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1.  Trends in Bronchiolitis Hospitalizations in the United States, 2000–2009 
Pediatrics  2013;132(1):28-36.
To examine temporal trend in the national incidence of bronchiolitis hospitalizations, use of mechanical ventilation, and hospital charges between 2000 and 2009.
We performed a serial, cross-sectional analysis of a nationally representative sample of children hospitalized with bronchiolitis. The Kids Inpatient Database was used to identify children <2 years of age with bronchiolitis by International Classification of Diseases, Ninth Revision, Clinical Modification code 466.1. Primary outcome measures were incidence of bronchiolitis hospitalizations, mechanical ventilation (noninvasive or invasive) use, and hospital charges. Temporal trends were evaluated accounting for sampling weights.
The 4 separated years (2000, 2003, 2006, and 2009) of national discharge data included 544 828 weighted discharges with bronchiolitis. Between 2000 and 2009, the incidence of bronchiolitis hospitalization decreased from 17.9 to 14.9 per 1000 person-years among all US children aged <2 years (17% decrease; Ptrend < .001). By contrast, there was an increase in children with high-risk medical conditions (5.9%–7.9%; 34% increase; Ptrend < .001) and use of mechanical ventilation (1.9%–2.3%; 21% increase; Ptrend = .008). Nationwide hospital charges increased from $1.34 billion to $1.73 billion (30% increase; Ptrend < .001); this increase was driven by a rise in the geometric mean of hospital charges per case from $6380 to $8530 (34% increase; Ptrend < .001).
Between 2000 and 2009, we found a significant decline in bronchiolitis hospitalizations among US children. By contrast, use of mechanical ventilation and hospital charges for bronchiolitis significantly increased over this same period.
PMCID: PMC3691534  PMID: 23733801
bronchiolitis; trends; hospitalization; incidence; mortality; hospital charge
2.  Comparison of Human Papillomavirus Detections in Urine, Vulvar, and Cervical Samples from Women Attending a Colposcopy Clinic 
Journal of Clinical Microbiology  2014;52(1):187-192.
While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.
PMCID: PMC3911475  PMID: 24197879
3.  The Anorectic Actions of the TGFβ Cytokine MIC-1/GDF15 Require an Intact Brainstem Area Postrema and Nucleus of the Solitary Tract 
PLoS ONE  2014;9(6):e100370.
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.
PMCID: PMC4074070  PMID: 24971956
4.  Norepinephrine Potentiates Proinflammatory Responses of Human Vaginal Epithelial Cells 
Journal of neuroimmunology  2013;259(0):8-16.
The vaginal epithelium provides a barrier to pathogens and recruits immune defenses through the secretion of cytokines and chemokines. Several studies have shown that mucosal sites are innervated by norepinephrine-containing nerve fibers. Here we report that norepinephrine potentiates the proinflammatory response of human vaginal epithelial cells to products produced by Staphylococcus aureus, a pathogen that causes menstrual toxic shock syndrome. The cells exhibit immunoreactivity for catecholamine synthesis enzymes and the norepinephrine transporter. Moreover, the cells secrete norepinephrine and dopamine at low concentrations. These results indicate that norepinephrine may serve as an autocrine modulator of proinflammatory responses in the vaginal epithelium.
PMCID: PMC3654033  PMID: 23571017
Norepinephrine; catecholamine; epithelium; superantigens; toxic shock syndrome; Staphylococcus aureus
5.  Left Ventricular Remodeling and Improvement in Diastolic Function after Balloon Aortic Valvuloplasty for Congenital Aortic Stenosis 
In congenital aortic stenosis (AS) chronic pressure load has detrimental effects on left ventricular (LV) systolic and diastolic function. Reduction in LV pressure load with balloon aortic valvuloplasty (BAVP) may improve diastolic function.
Methods and Results
Echocardiographic and catheterization data for 25 consecutive patients undergoing BAVP for congenital AS were retrospectively analyzed. Median age at BAVP was 11.5 years (3.2–40.1). LV end-diastolic pressure (EDP) pressure was elevated (≥ 15 mm Hg) in 72% of patients with a median of 17 mm Hg (range: 9–24). With BAVP, median AS gradient was reduced from 63 mm Hg (44–105) to 30 mm Hg (10–43). Aortic regurgitation (AR) increased from trivial (none to mild) to mild (trivial - moderate). Pre-BAVP early diastolic mitral inflow velocity/tissue Doppler early diastolic velocity (E/E') correlated with LVEDP (r= 0.52, p=0.007). On follow up echocardiogram (median 11 months post-BAVP), AS gradient was lower (p<0.001) and degree of AR was higher (P=0.01) compared to pre-BAVP echocardiograms. LV end-diastolic volume z-score increased (p=0.02), LV mass was unchanged, and LV mass: volume decreased (p=0.002). Mitral annular and septal E' (p<0.001) were higher and E/E' was lower post-dilation (10.8 vs. 14.2, p<0.001). Lower pre-BAVP E/E' and lower pre-BAVP LV mass z-score were associated with lower post-BAVP E/E'.
After BAVP, LV remodeling characterized by an increase in EDV and decrease in LV mass: volume occurs and echocardiographic measures of diastolic function and LVEDP improve in most patients. Risk factors for persistent diastolic dysfunction include higher pre-BAVP LV mass z-score and worse pre-BAVP diastolic function.
PMCID: PMC4030434  PMID: 22739787
congenital heart disease; aortic stenosis; balloon aortic valvuloplasty; diastolic function
6.  Poldip2 Knockout Results in Perinatal Lethality, Reduced Cellular Growth and Increased Autophagy of Mouse Embryonic Fibroblasts 
PLoS ONE  2014;9(5):e96657.
Polymerase-δ interacting protein 2 (Poldip2) is an understudied protein, originally described as a binding partner of polymerase delta and proliferating cell nuclear antigen (PCNA). Numerous roles for Poldip2 have been proposed, including mitochondrial elongation, DNA replication/repair and ROS production via Nox4. In this study, we have identified a novel role for Poldip2 in regulating the cell cycle. We used a Poldip2 gene-trap mouse and found that homozygous animals die around the time of birth. Poldip2−/− embryos are significantly smaller than wild type or heterozygous embryos. We found that Poldip2−/− mouse embryonic fibroblasts (MEFs) exhibit reduced growth as measured by population doubling and growth curves. This effect is not due to apoptosis or senescence; however, Poldip2−/− MEFs have higher levels of the autophagy marker LC3b. Measurement of DNA content by flow cytometry revealed an increase in the percentage of Poldip2−/− cells in the G1 and G2/M phases of the cell cycle, accompanied by a decrease in the percentage of S-phase cells. Increases in p53 S20 and Sirt1 were observed in passage 2 Poldip2−/− MEFs. In passage 4/5 MEFs, Cdk1 and CyclinA2 are downregulated in Poldip2−/− cells, and these changes are reversed by transfection with SV40 large T-antigen, suggesting that Poldip2 may target the E2F pathway. In contrast, p21CIP1 is increased in passage 4/5 Poldip2−/− MEFs and its expression is unaffected by SV40 transfection. Overall, these results reveal that Poldip2 is an essential protein in development, and underline its importance in cell viability and proliferation. Because it affects the cell cycle, Poldip2 is a potential novel target for treating proliferative conditions such as cancer, atherosclerosis and restenosis.
PMCID: PMC4010529  PMID: 24797518
7.  Amyloid-β and Proinflammatory Cytokines Utilize a Prion Protein-Dependent Pathway to Activate NADPH Oxidase and Induce Cofilin-Actin Rods in Hippocampal Neurons 
PLoS ONE  2014;9(4):e95995.
Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1∶1 cofilin∶actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5–30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ∼6 h) occurs in a subpopulation (∼20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Aβd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrPC is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrPC-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrPC-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
PMCID: PMC3997518  PMID: 24760020
8.  Foot force direction control during a pedaling task in individuals post-stroke 
Appropriate magnitude and directional control of foot-forces is required for successful execution of locomotor tasks. Earlier evidence suggested, following stroke, there is a potential impairment in foot-force control capabilities both during stationary force generation and locomotion. The purpose of this study was to investigate the foot-pedal surface interaction force components, in non-neurologically-impaired and stroke-impaired individuals, in order to determine how fore/aft shear-directed foot/pedal forces are controlled.
Sixteen individuals with chronic post-stroke hemiplegia and 10 age-similar non-neurologically-impaired controls performed a foot placement maintenance task under a stationary and a pedaling condition, achieving a target normal pedal force. Electromyography and force profiles were recorded. We expected generation of unduly large magnitude shear pedal forces and reduced participation of multiple muscles that can contribute forces in appropriate directions in individuals post-stroke.
We found lower force output, inconsistent modulation of muscle activity and reduced ability to change foot force direction in the paretic limbs, but we did not observe unduly large magnitude shear pedal surface forces by the paretic limbs as we hypothesized.
These findings suggested the preservation of foot-force control capabilities post-stroke under minimal upright postural control requirements. Further research must be conducted to determine whether inappropriate shear force generation will be revealed under non-seated, postural demanding conditions, where subjects have to actively control for upright body suspension.
PMCID: PMC3996495  PMID: 24739234
Stroke; Locomotion; Force control; Muscle activity; Pedaling
9.  Frequent utilization of the emergency department for acute exacerbation of chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):40.
Little is known about patients who frequently visit the emergency department (ED) for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We aimed to quantify the proportion and characteristics of patients with frequent ED visits for AECOPD and associated healthcare utilization.
We conducted a retrospective cohort study of adults aged ≥40 years with at least one ED visit for AECOPD between 2010 and 2011, derived from population-based all-payer data of State ED and Inpatient Databases for two large and diverse states: California and Florida. Outcome measures were frequency of ED visits for AECOPD, 30-day ED revisits, subsequent hospitalizations, near-fatal events (AECOPD involving mechanical ventilation), and charges for both ED and inpatient services (available only for Florida) during the year after the first ED visit.
The analytic cohort comprised 98,280 unique patients with 154,736 ED visits for AECOPD. During the 1-year period, 29.4% (95% CI, 29.1%-29.7%) of the patients had two or more (frequent) visits, accounting for 55.2% (95% CI, 54.9%-55.4%) of all ED visits for AECOPD. In the multivariable model, significant predictors of frequent ED visits were age 55–74 years (vs. 40–54 years), male sex, non-Hispanic white or black race, Medicaid insurance (vs. private), and lower median household income (all P < 0.001). At the visit-level, 12.3% of ED visits for AECOPD were 30-day revisit events (95% CI, 12.1%-12.4%). Additionally, 62.8% of ED visits for AECOPD (95% CI, 62.6%-63.0%) resulted in a hospitalization; patients with frequent ED visits comprised 55.5% (95% CI, 55.2%-55.8%) of all hospitalizations. Furthermore, 7.3% (95% CI, 7.3%-7.5%) of ED visits for AECOPD led to a near-fatal event; patients with frequent ED visits accounted for 64.4% (95% CI, 63.5%-65.3%) of all near-fatal events. Total charges for AECOPD were $1.94 billion (95% CI, $1.90-1.97 billion) in Florida; patients with frequent ED visits accounted for $1.07 billion (95% CI, $1.04-1.09 billion).
In this large cohort study, we found that 29% had frequent ED visits for AECOPD and that lower socioeconomic status was significantly associated with a higher frequency of ED visits. Individuals with frequent ED visits for AECOPD accounted for a substantial amount of healthcare utilization and financial burden.
PMCID: PMC3997196  PMID: 24717062
Chronic obstructive pulmonary disease; Exacerbation; Recurrence; Epidemiology; Emergency service; Hospitalization; Mechanical ventilation; Cost; Healthcare utilization
10.  In vivo efficacy of enabling formulations based on hydroxypropyl-β-cyclodextrins, micellar preparation and liposomes for the lipophilic cannabinoid CB2 agonist, MDA7. 
Journal of pharmaceutical sciences  2012;102(2):352-364.
Enabling formulation based on hydroxypropyl-β-cyclodextrins (HPβCD), micellar preparation and liposomes have been designed to deliver the racemic mixture of a lipophilic CB2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPβCD was determined by continuous variation plot, ESI-MS analysis, phase solubility and NMR studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by DLS and TEM show the presence of a homogenous population of closed round-shaped oligolamellar MDA7 containing-liposomes, with average size of 117nm [polydispersity index (PDI) <0.1]. Monodisperse micelles exhibited average size of 15 nm (PDI 0.1). HPβCD based formulation administrated in vivo was composed of two discrete particles populations with a narrow size distribution of 3 nm (PDI<0.1) and 510 nm (PDI<0.1). HPβCD based formulation dramatically improved antiallodynic effect of MDA7 in comparison to the liposomes preparation. Through inclusion complexation and possibly formation of aggregates, HPβCD can enhance the aqueous solubility of lipophilic drugs thereby improving their bioavailability for i.v. administration.
PMCID: PMC3981967  PMID: 23192786
Chirality; Complexation; Cyclodextrins; Micelle; Bioavailability; CNS; Liposomes
11.  Diagnosis, management and post-mortem findings of a human case of rabies imported into the United Kingdom from India: a case report 
Virology Journal  2014;11:63.
Human rabies infection continues to be a significant public health burden globally, and is occasionally imported to high income settings where the Milwaukee Protocol for intensive care management has recently been employed, with limited success in improving survival. Access to molecular diagnostics, pre- and post-mortem, and documentation of pathophysiological responses while using the Milwaukee protocol, can add useful insights for the future of rabies management.
Case presentation
A 58-year-old British Asian woman was referred to a regional general hospital in the UK with hydrophobia, anxiety and confusion nine weeks after receiving a dog bite in North West India. Nuchal skin biopsy, saliva, and a skin biopsy from the site of the dog bite wound, taken on the day of admission, all demonstrated the presence of rabies virus RNA. Within 48 hours sequence analysis of viral RNA confirmed the diagnosis and demonstrated that the virus was a strain closely related to canine rabies viruses circulating in South Asia. Her condition deteriorated rapidly with increased agitation and autonomic dysfunction. She was heavily sedated and intubated on the day after admission, treated according to a modified Milwaukee protocol, and remained stable until she developed heart block and profound acidosis and died on the eighth day. Analysis of autopsy samples showed a complete absence of rabies neutralizing antibody in cerebrospinal fluid and serum, and corresponding high levels of virus antigen and nucleic acid in brain and cerebrospinal fluid. Quantitative PCR showed virus was also distributed widely in peripheral tissues despite mild or undetectable histopathological changes. Vagus nerve branches in the heart showed neuritis, a probable Negri body but no demonstrable rabies antigen.
Rapid molecular diagnosis and strain typing is helpful in the management of human rabies infection. Post-mortem findings such as vagal neuritis highlight clinically important effects on the cardiovascular system which are typical for the clinical course of rabies in humans. Management guided by the Milwaukee protocol is feasible within well-resourced intensive care units, but its role in improving outcome for canine-derived rabies remains theoretical.
PMCID: PMC3977668  PMID: 24708671
Rabies; Milwaukee protocol; Diagnosis
12.  Evaluating a novel panel of sperm function tests for utility in predicting intracytoplasmic sperm injection (ICSI) outcome 
The objective of this study was to evaluate a panel of three sperm function tests; tests known to assess different aspects of sperm functionality and genomic integrity, the: 1) Sperm DNA Accelerated Decondensation (SDADTM) Test, 2) Sperm DNA Decondensation (SDDTM) Test, and 3) Sperm Penetration Assay (SPA), determining if positive and negative test scores correlated with failed and successful ICSI outcomes, respectfully.
A prospective, double blinded, cohort study was performed. One study sample (ejaculated semen) was collected by each of the 60 male partners of the 60 couples enrolled in the study; males whose female partners were found to have no major female factor issues. The sperm from each male was analyzed in the SPA, and SDAD and SDD Tests, and used for ICSI (1 ICSI cycle per couple).
The ICSI cycle pregnancy rate for this study was 50 %, with a delivery rate = 40 % (n = 60 ICSI cycles). The SPA and SDD Test scores did not significantly predict ICSI outcome when used as stand-alone tests (p> > 0.05). However, when the SPA and SDD Test scores were used together, ICSI outcomes for a subgroup of 10 (16.7 %) males, were significantly predicted (p = 0.03), with 1 live birth, and 9 negatives where the transferred embryos did not implant. In total, 38.4 % of the couples in this study were found to have a very poor chance for a successful ICSI cycle.
SDAD Test scores alone, and SPA and SDD Test scores used together, significantly predicted failed ICSI outcomes. This indicates that the scores obtained when analyzing patients’ sperm using a panel of sperm function tests; specifically, the SPA, and SDAD and SDD Tests, can be used to identify infertile couples who should not be directed to ICSI.
PMCID: PMC3644129  PMID: 23526053
Sperm function testing; DNA integrity testing; Sperm Penetration Assay (SPA); Sperm DNA Accelerated Decondensation (SDAD) Test; Sperm DNA Decondensation (SDD) Test; Intracytoplasmic Sperm Injection (ICSI); Assisted Reproductive Technology (ART)
13.  Criteria for Identifying and Evaluating Candidate Sites for Open-Field Trials of Genetically Engineered Mosquitoes 
Recent laboratory successes in the development of genetically engineered mosquitoes for controlling pathogen transmission have fostered the need for standardized procedures for advancing the technical achievements to practical tools. It is incumbent in many cases for the same scientists doing the in-laboratory discovery research to also take on the initial challenges of developing the pathway that will move the technologies to the field. One of these challenges is having a set of criteria for selecting collaborators and sites for efficacy and safety field trials that combine rigorous science with good ethical and legal practices. Specific site-selection criteria were developed in four categories—Scientific, Regulatory, Community Engagement, and Resources—in anticipation of open-field releases of a transgenic mosquito strain designed to suppress populations of the dengue vector mosquito, Aedes aegypti. The criteria are derived from previous published material, discussions, and personal experiences with the expectation of providing guidance to laboratory scientists for addressing the conceptual and operational considerations for identifying partner researchers and countries with whom to collaborate. These criteria are not intended to be prescriptive nor can they be applied to every circumstance where genetic approaches are proposed for deployment. However, we encourage those involved in the discovery phase of research to consider each criterion during project planning activities, and where appropriate, incorporate them into a “go/no-go” decision-making process for further development and testing of the technologies.
PMCID: PMC3993056  PMID: 24689963
Genetic control; Open-release; Transgenic mosquito; Field trial; Community engagement; GMO regulation
14.  Lower Extremity Passive Range of Motion in Community-Ambulating Stroke Survivors 
Physical therapists may prescribe stretching exercises for individuals with stroke to improve joint integrity and to reduce the risk of secondary musculoskeletal impairment. While deficits in passive range of motion (PROM) exist in stroke survivors with severe hemiparesis and spasticity, the extent to which impaired lower extremity PROM occurs in community-ambulating stroke survivors remains unclear. This study compared lower extremity PROM in able-bodied individuals and independent community-ambulatory stroke survivors with residual stroke-related neuromuscular impairments. Our hypothesis was that the stroke group would show decreased lower extremity PROM in the paretic but not the nonparetic side and that decreased PROM would be associated with increased muscle stiffness and decreased muscle length.
Individuals with chronic poststroke hemiparesis who reported the ability to ambulate independently in the community (n = 17) and age-matched control subjects (n = 15) participated. PROM during slow (5 degrees/sec) hip extension, hip flexion, and ankle dorsiflexion was examined bilaterally using a dynamometer that measured joint position and torque. The maximum angular position of the joint (ANGmax), torque required to achieve ANGmax (Tmax), and mean joint stiffness (K) were measured. Comparisons were made between able-bodied and paretic and able-bodied and nonparetic limbs.
Contrary to our expectations, between-group differences in ANGmax were observed only during hip extension in which ANGmax was greater bilaterally in people post-stroke compared to control subjects (P ≤ 0.05; stroke = 13 degrees, able-bodied = −1 degree). Tmax, but not K, was also significantly higher during passive hip extension in paretic and nonparetic limbs compared to control limbs (P ≤ 0.05; stroke = 40 Nm, able-bodied = 29 Nm). Compared to the control group, Tmax was increased during hip flexion in the paretic and nonparetic limbs of post-stroke subjects (P ≤ 0.05, stroke = 25 Nm, able-bodied = 18 Nm). K in the nonparetic leg was also increased during hip flexion (P ≤ 0.05, nonparetic = 0.52 Nm/degree, able-bodied = 0.37 Nm/degree.)
This study demonstrates that community-ambulating stroke survivors with residual neuromuscular impairments do not have decreased lower extremity PROM caused by increased muscle stiffness or decreased muscle length. In fact, the population of stroke survivors examined here appears to have more hip extension PROM than age-matched able-bodied individuals. The clinical implications of these data are important and suggest that lower extremity PROM may not interfere with mobility in community-ambulating stroke survivors. Hence, physical therapists may choose to recommend activities other than stretching exercises for stroke survivors who are or will become independent community ambulators.
PMCID: PMC3963266  PMID: 18463552
cerebral vascular accident (CVA); hemiparesis; muscle; range of motion (ROM); spasticity
16.  AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists 
Nature neuroscience  2003;6(6):564-571.
M-type (KCNQ2/3) potassium channels are suppressed by activation of Gq/11-coupled receptors, thereby increasing neuronal excitability. We show here that rat KCNQ2 can bind directly to the multivalent A-kinase-anchoring protein AKAP150. Peptides that block AKAP150 binding to the KCNQ2 channel complex antagonize the muscarinic inhibition of the currents. A mutant form of AKAP150, AKAP(ΔA), which is unable to bind protein kinase C (PKC), also attenuates the agonist-induced current suppression. Analysis of recombinant KCNQ2 channels suggests that targeting of PKC through association with AKAP150 is important for the inhibition. Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(ΔA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. Our data indicate that AKAP150-bound PKC participates in receptor-induced inhibition of the M-current.
PMCID: PMC3941299  PMID: 12754513
17.  Chronic Angiotensin-II Treatment Potentiates HR Slowing in Sprague-Dawley Rat during Acute Behavioral Stress5 
This study examined the effect of two-weeks infusion of angiotensin-II (Ang-II; 175 ng/kg/min) via minipump in rats (n=7) upon the mean arterial blood pressure (mBP) and heart rate (HR) response to an acute stress as compared to rats infused with saline (n=7). The acute stress was produced by a classical aversive conditioning paradigm: a 15 sec. tone (CS+) followed by a half second tail shock. Baseline mBP in Ang-II infused rats (167.7 ± 21.3 mm Hg; mean ± SD) significantly exceeded that of controls (127.6 ± 13.5 mm Hg). Conversely, baseline HR in the Ang-II infused rats (348 ± 33) was significantly lower than controls (384 ± 19 bpm). The magnitude of the mBP increase during CS+ did not differ between groups, but the HR slowing during CS+ in the Ang-II infused rats (−13.2 ± 8.9 bpm) was significantly greater than that seen in controls (−4.2 ± 5.5 bpm). This augmented bradycardia may be inferentially attributed to an accentuated increase in cardiac parasympathetic activity during CS+ in the Ang-II infused rats. The mBP increased above baseline immediately post-shock delivery in controls, but fell in the Ang-II infused rats, perhaps because of a ‘ceiling effect’ in total vascular resistance. This classical conditioning model of ‘acute stress’ differs from most stress paradigms in rats in yielding a HR slowing concomitant with a pressor response, and this slowing is potentiated by Ang-II.
PMCID: PMC3595344  PMID: 23317537
classical Pavlovian conditioning; anxiety; hypertension; renin angiotensin system (RAS)
18.  Immune cell trafficking from the brain maintains CNS immune tolerance 
The Journal of Clinical Investigation  2014;124(3):1228-1241.
In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.
PMCID: PMC3934177  PMID: 24569378
19.  Emergence of the GII-4 Norovirus Sydney2012 Strain in England, Winter 2012–2013 
PLoS ONE  2014;9(2):e88978.
Norovirus is the commonest cause of acute gastrointestinal disease and is the main aetiological agent of outbreaks of gastroenteritis, particularly in semi-closed environments. Norovirus infections in England typically peak between December and March each year. The most commonly detected norovirus strains belong to the genetically diverse genogroup-II genotype-4 (GII-4) genocluster and in the previous two norovirus winter seasons the majority of GII-4 strains in circulation worldwide have been genetically similar to the GII-4 strain New Orleans 1805/2009/USA. At the beginning of the 2012/13 season a genetically distinct GII-4 strain (Sydney 2012/NSW0514/2012/AU) was described which emerged worldwide during the winter of 2012/13. Here we describe the emergence of norovirus strains genetically related to Sydney2012 in England during the 2012/13 season to replace NewOrleans2009 strains as the most commonly detected variant of GII-4 norovirus in England. Furthermore, we demonstrate that whilst the emergence of Sydney2012 coincided with an early peak in the number of norovirus outbreaks, there was not an overall increase in norovirus activity compared to the previous season. Finally, we show that the Sydney2012 strain is associated with distinct genetic changes compared to the NewOrleans2009 strain, and these changes may have contributed to the emergence of the Sydney2012 strain.
PMCID: PMC3923861  PMID: 24551201
20.  Direction-Dependent Phasing of Locomotor Muscle Activity Is Altered Post-Stroke 
Journal of neurophysiology  2004;92(4):2207-2216.
A major contributor to impaired locomotion post-stroke is abnormal phasing of muscle activity. While inappropriate paretic muscle phasing adapts to changing body orientation, load, and speed, it remains unclear whether paretic muscle phasing adapts to reversal of locomotor direction. We examined muscle phasing in backward pedaling, a task that requires shifts in biarticular but not uniarticular muscle phasing relative to forward pedaling. We hypothesized that if paretic and neurologically intact muscle phasing adapt similarly, then paretic biarticular but not paretic uniarticular muscles would shift phasing in backward pedaling. Paretic and neurologically intact individuals pedaled forward and backward while recording electromyograms (EMGs) from vastus medialis (VM), soleus (SOL), rectus femoris (RF), semimembranosus (SM), and biceps femoris (BF). Changes in muscle phasing were assessed by comparing the probability of muscle activity in forward and backward pedaling throughout 18 pedaling cycles. Paretic uniarticular muscles (VM and SOL) showed phase-advanced activity in backward versus forward pedaling, whereas the corresponding neurologically intact muscles showed little to no phasing change. Paretic biarticular muscles were less likely than neurologically intact biarticular muscles to display phasing changes in backward pedaling. Paretic RF displayed no phase change during backward pedaling, and paretic BF displayed no consistent adaptation to backward pedaling. Paretic SM was the only muscle to display backward/forward phase changes that were similar to the neurologically intact group. We conclude that paretic uniarticular muscles are more susceptible and paretic biarticular muscles are less susceptible to direction-dependent phase shifts, consistent with altered sensory integration and impaired cortical control of locomotion.
PMCID: PMC3912995  PMID: 15175363
21.  Left Ventricular Diastolic Function in Children and Young Adults with Congenital Aortic Valve Disease 
The American journal of cardiology  2012;111(2):243-249.
Young patients with congenital aortic valve disease are at risk for left ventricular (LV) diastolic dysfunction (DD). We evaluated LV remodeling and prevalence of and risk factors for DD in patients with aortic stenosis (AS), pure aortic regurgitation (AR), and AS+AR. Patients age 8–39 years with congenital AS (n=103), AR (n=36), or AS+AR (n=107) were identified. Cross-sectional assessment of LV remodeling pattern and diastolic function was performed. A diastolic function score (DFS) (0–4) was assigned to each patient with 1 point for an abnormal value in each of 4 categories: mitral inflow (E:A and E-wave deceleration time), tissue Doppler E′, E/E′, and left atrial volume. Patients with DFS ≥2 were compared to those with a score <2. Concentric hypertrophy was the most common remodeling pattern in AS (51%), while mixed/physiologic hypertrophy in AS+AR (48%) and eccentric hypertrophy in AR (49%) predominated. In the entire cohort, 91 patients (37%) had DFS ≥ 2. Patients with AS or AS+AR had higher DFS than pure AR patients (p<0.001). In multivariable analysis, higher LV mass z-score and prior aortic valve balloon dilation were associated with DFS ≥2. In patients with catheterization data (n=65), E/E′ correlated with LV end-diastolic pressure. Those with DFS ≥2 had higher LV end-diastolic pressure and mean pulmonary artery pressure than those with DFS <2. In conclusion, DD is common in young patients with AS and AS+AR, but not in pure AR patients. Higher LV mass and prior aortic valve dilation were associated with DD.
PMCID: PMC3538891  PMID: 23102884
aortic valve disease; diastolic function; congenital heart disease
22.  Models of plasma membrane organization can be applied to mitochondrial membranes to target human health and disease with polyunsaturated fatty acids 
Bioactive n-3 polyunsaturated fatty acids (PUFA), abundant in fish oil, have potential for treating symptoms associated with inflammatory and metabolic disorders; therefore, it is essential to determine their fundamental molecular mechanisms. Recently, several labs have demonstrated the n-3 PUFA docosahexaenoic acid (DHA) exerts anti-inflammatory effects by targeting the molecular organization of plasma membrane microdomains. Here we briefly review the evidence that DHA reorganizes the spatial distribution of microdomains in several model systems. We then emphasize how models on DHA and plasma membrane microdomains can be applied to mitochondrial membranes. We discuss the role of DHA acyl chains in regulating mitochondrial lipid-protein clustering, and how these changes alter several aspects of mitochondrial function. In particular, we summarize effects of DHA on mitochondrial respiration, electron leak, permeability transition, and mitochondrial calcium handling. Finally, we conclude by postulating future experiments that will augment our understanding of DHA-dependent membrane organization in health and disease.
PMCID: PMC3391319  PMID: 22464052
23.  Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor suppressive functions of let-7 
Cancer research  2012;72(13):10.1158/0008-5472.CAN-11-3864.
microRNAs (miRNAs) regulate cancer cells but their potential effects on cancer stem/progenitor cells are still being explored. In this study we used quantitative RT-PCR to define miRNA expression patterns in various stem/progenitor cell populations in prostate cancer (PCa), including CD44+, CD133+, integrin α2β1+ and side population cells. We identified distinct and common patterns in these different tumorigenic cell subsets. Multiple tumor suppressive miRNAs were downregulated coordinately in several PCa stem/progenitor cell populations, namely, miR-34a, let-7b, miR-106a and miR-141, whereas miR-301 and miR-452 were commonly overexpressed. let-7 overexpression inhibited PCa cell proliferation and clonal expansion in vitro and tumor regeneration in vivo. In addition, let-7 and miR-34a exerted differential inhibitory effects in PCa cells, with miR-34a inducing G1 phase cell-cycle arrest accompanied by cell senescence and let-7 inducing G2/M phase cell-cycle arrest without senescence. Taken together, our findings define distinct miRNA expression patterns that coordinately regulate the tumorigenicity of PCa cells.
PMCID: PMC3872033  PMID: 22719071
miRNA; prostate cancer; cancer stem cells; let-7; miR-34a; tumor development
24.  Impact of Meropenem in Combination with Tobramycin in a Murine Model of Pseudomonas aeruginosa Pneumonia 
Pseudomonas aeruginosa pneumonia remains a difficult therapeutic problem. Optimal doses and modes of administration of single agents often do not result in acceptable outcomes. Further, emergence of resistance occurs frequently in this setting with single-agent chemotherapy. The purpose of these experiments was to evaluate combination chemotherapy with meropenem plus tobramycin for P. aeruginosa in a murine pneumonia model. Neutropenia was induced by cyclophosphamide. Pharmacokinetics of meropenem and tobramycin were determined using a population pharmacokinetic approach. Both drugs were given at 4-h intervals. Meropenem was administered as total daily doses of 30 to 600 mg/kg of body weight, while tobramycin doses ranged from 50 to 400 mg/kg. Combination therapy evaluated all combinations of 50, 100, and 150 mg/kg/day of tobramycin doses with 60 or 300 mg/kg/day of meropenem. Total and drug-resistant organisms were enumerated. Meropenem alone had a near-maximal effect at 60 mg/kg/day (3.18 log10 [CFU/g] kill from stasis). The time > MIC in epithelial lining fluid (ELF) at this dose was 35.25% of 24 h. For tobramycin alone, the near-maximal effect was at 150 mg/kg/day and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) in ELF was 240.3. Resistance suppression occurred at an ELF AUC/MIC ratio of 110.6. For combination therapy, the near-maximal effect was reached at 60 mg/kg/day and 50 mg/kg/day of meropenem and tobramycin, which produced a 35.25% time > MIC in ELF and an ELF AUC/MIC ratio of 80.1. The interaction was additive. All combination regimens suppressed resistance. Combination therapy produced additive drug interaction and suppressed all resistance amplification. It is likely that optimal therapy for Pseudomonas aeruginosa pneumonia will involve a combination of agents.
PMCID: PMC3716130  PMID: 23571540
25.  Novel Virus Discovery and Genome Reconstruction from Field RNA Samples Reveals Highly Divergent Viruses in Dipteran Hosts 
PLoS ONE  2013;8(11):e80720.
We investigated whether small RNA (sRNA) sequenced from field-collected mosquitoes and chironomids (Diptera) can be used as a proxy signature of viral prevalence within a range of species and viral groups, using sRNAs sequenced from wild-caught specimens, to inform total RNA deep sequencing of samples of particular interest. Using this strategy, we sequenced from adult Anopheles maculipennis s.l. mosquitoes the apparently nearly complete genome of one previously undescribed virus related to chronic bee paralysis virus, and, from a pool of Ochlerotatus caspius and Oc. detritus mosquitoes, a nearly complete entomobirnavirus genome. We also reconstructed long sequences (1503-6557 nt) related to at least nine other viruses. Crucially, several of the sequences detected were reconstructed from host organisms highly divergent from those in which related viruses have been previously isolated or discovered. It is clear that viral transmission and maintenance cycles in nature are likely to be significantly more complex and taxonomically diverse than previously expected.
PMCID: PMC3832450  PMID: 24260463

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