Microbial exposure during early human development primes fetal immune cells.

The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.

Automatic Radar-Based Step Length Measurement in the Home for Older Adults Living with Frailty.

With an aging population, numerous assistive and monitoring technologies are under development to enable older adults to age in place. To facilitate aging in place, predicting risk factors such as falls and hospitalization and providing early interventions are important. Much of the work on ambient monitoring for risk prediction has centered on gait speed analysis, utilizing privacy-preserving sensors like radar. Despite compelling evidence that monitoring step length in addition to gait speed is crucial for predicting risk, radar-based methods have not explored step length measurement in the home. Furthermore, laboratory experiments on step length measurement using radars are limited to proof-of-concept studies with few healthy subjects. To address this gap, a radar-based step length measurement system for the home is proposed based on detection and tracking using a radar point cloud followed by Doppler speed profiling of the torso to obtain step lengths in the home. The proposed method was evaluated in a clinical environment involving 35 frail older adults to establish its validity. Additionally, the method was assessed in people's homes, with 21 frail older adults who had participated in the clinical assessment. The proposed radar-based step length measurement method was compared to the gold-standard Zeno Walkway Gait Analysis System, revealing a 4.5 cm/8.3% error in a clinical setting. Furthermore, it exhibited excellent reliability (ICC(2,k) = 0.91, 95% CI 0.82 to 0.96) in uncontrolled home settings. The method also proved accurate in uncontrolled home settings, as indicated by a strong consistency (ICC(3,k) = 0.81 (95% CI 0.53 to 0.92)) between home measurements and in-clinic assessments.

Modulation of Oxidative Stress and Inflammation in the Aged Lacrimal Gland.

Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2)-/- and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 months of age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1ß, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2-/- mice showed an increase in IL-1ß, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1ß and TNF-α mRNA transcripts, while decreasing the frequency of CD45+CD4+ cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.

"It just never ends": Childhood cancer survivors' perceived psychosocial impacts of recurrence and second cancer.

OBJECTIVES: Childhood cancer survivors are at risk of developing primary recurrences and new second cancers. Experiencing a recurrence and/or second cancer can be highly distressing for survivors and families. We aimed to understand the psychological impacts of experiencing a recurrence or second cancer and how this potentially influences survivors' engagement with survivorship care. METHODS: We invited childhood cancer survivors or their parents if survivors were ≤16 years of age from 11 tertiary pediatric oncology hospitals across Australia and New Zealand to complete interviews. We conducted a thematic analysis facilitated by NVivo12. RESULTS: We interviewed 21 participants of whom 16 had experienced a recurrence, 3 had a second cancer, and 2 had both a recurrence and second cancer. Participants reported that a recurrence/second cancer was a stressful sudden disruption to life, accompanied by strong feelings of uncertainty. Participants tended to be less aware of their second cancer risk than recurrence risk. Some participants reported feelings of anxiousness and despair, describing varying responses such as gratitude or avoidance. Participants shared that the fear of cancer recurrence either motivated them to adopt protective health behaviors or to avoid information and disengage from survivorship care. SIGNIFICANCE OF RESULTS: Some survivors and their parents have a poor understanding and expressed reluctance to receive information about their risk of second cancer and other treatment-related late effects. Improving the delivery of information about late effects to families may improve their engagement with survivorship care and surveillance, although care must be taken to balance information provision and survivors' anxieties about their future health.

Sulfate transport mutants affect hydrogen sulfide and sulfite production during alcoholic fermentation.

Hydrogen sulfide is a common wine fault, with a rotten-egg odour, which is directly related to yeast metabolism in response to nitrogen and sulfur availability. In grape juice, sulfate is the most abundant inorganic sulfur compound, which is taken up by yeast through two high-affinity sulfate transporters, Sul1p and Sul2p, and a low affinity transporter, Soa1p. Sulfate contributes to H2 S production under nitrogen limitation, by being reduced via the Sulfur Assimilation Pathway (SAP). Therefore, yeast strains with limited H2 S are highly desirable. We report on the use of toxic analogues of sulfate following ethyl methane sulfate treatment, to isolate six wine yeast mutants that produce no or reduced H2 S and SO2 during fermentation in synthetic and natural juice. Four amino acid substitutions (A99V, G380R, N588K and E856K) in Sul1p were found in all strains except D25-1 which had heterozygous alleles. Two changes were also identified in Sul2p (L268S and A470T). The Sul1p (G380R) and Sul2p (A470T) mutations were chosen for further investigation as these residues are conserved amongst SLC26 membrane proteins (including sulfate permeases). The mutations were introduced into EC1118 using Crispr cas9 technology and shown to reduce accumulation of H2 S and do not result in increased SO2 production during fermentation of model medium (chemically defined grape juice) or Riesling juice. The Sul1p (G380R) and Sul2p (A470T) mutations are newly reported as causal mutations. Our findings contribute to knowledge of the genetic basis of H2 S production as well as the potential use of these strains for winemaking and in yeast breeding programmes.

Approach to Tremor Disorders.

Tremor disorders are diverse and complex. Historical clues and examination features play a major role in diagnosing these disorders, but diagnosis can be challenging due to phenotypic overlap. Ancillary testing, such as neuroimaging or laboratory testing, is driven by the history and examination, and should be performed particularly when there are other neurological or systemic manifestations. The pathophysiology of tremor is not entirely understood, but likely involves multiple networks along with the cerebello-thalamo-cortical pathways. Treatment options include medications, botulinum toxin, surgery, and nonpharmacologic interventions utilizing physical and occupational therapies and assistive devices. Further work is needed in developing accurate diagnostic tests and better treatment options for tremor disorders.

Single molecule glycosylase studies with engineered 8-oxoguanine DNA damage sites show functional defects of a MUTYH polyposis variant.

Proper repair of oxidatively damaged DNA bases is essential to maintain genome stability. 8-Oxoguanine (7,8-dihydro-8-oxoguanine, 8-oxoG) is a dangerous DNA lesion because it can mispair with adenine (A) during replication resulting in guanine to thymine transversion mutations. MUTYH DNA glycosylase is responsible for recognizing and removing the adenine from 8-oxoG:adenine (8-oxoG:A) sites. Biallelic mutations in the MUTYH gene predispose individuals to MUTYH-associated polyposis (MAP), and the most commonly observed mutation in some MAP populations is Y165C. Tyr165 is a 'wedge' residue that intercalates into the DNA duplex in the lesion bound state. Here, we utilize single molecule fluorescence microscopy to visualize the real-time search behavior of Escherichia coli and Mus musculus MUTYH WT and wedge variant orthologs on DNA tightropes that contain 8-oxoG:A, 8-oxoG:cytosine, or apurinic product analog sites. We observe that MUTYH WT is able to efficiently find 8-oxoG:A damage and form highly stable bound complexes. In contrast, MUTYH Y150C shows decreased binding lifetimes on undamaged DNA and fails to form a stable lesion recognition complex at damage sites. These findings suggest that MUTYH does not rely upon the wedge residue for damage site recognition, but this residue stabilizes the lesion recognition complex.

Detection of OG:A Lesion Mispairs by MutY Relies on a Single His Residue and the 2-Amino Group of 8-Oxoguanine.

MutY glycosylase excises adenines misincorporated opposite the oxidatively damaged lesion, 8-oxo-7,8-dihydroguanine (OG), to initiate base excision repair and prevent G to T transversion mutations. Successful repair requires MutY recognition of the OG:A mispair amidst highly abundant and structurally similar undamaged DNA base pairs. Herein we use a combination of in vitro and bacterial cell repair assays with single-molecule fluorescence microscopy to demonstrate that both a C-terminal domain histidine residue and the 2-amino group of OG base are critical for MutY detection of OG:A sites. These studies are the first to directly link deficiencies in MutY lesion detection with incomplete cellular repair. These results suggest that defects in lesion detection of human MutY (MUTYH) variants may prove predictive of early-onset colorectal cancer known an MUTYH-associated polyposis. Furthermore, unveiling these specific molecular determinants for repair makes it possible to envision new MUTYH-specific cancer therapies.

Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome.

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

Evaluating the effectiveness of aquatic therapy on mobility, balance, and level of functional independence in stroke rehabilitation: a systematic review and meta-analysis.

OBJECTIVE: To meta-analyze and systematically review the effectiveness of aquatic therapy in improving mobility, balance, and functional independence after stroke. DATA SOURCES: Articles published in Medline, Embase, CINAHL, PsycINFO, and Scopus up to 20 August 2019. STUDY SELECTION: Studies met the following inclusion criteria: (1) English, (2) adult stroke population, (3) randomized or non-randomized prospectively controlled trial (RCT or PCT, respectively) study design, (4) the experimental group received >1 session of aquatic therapy, and (5) included a clinical outcome measure of mobility, balance, or functional independence. DATA EXTRACTION: Participant characteristics, treatment protocols, between-group outcomes, point measures, and measures of variability were extracted. Methodological quality was assessed using Physiotherapy Evidence Database (PEDro) tool, and pooled mean differences (MD) ± standard error and 95% confidence intervals (CI) were calculated for Functional Reach Test (FRT), Timed Up and Go Test (TUG), gait speed, and Berg Balance Scale (BBS). DATA SYNTHESIS: Nineteen studies (17 RCTs and 2 PCTs) with a mean sample size of 36 participants and mean PEDro score of 5.6 (range 4-8) were included. Aquatic therapy demonstrated statistically significant improvements over land therapy on FRT (MD = 3.511 ± 1.597; 95% CI: 0.381-6.642; P = 0.028), TUG (MD = 2.229 ± 0.513; 95% CI: 1.224-3.234; P < 0.001), gait speed (MD = 0.049 ± 0.023; 95% CI: 0.005-0.094; P = 0.030), and BBS (MD = 2.252 ± 0.552; 95% CI: 1.171-3.334; P < 0.001). CONCLUSIONS: While the effect of aquatic therapy on mobility and balance is statistically significant compared to land-based therapy, the clinical significance is less clear, highly variable, and outcome measure dependent.

Rapamycin Eyedrops Increased CD4+Foxp3+ Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface.

Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-γ, IL-12, CIITA and Ctss); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.

Comparative multi-scale hierarchical structure of the tail, plantaris, and Achilles tendons in the rat.

Rodent tendons are widely used to study human pathologies such as tendinopathy and repair, and to address fundamental physiological questions about development, growth, and remodeling. However, how the gross morphology and multi-scale hierarchical structure of rat tendons, such as the tail, plantaris, and Achilles tendons, compare with that of human tendons are unknown. In addition, there remains disagreement about terminology and definitions. Specifically, the definitions of fascicle and fiber are often dependent on diameter sizes, not their characteristic features, and these definitions impair the ability to compare hierarchical structure across species, where the sizes of the fiber and fascicle may change with animal size and tendon function. Thus, the objective of the study was to select a single species that is commonly used for tendon research (rat) and tendons with varying mechanical functions (tail, plantaris, Achilles) to evaluate the hierarchical structure at multiple length scales using histology, SEM, and confocal imaging. With the exception of the specialized rat tail tendon, we confirmed that in rat tendons there are no fascicles and the fiber is the largest subunit. In addition, we provided a structurally based definition of a fiber as a bundle of collagen fibrils that is surrounded by elongated cells, and this definition was supported by both histologically processed and unprocessed samples. In all rat tendons studied, the fiber diameters were consistently between 10 and 50 µm, and this diameter range appears to be conserved across larger species. Specific recommendations were made highlighting the strengths and limitations of each rat tendon as a research model. Understanding the hierarchical structure of tendon can advance the design and interpretation of experiments and development of tissue-engineered constructs.

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

AIMS: Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. METHODS AND RESULTS: Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. CONCLUSION: The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Intensity of chemotherapy for the initial management of newly diagnosed acute myeloid leukemia in older patients.

Aim: This study evaluated the overall survival (OS) of older patients (≥60 years) with acute myeloid leukemia based on the intensity of treatment. Methods: This single center, retrospective study included 211 patients diagnosed between 2000 and 2016, who received 10-day decitabine, low-intensity therapy or high-intensity therapy. Cox regression examined the impact of therapy on OS. Results: Younger patients were more likely to receive high-intensity therapy. Patients who received low-intensity therapy had worse OS compared with high-intensity therapy (median OS: 1.2 vs 8.5 months; p < 0.01). OS was similar with 10-day decitabine (median OS of 6.3 months) compared with either low-intensity therapy or high-intensity therapy. Conclusion: Ten-day decitabine is an effective alternative in older patients with newly diagnosed acute myeloid leukemia.

ST-elevation myocardial infarction in a migrant population: a registry-based study of patient treatment and outcomes.

BACKGROUND: Internationally, a growing number of studies has identified race-related disparities in the presentation, treatment and outcomes of patients with ST-elevation myocardial infarction (STEMI). With a large migrant population, Australia presents a unique microcosm in which to study the impact of migrant status and ethnicity in STEMI patients. AIM: To investigate if first-generation migrants differed in presentation, treatment or outcomes following STEMI compared with the Australian-born population. METHODS: We conducted a retrospective observational study using data from a clinician-initiated registry. The study involved 2154 patients who presented to 12 hospitals between 2004 and 2012. Our main outcome measures included time to reperfusion, 30-day mortality and complications. RESULTS: Migrants (n = 1035, 48.8%) were more likely to be older (61 vs 58 years, P < 0.001), diabetic (29.3 vs 21.5%, P < 0.001) and have a prolonged symptom to door time (102 vs 91 min, P = 0.04). Despite lower rates of previous known ischaemic heart disease (22.5 vs 26.6%, P = 0.03), migrants had more diffuse disease (triple vessel or left main (3VD/LM): 29.8 vs 22.0%, P < 0.001) and higher troponin values (3.77 vs 3.22 µg/L, P = 0.01). We found no significant differences in hospital treatment times, intervention types or rates. Multivariate regression identified age, diabetes, female gender and multi-vessel disease as predictors of complications and death at 30 days. CONCLUSIONS: Migrants had longer pre-hospital delays and exhibited different cardiovascular risk profiles than Australian-born patients but received comparable treatment in the acute hospital setting. Higher rates of diabetes and multi-vessel coronary artery disease were seen among migrant patients, indicating a relatively higher risk population.

Evaluating Plastic Deformation and Damage as Potential Mechanisms for Tendon Inelasticity Using a Reactive Modeling Framework.

Inelastic behaviors, such as softening, a progressive decrease in modulus before failure, occur in tendon and are important aspects in degeneration and tendinopathy. These inelastic behaviors are generally attributed to two potential mechanisms: plastic deformation and damage. However, it is not clear which is primarily responsible. In this study, we evaluated these potential mechanisms of tendon inelasticity by using a recently developed reactive inelasticity model (RIE), which is a structurally inspired continuum mechanics framework that models tissue inelasticity based on the molecular bond kinetics. Using RIE, we formulated two material models, one specific to plastic deformation and the other to damage. The models were independently fit to published macroscale experimental tensile tests of rat tail tendons. We quantified the inelastic effects and compared the performance of the two models in fitting the mechanical response during loading, relaxation, unloading, and reloading phases. Additionally, we validated the models by using the resulting fit parameters to predict an independent set of experimental stress-strain curves from ramp-to-failure tests. Overall, the models were both successful in fitting the experiments and predicting the validation data. However, the results did not strongly favor one mechanism over the other. As a result, to distinguish between plastic deformation and damage, different experimental protocols will be needed. Nevertheless, these findings suggest the potential of RIE as a comprehensive framework for studying tendon inelastic behaviors.

HEMATOLOGY AND SERUM BIOCHEMISTRY VALUES OF THE RED PANDA SUBSPECIES ( AILURUS FULGENS STYANI).

Health evaluations were conducted on individuals ( n = 62, age < 1 to 11 yr) from a captive red panda ( Ailurus fulgens styani) population at the Chengdu Research Base for Giant Panda Breeding in Sichuan Province, People's Republic of China. Individuals were anesthetized using combinations of ketamine, dexmedetomidine, diazepam, isoflurane, and tiletamine/zolazepam. Whereas physical exams revealed no abnormalities for 40% of red pandas, 24% had dental abnormalities and 18% had orthopedic abnormalities. As the red panda is the only member of the family Ailuridae, complete blood count and serum biochemistry samples were collected and used to develop reference intervals for this species. When hematologic and serum chemistry values of male and female red pandas were compared within this A. f. styani population, males had higher mean cell hemoglobin, mean cell hemoglobin concentration, and blood urea nitrogen concentrations, whereas females had higher alkaline phosphatase, cholesterol, and iron. Adult red pandas (≥2 yr) had higher lymphocyte percentage, total protein, globulin, and chloride levels, whereas juveniles (<2 yr) had higher white blood cell concentrations, neutrophil percentage and absolute neutrophil values, alkaline phosphatase, creatine kinase, cholesterol, potassium, total and ionized calcium, and phosphorus levels. Reference values and expected age and sex differences will assist with health management of the captive A. f. styani population.

Sex differences in neuromuscular function after repeated eccentric contractions of the knee extensor muscles.

PURPOSE: This study examined the mechanisms for force and power reduction during and up to 48 h after maximal eccentric contractions of the knee extensor muscles in young men and women. METHODS: 13 men (22.8 ± 2.6 years) and 13 women (21.6 ± 2.2 years) performed 150 maximal effort eccentric contractions (5 sets of 30) with the knee extensor muscles at 60° s-1. Maximal voluntary isometric contractions (MVIC) and maximal voluntary concentric contractions (MVCC) were performed before and after the 150 eccentric contractions. The MVCCs involved a set of two isokinetic contractions at 60° s-1 and sets of isotonic contractions performed at seven different resistance loads (1 N m, 10, 20, 30, 40, 50, and 60% MVIC). Electrical stimulation was used during the MVICs and at rest to determine changes in voluntary activation and contractile properties. RESULTS: At baseline, men were stronger than women (MVIC: 276 ± 48 vs. 133 ± 37 N m) and more powerful (MVCC: 649 ± 77 vs. 346 ± 78 W). At termination of the eccentric contractions, voluntary activation, resting twitch amplitude, and peak power during concentric contractions at the seven loads and at 60° s-1 decreased (P < 0.05) similarly in the men and women. At 48 h post-exercise, the MVIC torque, power (for loads ≥20-60% MVIC), and voluntary activation remained depressed (P < 0.05), but the resting twitch had returned to baseline (P > 0.05) with no sex differences. CONCLUSION: Central mechanisms were primarily responsible for the depressed maximal force production up to 48 h after repeated eccentric contractions of the knee extensors and these mechanisms were similar in men and women.

Depression of home cage wheel running: a reliable and clinically relevant method to assess migraine pain in rats.

BACKGROUND: The development of new anti-migraine treatments is limited by the difficulty inassessing migraine pain in laboratory animals. Depression of activity is one of the few diagnostic criteria formigraine that can be mimicked in rats. The goal of the present study was to test the hypothesis thatdepression of home cage wheel running is a reliable and clinically relevant method to assess migraine painin rats. METHODS: Adult female rats were implanted with a cannula to inject allyl isothiocyanate (AITC) onto the dura to induce migraine pain, as has been shown before. Rats recovered from implantation surgery for 8 days in cages containing a running wheel. Home cage wheel running was recorded 23 h a day. AITC and the migraine medication sumatriptan were administered in the hour prior to onset of the dark phase. RESULTS: Administration of AITC caused a concentration-dependent decrease in wheel running that lasted 3 h. The duration and magnitude of AITC-induced depression of wheel running was consistent following three repeated injections spaced 48 h apart. Administration of sumatriptan attenuated AITC-induced depressionof wheel running when a large dose (1 mg/kg) was administered immediately following AITC administration. Wheel running patterns did not change when sumatriptan was given to naïve rats. CONCLUSIONS: These data indicate that home cage wheel running is a sensitive, reliable, and clinically relevant method to assess migraine pain in the rat.

Premature ventricular contraction-induced cardiomyopathy.

PURPOSE OF REVIEW: There has been a resurgent interest in frequent premature ventricular contractions (PVCs) led by the novel concept that they may be a potential cause of, or at least contribute to, cardiomyopathy. This review evaluates recent advances in our understanding of PVC-induced cardiomyopathy. RECENT FINDINGS: Recent studies have focused on identifying the predictors of PVC-induced cardiomyopathy, with the most consistent predictors being PVC burden and PVC QRS duration. Multiple studies have investigated the effect of catheter ablation on PVC burden and resultant left ventricular function, with the efficacy of catheter ablation and the overall PVC response rates varying between 60 and 88%. After successful ablation, the rates of improvement in left ventricular ejection fraction have varied between 47 and 100%. A recent study raises the question that perhaps even a lower PVC burden could result in PVC cardiomyopathy and adverse outcomes. SUMMARY: There is an increasing body of literature supporting a causal role of frequent PVCs in the development of left ventricular dysfunction. Effective therapy for PVCs exists; however, the optimal indications for therapy have yet to be determined.