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1.  The Viral Ubiquitin Ligase ICP0 Is neither Sufficient nor Necessary for Degradation of the Cellular DNA Sensor IFI16 during Herpes Simplex Virus 1 Infection 
Journal of Virology  2013;87(24):13422-13432.
The cellular protein IFI16 colocalizes with the herpes simplex virus 1 (HSV-1) ubiquitin ligase ICP0 at early times of infection and is degraded as infection progresses. Here, we report that the factors governing the degradation of IFI16 and its colocalization with ICP0 are distinct from those of promyelocytic leukemia protein (PML), a well-characterized ICP0 substrate. Unlike PML, IFI16 colocalization with ICP0 was dependent on the ICP0 RING finger and did not occur when proteasome activity was inhibited. Expression of ICP0 in the absence of infection did not destabilize IFI16, the degradation occurred efficiently in the absence of ICP0 if infection was progressing efficiently, and IFI16 was relatively stable in wild-type (wt) HSV-1-infected U2OS cells. Therefore, IFI16 stability appears to be regulated by cellular factors in response to active HSV-1 infection rather than directly by ICP0. Because IFI16 is a DNA sensor that becomes associated with viral genomes during the early stages of infection, we investigated its role in the recruitment of PML nuclear body (PML NB) components to viral genomes. Recruitment of PML and hDaxx was less efficient in a proportion of IFI16-depleted cells, and this correlated with improved replication efficiency of ICP0-null mutant HSV-1. Because the absence of interferon regulatory factor 3 (IRF3) does not increase the plaque formation efficiency of ICP0-null mutant HSV-1, we speculate that IFI16 contributes to cell-mediated restriction of HSV-1 in a manner that is separable from its roles in IRF3-mediated interferon induction, but that may be linked to the PML NB response to viral infection.
doi:10.1128/JVI.02474-13
PMCID: PMC3838218  PMID: 24089555
2.  Sputum Tobramycin Concentrations in Cystic Fibrosis Patients with Repeated Administration of Inhaled Tobramycin 
Abstract
Background
Dosing of tobramycin solution for inhalation (TSI) in cystic fibrosis (CF) patients was based on single-dose pharmacokinetic studies. This investigation was prompted by evidence of possible antibiotic accumulation in respiratory secretions with repeated dosing. The objectives were to evaluate whether tobramycin accumulates in respiratory secretions with repeated inhalation, compare total and biologically active tobramycin concentrations in CF sputum, and evaluate sputum induction for obtaining secretions for drug concentration assay.
Methods
: Individuals with CF ≥10 years of age were enrolled at the beginning of a course of TSI, 300 mg twice daily for 28 days. Two study visits were conducted, 1–2 days and 24–28 days after initiation of TSI treatment. Induced sputum and expectorated sputum samples were collected for measurement of trough and peak tobramycin concentrations at each visit. Total tobramycin concentrations were measured by high-pressure liquid chromatography and bioactive concentrations by bioassay.
Results
Twenty participants completed the study. Trough concentrations were similar at visits 1 and 2, as were peak concentrations. Trough bioactive and total tobramycin concentrations were similar (mean ratio 1.2, 95% CI 0.56, 1.87), but peak bioactive concentrations were significantly lower than peak total concentrations (mean ratio 0.33, 95% CI 0.23, 0.44). Sputum induction was well tolerated.
Conclusions
: No evidence of significant drug accumulation in respiratory secretions with repeat dosing of TSI was seen. Peak bioactive concentrations, although lower than peak total concentrations, were still generally well within the bactericidal range. Sputum induction as a method for determining airway drug concentrations appears safe and feasible.
doi:10.1089/jamp.2011.0942
PMCID: PMC3621259  PMID: 22620494
inhaled therapy; cystic fibrosis; sputum induction; antibiotics; bioassay
3.  A Comparison of the Effects of Nicotinamide and Progesterone on Functional Recovery of Cognitive Behavior following Cortical Contusion Injury in the Rat 
Journal of Neurotrauma  2012;29(18):2823-2830.
Abstract
The primary goal of this study was to compare clinically relevant doses of progesterone and nicotinamide within the same injury model. Progesterone has been shown to reduce edema and inflammation and improve functional outcomes following brain injury. Nicotinamide has also been shown to be an effective neuroprotective agent in a variety of neurological injury models. In the current study, nicotinamide was administered beginning 4 h post-cortical contusion injury (CCI) with a loading dose (75 mg/kg, i.p.) combined with continuous infusion (12 mg/h/kg, s.c.) for 72 h post-injury. Progesterone was administered beginning 4 h post-CCI at a dose of 10 or 20 mg/kg, i.p. every 12 h for 72 h. This resulted in the following groups: Injured-nicotinamide treated, Injured-progesterone-10 treated, Injured-progesterone-20 treated, Injured-vehicle treated, and Sham. Functional recovery was assessed with two spatial memory tasks in the Morris water maze (MWM) the acquisition of a reference memory task and a reversal learning task. Neuropathological assessments were conducted in the cortex and hippocampus. It was found that both progesterone (10 mg/kg) and nicotinamide improved reference memory acquisition and reversal learning in the MWM compared with vehicle treatment. The lower dose of progesterone and nicotinamide also reduced tissue loss in the injured cortex and ipsilateral hippocampus compared with vehicle. The beneficial effects of progesterone appear to be dose dependent with the lower 10 mg/kg dose producing significant effects that were not observed at the higher dose. Direct comparison between nicotinamide and low dose progesterone appears to suggest that both are equally effective. The general findings of this study suggest that both nicotinamide and progesterone produce significant improvements in recovery of function following CCI.
doi:10.1089/neu.2012.2471
PMCID: PMC3521133  PMID: 23016598
CCI; nicotinamide; progesterone; recovery of function; therapy; traumatic brain injury
4.  Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model 
The goal of this study was to compare the effects of two inflammatory modulators, erythropoietin (EPO) and anakinra, on functional recovery and brain gene expression following a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses. Functional recovery was assessed using both motor and spatial learning tasks and neuropathological measurements conducted in the cortex and hippocampus. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Ingenuity Pathway Analysis was used to evaluate the effect on relevant functional categories. EPO and anakinra treatment resulted in significant changes in brain gene expression in the CCI model demonstrating acceptable brain penetration. At all three time points, EPO treatment resulted in significantly more differentially expressed genes than anakinra. For anakinra at 24 h and EPO at 24 h, 72 h, and 7 days, the genes in the top 3 functional categories were involved in cellular movement, inflammatory response and cell-to-cell signaling. For EPO, the majority of the genes in the top 10 canonical pathways identified were associated with inflammatory and immune signaling processes. This was true for anakinra only at 24 h post-traumatic brain injury (TBI). The immunomodulation effects of EPO and anakinra did not translate into positive effects on functional behavioral and lesion studies. Treatment with either EPO or anakinra failed to induce significant beneficial effects on recovery of function or produce any significant effects on the prevention of injury induced tissue loss at 30 days post-injury. In conclusion, treatment with EPO or anakinra resulted in significant effects on gene expression in the brain without affecting functional outcome. This suggests that targeting these inflammatory processes alone may not be sufficient for preventing secondary injuries after TBI.
doi:10.3389/fphar.2013.00129
PMCID: PMC3798024  PMID: 24151467
traumatic brain injury; recovery of function; cortical contusion impact; gene expression; erythropoietin; anakinra
5.  Is ethnicity associated with morphine's side effects in children? morphine pharmacokinetics, analgesic response and side effects in children having tonsillectomy 
Paediatric Anaesthesia  2012;22(7):669-675.
Objectives/Aims
To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children.
Background
Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity.
Methods
Prospective cohort study in L and NL children, 3–17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6-and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Non-compartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in 8 genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were done.
Results
We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (p=0.001). Pruritus was 4 times (p=0.006) and emesis 7 times (p=0.025) more frequent in L compared to NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects.
Conclusions
We found statistically significant differences in occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined, explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.
doi:10.1111/j.1460-9592.2012.03844.x
PMCID: PMC3366036  PMID: 22486937
6.  Maternal and Paternal Genomes Differentially Affect Myofibre Characteristics and Muscle Weights of Bovine Fetuses at Midgestation 
PLoS ONE  2013;8(1):e53402.
Postnatal myofibre characteristics and muscle mass are largely determined during fetal development and may be significantly affected by epigenetic parent-of-origin effects. However, data on such effects in prenatal muscle development that could help understand unexplained variation in postnatal muscle traits are lacking. In a bovine model we studied effects of distinct maternal and paternal genomes, fetal sex, and non-genetic maternal effects on fetal myofibre characteristics and muscle mass. Data from 73 fetuses (Day153, 54% term) of four genetic groups with purebred and reciprocal cross Angus and Brahman genetics were analyzed using general linear models. Parental genomes explained the greatest proportion of variation in myofibre size of Musculus semitendinosus (80–96%) and in absolute and relative weights of M. supraspinatus, M. longissimus dorsi, M. quadriceps femoris and M. semimembranosus (82–89% and 56–93%, respectively). Paternal genome in interaction with maternal genome (P<0.05) explained most genetic variation in cross sectional area (CSA) of fast myotubes (68%), while maternal genome alone explained most genetic variation in CSA of fast myofibres (93%, P<0.01). Furthermore, maternal genome independently (M. semimembranosus, 88%, P<0.0001) or in combination (M. supraspinatus, 82%; M. longissimus dorsi, 93%; M. quadriceps femoris, 86%) with nested maternal weight effect (5–6%, P<0.05), was the predominant source of variation for absolute muscle weights. Effects of paternal genome on muscle mass decreased from thoracic to pelvic limb and accounted for all (M. supraspinatus, 97%, P<0.0001) or most (M. longissimus dorsi, 69%, P<0.0001; M. quadriceps femoris, 54%, P<0.001) genetic variation in relative weights. An interaction between maternal and paternal genomes (P<0.01) and effects of maternal weight (P<0.05) on expression of H19, a master regulator of an imprinted gene network, and negative correlations between H19 expression and fetal muscle mass (P<0.001), suggested imprinted genes and miRNA interference as mechanisms for differential effects of maternal and paternal genomes on fetal muscle.
doi:10.1371/journal.pone.0053402
PMCID: PMC3544898  PMID: 23341941
7.  Public health education for midwives and midwifery students: a mixed methods study 
Background
Current national and international maternity policy supports the importance of addressing public health goals and investing in early years. Health care providers for women during the reproductive and early postnatal period have the opportunity to encourage women to make choices that will impact positively on maternal and fetal health. Midwives are in a unique position, given the emphasis of the philosophy of midwifery care on building relationships and incorporating a holistic approach, to support women to make healthy choices with the aim of promoting health and preventing ill health. However, exploration of the educational preparation of midwives to facilitate public health interventions has been relatively limited. The aim of the study was to identify the scope of current midwifery pre registration educational provision in relation to public health and to explore the perspectives of midwives and midwifery students about the public health role of the midwife.
Methods
This was a mixed methods study incorporating a survey of Higher Educational Institutions providing pre registration midwifery education across the UK and focus groups with midwifery students and registered midwives.
Results
Twenty nine institutions (53% response) participated in the survey and nine focus groups were conducted (59 participants). Public health education was generally integrated into pre registration midwifery curricula as opposed to taught as a discrete subject. There was considerable variation in the provision of public health topics within midwifery curricula and the hours of teaching allocated to them. Focus group data indicated that it was consistently difficult for both midwifery students and midwives to articulate clearly their understanding and definition of public health in relation to midwifery.
Conclusions
There is a unique opportunity to impact on maternal and infant health throughout the reproductive period; however the current approach to public health within midwifery education should be reviewed to capitalise on the role of the midwife in delivering public health interventions. It is clear that better understanding of midwifery public health roles and the visibility of public health within midwifery is required in order to maximise the potential contribution of midwives to achieving short and long term public health population goals.
doi:10.1186/1471-2393-12-142
PMCID: PMC3557144  PMID: 23216855
Public health; Midwifery; Education; Training
8.  Continuous nicotinamide administration improves behavioral recovery and reduces lesion size following bilateral frontal controlled cortical impact injury 
Behavioural brain research  2011;224(2):311-317.
Previous research has demonstrated considerable preclinical efficacy of nicotinamide (NAM; vitamin B3) in animal models of TBI with systemic dosing at 50 and 500 mg/kg yielding improvements on sensory, motor, cognitive and histological measures. The current study aimed to utilize a more specific dosing paradigm in a clinically relevant delivery mechanism: continuously secreting subcutaneous pumps. A bilateral frontal controlled cortical impact (CCI) or sham surgery was performed and rats were treated with NAM (150 mg/kg/day) or saline (1 ml/kg) pumps 30 min after CCI, continuing until seven days post-CCI. Rats were given a loading dose of NAM (50 mg/kg) or saline (1 ml/kg) following pump implant. Rats received behavioral testing (bilateral tactile adhesive removal, locomotor placing task and Morris water maze) starting on day two post-CCI and were sacrificed at 31 days post-CCI and brains were stained to examine lesion size. NAM-treated rats had reductions in sensory, motor and cognitive behavioral deficits compared to vehicle-treated rats. Specifically, NAM-treated rats significantly improved on the bilateral tactile adhesive removal task, locomotor placing task and the reference memory paradigm of the Morris water maze. Lesion size was also significantly reduced in the NAM-treated group. The results from this study indicate that at the current dose, NAM produces beneficial effects on recovery from a bilateral frontal brain injury and that it may be a relevant compound to be explored in human studies.
doi:10.1016/j.bbr.2011.06.009
PMCID: PMC3159802  PMID: 21704653
Traumatic Brain Injury; Vitamin B3; Treatment; Recovery of Function; Rat
9.  The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury 
Journal of Neurotrauma  2011;28(9):1827-1843.
Abstract
Microarray-based transcriptional profiling was used to determine the effect of progesterone in the cortical contusion (CCI) model. Gene ontology (GO) analysis then evaluated the effect of dose on relevant biological pathways. Treatment (vehicle, progesterone 10 mg/kg or 20 mg/kg given i.p.) was started 4 h post-injury and administered every 12 h post-injury for up to 72 h, with the last injection 12 hr prior to death for the 24 h and 72 h groups. In the CCI-injured vehicle group compared to non-injured animals, expression of 1,114, 4,229, and 291 distinct genes changed >1.5-fold (p<0.05) at 24 h, 72 h, and 7 days, respectively. At 24 h, the effect of low-dose progesterone on differentially expressed genes was <20% the effect of higher dose compared to vehicle. GO analysis identified a significant effect of low- and high-dose progesterone treatment compared to vehicle on DNA damage response. At 72 h, high-dose progesterone treatment compared to vehicle affected expression of almost twice as many genes as did low-dose progesterone. Both low- and high-dose progesterone resulted in expression of genes regulating inflammatory response and apoptosis. At 7 days, there was only a modest difference in high-dose progesterone compared to vehicle, with only 14 differentially expressed genes. In contrast, low-dose progesterone resulted in 551 differentially expressed genes compared to vehicle. GO analysis identified genes for the low-dose treatment involved in positive regulation of cell proliferation, innate immune response, positive regulation of anti-apoptosis, and blood vessel remodeling.
doi:10.1089/neu.2011.1911
PMCID: PMC3172874  PMID: 21770760
CCI injury model; gene expression; neurotrauma; progesterone
10.  Ketorolac tromethamine: Stereo-specific Pharmacokinetics and Single dose Use in Postoperative Infants aged 2– 6 months 
Paediatric anaesthesia  2010;21(3):325-334.
Objective
We determined the postoperative pharmacokinetics (PK), safety and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo.
Background
Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants.
Methods
This double-blind, placebo-controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6–18 hours after surgery, infants were randomized to receive placebo, 0.5 mg/kg, or 1 mg/kg ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-hours post-dosing. Analysis used non-compartmental and compartmental population modeling methods.
Results
In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied dataset comprising 25 infants and toddlers (aged 6–18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, clearance from the central compartment 7.40 (8%) ml/min. Those of the S (−) isomer were 1930 (15%) ml, 319 (58%) ml, 39.5 (13%) ml/min. Typical elimination half-lives were 191, and 33 min respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (−) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large interpatient variability and was not different between groups.
Conclusion
Stereo-isomer specific clearance of ketorolac in infants (aged 2–6 months) shows rapid elimination of the analgesic S (−) isomer as reported in infants aged 6–18 months. No adverse effects were seen after a single IV ketorolac dose.
doi:10.1111/j.1460-9592.2010.03484.x
PMCID: PMC3078765  PMID: 21199130
ketorolac pharmacokinetics; stereo-isomers; infants; post-operative analgesia; safety
11.  Atenolol Pharmacokinetics and Excretion in Breast Milk during the first 6–8 Months Postpartum 
Journal of clinical pharmacology  2010;50(11):1301-1309.
Our objectives were to evaluate the time course for atenolol pharmacokinetics in lactating women postpartum and to quantify atenolol plasma concentrations in their 3–4 months old nursing infants. Data were collected over one dosing interval from lactating women treated with atenolol for therapeutic reasons, at 2–4 weeks (n=32), 3–4 months (n=22), and 6–8 months (n=17) postpartum. A single blood sample was collected from 15 nursing infants (3–4 months of age) of the mothers participating in the study. At 2–4 weeks, 3–4 months, and 6–8 months postpartum, atenolol infant dose, relative to the mother’s weight-adjusted dose, were 14.6 ± 7.6%, 8.3 ± 5.2% and 5.9 ± 2.9%, respectively. Over this time, maternal atenolol pharmacokinetics did not change to a clinically significant extent. Atenolol concentrations were below assay quantification limits (< 10 ng/mL) in the plasma of all 3–4 months old nursing infants studied. Our findings support the careful use of atenolol during breastfeeding, since in the vast majority of healthy, term infants, atenolol concentrations will be too low to be clinically relevant. Premature infants and those with kidney disease require further study. Infant exposure depends on maternal dose and decreases during the first 6–8 months postpartum.
doi:10.1177/0091270009358708
PMCID: PMC2940977  PMID: 20145263
atenolol; pharmacokinetics; breast milk; postpartum; kidney function
12.  Haptoglobin Phenotype and Apolipoprotein E Polymorphism: Relationship to Post-Traumatic Seizures and Neuropsychological Functioning after Traumatic Brain Injury 
Epilepsy & behavior : E&B  2009;16(3):501-506.
The relationship between genetic predisposition to reduced iron capacity and apolipoprotein E (APOE) with post-traumatic seizures (PTS) and neuropsychological outcomes was investigated in patients with traumatic brain injuries (TBI) from a prior valproate clinical study. Haptoglobin (Hp) concentration/phenotype and APOE genotype was determined in 25 PTS and 26 controls (no PTS) subjects ~10 year after TBI. Hp phenotype was also determined in previously collected frozen samples for 25 additional PTS and 32 no PTS subjects. There was no relationship between Hp phenotype or APOE genotype and occurrence of PTS. APOE genotype was not related to neuropsychological outcome; however when adjustments were made for differences in educational levels, APOE ε4 subjects did worse especially on verbal intellectual and verbal memory skills. In contrast to our hypothesis, those with Hp 1-1 (high affinity binder of hemoglobin), scored somewhat worse on verbal IQ and Tapping D at 1 and 12 month after injury.
doi:10.1016/j.yebeh.2009.08.025
PMCID: PMC2783358  PMID: 19766540
Traumatic Brain Injury; Post-Traumatic Seizures; haptoglobin; apolipoprotein E
13.  A RANDOMIZED CLINICAL TRIAL OF VALERIAN FAILS TO IMPROVE SELF-REPORT, POLYSOMNOGRAPHIC, AND ACTIGRAPHIC SLEEP IN OLDER WOMEN WITH INSOMNIA 
Sleep medicine  2008;10(3):319-328.
Objective
To test the effects of nightly valerian (Valeriana officinalis) extract to improve sleep of older women with insomnia.
Methods
Participants in this phase 2 randomized, double-blind, cross-over controlled trial were 16 older women (mean age = 69.4 ± 8.1 years) with insomnia. Participants took 300 mg of concentrated valerian extract or placebo 30 minutes before bedtime for two weeks. Sleep was assessed in the laboratory by self-report and polysomnography (PSG) at baseline and again at the beginning and end of each treatment phase (total of 9 nights in the laboratory) and at home by daily sleep logs and actigraphy.
Results
There were no statistically significant differences between valerian and placebo after a single dose or after two weeks of nightly dosing on any measure of sleep latency, wake after sleep onset (WASO), sleep efficiency, and self-rated sleep quality. In comparing each treatment to baseline in separate comparisons, WASO significantly increased (+17.7 ± 25.6 min, p=.02) after two weeks of nightly valerian, but not after placebo (+6.8 ± 26.4 min, NS). Side effects were minor and did not differ significantly between valerian and placebo.
Conclusion
Valerian did not improve sleep in this sample of older women with insomnia. Findings from this study add to the scientific evidence that does not support use of valerian in the clinical management of insomnia.
doi:10.1016/j.sleep.2008.02.001
PMCID: PMC2709274  PMID: 18482867
Valerian; women; aging; phytotherapy; sleep; insomnia; complementary therapies; alternative medicine
14.  Effects of Cranberry Juice on Pharmacokinetics of β-Lactam Antibiotics following Oral Administration▿  
Cranberry juice consumption is often recommended along with low-dose oral antibiotics for prophylaxis for recurrent urinary tract infection (UTI). Because multiple membrane transporters are involved in the intestinal absorption and renal excretion of β-lactam antibiotics, we evaluated the potential risk of pharmacokinetic interactions between cranberry juice and the β-lactams amoxicillin (amoxicilline) and cefaclor. The amoxicillin-cranberry juice interaction was investigated in 18 healthy women who received on four separate occasions a single oral test dose of amoxicillin at 500 mg and 2 g with or without cranberry juice cocktail (8 oz) according to a crossover design. A parallel cefaclor-cranberry juice interaction study was also conducted in which 500 mg cefaclor was administered with or without cranberry juice cocktail (12 oz). Data were analyzed by noncompartmental methods and nonlinear mixed-effects compartmental modeling. We conclude that the concurrent use of cranberry juice has no significant effect on the extent of oral absorption or the renal clearance of amoxicillin and cefaclor. However, delays in the absorption of amoxicillin and cefaclor were observed. These results suggest that the use of cranberry juice at usual quantities as prophylaxis for UTI is not likely to alter the pharmacokinetics of these two oral antibiotics.
doi:10.1128/AAC.00774-08
PMCID: PMC2704661  PMID: 19398645
15.  The effect of vaccination against Porcine reproductive and respiratory syndrome virus (PRRSV) on the Porcine circovirus-2 (PCV-2) load in porcine circovirus associated disease (PCVAD) affected pigs 
A diagnostic project was initiated across the United States in 2006 to improve the understanding of porcine circovirus associated diseases (PCVAD) as well as to identify co-factors in PCVAD-affected farms. A Porcine circovirus-2 (PCV-2) DNA real-time polymerase chain reaction quantitation (qPCR) was established according to a published method and sera from a total of 23pig farms across the United States were examined for viral loads for PCV-2 and analyzed for any possible effects of Porcine reproductive and respiratory syndrome virus (PRRSV) vaccination on this parameter. Vaccination against PRRS resulted in significantly lower viral loads for PCV-2 in animals 13 wk or older compared with nonvaccinated animals, but vaccination of pigs against PRRS had no effect on qPCR results for PCV-2 in 4- to 12-week-old pigs. Interestingly, PRRS vaccinates had significantly lower viral loads when peak wasting disease was observed in the herds. The qPCR method for PCV-2 proved to be an important tool for help in the antemortem diagnosis of PCVAD as well as in the monitoring of infection dynamics.
PMCID: PMC2666324  PMID: 19436588
16.  Onset of action and seizure control in Lennox-Gaustaut syndrome: focus on rufinamide 
Lennox-Gaustaut syndrome is an electroclinical epilepsy syndrome characterized by the triad of electroencephalogram showing diffuse slow spike-and-wave discharges and paroxysmal fast activity, multiple intractable seizure types, and cognitive impairment. The intractability to seizure medications and cognitive impairment gives rise to eventual institutionalized patient care. Only a small subset of seizure medications has been shown to be helpful in seizure control. Most patients take up to 3 medications at high therapeutic dosing and are susceptible to medication-induced side effects. The lack of medication efficacy in seizure control has led one meta-analysis to conclude that there is no single medication that is highly efficacious in controlling seizures in this syndrome. On this background, a new and structurally novel seizure medication, rufinamide, has been found to be beneficial in the treatment of seizures in this syndrome. In a multicenter, double-blinded, randomized, placebo-controlled study, rufinamide was found to reduce seizures by over 30%. More importantly, it reduced the frequency of the seizure type that induces most of the morbidity of this syndrome, the drop seizure, by over 40%. There were few side effects, the medication was well tolerated, and in the open labeled extension study, tolerance was not found. In this review, we describe the main electroclinical features of Lennox-Gaustaut syndrome and summarize the few controlled studies that have contributed to its rational treatment. Currently, there is no single agent or combination of agents that effectively treat the multiple seizure types and co-morbidities in this syndrome. Our focus will be on the role of the new medication rufinamide in seizure reduction in patients with Lennox-Gaustaut syndrome.
PMCID: PMC2697537  PMID: 19536315
Lennox-Gaustaut syndrome; catastrophic pediatric epilepsy; rufinamide
17.  In vitro heterogeneity of osteogenic cell populations at various equine skeletal sites 
Bone cell cultures were evaluated to determine if osteogenic cell populations at different skeletal sites in the horse are heterogeneous. Osteogenic cells were isolated from cortical and cancellous bone in vitro by an explant culture method. Subcultured cells were induced to differentiate into boneforming osteoblasts. The osteoblast phenotype was confirmed by immunohistochemical testing for osteocalcin and substantiated by positive staining of cells for alkaline phosphatase and the matrix materials collagen and glycosaminoglycans. Bone nodules were stained by the von Kossa method and counted. The numbers of nodules produced from osteogenic cells harvested from different skeletal sites were compared with the use of a mixed linear model. On average, cortical bone sites yielded significantly greater numbers of nodules than did cancellous bone sites. Between cortical bone sites, there was no significant difference in nodule numbers. Among cancellous sites, the radial cancellous bone yielded significantly more nodules than did the tibial cancellous bone. Among appendicular skeletal sites, tibial metaphyseal bone yielded significantly fewer nodules than did all other long bone sites. This study detected evidence of heterogeneity of equine osteogenic cell populations at various skeletal sites. Further characterization of the dissimilarities is warranted to determine the potential role heterogeneity plays in differential rates of fracture healing between skeletal sites.
PMCID: PMC1562541  PMID: 17042380
18.  Myiasis in pet animals in British Columbia: The potential of forensic entomology for determining duration of possible neglect 
The Canadian Veterinary Journal  2004;45(12):993-998.
Abstract
Results of a survey of veterinarians in British Columbia included 25 past cases of myiasis and 10 active cases. Most respondents received at least 5 to 10 cases per year, with some as high as 30 per year. This study revealed some advantages and disadvantages of using forensic entomology in living animals.
PMCID: PMC554754  PMID: 15646845
19.  The Hypersensitivity of Horses to Culicoides Bites in British Columbia 
The Canadian Veterinary Journal  1988;29(9):718-723.
Culicoides hypersensitivity is a chronic, recurrent, seasonal dermatitis of horses that has a worldwide distribution, but has only recently been reported in Canada. It is characterized by intense pruritus resulting in lesions associated with self-induced trauma.
A survey of veterinarians and horse-owners in British Columbia showed no differences in susceptibility due to the sex, color, breed, or height of the horses. The prevalence of the disease in the 209 horses surveyed was 26%. Horses sharing the same pasture could be unaffected. The disease was reported primarily from southwestern British Columbia; it occurred between April and October and usually affected the ventral midline, mane, and tail. Horses were generally less than nine years old when the clinical signs first appeared ([unk]=5.9 yr). Culicoides hypersensitivity was common in the lineage of several affected horses, possibly indicating a genetic susceptibility. Most cases were severe enough to require veterinary attention and some horses were euthanized.
PMCID: PMC1680856  PMID: 17423117
20.  Sustained delivery of nicotinamide limits cortical injury and improves functional recovery following traumatic brain injury 
Previously, we have demonstrated that nicotinamide (NAM), a neuroprotective soluble B-group vitamin, improves recovery of function following traumatic brain injury (TBI). However, no prior studies have examined whether NAM is beneficial following continuous infusions over 7 days post-TBI. The purpose of this study was to investigate the preclinical efficacy of NAM treatment as it might be delivered clinically; over several days by slow infusion. Rats were prepared with either unilateral controlled cortical impact (CCI) injuries or sham procedures and divided into three groups: CCI-NAM, CCI-vehicle and sham. Thirty minutes following CCI, Alzet osmotic mini-pumps were implanted subcutaneously. NAM was delivered at a rate of 50 mg/kg/day for 7 days immediately post-CCI. On day 7 following injury, the pumps were removed and blood draws were collected for serum NAM and nicotinamide adenine dinucleotide (NAD+) analyses. Starting on day 2 post-CCI, animals were tested on a battery of sensorimotor tests (bilateral tactile adhesive removal, locomotor placing and limb-use asymmetry). Continuous infusion of NAM resulted in a significant serum elevation in NAM, but not NAD+. Statistical analyses of the tactile removal and locomotor placing data revealed that continuous administration of NAM significantly reduced the initial magnitude of the injury deficit and improved overall recovery compared to the vehicle-treated animals. NAM treatment also significantly decreased limb-use asymmetries compared to vehicle-treated animals. The overall extent of the cortical damage was also reduced by NAM treatment. No detrimental effects were seen following continuous infusion. The present results suggest that NAM delivered via a clinically relevant therapeutic regimen may truncate behavioral damage following TBI. Thus our results offer strong support for translation into the clinical population.
doi:10.4161/oxim.3.2.8
PMCID: PMC2952098  PMID: 20716938
neurorehabilitation; therapy; brain injury; behavior; restorative neurology
21.  APPENDICITIS AND PREGNANCY 
California Medicine  1962;97(3):158-162.
In 74,000 obstetrical patients at Los Angeles County Hospital the incidence of acute appendicitis in pregnancy was 0.05 per cent. In a study of 36 cases of clinically diagnosed appendicitis in pregnancy between 1956 and 1960, it was shown that the fetal and maternal morbidity and mortality were decreased when a definite operative procedure was done early. The difficulty in diagnosis is increased by the necessary consideration of pyelonephritis and twisted ovarian cyst. Rupture of the appendix increased hazards to maternal and fetal survival. It was noted also that threatened premature labor may indicate a ruptured appendix. Emergency operation with the use of antibiotics in such cases was effective therapy. The incidence of premature delivery was proportionate to the delay in operating. If operation was performed in less than eight hours after admission to the hospital, there was no maternal or fetal loss. A delay greater than eight hours resulted in a 17 per cent fetal loss in premature delivery and 4 per cent fetal loss of infants at term.
PMCID: PMC1575222  PMID: 14456125

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