < 0.001, respectively). The lower adjusted risk of G2-DES relative to G1-DES for definite ST and TVR remained significant (HR: 0.53; 95% CI: 0.37-0.76; P < 0.001; and HR: 0.74; 95% CI: 0.68-0.81; P < 0.001, respectively). In the landmark analysis that was based on the DAPT status at 1 year, the lower adjusted risk of on-DAPT status relative to off-DAPT was significant for definite ST beyond 1 year in the G1-DES stratum (HR: 0.42; 95% CI: 0.24-0.76; P = 0.004) but not in the G2-DES stratum (HR: 0.66; 95% CI: 0.26-1.68; P = 0.38) (P interaction = 0.14). G2-DES compared with G1-DES were associated with a significantly lower risk for stent-related adverse events, including definite ST and TVR. DAPT beyond 1 year was associated with a significantly lower risk for very late ST of G1-DES but not for that of G2-DES.


An atypical pacemaker pocket hematoma containing chyliform fluid.
Subcutaneous hematoma is a complication of cardiac device implantation. In most cases, it is drained or spontaneously reabsorbed. While cases of chylothorax are rare, and cases of pseudochylothorax even rarer, previous cases of accumulation of chyliform material in the subcutaneous pockets of cardiac devices are anecdotal. We present a case of a 60-year-old man with antiphospholipids antibody syndrome and rheumatoid arthritis, who underwent dual-chamber ICD implantation in December 2020; the procedure was complicated by a pocket hematoma, which required surgical drainage. After 7 months, the man returned owing to heart failure, with evidence of the reappearance of a large swelling in the ICD pocket; this was tolerated for months by the patient and was no longer controlled. We drained 100ml of gold-colored, odorless liquid, and found no evidence of blood material in the pocket. The liquid was not pus, as culture testing proved negative for bacterial growth. Chemical-physical examination revealed elevated cholesterol concentration (704 mg/dl) and low levels of triglycerides (80 mg/dl; plasma cholesterol values were 91mg/dl, and triglycerides 48 mg/dl). Microscopic examination revealed isolated leukocytes and rare erythrocytes immersed in mucoid material; cytological analysis showed a carpet of macrophages filled with cholesterol. This evidence supports the diagnosis of pseudochyle fluid, formed by the degradation of a hematoma left intact in a closed cavity for more than 6 months. This is an extremely rare case of chyliform fluid documented in an ICD pocket.


Sparse and stereotyped encoding implicates a core glomerulus for ant alarm behavior.
Ants communicate via large arrays of pheromones and possess expanded, highly complex olfactory systems, with antennal lobes in the brain comprising up to ∼500 glomeruli. This expansion implies that odors could activate hundreds of glomeruli, which would pose challenges for higher-order processing. To study this problem, we generated transgenic ants expressing the genetically encoded calcium indicator GCaMP in olfactory sensory neurons. Using two-photon imaging, we mapped complete glomerular responses to four ant alarm pheromones. Alarm pheromones robustly activated ≤6 glomeruli, and activity maps for the three pheromones inducing panic alarm in our study species converged on a single glomerulus. These results demonstrate that, rather than using broadly tuned combinatorial encoding, ants employ precise, narrowly tuned, and stereotyped representations of alarm pheromones. The identification of a central sensory hub glomerulus for alarm behavior suggests that a simple neural architecture is sufficient to translate pheromone perception into behavioral outputs.


The SABRE Trial (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis): Angiographic Results and 1-Year Clinical Outcomes.
The aim of this first-in-human study was to assess the safety and effectiveness of the Virtue sirolimus-eluting balloon in a cohort of patients with in-stent restenosis (ISR). Angioplasty balloons coated with the cytotoxic drug paclitaxel have been widely used for ISR treatment. The Virtue angioplasty balloon (Caliber Therapeutics, New Hope, Pennsylvania) delivers sirolimus in a nanoencapsulated liquid formulation. This clinical trial is the first to examine a sirolimus-eluting balloon for ISR. In this prospective, single-arm feasibility study at 9 European centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up. Procedural success in the intention-to-treat population was 100%. The primary safety endpoint was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization) assessed at 30 days (0%, n = 50). The primary performance endpoint was in-segment late lumen loss (LLL) at 6 months (0.31 ± 0.52 mm; n = 47). Secondary 6-month endpoints include binary restenosis (19.1%), diameter stenosis (30.3 ± 19.9%), and major adverse cardiac events (MACE) (10.2%, n = 49). In the 36-patient per-protocol population (excluding major protocol violations and previously stented ISR), LLL was 0.12 ± 0.33 mm at 6 months. Clinical outcomes at 1 year for the intention-to-treat group were 12.2% TLF and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE. This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes that warrant further evaluation in dedicated randomized studies.


Interferon treatment of murine Meth-A sarcoma cells: effects on the malignant phenotype and expression of tumor-specific and H-2 antigens.
A virus-free methycholanthrene-induced sarcoma (Meth-A) in BALB/c mice was grown in culture and treated with purified mouse interferon (alpha and beta mixture) prior to testing for oncogenicity in the host animal. Use of interferon in vitro caused growth inhibition, but not cytotoxic effects; such effects were fully reversible upon interferon removal from the system. There was a significant decrease in tumor incidence in mice challenged with interferon-treated cells, but this could be overcome by sufficiently increasing the number of cells in the inoculating dose. By transplanting these BALB/c sarcoma cells into Sprague-Dawley nude mice, the effects of interferon could be negated. Since these mice have an unaltered activity of NK cells, the results suggest that NK cells do not play a major role in rejection of the Meth-A tumor, but that the reduction in tumor incidence is dependent on the presence of functional T cells. Interferon caused a detectable reduction in the expression of the tumor-specific transplantation antigen (TSTA) associated with Meth-A cells, but increased the expression of H-2 antigens. It has recently been shown that H-2 antigens play a role in host recognition of the TSTA of methylcholanthrene-induced sarcomas. It is suggested that the increased expression of H-2 antigens on interferon-treated Meth-A cells could lead to an increased frequency of recognition by T-cells.


Rho2 involved in development, stress response and pathogenicity of Fusarium oxysporum.
Rho GTPases regulate the activity of cell wall biosynthesis, actin assembly and polar cell secretion. However, the function of Rho GTPase in filamentous fungi is poorly understood. To understand the role of Rho2 GTPase in Fusarium oxysporum, which is one of root rot pathogens of Panax notoginseng, △rho2 mutant was constructed. Phenotypes of △rho2, including conidiation, germination of spores, stresses (osmotic-, cell membrane-, cell wall disturbing-, metal-, and high temperature-) tolerance and pathogenicity were analyzed. The results showed that the growth of △rho2 was destroyed under cell wall disturbing stress and high temperature stress, suggesting that Rho2 regulated the response of F. oxysporum to cell wall synthesis inhibitors and high temperature stress. Germination of spores and pathogenicity to P. notoginseng were reduced in △rho2 mutant. Western blot results showed that rho2 deletion increased the phosphorylation level of Mpk1. To identify genes regulated by Rho2, transcriptome sequencing was carried out. 2477 genes were identified as upregulated genes and 2177 genes were identified as downregulated genes after rho2 was deleted. These genes provide clues for further study of rho2 function.


Radiotherapy and Immunotherapy Combinations for Lung Cancer.
Positive results from recent immunotherapy trials of non-small cell lung cancer (NSCLC) have coincided with a greater appreciation for the impact of radiation therapy (RT) on tumor immunity. Here, we summarize key clinical findings and ongoing efforts to combine immunotherapy and RT for the treatment of NSCLC. The role of immunotherapy for NSCLC has expanded significantly following the pivotal approvals of nivolumab and pembrolizumab for metastatic NSCLC, maintenance durvalumab in unresectable stage III NSCLC, and atezolizumab for metastatic NSCLC. Several small early-phase trials have demonstrated the ability of RT to elicit clinically significant tumor immunity. These positive findings support current trial efforts combining RT with immunotherapy for NSCLC. Recently initiated trials of RT and immunotherapy hold significant promise in expanding the therapeutic options for NSCLC. Optimization of therapy will require careful patient selection to yield meaningful improvements in clinical outcomes.


Small-angle X-ray scattering of reduced ribonuclease A: effects of solution conditions and comparisons with a computational model of unfolded proteins.
The disulfide-reduced form of bovine ribonuclease A, with the Cys thiols irreversibly blocked, was characterized by small-angle x-ray scattering. To help resolve the conflicting results and interpretations from previous studies of this model unfolded protein, we measured scattering profiles using a range of solution conditions and compared them with the profiles predicted by a computational model for a random-coil polypeptide. Analysis of the simulated and experimental profiles reveals that scattering intensities at intermediate angles, corresponding to interatomic distances in the range of 5-20 A, are particularly sensitive to changes in solvation and can be used to assess the internal scaling behavior of the polypeptide chain, expressed as a mass fractal dimension, D(m). This region of the scattering curve is also much less sensitive to experimental artifacts than is the very small angle regime (the Guinier region) that has been more typically used to characterize unfolded proteins. The experimental small-angle x-ray scattering profiles closely matched those predicted by the computational model assuming relatively small solvation energies. The scaling behavior of the polypeptide approaches that of a well-solvated polymer under conditions where it has a large net charge and at high urea concentrations. At lower urea concentrations and neutral pH, the behavior of the chain approaches that expected for theta-conditions, where the effects of slightly unfavorable interactions with solvent balance those of excluded volume, leading to scaling behavior comparable to that of an idealized random walk chain. Though detectable, the shift toward more compact conformations at lower urea concentrations does not correspond to a transition to a globule state and is associated with little or no reduction in conformational entropy. This type of collapse, therefore, is unlikely to greatly reduce the conformational search for the native state.


Aspergillus Biofilms in Human Disease.
The biofilm phenotype of Aspergillus species is an important and accepted clinical entity. While industrially these biofilms have been used extensively in important biofermentations, their role in clinical infection is less well defined. A recent flurry of activity has demonstrated that these interesting filamentous moulds have the capacity to form biofilms both in vitro and in vivo, and through various investigations have shown that these are exquisitely resistant to antifungal therapies through a range of adaptive resistance mechanisms independent of defined genetic changes. This review will explore the clinical importance of these biofilms and provide contemporary information with respect to their clinical management.


Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.


Design and synthesis of novel imidazo[1,2-a]quinoxalines as PDE4 inhibitors.
New imidazo[1,2-a]quinoxaline derivatives have been synthesised by condensation of an appropriate alpha-aminoalcohol with a quinoxaline followed by intramolecular cyclisation and nucleophilic substitutions. Their phosphodiesterase inhibitory activities have been assessed on a preparation of the PDE4 isoform purified from a human alveolar epithelial cell line (A549). These studies showed potent inhibitory properties that emphasize the importance of a methyl amino group at position 4 and a weakly hindered group at position 1.


GSH-Activatable NIR Nanoplatform with Mitochondria Targeting for Enhancing Tumor-Specific Therapy.
Developing smart photosensitizers that are sensitive to tumor-specific signals for minimal side effects and enhanced antitumor efficacy is a tremendous challenge for tumor phototherapies. Herein, we construct a nanoplatform with glutathione (GSH)-activatable and mitochondria-targeted pro-photosensitizer encapsulated by ultrasensitive pH-responsive polymer for achieving imaging-guided tumor-specific photodynamic therapy (PDT). The GSH-activatable pro-photosensitizer, di-cyanine (DCy7), has been synthesized where two cyanine moieties are covalently conjugated by a disulfide bond, and the hydrophobic DCy7 is further encapsulated with an amphiphilic pH-responsive diblock copolymer POEGMA-b-PDPA to form P@DCy7 nanoparticles. Upon endocytosis by cancer cells, P@DCy7 nanoparticles dissociate at endosome first and then DCy7 is released to cytoplasm and subsequently activated by the high concentration of GSH, finally targets mitochondria for organelle-targeted PDT. Moreover, intracellular antioxidant GSH is consumed during the activation procedure that is beneficial to efficient PDT. These P@DCy7 nanoparticles display selective phototoxicity against tumor cells (HepG2 or 4T1 cells) over normal cells (BEAS-2B cells) in vitro, and their GSH-activatable enhanced PDT efficacy is further confirmed in tumor-bearing mice. Thus, P@DCy7 nanoparticles allow for accurate and highly efficient PDT with minimal side effects, providing an attractive nanoplatform for organelle-targeted precise PDT.


Longitudinal findings of acute macular neuroretinopathy with multifocal electroretinogram and optical coherence tomography.
A 34-year-old woman, with preceding flu-like febrile illness, developed acute macular neuroretinopathy in her left eye with typical reddish brown macular lesions and a dense paracentral scotoma. Her condition was evaluated with multifocal electroretinogram and optical coherence tomography in her acute and recovery phases. The findings assist ophthalmologists striving for better understanding and diagnosis of acute macular neuroretinopathy.


COVID-19 vaccine hesitancy in underserved communities of North Carolina.
In the United States, underserved communities including Blacks and Latinx are disproportionately affected by COVID-19. This study sought to estimate the prevalence of COVID-19 vaccine hesitancy, describe attitudes related to vaccination, and identify correlates among historically marginalized populations across 9 counties in North Carolina. We conducted a cross-sectional survey distributed at free COVID-19 testing events in underserved rural and urban communities from August 27 -December 15, 2020. Vaccine hesitancy was defined as the response of "no" or "don't know/not sure" to whether the participant would get the COVID-19 vaccine as soon as it became available. The sample comprised 948 participants including 27.7% Whites, 59.6% Blacks, 12.7% Latinx, and 63% female. 32% earned <$20K annually, 60% owned a computer and ~80% had internet access at home. The prevalence of vaccine hesitancy was 68.9% including 62.7%, 74%, and 59.5% among Whites, Blacks, and Latinx, respectively. Between September and December, the largest decline in vaccine hesitancy occurred among Whites (27.5 percentage points), followed by Latinx (17.6) and only 12.0 points among Blacks. 51.2% of respondents reported vaccine safety concerns, 23.7% wanted others to get vaccinated first, and 63.1% would trust health care providers about the COVID-19 vaccine. Factors associated with hesitancy in multivariable logistic regression included being female (OR = 1.90 95%CI [1.36, 2.64]), being Black (OR = 1.68 1.16, 2.45]), calendar month (OR = 0.76 [0.63, 0.92]), safety concerns (OR = 4.28 [3.06, 5.97]), and government distrust (OR = 3.57 [2.26, 5.63]). This study engaged the community to directly reach underserved minority populations at highest risk of COVID-19 that permitted assessment of vaccine hesitancy (which was much higher than national estimates), driven in part by distrust, and safety concerns.


Photoactivated state of rhodopsin and how it can form.
A variety of spectroscopic and biochemical studies of the photoreceptor rhodopsin have revealed conformation changes which occur upon its photoactivation. Assignment of these molecular alterations to specific regions in the receptor has been attempted by studying native opsin regenerated with synthetic retinal analogs or recombinant opsins regenerated with 11-cis retinal. We propose a model for the photoactivation mechanism which defines 'off' and 'on' states for individual molecular groups. These groups have been identified to undergo structural alterations during photoactivation. Analysis of mutant pigments in which specific groups are locked into their respective 'on' or 'off' states provides a framework to identify determinants of the active conformation as well as the minimal number of intramolecular transitions to switch to this conformation. The simple model proposed for the active-state of rhodopsin can be compared to structural models of its ground-state to localize chromophore-protein interactions that may be important in the photoactivation mechanism.


Mesenchymal stem cell-conditioned medium accelerates wound healing with fewer scars.
Mesenchymal stem cells (MSCs) derived from umbilical cords (UC-MSCs) have been shown to enhance cutaneous wound healing by means of the paracrine activity. Fibroblasts are the primary cells involved in wound repair. The paracrine effects of UC-MSCs on dermal fibroblasts have not been fully explored in vitro or in vivo. Dermal fibroblasts were treated with conditioned media from UC-MSCs (UC-MSC-CM). In this model, UC-MSC-CM increased the proliferation and migration of dermal fibroblasts. Moreover, adult dermal fibroblasts transitioned into a phenotype with a low myofibroblast formation capacity, a decreased ratio of transforming growth factor-β1,3 (TGF-β1/3) and an increased ratio of matrix metalloproteinase/tissue inhibitor of metalloproteinases (MMP/TIMP). Additionally, UC-MSC-CM-treated wounds showed accelerated healing with fewer scars compared with control groups. These observations suggest that UC-MSC-CM may be a feasible strategy to promote cutaneous repair and a potential means to realise scarless healing.


The effect of pasteurization on trace elements in donor breast milk.
Premature infants often receive pasteurized donor human milk when mothers are unable to provide their own milk. This study aims to establish the effect of the pasteurization process on a range of trace elements in donor milk. Breast milk was collected from 16 mothers donating to the milk bank at the Royal Brisbane and Women's Hospital. Samples were divided into pre- and post-pasteurization aliquots and were Holder pasteurized. Inductively coupled plasma mass spectrometry was used to analyze the trace elements zinc (Zn), copper (Cu), selenium (Se), manganese (Mn), iodine (I), iron (Fe), molybdenum (Mo) and bromine (Br). Differences in trace elements pre- and post-pasteurization were analyzed. No significant differences were found between the trace elements tested pre- and post-pasteurization, except for Fe (P<0.05). The median (interquartile range, 25 to 75%; μg l(-1)) of trace elements for pre- and post- pasteurization aliquots were-Zn: 1639 (888-4508), 1743 (878-4143), Cu: 360 (258-571), 367 (253-531), Se: 12.34 (11.73-17.60), 12.62 (11.94-16.64), Mn: (1.48 (1.01-1.75), 1.49 (1.11-1.75), I (153 (94-189), 158 (93-183), Fe (211 (171-277), 194 (153-253), Mo (1.46 (0.37-2.99), 1.42 (0.29-3.73) and Br (1066 (834-1443), 989 (902-1396). Pasteurization had minimal effect on several trace elements in donor breast milk but high levels of inter-donor variability of trace elements were observed. The observed decrease in the iron content of pasteurized donor milk is, however, unlikely to be clinically relevant.


Blood volume measurement at the bedside using ICG pulse spectrophotometry.
In the treatment of critically ill patients, blood volume (BV) measurement requires injection of some tracer substance and subsequent blood sampling to analyze the tracer concentration. To obviate both the sampling and laboratory analysis, techniques of pulse oximetry have been adapted to the noninvasive optical measurement in the patient's nose or finger of the arterial concentration of an injectable dye. The authors report the clinical accuracy of a new noninvasive bedside BV measurement test that uses pulse spectrophotometry (the pulse method). The device detects pulsatile changes of tissue optical density of a nostril or a finger spanned by a probe emitting two infrared wavelengths (805 and 890 nm). After a peripheral or central intravenous injection of indocyanine green, the arterial dye concentration is continuously computed by reference to the previously measured blood hemoglobin concentration. Three types of tests of its accuracy are described here. In 10 healthy volunteers, the authors compared BV determined by the pulse method with an (131)I-labeled human serum albumin method. Three subject data sets were excluded because of motion artifact, a low signal:noise ratio, or both. For the other seven volunteers, the bias+/-SD of pulse spectrophotometric BV values were 0.20+/-0.24 l (or 4.2+/-4.9%) for the nose probe and 0.34+/-0.31 l (or 7.3+/-6.9%) for the finger probe, with a mean BV of 5 l. In 30 patients who underwent cardiac surgery, the pulse method was compared with a standard indocyanine green method using intermittent blood sampling. In three patients, the BV could not be determined by the pulse method because of motion artifact, low signal:noise ratio, or both. In 27 patients, the bias+/-SD of the BV by the pulse method was -0.23+/-0.37 l (-5.3+/-8.7%) for the nose and -0.25+/-0.5 l (-4.2+/-8.4%) for the finger. Patient BV ranged from 2.51 to 7.13 l (mean, 4.48 l). In 10 additional patients before cardiac surgery, BV was measured by the pulse method before and shortly after removal of 400 ml blood. The pulse method recorded a decrease of BV of 480+/-114 mL Three days after venesection, the mean BV was 117+/-159 ml less than the predonation control. In most patients, the pulse method provides bedside measurement of BV without blood sampling (except for hemoglobin determination), with an estimated error less than 10%. In 10-30% of tests the method failed because of motion distortion of the record during the 10-min data collection period or because of insufficient pulse amplitude in the test tissue.


Trans-translation mediated by Bacillus subtilis tmRNA.
Trans-translation, in which a ribosome switches between translation of an mRNA and a tmRNA, produces a chimera polypeptide of an N-terminal truncated polypeptide and a C-terminal tag-peptide encoded by tmRNA. One of the tmRNA binding proteins, a ribosomal protein S1, has not been found in a group of Gram-positive bacteria. In this study, the trans-translation reaction with tmRNA from Bacillus subtilis belonging to this group was examined. When a truncated gene lacking a termination codon was expressed in B. subtilis, a 15-amino acid tag-peptide derived from tmRNA was identified in the C-termini of the trans-translation products. An identical tag-peptide was also found at the C-termini of the products from a truncated gene, when it was coexpressed with B. subtilis tmRNA in Escherichia coli. B. subtilis tmRNA was functional, although much less efficiently, in the in vitro poly(U)-dependent tag-peptide synthesis system of E. coli. A comparison of two bacterial tmRNAs suggests that the rule for determining the tag-initiation point on tmRNA may be the same in Gram-positive and Gram-negative bacteria.


Predictive value of quantitative ultrasound parameters in individuals with chronic kidney disease: A population-based analysis of CARTaGENE.
The use of calcaneal quantitative ultrasound (QUS) to predict fractures has not been well studied in early CKD populations. We compared the association of QUS with incidental fractures and its predictive properties in non-CKD and CKD individuals. Analysis of a prospective population-based survey of 40- to 69-year-old individuals recruited between 2009 and 2010. QUS parameters (stiffness index [SI], speed of sound [SOS], broadband attenuation [BUA]) were measured at baseline. Renal function was measured using baseline creatinine and was classified into CKD stages (non-CKD, stage 2, stage 3). Fracture incidence at any site or at major osteoporotic fracture sites for up to 7 years of follow-up was identified in administrative databases using a validated algorithm. The association (age-adjusted hazard ratio per standard deviation decrease in Cox models), discrimination (c-statistic) and calibration (standardized incidence ratio [SIR]) of QUS parameters with fracture outcomes was computed in each CKD stratum. We included 18,306 individuals (9,011 non-CKD; 8,595 CKD stage 2; 700 CKD stage 3). During a median follow-up of 70 months, we identified 782 fractures at any site and 326 major osteoporotic fractures. Although all QUS parameters (SI, SOS and BUA) were associated with any or major fracture incidence in non-CKD and CKD patients, the magnitude of these associations was lower for any fracture and for BUA. QUS parameters moderately discriminated incidental fractures across CKD strata but underestimated fracture incidence in CKD stage 3 even after adjustment for demographics and clinical risk factors. At a given QUS value, CKD stage 3 patients had higher fracture risk than non-CKD and CKD stage 2 patients. QUS parameters are associated with fracture incidence in both non-CKD and CKD but underestimate fracture incidence in individuals with early CKD.


Fluorescence temperature jump relaxations of dansylphosphatidylethanolamine in aqueous dispersions of dipalmitoylphosphatidylcholine during the gel to liquid-crystal transition.
The change of fluorescence of the probe dansylphosphatidylethanolamine embedded in multilamellar liposomes of dipalmitoylphosphatidylcholine was used to investigate the dynamics of the thermotropic gel to liquid-crystalline phase transition by use of the temperature-jump technique. The results are discussed and compared to published observations on the same system in which the phenomenon was reported by turbidity changes.


Pendred Syndrome in a Newborn with Neck Swelling: A Case Report.
Pendred syndrome is a rare autosomal recessive condition, characterized by functional impairment of thyroid gland and sensorineural hearing loss. The syndrome presents in patients with homozygous or compound heterozygous mutation. The presentation in the form of neck mass in a newborn is rare. A 1 month old baby presented to us with neck mass, which was found to be an enlarged thyroid gland. Thyroid function tests were consistent with hypothyroidism. Further evaluation revealed moderate sensorineural hearing loss; genetic analysis showed that baby was homozygous for the known mutations causing the disease. Thyroid hormone replacement and hearing habilitation were done. Follow up showed regression of the neck mass and normalization of thyroid function tests. Genetic counseling of the family was done. Identification of the exact cause of congenital hypothyroidism can prevent grave consequences later on for the patient as well as for the family.


Performance analysis of screening mammography in Asian women under 40 years.
Screening mammography performance among young women remains uncertain in East Asia, where the proportion of young breast cancer patients is higher than that in Western countries. Thus, we analyzed the performance of screening mammography in women under 40 years in comparison with older age groups. This retrospective study comprised 95,431 Asian women with 197,525 screening mammograms. The reference standard was determined by linkage to the national cancer registry data and the 12-month follow-up outcomes after the index mammogram. The performance metrics included sensitivity, specificity, cancer detection rate (CDR), positive predictive value (PPV), recall rate, and areas under the receiver operating characteristic curve (AUCs), with comparisons across age groups (30 s, 40 s, and ≥ 50 s). For young women aged < 40 years, sensitivity and AUC (95% confidence interval [CI]) of screening mammography were 60.4% (50.4-69.7) and 0.73 (0.68-0.77), respectively, with no significant difference compared to women in their 40 s (sensitivity: 64.0% [95% CI: 57.8-69.8], P = 0.52; AUC: 0.75 [95% CI: 0.73-0.78], P = 0.35). The CDR (95% CI) was 0.8 (0.6-1.1) per 1,000 mammograms for young women, poorer than 1.8 (1.6-2.1) per 1,000 mammograms for women in their 40 s (P < 0.001). The PPV and recall rate (95% CI) for young women were 0.6% (0.4-0.7) and 14.9% (14.6-15.1), poorer than 1.4% (1.2-1.6) and 13.3% (13.1-13.5) for women in their 40 s (P < 0.001), respectively. The accuracy of screening mammography for young women in their 30 s was not significantly different from that for women in their 40 s, but the cancer detection and recall rates were poorer.


An overview of image registration for aligning mass spectrometry imaging with clinically relevant imaging modalities.
Mass spectrometry imaging (MSI) is used in many aspects of clinical research, including pharmacokinetics, toxicology, personalised medicine, and surgical decision-making. Maximising its potential requires the spatial integration of MSI images with imaging data from existing clinical imaging modalities, such as histology and MRI. To ensure that the information is properly integrated, all contributing images must be accurately aligned. This process is called image registration and is the focus of this review. In light of the ever-increasing spatial resolution of MSI instrumentation and a diversification of multi-modal MSI studies (e.g., spatial omics, 3D-MSI), the accuracy, versatility, and precision of image registration must increase accordingly. We review the application of image registration to align MSI data with different clinically relevant ex vivo and in vivo imaging techniques. Based on this, we identify steps in the current image registration processes where there is potential for improvement. Finally, we propose a roadmap for community efforts to address these challenges in order to increase registration quality and help MSI to fully exploit its multi-modal potential.


Impact of methotrexate treatment on vaccines immunogenicity in adult rheumatological patients - Lessons learned from the COVID-19 pandemic.
Despite the development of new biological and synthetic targeted therapies, methotrexate remains one of the most commonly used immunomodulatory drugs in rheumatology. However, its effect on the immunogenicity of vaccines has been studied only to a limited extent until recently, resulting in the lack of clear guidelines on the use of methotrexate during vaccination. Significant progress was made during the COVID-19 pandemic due to the dynamic development of research on vaccines, including patients with autoimmune inflammatory rheumatic diseases. In the following literature review, we present a summary of what we know so far on the impact of methotrexate on post-vaccination response in adult rheumatology patients, taking into account the lessons learned from the COVID-19 pandemic. Studies on the effect of methotrexate on the immunogenicity of influenza, pneumococcal, herpes zoster, tetanus/diphtheria/pertussis, hepatitis A, yellow fever, and COVID-19 vaccines are described in detail, including the effect of methotrexate on the humoral and cellular response of individual vaccines. The available evidence for recommendations for withholding methotrexate in the post-vaccination period is presented. Lastly, an overview of potential immunological mechanisms through which MTX modulates the immunogenicity of vaccinations is also provided.


A framework for adaptive surveillance of emerging tick-borne zoonoses.
Significant global ecological changes continue to drive emergence of tick-borne zoonoses around the world. This poses an important threat to both human and animal health, and highlights the need for surveillance systems that are capable of monitoring these complex diseases effectively across different stages of the emergence process. Our objective was to develop an evidence-based framework for surveillance of emerging tick-borne zoonoses. We conducted a realist review to understand the available approaches and major challenges associated with surveillance of emerging tick-borne zoonoses. Lyme disease, with a specific focus on emergence in Canada, was used as a case study to provide real-world context, since the process of disease emergence is ongoing in this country. We synthesize the results to propose a novel framework for adaptive surveillance of emerging tick-borne zoonoses. Goals for each phase of disease emergence are highlighted and approaches are suggested. The framework emphasizes the needs for surveillance systems to be inclusive, standardized, comprehensive and sustainable. We build upon a growing body of infectious disease literature that is advocating for reform to surveillance systems. Although our framework has been developed for tick-borne zoonoses, it is flexible and has the potential to be applied to a variety of other vector-borne and zoonotic diseases.


An optimized finite element extrapolating method for 2D viscoelastic wave equation.
In this study, we first present a classical finite element (FE) method for a two-dimensional (2D) viscoelastic wave equation and analyze the existence, stability, and convergence of the FE solutions. Then we establish an optimized FE extrapolating (OFEE) method based on a proper orthogonal decomposition (POD) method for the 2D viscoelastic wave equation and analyze the existence, stability, and convergence of the OFEE solutions and furnish the implement procedure of the OFEE method. Finally, we furnish a numerical example to verify that the numerical computing results correspond with the theoretical ones. This signifies that the OFEE method is feasible and efficient for solving the 2D viscoelastic wave equation.


Flower-like ZnO nanostructure based electrochemical DNA biosensor for bacterial meningitis detection.
Zinc oxide (ZnO) nanostructures possessing flower-like morphology have been synthesised onto platinized silicon substrate by simple and economical hydrothermal method. The interaction of physically immobilized single stranded thiolated DNA (ss th-DNA) probe of N. meningitides onto the nanostructured ZnO (ZNF) matrix surface have been investigated using cyclic voltammetry (CV) and electrochemical impeadance spectroscopy (EIS). The electrochemical sensing response behaviour of the DNA bioelectrode (ss th-DNA/ZNF/Pt/Si) has been studied by both differential pulse voltammetric (DPV) as well as impedimetric techniques. The fabricated DNA biosensor can quantify wide range of the complementary target ss th-DNA in the range 5-240 ng μl(-1) with good linearity (R=0.98), high sensitivity (168.64 μA ng(-1) μl cm(-2)) and low detection limit of about 5 ng μl(-1). Results emphasise that the fabricated flower-like ZnO nanostructures offer a useful platform for the immobilization of DNA molecules and could be exploited for efficient detection of complementary target single stranded DNA corresponding to N. meningitides.


Total ear reconstruction in post burn deformity.
Severe thermal injuries to the external ear, in most cases, lead to a total destruction of the pinna. Total ear reconstruction in such cases of burns is one of the most difficult problems faced by a plastic surgeon. This is because of the paucity and poor quality of the skin available in the auricular region. Depending upon the quality and quantity of skin available in the auricular region, patients with total loss of ear following burns were divided into five groups. The surgical procedure for ear reconstruction differed in each group due to differences in skin available for coverage of the cartilage framework. Different covering methods which were used for the draping of the cartilage framework were, normal post auricular skin, local grafted or scarred but soft and supple skin, post auricular fascia, temporoparietal fascia (pedicled or free) and free radial forearm fascial flap. A temporoparietal fascial flap was the cover of choice if local skin was not healthy. During the past eight years, seventy six cases of total ear reconstruction were done for post burn ear deformities. The technique and results are presented here.


Comparative Effects of Bile Diversion and Duodenal-Jejunal Bypass on Glucose and Lipid Metabolism in Male Diabetic Rats.
Duodenal-jejunal bypass (DJB) induces rapid and durable improvement in glucose and lipid metabolism. Besides bypassing the proximal gut, DJB also diverts bile acids (BAs) into the distal gut, increasing luminal and systemic BAs that are essential to metabolic homeostasis. The aim of this study is to evaluate whether bile diversion (BD) alone can recapitulate the effects of DJB on glucose and lipid metabolism. BD, DJB and SHAM procedures were performed in a diabetic rat model induced by high-fat diet (HFD)/streptozotocin (STZ). Body weight, energy intake, blood glucose, serum hormones, insulin sensitivity, lipid profiles, and luminal and systemic BAs were measured postsurgery. BD reduced body weight, independently of energy intake, whereas DJB had no effects. Luminal and serum BAs were increased after both DJB and BD, and were higher after BD than DJB. During glucose tolerance test, both fasting and postprandial blood glucose concentrations were reduced with DJB and BD, and were lower after DJB than BD. Insulin sensitivity was improved after DJB, but remained unchanged after BD. Fasting and postprandial GLP-1 were equally increased after DJB and BD. Serum triglyceride and free fatty acids were decreased more after BD than DJB, while hepatic triglyceride storage was reduced more after DJB. These observations indicate that BD, which increases luminal and systemic BAs and postprandial GLP-1, represents an important component of DJB in restoring glucose and lipid homeostasis in diabetic state. However, other mechanisms associated with DJB also appear to make complementary contributions to metabolic regulation.


Differences in leucocytes and inflammation-based indices among critically ill patients owing to SARS-CoV-2 variants during several successive waves of COVID-19 pandemic.
Inflammatory indices are useful informative markers in assessing the severity of the COVID-19 disease course; however, their involvements during series waves of SARS-CoV-2 virus outbreaks in critical patients with COVID-19 remain unclear. Hence, we aimed to ascertain the changing dynamics of the combined inflammatory indices (NLR, dNLR, CLR, LMR, PLR, SII, and SIRI) and their associations with clinical outcomes in severe COVID-19 patients during serial waves of SARS-CoV-2. We retrospectively enrolled 163 severe COVID-19 patients admitted to the ICU during six SARS-CoV-2 waves. We found that most of patients admitted to the ICU were from the fourth wave. Patients in the fourth wave were considerably younger and had the highest percentage of ARDS than other waves. The highest CRP was found in the first wave, while the lowest in patients admitted in the sixth wave. Although most of the COVID-19 waves were marked with leukocytosis, neutrophilia, and lymphocytopenia, the lowest of both NLR and dNLR were found in the fourth wave "Delta wave" and the lowest of both CLR and SII were observed in "Omicron wave". Interestingly, during most of the COVID-19 waves, the derived combined inflammatory ratio NLR, dNLR, CLR, SII and SIRI were sustained at high levels in fatal cases at the last day of hospitalization, while these indices declined in the alive group at the end of ICU hospitalization. No major difference was identified in lymphocyte count between admission and the last day of hospitalization in both deceased and recovered COVID-19 patients during Delta and Omicron waves. Moreover, patients admitted in the Omicron wave had less severe disease compared to those admitted in the Delta wave. The Kaplan-Meier analysis revealed no significant difference in survival rates or the probability of respiratory failure between six successive COVID-19 waves. Taken together, our results showed marked differences in the alteration of nonspecific inflammation and damage in the adaptive immune response during the six serial SARS-CoV-2 waves. Considering the inflammatory response of infectious diseases, embedding inflammatory indices informative markers into routine clinical testing offers the potential to mitigate the impact of future pandemics of COVID-19 and other infectious diseases.


Threats to reliability risk erroneous conclusions: a survey of prospective registration and sample sizes of randomised trials in women's health.
Prospective registration of clinical trials has been required since 2005. We aimed to assess concordance between registered and reported sample sizes among prospectively registered randomised controlled trials (RCTs) in obstetrics and gynaecology. Analysis of prospectively registered and published data. Women's health. Obstetrics and gynaecology RCTs published in eight journals in 2015. Specialist (Acta Obstet Gynecol Scand, BJOG, Obstet Gynecol and Am J Obstet Gynecol) and general (BMJ, N Engl J Med, JAMA and Lancet) journals were searched from 1 January to 31 December 2015 for main reports of obstetrics and gynaecology RCTs. Their corresponding registries and protocols were sought and data were extracted. Proportions and 95% CI were calculated using exact methods. Prospective registration of RCT and sample size concordance between RCTs and their registries within those where registration took place before patients were recruited. Of the 75 relevant RCTs, 51 (68%, 95% CI 56-78%, P < 0.001 using a null hypothesis requiring 100% compliance) were prospectively registered, a feature found to be more common in general journals versus specialist journals (21/22 versus 30/53, 95% versus 57%, P = 0.001). Of the 51 prospectively registered RCTs, 31 (61%, 95% CI 46-74%, P = 0.003 using a null hypothesis requiring 40% of studies to achieve their stated sample size) did not reach the target sample size. There are gaps in universal adoption of the prospective trial registration rule. Inability to meet target sample size risks deficiencies in statistical power with unreliability in results. Only two-thirds of RCTs in women's health are prospectively registered, and over half fail to achieve target sample sizes.


Evaluation of different algorithms for automatic segmentation of head-and-neck lymph nodes on CT images.
To investigate the performance of 4 atlas-based (multi-ABAS) and 2 deep learning (DL) solutions for head-and-neck (HN) elective nodes (CTVn) automatic segmentation (AS) on CT images. Bilateral CTVn levels of 69 HN cancer patients were delineated on contrast-enhanced planning CT. Ten and 49 patients were used for atlas library and for training a mono-centric DL model, respectively. The remaining 20 patients were used for testing. Additionally, three commercial multi-ABAS methods and one commercial multi-centric DL solution were investigated. Quantitative evaluation was assessed using volumetric Dice Similarity Coefficient (DSC) and 95-percentile Hausdorff distance (HD95%). Blind evaluation was performed for 3 solutions by 4 physicians. One recorded the time needed for manual corrections. A dosimetric study was finally conducted using automated planning. Overall DL solutions had better DSC and HD95% results than multi-ABAS methods. No statistically significant difference was found between the 2 DL solutions. However, the contours provided by multi-centric DL solution were preferred by all physicians and were also faster to correct (1.1 min vs 4.17 min, on average). Manual corrections for multi-ABAS contours took on average 6.52 min Overall, decreased contour accuracy was observed from CTVn2 to CTVn3 and to CTVn4. Using the AS contours in treatment planning resulted in underdosage of the elective target volume. Among all methods, the multi-centric DL method showed the highest delineation accuracy and was better rated by experts. Manual corrections remain necessary to avoid elective target underdosage. Finally, AS contours help reducing the workload of manual delineation task.


Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.


Quantitative Mass Spectrometry Analysis of Cerebrospinal Fluid Protein Biomarkers in Alzheimer's Disease.
Alzheimer's disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) β-amyloid (Aβ), total Tau, and phosphorylated Tau (pTau) providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond amyloid (A) and Tau (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method with isotopically labeled standards for relative protein quantification in CSF. Biomarker positive (AT+) and negative (AT-) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) with an average coefficient of variation (CV) of ~13% across 30 QCs and 133 controls (cognitively normal, AT-), 127 asymptomatic (cognitively normal, AT+) and 130 symptomatic AD (cognitively impaired, AT+). Proteins that could distinguish AT+ from AT- individuals included SMOC1, GDA, 14-3-3 proteins, and those involved in glycolysis. Proteins that could distinguish cognitive impairment were mainly neuronal proteins (VGF, NPTX2, NPTXR, and SCG2). This demonstrates the utility of SRM-MS to quantify CSF protein biomarkers across stages of AD.


Aeromedical Retrieval for Stroke in Australia.
Rural, remote, and Indigenous stroke patients have worse stroke outcomes than urban Australians. This may be due to lack of timely access to expert facilities. We aimed to describe the characteristics of patients who underwent aeromedical retrieval for stroke, estimate transfer times, and investigate if flight paths corresponded with the locations of stroke units (SUs) throughout Australia. Prospective review of routinely collected Royal Flying Doctor Service (RFDS) data. Patients who underwent an RFDS aeromedical retrieval for stroke, July 2014-June 2018 (ICD-10 codes: I60-I69), were included. To define the locations of SUs throughout Australia, we accessed data from the 2017 National Stroke Audit. The main outcome measures included determining the characteristics of patients with an in-flight diagnosis of stroke, their subsequent pickup and transfer locations, and corresponding SU and imaging capacity. The RFDS conducted 1,773 stroke aeromedical retrievals, consisting of 1,028 (58%) male and 1,481 (83.5%) non-Indigenous and 292 (16.5%) Indigenous patients. Indigenous patients were a decade younger, 56.0 (interquartile range [IQR] 45.0-64.0), than non-Indigenous patients, 66.0 (IQR 54.0-76.0). The most common diagnosis was "stroke not specified," reflecting retrieval locations without imaging capability. The estimated median time for aeromedical retrieval was 238 min (95% confidence interval: 231-244). Patients were more likely to be transferred to an area with SU and imaging capability (both p < 0.0001). Stroke patients living in rural areas were younger than those living in major cities (75 years, Stroke Audit Data), with aeromedically retrieved Indigenous patients being a decade younger than non-Indigenous patients. The current transfer times are largely outside the time windows for reperfusion methods. Future research should aim to facilitate more timely diagnosis and treatment of stroke.


In response to "The Knowledge of Our Knowledge": 2 decades and not much has changed.
The chiropractic profession has struggled with how it is viewed and perceived by those within the profession and the powerful forces outside the profession. This commentary suggests that the vast majority of professional unrest is largely due to lines drawn upon philosophical boundaries and how we perceive what we know. For the profession to advance, it is imperative that unsubstantiated claims are eliminated from our justification for being and that we continue to test theories using scientific methods. Theories espoused must be able to be supported by valid research, and we must be ready to accept the results of these investigations and either build upon that body of research or accept the findings and move in alternative directions that science will take us. In doing so, we will contribute to the philosophy of health and perhaps help to change the health care paradigm from disease focused to wellness, which is based upon evidence and not emotion.


A2Ar-dependent PD-1+ and TIGIT+ Treg cells have distinct homing requirements to suppress autoimmune uveitis in mice.
The proper function of regulatory T cells (Tregs) to suppress inflammation requires homing to the correct tissue site. Resolution of autoimmune uveitis generates distinct programmed death receptor 1 (PD-1+) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT+) Tregs in an adenosine 2A receptor (A2Ar)-dependent manner found in the spleen. Where and how these Tregs migrate from the spleen to prevent uveitis is not known. In this work, we show that A2Ar-dependent Tregs migrated to the eye and secondary lymphoid tissue and expressed chemokine receptor (CCR)6 and CCR7. Suppression of autoimmune uveitis required CCR6 and CCR7 expression for TIGIT+ Tregs but not PD-1+ Tregs. Moreover, stimulation of A2Ar on T cells from patients showed a decreased capacity to induce TIGIT+ Tregs that expressed CCR6 or CCR7, and PD-1+ Treg that expressed CCR6. This work provides a mechanistic understanding of the homing requirements of each of these Treg populations. Importantly, this work is clinically relevant because patients with chronic autoimmune uveitis are unable to induce the Treg populations identified in mice that home to the target tissue.


Ultrasensitive visual detection of DNA with tunable dynamic range by using unmodified gold nanoparticles and target catalyzed hairpin assembly amplification.
A simple and novel strategy for enzyme-free ultrasensitive DNA detection platform has been present here based on gold nanoparticles (AuNPs) colorimetry and target catalyzed hairpin assembly amplification. Three hairpin auxiliary probes (H1, H2, and H3) are designed with signal-stranded DNA (ssDNA) sticky ends which could effectively stabilize AuNPs against salt-induced aggregation. However, a cascade of assembly steps with H1, H2, and H3 are activated in the presence of the target DNA, followed by a disassembly step in which H3 displaces the target DNA from the complex, freeing the target DNA to catalyze the self-assembly of additional branched junctions. The formed branched junction consisted with dsDNA is stiffer, and cannot prevent salt-induced AuNPs aggregation, corresponding to a red-to-blue color change. The result can be read out by naked eyes or UV-vis spectrometer. The detection limit of this method is 0.1 pM by naked eyes, and this result is comparable or even better than enzyme or hybridization chain reaction (HCR) based amplification AuNPs colorimetric assays. Moreover, the dynamic range of sensor could be tuned by using different concentration of hairpins. Importantly, this strategy provides a versatile ultrasensitive detection platform for the DNA and related filed targets including metal ions, small molecules, proteins, cells et al. by combining with specific DNAzymes and aptamers.


O-GlcNAcylation of MORC2 at threonine 556 by OGT couples TGF-β signaling to breast cancer progression.
MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-β1 (TGF-β1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-β1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-β1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.


Assessing dual-role staff-interpreter linguistic competency in an integrated healthcare system.
Interpreter services for medical care increase physician-patient communication and safety, yet a "formal certification" process to demonstrate interpreter competence does not exist. Testing and training is left to individual health care facilities nationwide. Bilingual staff are often used to interpret, without any assessment of their skills. Assessing interpreters' linguistic competence and setting standards for testing is a priority. To assess dual-role staff interpreter linguistic competence in an integrated health care system to determine skill qualification to work as medical interpreters. Dual-role staff interpreters voluntarily completed a linguistic competency assessment using a test developed by a language school to measure comprehension, completeness, and vocabulary through written and oral assessment in English and the second language. Pass levels were predetermined by school as not passing, basic (limited ability to read, write, and speak English and the second language) and medical interpreter level. Five staff-interpreter focus groups discussed experiences as interpreters and with language test. A total of 840 dual-role staff interpreters were tested for Spanish (75%), Chinese (12%), and Russian (5%) language competence. Most dual-role interpreters serve as administrative assistants (39%), medical assistants (27%), and clinical staff (17%). Two percent did not pass, 21% passed at basic level, 77% passed at medical interpreter level. Staff that passed at the basic level was prone to interpretation errors, including omissions and word confusion. Focus groups revealed acceptance of exam process and feelings of increased validation in interpreter role. We found that about 1 in 5 dual-role staff interpreters at a large health care organization had insufficient bilingual skills to serve as interpreters in a medical encounter. Health care organizations that depend on dual-role staff interpreters should consider assessing staff English and second language skills.


Preliminary structure-activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains.
Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis , with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay.


Cardiogenic mixing increases aerosol deposition in the human lung in the absence of gravity.
Exposure to extraterrestrial dusts is an almost inevitable consequence of any proposed planetary exploration. Previous studies in humans showed reduced deposition in low-gravity compared with normal gravity (1G). However, the reduced sedimentation means that fewer particles deposit in the airways, increasing the number of particles transported to the lung periphery where they eventually deposit albeit at a smaller rate than in 1G. In this study, we determined the role that gravity and other mechanisms such as cardiogenic mixing play in peripheral lung deposition during breath holds. Eight healthy subjects inhaled boluses of 0.5 μm-diameter particles to penetration volumes (Vp) of 300 and 1200ml that were followed by breath holds of up to 10 sec. Tests were performed in 1G and during short periods of microgravity (μG) aboard the NASA Microgravity Research Aircraft. Aerosol deposition and dispersion were calculated from these data. Results show that, for both Vp, deposition in 1G was significantly higher than in μG. In contrast, while dispersion was significantly higher in 1G compared to μG at Vp=1200ml, there was no significant gravitational effect on dispersion at Vp=300ml. Finally, for each G level and Vp, deposition and dispersion significantly increased with increasing breath-hold time. The most important finding of this study is that, even in the absence of gravity, aerosol deposition in the lung periphery increased with increasing residence time. Because the particles used in this study were too large to be significantly affected by Brownian diffusion, the increase in deposition is likely due to cardiogenic motion effects.


Family involvement in medical decision making in Europe and the United States: A replication and extension in five Countries.
In 2018, Alden et al. showed that the desired degree of family involvement in medical decisions is an individual preference that is largely independent from East-West cultural stereotypes. At the same time, individual-level interdependence influenced whether patients preferred more individual or more family involvement in their decision making together with their medical care provider. The present study provides empirical evidence and adds evidence for Europe for which no such data previously existed. The present study is a direct replication and extension of the original Alden et al. (2018) study (N = 2031; Australia, China, Malaysia, India, South Korea, Thailand, United States [U.S.]), however, using survey data from four European countries (Austria, Belgium, Germany, Netherlands) and the United States (U.S.) with a total sample size of N = 2750. Random effects within-between models replicated the original primary finding that those with higher self-involvement in medical decision making preferred less family involvement. Furthermore, patients with lower self-independence, higher relational interdependence, and stronger beliefs in social hierarchy are more likely to want their families involved in medical decisions besides their health care provider. These observed relationships are largely consistent both within and across the four European countries and the U.S. In conclusion, the results point to the importance of avoiding cultural stereotypes and instead, recognizing that patient desires for family involvement in medical decision making vary dramatically within cultures depending on multiple individual differences. Furthermore, a growing body of evidence suggests that these antecedents of family involvement as well as the construct itself may be measurable in diverse cultures with high levels of confidence in their reliability and validity.


Evaluation of polymerase chain reaction for the detection of Paracoccidioides brasiliensis DNA on serum samples from patients with paracoccidioidomycosis.
The aim of this study was to demonstrate the DNA of Paracoccidioides brasiliensis in human serum samples of patients with paracoccidioidomycosis using the polymerase chain reaction (PCR). The diagnosis of paracoccidioidomycosis (PCM) was defined by microscopic observation of the fungus on direct exam or histopathology, culture, and serological positivity. DNA from serum of 33 patients with PCM was extracted and submitted to nested-PCR using primers from the gp 43 gene. Only one sample was positive on nested-PCR. We conclude that the prevalence of fungemia in patients with different clinical forms of PCM is low, limiting the use of serum DNA detection as an alternative diagnostic tool.


A layered solid-state culture system for investigating the fungal growth and decay behaviour on the cellulosic substrate.
Mycelium-based materials have attracted growing interest, facilitating their development for various new applications. Finding for suitable fungal species and strains enables further technical breakthroughs in their development and quality control. Here, we developed a model solid-state culture system to screen fungal strains efficiently for mycelium-based materials production. A piece of silicone-coated paper set on the general agar plate allows for isolation of the mycelial mat from the substrate. The mycelial growth and density can be evaluated by weighing the mycelial mat. We used the paper substrate after fungal incubation to investigate the relationship between substrate degradation and the contact time with hyphae. It yielded further insights into the fungal decay. Ten basidiomycetes were assessed for their fungal growth and degradation behaviour of the substrate using this method. Pleurotus floridanus FBCC375 showed a dense and elastic mycelial mat and mild degradation of the substrate. A unique decay behaviour was found in Hypsizygus ulmarius FBCC573 and Trametes versicolor FBCC564. They indicated a positional imbalance in the decay activity within the colony. This simple method is helpful for screening fungal strains and facilitates the further development of mycelium-based materials.


Restoration of cough reflex in lung transplant recipients.
Lung transplantation involves vagal nerve interruption resulting in sensory airway denervation and impairment of the cough reflex. Following lung transplantation, it is unclear whether functional recovery of the cough reflex occurs over time. Our objective was to evaluate the afferent limb of the cough reflex in lung transplant recipients. The assessment of cough reflex involved upper airway anesthesia, conscious sedation, and fiberoptic bronchoscopy; the biopsy forceps and a 5% dextrose solution were applied through the bronchoscope to the airway mucosa at the main carina, proximal and distal to the anastomosis. A cross-sectional group of seven subjects underwent a single assessment, while eight subjects in a longitudinal group underwent assessment at 1.5 and 12 months. Cough frequency was determined by counting the number of audible coughs and abdominal muscle contractions measured with a surface electromyogram recorder. The airway anastomosis from deceased subjects in the longitudinal group was examined for nerves. All seven subjects from the cross-sectional group demonstrated a similar cough frequency after mechanical and chemical irritation of all airway sites. All subjects in the longitudinal group who were evaluated at 1.5 weeks had a cough response at all sites except distal to the anastomosis. Twelve months after transplantation, cough was present at all sites. Immunohistochemical staining for protein gene product 9.5, low-affinity neurotrophin, and vanilloid receptors demonstrated nerves in subepithelial regions proximal and distal to the airway anastomosis. In human lung transplant recipients, recovery of the cough reflex was noted 12 months after lung transplantation.


The Variable Appearance of Third Ventricular Colloid Cysts: Correlation with Histopathology and the Risk of Obstructive Ventriculomegaly.
While third ventricular colloid cysts may present as an incidental finding, they also harbor the potential to cause ventricular obstruction and sudden death. Herein we analyze the relationship between imaging appearance and the risk of obstructive ventriculomegaly. This is a retrospective review of the MR imaging appearance of 64 patients with colloid cysts, 46 of whom also had a CT scan, obtained by a tertiary hospital imaging report data base search over a 10-year period. Cysts were categorized by appearance on T2-FLAIR and correlated with patient age, cyst size, and the risk of obstructive ventriculomegaly. Histopathologic correlation was available for 28 cases. The 64-patient cohort was 52% female, median age 50 years (range 10 to 99 years). Cysts hyperintense on T2-FLAIR (53.1%) were larger (P <.001), occurred in younger patients (P = .01), and had a higher risk of obstructive ventriculomegaly than homogeneously hypointense cysts (relative risk 6.18, 95% CI [2.04, 18.67]). Three patterns of T2 hyperintensity were identified: homogeneously hyperintense, hyperintense rim, and cysts with "dot sign." Although "dot sign" cysts were larger (P < .001), there was no significant difference in patient age or the risk of ventricular obstruction among T2 hyperintense cysts. Cyst wall histopathology did not vary with imaging appearance. Hyperintensity on T2-FLAIR, whether homogeneous, rim, or "dot sign," is associated with larger cyst size and younger patient age, and is an imaging risk factor for obstructive ventriculomegaly. The hyperintense rim does not represent a thickened cyst wall.


Effect of mesoporous silica nanoparticles-based nano-fragrance on the central nervous system.
Fragrances are widely used in our daily lives and can make us feel happy. However, traditional aromatic products release fragrance quickly and have a strong aroma. This not only worsens our scenting experience, but also severely shortens the useful life of fragrance products. In this study, nano-fragrances based on mesoporous silica nanoparticles with great encapsulation efficiency and slow-release function were designed and prepared. In addition, this nano-fragrances are applied to wallpapers. Open field tests showed that this nano-fragrance had significant stress relief and anti-depressant effects.


Gender- and race-specific comparison of tobacco-associated cancer incidence trends in Florida with SEER regional cancer incidence data.
Analysis of state and national tobacco-associated cancer trends is critical for the identification of high-risk regions of the country that require the attention of the public health community. This study compares Florida race- and gender-specific cancer trends with pooled data obtained from nine Surveillance, Epidemiology, and End Results (SEER-9) registries. Age-adjusted, race- and gender-specific cancer incidence trends were evaluated using joinpoint regression analysis. Pooled, age-adjusted incidence rates and standardized incidence rate ratios were computed for each cancer for the years 1999-2003 to compare Florida to SEER-9. Relative to SEER-9 whites and irrespective of gender, lung cancer rates in white Floridians were elevated through the 1990s. However, lung cancer rates have recently declined at a steeper rate among white Floridians than among SEER-9 whites. For years 1999-2003, black Floridians had significantly lower rates of lung, bladder, pancreas, and kidney cancer relative to SEER-9 blacks. The opposite pattern was evident for white Floridians with significantly higher rates of lung and laryngeal cancer relative to SEER-9 whites. Progress in the reduction of tobacco-associated cancers among white Floridians lags behind the progress noted in SEER-9 registries suggesting that additional state-directed smoking prevention and smoking cessation measures are needed.


Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients.
Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel-induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12-weekly paclitaxel-based regimen. Patients were clinically examined by means of the Total Neuropathy Score-clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0-1 and 26 (44%) grade 2-3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week-12 was determined, whereas patients with TNSc grade 2-3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0-1. receiver-operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2-3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2-3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro-axonal injury in PIPN. An early increase of this biomarker after a 3-weekly chemotherapy course can be a predictive marker of final PIPN severity.


Ultrasound Elastography for Rapid, Real-time Detection of Localized Muscular Reaction in Malignant Hyperthermia-susceptible Pigs.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Halothane and caffeine induce excessive sarcoplasmic calcium liberation and skeletal muscle contracture in patients susceptible to malignant hyperthermia (MH) and are utilized for diagnosis in the in vitro contracture test. Intramuscular injection previously caused a marked local lactate increase in MH-susceptible but not in MH-nonsusceptible individuals in vivo. Using shear-wave elastography, this study evaluated localized changes in muscle stiffness after intramuscular injection of halothane and caffeine. Microdialysis probes were placed into the gracilis muscle of 16 pigs (9 MH-susceptible and 7 MH-nonsusceptible). After local injection of either halothane or caffeine in different concentrations, changes of tissue elasticity surrounding the probe were examined by quantitative shear-wave elastography. Local lactate concentrations were analyzed spectrophotometrically. Ultrasound elastography detected a temporary increase in local muscle rigidity in MH-susceptible but not in MH-nonsusceptible pigs after 2.5 and 5 vol% halothane and after 10, 40, and 80 mM caffeine, whereas there were no differences in the control groups (median [interquartile range] for maximum effect after 5 vol% halothane: MH-susceptible: 97 [31 to 148] vs. MH-nonsusceptible: 5 [-6 to 18] kPa; P = 0.0006; maximum effect after 80 mM caffeine: 112 [64 to 174] vs. -3 [-6 to 35] kPa; P = 0.0002). These effects were seen rapidly within 5 min. Local lactate concentrations were higher in MH-susceptible versus nonsusceptible pigs after 1 and 2.5 vol% halothane and 10, 40, and 80 mM caffeine (2.5 vol% halothane: MH-susceptible: 2.8 [1.9 to 4.4] vs. MH-nonsusceptible: 0.6 [0.6 to 0.7] mmol/l; P < 0.0001; 80 mM caffeine: 5.2 [4.1 to 6.3] vs. 1.6 [1.2 to 2.4] mmol/l; P < 0.0001). After 10 vol% halothane, rigidity and lactate levels were increased in both MH-susceptible and MH-nonsusceptible animals. This pilot study revealed shear-wave elastography as a suitable technique for real-time detection of altered tissue elasticity in response to pharmacologic stimulation. By considering the variability of these results, further test protocol optimization is required before elastography could serve as a minimally invasive MH diagnostic test.


Habitat modification contributes to associational resistance between herbivores.
Associational resistance, in which one species gains protection from its consumers by association with a competitor, is common among plants but has seldom been documented among insects. Here we show that parasitism of an aboveground herbivore, European corn borer, by its specialist parasitoid Macrocentrus grandii, is reduced 98% in the presence of a belowground herbivore, corn rootworm. We tested the hypothesis that this positive indirect interaction between corn rootworm and corn borer was mediated by corn rootworm's influence on the habitat: plant height was diminished by 33% and plant density by 20%, resulting in a more open habitat. We found that M. grandii showed a two- to five-fold preference for dense versus open habitats, and that experimental reduction of plant density in the absence of corn rootworm reduced M. grandii parasitism of corn borer by 13%. This result supports the presence of a habitat modification effect as a contributing factor to associational resistance for corn borer. We argue that associational resistance may be more common among phytophagous insects than previously appreciated.


The Neurobiology of Cancer Pain.
Oral cancers are often severely painful and clinically difficult to manage. Few researchers have investigated the neurobiologic factors responsible for cancer pain; however, the study of oral cancer pain might inform us about the fundamental biology of cancer. The purpose of the present report was to summarize the clinical challenges inherent in oral cancer pain management, oral cancer pain mechanisms and mediators, and the convergence of the investigation of carcinogenesis and pain.


Omenn's syndrome--pathologic arguments in favor of a graft versus host pathogenesis: a report of nine cases.
Histologic, histochemical, and histoenzymatic investigations of nine cases of Omenn's disease showed generalized lymphoid depletion, including B cells and all T-cell subpopulations; an apparent proliferation of alpha-naphthyl acetate esterase-, acid phosphatase-, OKM1-positive macrophages and T6 interdigitating cells; a thymic hypoplasia with arrest of hassallian epithelial maturation; starlike fibrinous deposits in the bone marrow; and extensive cutaneous lesions characterized by hyperkeratosis, apoptotic cell death associated with the intraepidermal presence of T4+ and T8+ cells, localized necrosis of the basement membrane, expression of Ia antigens by malpighian cells, and progressive loss of the T6+ Langerhans' cells. These lesions, mainly the skin and bone marrow changes, are reminiscent of those observed in acute graft versus host reaction. Although a blood chimerism has never been demonstrated, these pathologic observations support the hypothesis of graft versus host disease in a primary cellular immunodeficiency and the persistence of the proliferating maternal cells in the peripheral target organs.


Proton NMR studies of human hemoglobin variants modified in the proximal side of beta heme pocket. Implications for the affinity control and cooperative mechanism.
Using high resolution proton NMR spectroscopy, we have investigated 10 human hemoglobin variants modified in the proximal side of the heme pocket in beta subunits. Comparative observation of several resonances in the spectra of liganded and unliganded hemoglobins allowed us to characterize the localization and nature of the structural perturbations induced by amino acid substitutions or chemical modification. The present data indicate that the structural perturbations are localized in the beta subunits, mainly in the tertiary domain surrounding the modification site. Analysis of the aromatic region of the liganded hemoglobin spectra gives substantial information for the assignment of the His-beta 97 C-2H resonance. Correlation of the spectroscopic observations with the functional characteristics of the studied hemoglobins demonstrates that structural factors localized in the proximal side of the heme pocket can control the ligand-iron interaction taking place on the other heme side. The structural perturbations induced by the modifications in the F or FG segments of the beta subunits do not extend to the distal side but rather to the alpha 1 beta 2 interface. This argues the existence of a gradient of tertiary structural stability, indicating a possible structural pattern of heme-heme interaction in the cooperativity control.


Perturbations in the development of infants with Rett disorder and the implications for early diagnosis.
The gene discovery in Rett disorder has opened the way for the development of clinical intervention. Initial recognition of affected infants will depend on observation by clinicians and the development of key diagnostic criteria is of crucial importance. Perturbations in the development of very young infants are emerging in studies of home videos. Observations from experienced health practitioners and home video transcriptions are presented which indicate the nature of early clues to the disorder and their fluctuating nature. Early diagnosis is likely to be available before the development of effective treatment. Most children are not diagnosed before regression and, currently, no therapies are equipped to offer support to pre-regression infants and their families. When earlier diagnosis becomes available, parents of the newly-diagnosed infant will be aware of their infant's difficult future before her problems are fully apparent. Practitioners in regular contact with families will have the sensitive task of supporting infants in early infancy and into regression.


Optimizing Anti-EGFR Therapy in Colorectal Cancer.
Treatment with anti-EGFR monoclonal antibodies has been successfully integrated in the continuum of care for metastatic colorectal cancer. The major challenge is the identification of patients who would benefit from treatment. Currently, the best predictor of efficacy is the absence of mutations in KRAS and NRAS genes. Clin Cancer Res; 21(24); 5415-6. ©2015 AACR.See related article by Peeters et al., p. 5469.


Underwater refraction-polarization patterns of skylight perceived by aquatic animals through Snell's window of the flat water surface.
The grass shrimp (Palaemonetes vulgaris) orients itself by means of the polarization pattern of the sky visible through Snell's window of the water surface. The celestial polarization pattern viewed from water is distorted and modified because of refraction and repolarization of skylight at the air-water interface. This work provides a quantitative account of the repolarization of skylight transmitted through a flat water surface. The degree and direction of linear polarization, the transmissivity and the shape of the refraction-polarization oval are calculated at the air-water interface as functions of the polarization characteristics and the incident angle of partially linearly polarized incoming light. Two-dimensional patterns of linear polarization ellipses and of the degree and direction of polarization of skylight are presented for different zenith distances of the sun. The corresponding underwater refraction-polarization patterns are computed. Transmissivity patterns of a flat water surface are calculated for unpolarized light of an overcast sky and for partially polarized light of clear skies as a function of the zenith distance of the sun. The role of these refraction-polarization patterns in orientation and polarization vision of the grass shrimp (P. vulgaris) and rainbow trout (Oncorhyncus mykiss) is reviewed. The effects of cloud cover, surface waves and water turbidity on the refraction-polarization patterns are briefly discussed.


First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action.
EP217609 is a parenteral antithrombotic compound combining in one molecule an indirect anti-factor Xa inhibitor, a direct thrombin active site inhibitor and a biotin moiety. The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609. In this randomised double-blind placebo-controlled study, healthy male subjects were administered intravenously single ascending doses (1, 3 or 10 mg) of EP217609 or placebo. Each treatment group consisted of 10 subjects of whom 8 received EP217609 and 2 received placebo. All doses of EP217609 were well tolerated. A total of five treatment-emergent adverse events were reported, all considered unrelated, but no bleedings or other significant adverse events occurred during this study. In both plasma and urine, there was a strong correlation between EP217609 concentrations as measured by anti-factor IIa and Xa specific bioassays indicating that the two pharmacological activities of EP217609 did not dissociate in vivo. EP217609 pharmacokinetics were dose proportional and characterised by a low clearance, a small volume of distribution and a terminal half-life of 20.4 h. The long half-life was reflected in long-lasting, dose-dependent effects on activated and ecarin clotting time, thrombin and prothrombin time, activated partial thromboplastin time, thrombin generation time and anti-factor Xa activity. Pharmacokinetic/pharmacodynamic modelling indicated that the concentration of EP217609 producing 50 % of the pharmacodynamic effect was 3400 and 2210 ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609. • There is a limited number of neutralisable anticoagulants, particularly when rapid neutralisation is required. • Synthetic anti-Xa compounds have predictable pharmacokinetic profiles. However, problems with thrombin rebound remain because of the inability to inhibit clot-bound thrombin. • This manuscript provides a comprehensive investigation of the pharmacokinetics, pharmacodynamics and safety of EP217609, and the results were the basis of future clinical studies in both healthy subjects and patients. • The pharmacokinetic/pharmacodynamic modelling provided information for dose selection in such future studies.