Search

Abstract Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.

Abstract Genetic management is a critical component of threatened species conservation. Understanding spatial patterns of genetic diversity is essential for evaluating the resilience of fragmented populations to accelerating anthropogenic threats. Nowhere is this more relevant than on the Australian continent, which is experiencing an ongoing loss of biodiversity that exceeds any other developed nation. Using a proprietary genome complexity reduction‐based method (DArTSeq), we generated a data set of 3239 high quality Single Nucleotide Polymorphisms (SNPs) to investigate spatial patterns and indices of genetic diversity in the koala (Phascolarctos cinereus), a highly specialised folivorous marsupial that is experiencing rapid and widespread population declines across much of its former range. Our findings demonstrate that current management divisions across the state of New South Wales (NSW) do not fully represent the distribution of genetic diversity among extant koala populations, and that care must be taken to ensure that translocation paradigms based on these frameworks do not inadvertently restrict gene flow between populations and regions that were historically interconnected. We also recommend that koala populations should be prioritised for conservation action based on the scale and severity of the threatening processes that they are currently faced with, rather than placing too much emphasis on their perceived value (e.g., as reservoirs of potentially adaptive alleles), as our data indicate that existing genetic variation in koalas is primarily partitioned among individual animals. As such, the extirpation of koalas from any part of their range represents a potentially critical reduction of genetic diversity for this iconic Australian species.

The microvasculature facilitates gas exchange, provides nutrients to cells, and regulates blood flow in response to stimuli. Vascular abnormalities are an indicator of pathology for various conditions, such as compromised vessel integrity in small vessel disease and angiogenesis in tumors. Traditional immunohistochemistry enables the visualization of tissue cross-sections containing exogenously labeled vasculature. Although this approach can be utilized to quantify vascular changes within small fields of view, it is not a practical way to study the vasculature on the scale of whole organs. Three-dimensional (3D) imaging presents a more appropriate method to visualize the vascular architecture in tissue. Here we describe the complete protocol that we use to characterize the vasculature of different organs in mice encompassing the methods to fluorescently label vessels, optically clear tissue, collect 3D vascular images, and quantify these vascular images with a semi-automated approach. To validate the automated segmentation of vascular images, one user manually segmented one hundred random regions of interest across different vascular images. The automated segmentation results had an average sensitivity of 83±11% and an average specificity of 91±6% when compared to manual segmentation. Applying this procedure of image analysis presents a method to reliably quantify and characterize vascular networks in a timely fashion. This procedure is also applicable to other methods of tissue clearing and vascular labels that generate 3D images of microvasculature.

Category: Basic Sciences/Biologics; Basic Sciences/Biologics Introduction/Purpose: Zinc and magnesium are crucial for bone health, and their deficiencies can lead to impaired bone metabolism and repair. Although enhancing their bioavailability has been linked to better fracture healing, their levels during healing have not been studied. We hypothesized that zinc and magnesium levels transiently decrease at the fracture site compared to intact bone. This study is the first to explore temporal trace element levels during the initial stages of fracture healing. The findings will reveal when each element changes its concentration at the fracture site, which is associated with specific functions necessary for appropriate healing. Understanding the connection between trace element concentration and repair processes could lead to more effective treatment or supplementation during fracture healing. Methods: Following induction of a femur fracture in male BB Wistar rats, injured and intact contralateral femurs were harvested at 1- (n=3), 3- (n=4), and 7-days (n=3) after fracture. Fracture segments 10mm in length were resected 5mm from the center of the callus in either direction. Contralateral non-fractured femur segments were resected from the same region within the femoral diaphysis. Samples were analyzed via inductively coupled mass spectrometry using an Agilent ICP-MS 7900 (Agilent Technologies, Santa Clara, CA). Data was converted from ppb to percent weight zinc and magnesium per weight of bone (w/w%). The difference between zinc and magnesium in contralateral intact bone vs. fractured bone was calculated and averaged (∆) for each group. The average % change were also determined. An independent sample two-tailed t-test was performed comparing average w/w% of zinc and magnesium between fracture and contralateral samples. A p-value of < 0.05 was considered significant. Results: After 1-day post-fracture, there was a -29.09 average % change in zinc levels (∆ 6.90x10^-03 ± 5.05x10^-03) (p = 0.033) and a -25.76 average % change in magnesium levels (∆ 1.21x10^-01 ± 7.36x10^-02 w/w%) (p = 0.241) between fractured and non- fractured femurs. After 3-days post-fracture, there was a -22.51 average % change in zinc levels (∆ 5.45x10^-03 ± 3.95x10^-03 w/w%) (p = 0.022) and a -33.07 average % change in magnesium levels (∆ 1.84x10^-01 ± 1.05x10^-01 w/w%) (p = 0.025). After 7- days post-fracture, there was a -9.40 average % change in zinc levels (∆ 1.90x10^-03 ± 3.98x10^-03) (p = 0.377) and a -17.88 average % change in magnesium levels (∆ 9.04x10^-02 ± 1.24x10^-01 w/w%) (p = 0.159) between fractured and non-fractured femurs. Conclusion: Previous research has established the significance of trace elements, namely zinc and magnesium, in the process of fracture healing. Zinc has been shown to improve fracture healing, while magnesium has been found to play a role regulating inflammation during early fracture healing. The findings of this study corroborate our hypothesis that levels of these elements transiently decline following fracture. By evaluating these changes in trace element levels, we can gain a better understanding of their function in the fracture healing process. These observations may offer insight into potential therapeutic approaches utilizing zinc and magnesium for fracture healing in the future.

Category: Hindfoot; Midfoot/Forefoot Introduction/Purpose: The treatment of relapsed, resistant, or neglected clubfoot presents a challenge — some patients may not respond to the traditional Ponseti method. Studies involving gradual distraction using external fixators for treatment of these cases have been performed, but no systematic review has been conducted on the subject. Methods: A comprehensive search was conducted of PubMed, Cochrane, CINAHL, Scopus, and Web of Science according to PRISMA guidelines. Only articles that pertained to the treatment of pediatric patients with clubfoot using external fixation and contained three or more human subjects were included. Reviews, professional opinions, and studies with non-human subjects were excluded. Results: Of 6,469 articles generated from the initial search, 25 met inclusion criteria. 609 total feet (490 total patients) were included, and 533 of these feet (445 patients) were treated with external fixation. The mean age of patients was 8.5 [2-18] years with a mean follow-up length of 40.9 [5-126] months. 21 (84%) studies used the Ilizarov apparatus, two used Joshi’s external stabilization system, and one used the Taylor spatial frame. The most reported primary scoring systems were the 60-point International Clubfoot Study Group (ICFSG) score (20%), Dimeglio classification (12%), Pirani score (8%), and Reinker and Carpenter scales (8%). All but one study found significantly improved primary outcomes for the majority of respective patients. Conclusion: External fixation, which may or may not include open surgery, is a promising intervention for neglected or relapsed clubfoot. However, encouraging more standardized outcome measurements would allow for more thorough comparisons between studies.

Abstract Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. Methods CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. Results CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p

Abstract A system that reconstructs 3D models from a single camera monitoring fish transported on a conveyor system is investigated. Models are subsequently used for training a species classifier and for improving estimates of discarded biomass. It is demonstrated that a monocular camera, combined with a conveyor's linear motion produces a constrained form of multiview structure from motion, that allows the 3D scene to be reconstructed using a conventional stereo pipeline analogous to that of a binocular camera. Although motion stereo was proposed several decades ago, the present work is the first to compare the accuracy and precision of monocular and binocular stereo cameras monitoring conveyors and operationally deploy a system. The system exploits Convolutional Neural Networks (CNNs) for foreground segmentation and stereo matching. Results from a laboratory model show that when the camera is mounted 750 mm above the conveyor, a median accuracy of

Football exposes its players to traumatic brain, neck, and spinal injury. It is unknown whether the adolescent football player develops imaging abnormalities of the brain and spine that are detectable on magnetic resonance imaging (MRI). The objective of this observational study was to identify potential MRI signatures of early brain and cervical spine (c-spine) injury in high school football players. Eighteen football players (mean age, 17.0???1.5 years; mean career length, 6.3???4.0 years) had a baseline brain MRI, and 7 had a follow-up scan 9?42 months later. C-spine MRIs were performed on 11 of the 18 subjects, and 5 had a follow-up scan. C-spine MRIs from 12 age-matched hospital controls were also retrospectively retrieved. Brain MRIs were reviewed by a neuroradiologist, and no cerebral microbleeds were detected. Three readers (a neuroradiologist, a neurosurgeon, and an orthopedic spine surgeon) studied the cervical intervertebral discs at six different cervical levels and graded degeneration using an established five-grade scoring system. We observed no statistically significant difference in disc degeneration or any trend toward increased disc degeneration in the c-spine of football players as compared with age-matched controls. Further research is needed to validate our findings and better understand the true impact of contact sports on young athletes.

Abstract Effective conservation and management necessitate an understanding of the ecological mechanisms that shape species life histories in order to predict how variability in natural and anthropogenic impacts will alter growth rates, recruitment, and survival. Among these mechanisms, the interaction between parturition timing and prey availability frequently influences offspring success, particularly when postnatal care is absent. Here, we assess how parturition timing and nursery conditions, including prey abundance and environmental conditions, influence the growth and potential survival of blacktip sharks (Carcharhinus limbatus) in western Gulf of Mexico (GOM) estuaries over their first year. Catch data from long‐term gillnet monitoring allowed for clear delineation of cohorts based on size frequency distribution plots, and showed that late parturition cohorts born in estuaries with fewer prey resources exhibited more rapid growth than early parturition cohorts that experienced more abundant prey. Compensatory behaviors that promoted accelerated growth led to reduced second year residency, likely due to reduced survival resultant from greater risk taking and potentially due to reduced site fidelity attributed to larger body size. Water temperatures influenced blacktip growth rates through physiological increases in metabolism and potential premigratory foraging cues associated with cooling temperatures. Gradual warming of the GOM (0.03°C year−1) was also correlated with earlier parturition across the study period (1982–2017), similar to other migratory species. Considering current trends in climate and associated phenological shifts in many animals, testing hypotheses assessing compensatory growth‐risk trade‐offs is important moving forward to predict changes in life histories and associated recruitment in concert with current and future conservation actions, like wildlife management.

The association between rider–saddle interaction and horse kinematics has been little studied. It was hypothesized that differences in a thigh block design would influence (a) rider–saddle interface pressures, (b) rider kinematics, and (c) equine limb/spinal kinematics. Eighteen elite sport horses/riders were trotted using correctly fitted dressage saddles with thigh blocks S (vertical face) and F (deformable face). Contact area, mean, and peak pressure between rider and saddle were determined using an on-saddle pressure mat. Spherical markers allowed for the measurement of horse/rider kinematics using two-dimensional video analysis. The kinematics of the equine thoracolumbosacral spine were obtained using skin-mounted inertial measuring units. Results were compared between thigh blocks (paired t-test p ≤ 0.05). With F, the contact area, mean, and peak pressure between rider and saddle were significantly higher (p = 0.0001), and the rider trunk anterior tilt was reduced, indicating altered rider–saddle interaction. The horse thoracic axial rotation and flexion/extension were reduced (p = 0.01–0.03), caudal thoracic and lumbar lateral bend was increased (p = 0.02–0.04), and carpal flexion increased (p = 0.01–0.05) with F compared to S. During straight-line locomotion when in sitting trot, thigh block F was associated with altered rider–saddle interaction and rider and equine kinematics, leading to a more consistent rider–saddle interface, a more upright rider trunk during stance, an increased horse thoracic stability and lumbar lateral bend, and forelimb flexion, supporting the importance of optimising rider–saddle–horse interaction.

Abstract Cerebral microhemorrhages (CMHs) are associated with cerebrovascular disease, cognitive impairment, and normal aging. One method to study CMHs is to analyze histological sections (5–40 μm) stained with Prussian blue. Currently, users manually and subjectively identify and quantify Prussian blue-stained regions of interest, which is prone to inter-individual variability and can lead to significant delays in data analysis. To improve this labor-intensive process, we developed and compared three digital pathology approaches to identify and quantify CMHs from Prussian blue-stained brain sections: (1) ratiometric analysis of RGB pixel values, (2) phasor analysis of RGB images, and (3) deep learning using a mask region-based convolutional neural network. We applied these approaches to a preclinical mouse model of inflammation-induced CMHs. One-hundred CMHs were imaged using a 20 × objective and RGB color camera. To determine the ground truth, four users independently annotated Prussian blue-labeled CMHs. The deep learning and ratiometric approaches performed better than the phasor analysis approach compared to the ground truth. The deep learning approach had the most precision of the three methods. The ratiometric approach has the most versatility and maintained accuracy, albeit with less precision. Our data suggest that implementing these methods to analyze CMH images can drastically increase the processing speed while maintaining precision and accuracy.

Objective: To characterize the prevalence of brain ischemia and cerebral small vessel disease in a cohort of patients with Fabry disease (FD) seen at an academic medical center. Background: FD is an inherited X-linked lysosomal storage disorder with central nervous system involvement. Limited data are available in the literature on the cerebrovascular neuroimaging findings in FD, and the reported prevalence of stroke symptoms and cerebral small vessel disease has varied widely. Design/methods: Brain MRI was performed in 21 patients with FD followed at University of California Irvine Medical Center. Stroke symptoms were assessed and quantification of cerebral microvascular disease was performed using small vessel disease (SVD) score. Lacunes and deep white matter hyperintensities were scored on a four-point scale of 0 (absent) and 1–3 to account for increasing severity; microbleeds were scored 0 (absent) or 1 (present). The total SVD score is the sum of the three components and ranges from 0 to 7. Results: Nearly 43% (9/21) of our FD cohort (aged 32–81 years, mean = 50) had a SVD score of one or higher, all of whom were aged 50 or more years. The most common MRI-defined SVD was white matter hyperintensities (9/9, 100%), followed by microbleeds (6/9, 66%), and lacunes (3/9, 33%). The three patients with previous strokes had some of the highest SVD scores reported in the cohort (scores 3–5). Conclusions: In this cohort, the prevalence of SVD (43%) was three times higher than prevalence of stroke symptoms. SVD score was highest in the those who had experienced a stroke. These findings emphasize the importance of routine MRI screening of patients with FD in order to identify and treat high risk patients.

Cognitive decline is common in chronic kidney disease (CKD). While the evidence of vascular cognitive impairment in this population is robust, the role of Alzheimer's pathology is unknown. We evaluated serum cystatin C-estimated glomerular filtration rate (eGFR), brain amyloid-β positron emission tomography (PET) imaging, and cognitive function in 166 participants from The 90+ Study. Mean age was 93 years (range 90-107) and 101 (61%) were women; 107 participants had normal cognitive status while 59 participants had cognitive impairment no dementia (CIND) or dementia. Mean ± standard deviation cystatin C was 1.59 ± 0.54 mg/L with eGFR 40.7 ± 18.7 ml/min/1.73m2. Higher amyloid-β burden was associated with dementia, but not with age, diabetes, hypertension, or cardiovascular disease. We found no association between brain amyloid-β burden and cystatin C eGFR. We previously reported that kidney function was associated with cognition and cerebral microbleeds in the same cohort of oldest-old adults (90+ years old). Collectively, these findings suggest that microvascular rather than Alzheimer's pathology drives CKD-associated cognitive dysfunction in this population.

We used metagenomic next-generation sequencing to longitudinally assess the gut microbiota and antimicrobial resistomes of international travelers to clarify global exchange of resistant organisms. Travel resulted in an increase in antimicrobial resistance genes and a greater proportion of Escherichia species within gut microbial communities without impacting diversity.

Objective: The preventability of strokes treated by mechanical thrombectomy is unknown. The purpose of this study was to analyze stroke preventability for patients treated with mechanical thrombectomy for large vessel occlusion.Methods: We conducted retrospective analyses of 300 patients (mean ± SE age 69 ± 0.9 years, range 18–97 years; 53% male) treated with mechanical thrombectomy for large vessel occlusion from January 2008 to March 2019. We collected data including demographics, NIH Stroke Scale (NIHSS) at onset, and (beginning in 2015) classified 90-day outcome by modified Rankin Scale (mRS). Patients were evaluated using a Stroke Preventability Score (SPS, 0 to 10 points) based on how well patients had been treated given their hypertension, hyperlipidemia, atrial fibrillation, and prior stroke history. We examined the relationship of SPS with NIHSS at stroke onset and with mRS outcome at 90 days.Results: SPS was calculated for 272 of the 300 patients, with mean ± SE of 2.1 ± 0.1 (range 0–8); 89 (33%) had no preventability (score 0), 120 (44%) had low preventability (score 1–3), and 63 (23%) had high preventability (score 4 or higher). SPS was significantly correlated with age (r = 0.32, p < 0.0001), while NIHSS (n = 267) was significantly higher (p = 0.03) for patients with high stroke preventability vs. low/no preventability [18.8 ± 0.92 (n = 62) vs. 16.5 ± 0.51 (n = 205)]. Among 118 patients with mRS, outcome was significantly worse (p = 0.04) in patients with high stroke preventability vs. low/no preventability [4.7 ± 0.29 (n = 28) vs. 3.8 ± 0.21 (n = 90)]. The vast majority of patients with high stroke preventability had inadequately treated atrial fibrillation (85%, 53/62).Conclusions: Nearly one quarter of stroke patients undergoing mechanical thrombectomy had highly preventable strokes. While stroke preventability showed some relationship to stroke severity at onset and outcome after treatment, preventability had the strongest association with age. These findings emphasize the need for improved stroke prevention in the elderly.

This paper explores the realities of facilitating online theatre criticism workshops in the time of COVID-19. Its author reminisces on teaching these workshops pre-COVID and speaks to the added challenges and unexpected successes of migrating them online to a larger base of participants.

Background:. More than 100,000 reduction mammaplasties are performed in the United States each year. There is large variance in reported incidence of cancerous/high-risk lesions, ranging from 0.06% to 4.6%. There has been debate whether histological review of breast reduction specimen is necessary. This study aimed to determine the incidence of cancerous/high-risk lesions and to evaluate risk factors for their occurrence. Methods:. A retrospective review was conducted for all patients who underwent reduction mammaplasty in 2018 by the senior author. Variables collected included demographics, comorbidities, history of breast surgery, family/personal history of breast cancer, weight of specimen, and pathologic findings. All specimens underwent pathologic evaluation and categorized as benign, proliferative, or malignant. Results. A total of 155 patients underwent 310 reduction mammaplasties. Pathologic evaluations found that 11 patients (7.1%) had positive findings, 9 (5.8%) had proliferative lesions, and 2 (1.29%) had cancerous lesions. Patients with pathology were older (P = 0.038), had a family history of breast cancer (P = 0.026), and had a greater weight of resected tissue (P = 0.005). Multivariable analysis showed family history of breast cancer (P = 0.001), prior breast surgery (P = 0.026), and greater weight of resected breast tissue (P = 0.008) had a higher likelihood of positive pathology. Conclusions:. These findings demonstrate an incidence of positive pathology higher than that reported and illustrate the importance of histologic review of breast reduction specimens. Family history of breast cancer, prior breast surgery, and a greater weight of resected tissue increase risk for proliferative/cancerous lesions.

Despite advances in our understanding of the molecular biology of the disease and improved therapeutics, lung cancer remains the most common cause of cancer-related deaths worldwide. Therefore, an unmet need remains for improved treatments, especially in advanced stage disease. Genomic instability is a universal hallmark of all cancers. Many of the most commonly prescribed chemotherapeutics, including platinum-based compounds such as cisplatin, target the characteristic genomic instability of tumors by directly damaging the DNA. Chemotherapies are designed to selectively target rapidly dividing cells, where they cause critical DNA damage and subsequent cell death (1, 2). Despite the initial efficacy of these drugs, the development of chemotherapy resistant tumors remains the primary concern for treatment of all lung cancer patients. The correct functioning of the DNA damage repair machinery is essential to ensure the maintenance of normal cycling cells. Dysregulation of these pathways promotes the accumulation of mutations which increase the potential of malignancy. Following the development of the initial malignancy, the continued disruption of the DNA repair machinery may result in the further progression of metastatic disease. Lung cancer is recognized as one of the most genomically unstable cancers (3). In this review, we present an overview of the DNA damage repair pathways and their contributions to lung cancer disease occurrence and progression. We conclude with an overview of current targeted lung cancer treatments and their evolution toward combination therapies, including chemotherapy with immunotherapies and antibody-drug conjugates and the mechanisms by which they target DNA damage repair pathways.

Thermography is a non-invasive method for measuring surface temperatures and may be a convenient way of identifying hypo/hyperthermic areas under a saddle that may be related to saddle pressures. A thermal camera quantified minimum/maximum/mean temperatures at specific locations (left/right) of the thoracic region at three-time points: (1) baseline; (2) post lunging; (3) post ridden exercise in eight non-lame sports horses ridden by the same rider. A Pliance (Novel) pressure mat determined the mean/peak saddle pressures (kPa) in the cranial and caudal regions. General linear mixed models with the horse as the random factor investigated the time point (fixed factor: baseline; lunge; ridden) and saddle fit (fixed factor: correct; wide; narrow) on thermal parameters with Bonferroni post hoc comparison. The saddle pressure data (grouped: saddle width) were assessed with an ANOVA and Tukey post hoc comparison (p ≤ 0.05). Differences between the saddle widths in the cranial/caudal mean (p = 0.05) and peak saddle pressures (p = 0.01) were found. The maximum temperatures increased post lunge (p ≤ 0.0001) and post ridden (p ≤ 0.0001) compared to the baseline. No difference between post lunge and post ridden exercise (all p ≥ 0.51) was found. The thermal activity does not appear to be representative of increased saddle pressure values. The sole use of thermal imaging for saddle fitting should be applied with caution.

The objective of this study was to assess the effectiveness of a stroke clinic in stroke prevention and progression of cerebral microbleeds (CMB). We conducted a retrospective observational study of patients who visited a stroke clinic between January 2011 and March 2017. Susceptibility-weighted imaging (SWI) MRI studies were obtained at baseline and follow-up visits to identify new infarctions and CMB progression. Patients with CMB who also underwent brain computed tomography (CT) imaging were identified and their cerebral arterial calcification was quantified to evaluate the relationship between the extent of intracranial calcification and CMB burden. A total of 64 stroke patients (mean age 73.1 ± 11.0, 47% males) had CMB on baseline and follow-up MRI studies. During a mean follow-up period of 22.6 months, four strokes occurred (4/64, 6%; 3 ischemic, 1 hemorrhagic), producing mild neurological deficit. Progression of CMB was observed in 54% of patients with two MRIs and was significantly associated with length of follow-up. Subjects with intracranial calcification score > 300 cm3 had higher CMB count than those with scores 3 at both baseline (12.6 ± 11.7 vs. 4.9 ± 2.2, p = 0.02) and follow-up (14.1 ± 11.8 vs. 5.6 ± 2.4, p = 0.03) MRI evaluations. Patients with CMB had a relatively benign overall clinical course. The association between CMB burden and intracranial calcification warrants further study.

BackgroundAnterior and posterior circulation atherosclerosis differ in vascular risk factors and stroke mechanisms. However, few studies have compared the pathological features between these lesions. Using a series of intracranial artery specimens, we characterized the intracranial atherosclerotic lesions and compared pathological features among different arteries of the intracranial vasculature.MethodsIntracranial large arteries of 32 consecutively recruited autopsy cases of Chinese adults aged 45 years or older were examined pathologically using routine histology and immunostaining, to characterize the pathological features of the atherosclerotic lesions. We analyzed middle cerebral arteries (MCAs) (both left and right), vertebral arteries (VAs) (side more affected), and basilar arteries (BAs).ResultsProgressive atherosclerotic lesions were present in 91(71%) of the 128 arteries examined. Features of complicated plaques were infrequently detected: plaque hemorrhage was encountered in 12%, neovasculature in 12%, lumen thrombi in 13%, macrophage infiltration in 20%, and calcification in 25% of arteries. Luminal narrowing of MCA was the most severe, followed by VA; the BA least stenotic (37 ± 25 vs. 30 ± 24 vs. 20 ± 20%, all p

BackgroundCerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of stroke. In addition to ischemic stroke, CADASIL predisposes to development of cerebral microbleeds (CMB). CMB and hypertension are known to be associated with intracerebral hemorrhage (ICH). The purpose of this study was to analyze the relationships among CMB, hypertension, and ICH in CADASIL.Materials and methodsWe enrolled 94 genetically confirmed CADASIL patients from 76 unrelated families at Jeju National University Hospital (Korea) between March 2012 and February 2015. We analyzed CMB presence, number, and distribution on susceptibility-weighted imaging MRI using the microbleed anatomical rating scale. Multiple logistic regression was used to determine factors associated with the presence of CMB and ICH.ResultsCMB were observed in 62 patients (66%), median number of CMB per patient was 4 (range 0–121). Twenty-two ICHs were found in 16 patients (17%). There was incongruence between the most common site of CMB (thalamus) and that of ICH (basal ganglia). Hypertension was independently associated with the presence of CMB (multiple regression OR, 2.71; 95% CI 1.02–7.18, p

This study evaluated the effect of saddle tree width on thoracolumbar and limb kinematics, saddle pressure distribution, and thoracolumbar epaxial musculature dimensions. Correctly fitted saddles were fitted by a Society of Master Saddler Qualified Saddle Fitter in fourteen sports horses (mean ± SD age 12 ± 8.77 years, height 1.65 ± 0.94 m), and were altered to one width fitting wider and narrower. Horses were equipped with skin markers, inertial measurement units, and a pressure mat beneath the saddle. Differences in saddle pressure distribution, as well as limb and thoracolumbosacral kinematics between saddle widths were investigated using a general linear model with Bonferroni adjusted alpha (p ≤ 0.05). Compared with the correct saddle width, in trot, in the wide saddle, an 8.5% increase in peak pressures was found in the cranial region of the saddle (p = 0.003), a 14% reduction in thoracolumbar dimensions at T13 (p = 0.02), and a 6% decrease in the T13 range of motion in the mediolateral direction (p = 0.02). In the narrow saddle, a 14% increase in peak pressures was found in the caudal region of the saddle (p = 0.01), an 8% decrease in the range of motion of T13 in the mediolateral direction (p = 0.004), and a 6% decrease in the vertical direction (p = 0.004) of T13. Compared with the correct saddle width, in canter, in the wide saddle, axial rotation decreased by 1% at T5 (p = 0.03) with an 5% increase at T13 (p = 0.04) and a 5% increase at L3 (p = 0.03). Peak pressures increased by 4% (p = 0.002) in the cranial region of the wide saddle. Altering the saddle fit had an effect on thoracolumbar kinematics and saddle pressure distribution; hence, correct saddle fit is essential to provide unhindered locomotion.

In November 2013, a group of international experts in animal research policy (n = 11) gathered in Vancouver, Canada, to discuss openness and accountability in animal research. The primary objective was to bring together participants from various jurisdictions (United States, Sweden, Australia, New Zealand, Germany, Canada and the United Kingdom) to share practices regarding the governance of animals used in research, testing and education, with emphasis on the governance process followed, the methods of community engagement, and the balance of openness versus confidentiality. During the forum, participants came to a broad consensus on the need for: (a) evidence-based metrics to allow a “virtuous feedback” system for evaluation and quality assurance of animal research, (b) the need for increased public access to information, together with opportunities for stakeholder dialogue about animal research, (c) a greater diversity of views to be represented on decision-making committees to allow for greater balance and (d) a standardized and robust ethical decision-making process that incorporates some sort of societal input. These recommendations encourage aspirations beyond merely imparting information and towards a genuine dialogue that represents a shared agenda surrounding laboratory animal use.

There has always been an intrinsically “hauntological” dimension to recorded music. But Derrida’s concept of hauntology has gained a new currency in the 21st century, when music has lost its sense of futurism, and succumbed to the pastiche- and retro-time of postmodernity. The emergence of a 21st century sonic hauntology is a sign that “white” culture can no longer escape the temporal disjunctions that have been constitutive of the Afrodiasporic experience since Africans were first abducted by slavers and projected from their own lifeworld into the abstract space-time of Capital. Time was always-already out of joint for the slave, and Afrofuturism and hauntology can now be heard as two versions of the same condition.

PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p

Despite extensive study, little is known about the origins of the mutualistic bacterial endosymbionts that inhabit approximately 10% of the world's insects. In this study, we characterized a novel opportunistic human pathogen, designated "strain HS," and found that it is a close relative of the insect endosymbiont Sodalis glossinidius. Our results indicate that ancestral relatives of strain HS have served as progenitors for the independent descent of Sodalis-allied endosymbionts found in several insect hosts. Comparative analyses indicate that the gene inventories of the insect endosymbionts were independently derived from a common ancestral template through a combination of irreversible degenerative changes. Our results provide compelling support for the notion that mutualists evolve from pathogenic progenitors. They also elucidate the role of degenerative evolutionary processes in shaping the gene inventories of symbiotic bacteria at a very early stage in these mutualistic associations.