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1.  Impaired Laparotomy Wound Healing in Obese Rats 
Obesity surgery  2011;21(12):1937-1946.
Obesity increases the risk of laparotomy dehiscence and incisional hernia. The aim of this study was to measure the biological effect of obesity on laparotomy wound healing and the formation of incisional hernias.
Normal-weight Sprague–Dawley (SD) and obese Zucker rats were used in an established laparotomy wound healing and incisional ventral hernia model. Mechanical testing was performed on abdominal wall strips collected from laparotomy wounds. Hernia size was measured by digital imaging. Picrosirius staining for collagen isoforms was observed with polarized microscopy. Abdominal wall fibroblasts were cultured to measure collagen matrix remodeling and proliferation.
Laparotomy wound healing was significantly impaired in obese rats. Mechanical strength was lower than in normal-weight rats. Yield load was reduced in the obese group at all time points. Picrosirius red staining showed increased immature type III collagen content and disorganized type I collagen fibers within laparotomy wounds of obese rats. Wound size was significantly larger in the obese group. Collagen matrix remodeling was impaired with fibroblasts from obese rats, but there was no difference in fibroblast proliferation between the obese and normal-weight groups.
We observed for the first time that laparotomy wound healing is impaired in obese rats. The recovery of laparotomy wound strength is delayed due to abnormal collagen maturation and remodeling, possibly due to a defect in fibroblast function. Strategies to improve outcomes for laparotomy wound healing in obese patients should include correcting the wound healing defect, possibly with growth factor or cell therapy.
PMCID: PMC4492698  PMID: 21347822
Wound healing; Hernia; Collagen; Fibroblast; Laparotomy; Obesity
2.  Effect of mushroom diet on pharmacokinetics of gabapentin in healthy Chinese subjects 
This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption.
Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg.
Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min−1, P = 0.031). No significant changes in AUC(0,tlast) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin.
These data suggest that diet–drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.
PMCID: PMC4168387  PMID: 24168107
ergothioneine; gabapentin; mushroom; novel human organic cation transporter 1; pharmacokinetics
3.  Ensuring good quality rna for quantitative real-time pcr isolated from renal proximal tubular cells using laser capture microdissection 
BMC Research Notes  2014;7:62.
In order to provide gene expression profiles of different cell types, the primary step is to isolate the specific cells of interest via laser capture microdissection (LCM), followed by extraction of good quality total RNA sufficient for quantitative real-time polymerase chain reaction (qPCR) analysis. This LCM-qPCR strategy has allowed numerous gene expression studies on specific cell populations, providing valuable insights into specific cellular changes in diseases. However, such strategy imposed challenges as cells of interests are often available in limited quantities and quality of RNA may be compromised during long periods of time spent on collection of cells and extraction of total RNA; therefore, it is crucial that protocols for sample preparation should be optimised according to different cell populations.
We made several modifications to existing protocols to improve the total RNA yield and integrity for downstream qPCR analyses. A modified condensed hematoxylin and eosin (H&E) staining protocol was developed for the identification of rat renal proximal tubular cells (PTCs). It was then determined that a minimal of eight thousands renal PTCs were required to meet the minimal total RNA yield required for downstream qPCR. RNA integrity was assessed using at every progressive step of sample preparation. Therefore, we decided that the shortened H&E staining, together with microdissection should be performed consecutively within twenty minutes for good quality for gene expression analysis. These modified protocols were later applied on six individual rat samples. A panel of twenty rat renal drug transporters and five housekeeping genes showed Ct values below thirty-five, confirming the expression levels of these drug transporters can be detected.
We had successfully optimized the protocols to achieve sufficient good quality total RNA from microdissected rat renal PTCs for gene expression profiling via qPCR. This protocol may be suitable for researchers who are interested in employing similar applications for gene expression studies.
PMCID: PMC3905289  PMID: 24467986
4.  Fast oscillations during gasping and other non-eupneic respiratory behaviors: Clues to central pattern generation 
The mammalian nervous system exhibits fast synchronous oscillations, which are especially prominent in respiratory-related nerve discharges. In the phrenic nerve, they include high- (HFO), medium- (MFO), and low-frequency (LFO) oscillations. Because motoneurons firing at HFO-related frequencies had never been recorded, an epiphenomenological mechanism for their existence had been posited. We have recently recorded phrenic motoneurons firing at HFO-related frequencies in unanesthetized decerebrate rats and showed that they exhibit dynamic coherence with the phrenic nerve, validating synchronous motoneuronal discharge as a mechanism underlying the generation of HFO. In so doing, we have helped validate the conclusions of previous studies by us and other investigators who have used changes in fast respiratory oscillations to make inferences about central respiratory pattern generation. Here, we seek to review changes occurring in fast synchronous oscillations during non-eupneic respiratory behaviors, with special emphasis on gasping, and the inferences that can be drawn from these dynamics regarding respiratory pattern formation.
PMCID: PMC3696890  PMID: 23545119
Breathing; Motor synchrony; Gasping; Apneusis
5.  Emotional enhancement of immediate memory: Positive pictorial stimuli are better recognized than neutral or negative pictorial stimuli 
Advances in Cognitive Psychology  2012;8(3):255-266.
We examined emotional memory enhancement (EEM) for negative and positive pictures while manipulating encoding and retrieval conditions. Two groups of 40 participants took part in this study. Both groups performed immediate implicit (categorization task) and explicit (recognition task) retrieval, but for one group the tasks were preceded by incidental encoding and for the other group by intentional encoding. As indicated by the sensitivity index (dʹ), after incidental encoding positive stimuli were easier to recognize than negative and neutral stimuli. Participants’ response criterion was more liberal for negative stimuli than for both positive and neutral ones, independent of encoding condition. In the implicit retrieval task, participants were slower in categorizing positive than negative and neutral stimuli. However, the priming effect was larger for emotional than for neutral stimuli. These results are discussed in the context of the idea that the effect of emotion on immediate memory enhancement may depend on the intentionality to encode and retrieve information.
PMCID: PMC3434683  PMID: 22956991
emotional memory enhancement; explicit/ implicit retrieval; intentional/ incidental encoding
6.  In Vitro Interactions of Antimicrobial Combinations with Fosfomycin against KPC-2-Producing Klebsiella pneumoniae and Protection of Resistance Development▿ 
Using time-kill methodology, we investigated the interactions of fosfomycin with meropenem or colistin or gentamicin against 17 genetically distinct Klebsiella pneumoniae clinical isolates carrying blaKPC-2. Synergy was observed with meropenem or colistin against 64.7 and 11.8% of tested isolates, while the combination with gentamicin resulted in indifference. All studied combinations showed improved bactericidal activity, compared to fosfomycin alone and prevented the development of fosfomycin resistance in 69.2, 53.8, and 81.8% of susceptible isolates, respectively.
PMCID: PMC3088223  PMID: 21321144
7.  Early Estimation of the Reproduction Number in the Presence of Imported Cases: Pandemic Influenza H1N1-2009 in New Zealand 
PLoS ONE  2011;6(5):e17835.
We analyse data from the early epidemic of H1N1-2009 in New Zealand, and estimate the reproduction number . We employ a renewal process which accounts for imported cases, illustrate some technical pitfalls, and propose a novel estimation method to address these pitfalls. Explicitly accounting for the infection-age distribution of imported cases and for the delay in transmission dynamics due to international travel, was estimated to be (95% confidence interval: ). Hence we show that a previous study, which did not account for these factors, overestimated . Our approach also permitted us to examine the infection-age at which secondary transmission occurs as a function of calendar time, demonstrating the downward bias during the beginning of the epidemic. These technical issues may compromise the usefulness of a well-known estimator of - the inverse of the moment-generating function of the generation time given the intrinsic growth rate. Explicit modelling of the infection-age distribution among imported cases and the examination of the time dependency of the generation time play key roles in avoiding a biased estimate of , especially when one only has data covering a short time interval during the early growth phase of the epidemic.
PMCID: PMC3102662  PMID: 21637342
8.  UGT1A6 genotype-related pharmacokinetics of deferiprone (L1) in healthy volunteers 
To examine the effects of UGT1A6 polymorphisms on the pharmacokinetics of deferiprone in healthy volunteers.
Twenty-two healthy volunteers were enrolled and grouped according to UGT1A6 genotype. After an overnight fast, the subjects received a single oral dose of 25 mg kg−1 deferiprone. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after dosing. Urine output was collected at 0, 0–2, 2–4, 4–8, 8–12 and 12–24 h. Deferiprone (L1) and deferiprone-glucuronide (L1G) concentrations in serum and urine were determined using a validated high-performance liquid chromatography method. UGT1A6 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis.
No statistically significant differences in any pharmacokinetic parameters of either deferiprone or deferiprone-glucuronide among the genotype groups were noted. Likewise, there were no statistically significant differences in 24-h urinary deferiprone and deferiprone-glucuronide excretion among the genotype groups. Significant differences between men and women were found in AUC0–∞, Vd/F, and CL/F of deferiprone. Gender differences in 24-h urinary deferiprone and its metabolite excretion, however, failed to reach statistical significance. The Vd/F of deferiprone was found to correlate significantly with serum ferritin (rs = 0.665; P = 0.001).
The studied single nucleotide polymorphisms in UGT1A6 do not appear to exert statistically significant effects on the single-dose pharmacokinetics of deferiprone. Gender appears to influence the serum pharmacokinetics of deferiprone, but not urinary excretion of deferiprone and its metabolite. Body iron stores may have an influence on the extent of extravascular deferiprone distribution.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTUGT1A6 has been proposed as the predominant isoform responsible for the glucuronidation of deferiprone.UGT1A6*2 allele has been associated with the altered enzyme activity.
WHAT THIS STUDY ADDSThere is no statistically significant effect of UGT1A6 genotype on the single-dose pharmacokinetics of deferiprone in healthy volunteers.Gender influences serum pharmacokinetics of deferiprone.Body iron stores reflected by serum ferritin levels may have an influence on the extent of extravascular deferiprone distribution.
PMCID: PMC2485226  PMID: 18318774
deferiprone; iron; L1; pharmacokinetics; UGT1A6

Results 1-8 (8)