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1.  20(S)-Protopanaxadiol-aglycone Downregulation of the Full-length and Splice Variants of Androgen Receptor 
As a public health problem, prostate cancer engenders huge economic and life-quality burden. Developing effective chemopreventive regimens to alleviate the burden remains a major challenge. Androgen signaling is vital to the development and progression of prostate cancer. Targeting androgen signaling via blocking the production of the potent ligand dihydrotestosterone has been shown to decrease prostate cancer incidence. However, the potential of increasing the incidence of high-grade prostate cancers has been a concern. Mechanisms of disease progression after the intervention may include increased expression of androgen receptor (AR) in prostate tissue and expression of the constitutively-active AR splice variants (AR-Vs) lacking the ligand-binding domain. Thus, novel agents targeting the receptor, preferentially both the full-length and AR-Vs, are urgently needed. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of both the full-length AR and AR-Vs. The effects of PPD on AR and AR-Vs are manifested by an immediate drop in proteins followed by a reduction in transcripts, attributed to PPD induction of proteasome-mediated degradation and inhibition of the transcription of the AR gene. We further show that although PPD inhibits the growth as well as AR expression and activity in LNCaP xenograft tumors, the morphology and AR expression in normal prostates are not affected. This study is the first to show that PPD suppresses androgen signaling through downregulating both the full-length AR and AR-Vs, and provides strong rationale for further developing PPD as a promising agent for the prevention and/or treatment of prostate cancer.
PMCID: PMC3509250  PMID: 22907191
20(S)-protopanaxadiol-aglycone; androgen receptor; prostate cancer
3.  The antiviral effect of sorafenib in hepatitis c-related hepatocellular carcinoma 
Background and Aim
Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In-vitro data suggest that sorafenib may exert antiviral properties and thus our aim in this study, was to evaluate potential antiviral activity of sorafenib in patients with HCV-related HCC.
We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to six months. Baseline clinical, viral, and oncologic data were collected. Patients’ HCV viral loads were obtained at various timepoints, and compared to their baseline viral levels. No patients received any known antiviral therapy during this time.
Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed six months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, C.I. = −0.1799 to 0.8799, p = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumor response to sorafenib showed no significant changes at any time point.
Despite preclinical data and previous subgroup analyses suggesting that sorafenib has antiviral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.
PMCID: PMC3682667  PMID: 23094860
hepatitis; viral suppression; hepatoma; virological response; cirrhosis
4.  Hyperpolarization-Activated Current (Ih) in Vestibular Calyx Terminals: Characterization and Role in Shaping Postsynaptic Events 
Calyx afferent terminals engulf the basolateral region of type I vestibular hair cells, and synaptic transmission across the vestibular type I hair cell/calyx is not well understood. Calyces express several ionic conductances, which may shape postsynaptic potentials. These include previously described tetrodotoxin-sensitive inward Na+ currents, voltage-dependent outward K+ currents and a K(Ca) current. Here, we characterize an inwardly rectifying conductance in gerbil semicircular canal calyx terminals (postnatal days 3–45), sensitive to voltage and to cyclic nucleotides. Using whole-cell patch clamp, we recorded from isolated calyx terminals still attached to their type I hair cells. A slowly activating, noninactivating current (Ih) was seen with hyperpolarizing voltage steps negative to the resting potential. External Cs+ (1–5 mM) and ZD7288 (100 μM) blocked the inward current by 97 and 83 %, respectively, confirming that Ih was carried by hyperpolarization-activated, cyclic nucleotide gated channels. Mean half-activation voltage of Ih was −123 mV, which shifted to −114 mV in the presence of cAMP. Activation of Ih was well described with a third order exponential fit to the current (mean time constant of activation, τ, was 190 ms at −139 mV). Activation speeded up significantly (τ = 136 and 127 ms, respectively) when intracellular cAMP and cGMP were present, suggesting that in vivo Ih could be subject to efferent modulation via cyclic nucleotide-dependent mechanisms. In current clamp, hyperpolarizing current steps produced a time-dependent depolarizing sag followed by either a rebound afterdepolarization or an action potential. Spontaneous excitatory postsynaptic potentials (EPSPs) became larger and wider when Ih was blocked with ZD7288. In a three-dimensional mathematical model of the calyx terminal based on Hodgkin–Huxley type ionic conductances, removal of Ih similarly increased the EPSP, whereas cAMP slightly decreased simulated EPSP size and width.
PMCID: PMC3505587  PMID: 22825486
HCN channel; balance; crista; cAMP; efferent
5.  A unique case of phaeohyphomycosis subretinal abscess in a patient with arthropathy and lung pathology 
Indian Journal of Ophthalmology  2013;61(12):763-765.
A 67-year-old former gold miner with rheumatoid arthritis, treated with steroids and methotrexate, presented to eye casualty with a painful right eye. Examination revealed an anterior uveitis and despite an initial response to topical steroids, the intraocular inflammation worsened with anterior and posterior uveitis development. Re-examination showed a white mass in the peripheral nasal retina initially suspected of being active Toxoplasmosis infection and anti-toxoplasmosis treatment commenced. After improvement and tapering of this treatment, the intraocular inflammation reoccurred. Cytopathological examination of a pars plana vitrectomy obtained vitreous sample that showed a non-diagnostic non-infectious chronic vitritis. The vitreoretinal surgeons elected to do a direct biopsy of the white subretinal mass in the peripheral nasal area. This revealed, quite unexpectedly, an abscess containing pigmented phaeohyphomycosis fungi. This case report documents the multidisciplinary approach that assisted in clinching a final diagnosis and the role of sub-retinal biopsy in this unprecedented scenario.
PMCID: PMC3917400  PMID: 24413827
Phaeohyphomycosis; pigmented fungi; subretinal abscess; subretinal biopsy
6.  CD14 Gene Variants and Their Importance for Childhood Croup, Atopy, and Asthma 
Disease Markers  2013;35(6):765-771.
Background. The CD14 gene has an important role in the detection of inflammatory provoking pathogens and in the ensuing signaling of the innate immune response. We assessed the role of CD14 C-159T, G-1359T in the expression of asthma, croup, and allergy in Canadian school children of ages 6 to 14 years. Methods. Children attending schools in a rural community participated in a cross-sectional survey of respiratory health. Following consent, we conducted clinical assessments to collect buccal swabs for genotyping and perform skin prick testing (SPT) to determine atopic status. Genotyping and SPT results were available for 533 and 499 children, respectively. Separate multivariable analyses that included both polymorphisms were conducted for each phenotype. Results. The prevalence of asthma, allergy, and croup was 18.6%, 22.4%, and 6.6%, respectively. Children with the T/T variant of CD14 G-1359T were more likely to have physician diagnosed asthma (26.8%). Children with C/C variant of CD14 C-159T had a significantly lower prevalence of croup (2.6%). Haplotype analyses of the two CD14 polymorphisms showed that individuals with the T|T haplotype combination were significantly more likely to have asthma (P = 0.014). Conclusions. In this study, CD14 variants are important for the expression of croup and asthma but not atopy.
PMCID: PMC3856132  PMID: 24347797
7.  Biomechanics of Early Cardiac Development 
Biomechanics affect early cardiac development, from looping to the development of chambers and valves. Hemodynamic forces are essential for proper cardiac development, and their disruption leads to congenital heart defects. A wealth of information already exists on early cardiac adaptations to hemodynamic loading, and new technologies, including high resolution imaging modalities and computational modeling, are enabling a more thorough understanding of relationships between hemodynamics and cardiac development. Imaging and modeling approaches, used in combination with biological data on cell behavior and adaptation, are paving the road for new discoveries on links between biomechanics and biology and their effect on cardiac development and fetal programming.
PMCID: PMC3475730  PMID: 22760547
Early cardiac development; Cardiogenesis; Computational modeling; Computational biomechanics; Valveless pumping; Blood flow modeling
8.  Administration of Heme Arginate Ameliorates Murine Type 2 Diabetes Independently of Heme Oxygenase Activity 
PLoS ONE  2013;8(10):e78209.
Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.
PMCID: PMC3813508  PMID: 24205160
9.  Obesity, Diet, and Activity in relation to Asthma and Wheeze among Rural Dwelling Children and Adolescents 
Journal of Obesity  2013;2013:315096.
Aims and Objectives. We investigated associations between weight status, activity level, and diet with asthma or wheeze as well as the interrelationship between these factors. Methods. We conducted a case-control study of 6–18-year olds from 2005 to 2007. Cases (n = 87) were subjects reporting episodes or breathing medication use along with doctor-diagnosed asthma or wheeze in the past 12 months. Controls were randomly selected (n = 208) and without asthma or wheeze. Data regarding health outcomes, diet, and activity were obtained from questionnaire. Objectively measured height and weight were collected. Results. In the adjusted analysis, there was a trend (P = 0.07) towards an increased risk of asthma or wheeze associated with high fast food and/or pop consumption. Among cases, a significantly lower proportion (66%) classified as overweight participated in hard exercise in ≥9 of the past 14 days compared to those who were not overweight (86%). This pattern was not seen among controls (76% participating in hard exercise versus 78%, resp.). However, based on perceived weight status by the parent, the patterns were similar regardless of case-control status. Conclusions. Overweight status may negatively impact activity level among those with asthma or wheeze. Efforts should be made to encourage healthy food choices, and activity programming must consider the needs of overweight children with asthma.
PMCID: PMC3804370  PMID: 24191194
11.  Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer 
Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional arsenal to treat castration-resistant prostate cancer.
PMCID: PMC3709796  PMID: 23771019
androgen receptor; prostate cancer; castration resistance; anti-androgens; protein structure; structure-based drug design
12.  Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor Through Virtual Screening 
Journal of medicinal chemistry  2011;54(24):8563-8573.
The androgen receptor (AR) is the best studied drug target for the treatment of prostate cancer. While there are a number of drugs that target the AR, they all work through the same mechanism of action and are prone to the development of drug resistance. There is a large unmet need for novel AR inhibitors which work through alternative mechanism(s). Recent studies have identified a novel site on the AR called Binding Function 3 (BF3) that is involved into AR transcriptional activity. In order to identify inhibitors that target the BF3 site, we have conducted a large-scale in-silico screen followed by experimental evaluation. A number of compounds were identified that effectively inhibited the AR transcriptional activity with no obvious cytotoxicity. The mechanism of action of these compounds was validated by biochemical assays and x-ray crystallography. These findings lay a foundation for the development of alternative or supplementary therapies capable of combating prostate cancer even in its anti-androgen resistant forms.
PMCID: PMC3668559  PMID: 22047606
anti-androgens; androgen receptor; virtual screening; prostate cancer; drug resistance; protein-protein interactions; protein-protein interactions; co-regulation
13.  CLIP-based prediction of mammalian microRNA binding sites 
Nucleic Acids Research  2013;41(14):e138.
Prediction and validation of microRNA (miRNA) targets are essential for understanding functions of miRNAs in gene regulation. Crosslinking immunoprecipitation (CLIP) allows direct identification of a huge number of Argonaute-bound target sequences that contain miRNA binding sites. By analysing data from CLIP studies, we identified a comprehensive list of sequence, thermodynamic and target structure features that are essential for target binding by miRNAs in the 3′ untranslated region (3′ UTR), coding sequence (CDS) region and 5′ untranslated region (5′ UTR) of target messenger RNA (mRNA). The total energy of miRNA:target hybridization, a measure of target structural accessibility, is the only essential feature common for both seed and seedless sites in all three target regions. Furthermore, evolutionary conservation is an important discriminating feature for both seed and seedless sites. These features enabled us to develop novel statistical models for the predictions of both seed sites and broad classes of seedless sites. Through both intra-dataset validation and inter-dataset validation, our approach showed major improvements over established algorithms for predicting seed sites and a class of seedless sites. Furthermore, we observed good performance from cross-species validation, suggesting that our prediction framework can be valuable for broad application to other mammalian species and beyond. Transcriptome-wide binding site predictions enabled by our approach will greatly complement the available CLIP data, which only cover small fractions of transcriptomes and known miRNAs due to non-detectable levels of expression. Software and database tools based on the prediction models have been developed and are available through Sfold web server at
PMCID: PMC3737542  PMID: 23703212
14.  Feasibility of Using Flash-heated Breastmilk as an Infant Feeding Option for HIV-exposed, Uninfected Infants after 6 Months of Age in Urban Tanzania 
Heat-treating expressed breastmilk is recommended as an interim feeding strategy for HIV-exposed infants in resource-poor countries, but data on its feasibility are minimal. Flash-heating (FH) is a simple in-home technique for heating breastmilk that inactivates HIV while preserving its nutritional and anti-infective properties. Our primary objective was to determine, among HIV-infected mothers, the feasibility and protocol adherence of FH expressed breastmilk after 6 months of exclusive breastfeeding.
Prospective longitudinal
101 HIV-infected breastfeeding mothers
Dar es Salaam, Tanzania
Peer counselors provided in-home counseling and support on infant feeding from 2 to 9 months postpartum. Mothers were encouraged to exclusively breastfeed for 6 months followed by FH expressed breastmilk if her infant was HIV-negative. Clinic-based staff measured infant growth and morbidity monthly and mothers kept daily logs of infant morbidity. FH behavior was tracked until 9 months postpartum using daily logs, in-home observations, and clinic-and home-based surveys. Bacterial cultures of unheated and heated milk samples were performed.
Thirty-seven of 72 eligible mothers (51.4%) chose to Flash-heat. Median (range) frequency of milk expression was 3 (1–6) times daily and duration of method use on-study was 9.7 (0.1–15.6) weeks. Mean (SD) daily milk volume was 322 (201) mL (range 25–1120). No heated and 32 (30.5%) unheated samples contained bacterial pathogens.
FH is a simple technology that many HIV-positive women can successfully use after exclusive breastfeeding to continue to provide the benefits of breastmilk while avoiding maternal-to-child transmission associated with non-exclusive breastfeeding. Based on these feasibility data, a clinical trial of the effects of FH breastmilk on infant health outcomes is warranted.
PMCID: PMC3380080  PMID: 22362154
HIV; infant feeding; breastmilk; pasteurization; feasibility; heat-treatment; Flash-heat; maternal-to-child transmission
15.  The Bin3 RNA methyltransferase (MePCE) targets 7SK RNA to control transcription and translation 
Bin3 is a conserved RNA methyltransferase found in eukaryotes ranging from fission yeast to humans. It was originally discovered as a Bicoid-interacting protein in Drosophila, where it is required for anterior-posterior and dorso-ventral axis determination in the early embryo. The mammalian ortholog of Bin3 (BCDIN3), also known as methyl phosphate capping enzyme (MePCE), plays a key role in repressing transcription. In transcription, MePCE binds the non-coding 7SK RNA, which forms a scaffold for an RNA-protein complex that inhibits P-TEFb, an RNA polymerase II elongation factor. MePCE uses S-adenosyl methionine to transfer a methyl group onto the γ-phosphate of the 5′ guanosine of 7SK RNA generating an unusual cap structure that protects 7SK RNA from degradation. Bin3/MePCE also has a role in translation regulation. Initial studies in Drosophila indicate that Bin3 targets 7SK RNA and stabilizes a distinct RNA-protein complex that assembles on the 3′ UTR of caudal mRNAs to prevent translation initiation. Much remains to be learned about Bin3/MeCPE function, including how it recognizes 7SK RNA, what other RNA substrates it might target, and how widespread a role it plays in gene regulation and embryonic development.
PMCID: PMC3629726  PMID: 22740346
16.  Predictors of Early Post-discharge Mortality in Critically Ill Patients: A Retrospective Cohort Study from the California Intensive Care Outcomes Project 
Journal of critical care  2010;26(1):65-75.
Existing intensive care unit (ICU) mortality measurement systems address in-hospital mortality only. However, early post-discharge mortality contributes significantly to overall 30-day mortality. Factors associated with early post-discharge mortality are unknown.
We performed a retrospective study of 8,484 ICU patients. Our primary outcome was early post-discharge mortality: death after hospital discharge and ≤ 30 days from ICU admission. Cox regression models assessed the association between patient, hospital, and utilization factors and the primary outcome.
In multivariate analyses, the hazard for early post-discharge mortality increased with rising severity of illness and decreased with full code status (HR = 0.33, 95% CI 0.21 to 0.49). Compared to discharges home, early post-discharge mortality was highest for acute care transfers (HR 3.18, 95% CI 2.45 to 4.12). Finally, patients with very short ICU length of stay (< 1 day) had greater early post-discharge mortality (HR 1.86, 95% CI 1.32 to 2.61) than those with longest stays (≥ 7 days).
Early post-discharge mortality is associated with patient preferences (full-code status) and decisions regarding timing and location of discharge. These findings have important implications for anyone attempting to measure or improve ICU performance and who rely upon in-hospital mortality measures to do so.
PMCID: PMC3622215  PMID: 20716477
Intensive Care Unit; Hospital Mortality; Patient Discharge; Outcome Assessment (Health Care); Health Services Research
17.  Prevalence of high Epworth Sleepiness Scale scores in a rural population 
Increased daytime sleepiness is an important symptom of obstructive sleep apnea (OSA). OSA is frequently underdiagnosed, and the Epworth Sleepiness Scale (ESS) can be a useful tool in alerting physicians to a potential problem involving OSA.
To measure the prevalence and determinants of daytime sleepiness measured using the ESS in a rural community population.
A community survey was conducted to examine the risk factors associated with ESS in a rural population in 154 households comprising 283 adults. Questionnaire information was obtained regarding physical factors, social factors, general medical history, family medical history, ESS score, and self-reported height and weight. Multivariable binary logistic regression analysis based on the generalized estimating equations approach to account for clustering within households was used to predict the relationship between a binary ESS score outcome (normal or abnormal) and a set of explanatory variables.
The population included 140 men (49.5%) and 143 women (50.5%) with an age range of 18 to 97 years (mean [± SD] 52.0±14.9 years). The data showed that 79.2% of the study participants had an ESS score in the normal range (0 to 10) and 20.8% had an ESS score >10, which is considered to be abnormal or high sleepiness. Multivariable regression analysis revealed that obesity was significantly associated with an abnormal or high sleepiness score on the ESS (OR 3.40 [95% CI 1.31 to 8.80).
High levels of sleepiness in this population were common. Obesity was an important risk factor for high ESS score.
PMCID: PMC3373290  PMID: 22536583
Epworth Sleepiness Scale; Obesity; Rural; Snoring
18.  Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot study 
Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes.
We followed age-matched healthy controls and CC patients without distant metastasis on radiological imaging before and 6 weeks after hemi-colectomy surgery. Body composition was analysed using dual energy X-ray absorptiometry. Mitochondrial enzyme activity and protein concentrations were analysed in vastus lateralis muscle biopsies.
In pre-surgery, there were no differences in lean mass between CC patients and age-matched controls (46.1 + 32.5 vs. 46.1 + 37.3 kg). Post-resection lean mass was reduced in CC patients (43.8 + 30.3 kg, P < 0.01). When comparing markers of mitochondrial function, the following were observed: pyruvate dehydrogenase (PDH) activity was lower in CC patients pre-surgery (P < 0.001) but normalized post-resection and cytochrome c oxidase and pyruvate dehydrogenase E2 subunit protein expression were lower in CC patients pre-surgery and not restored to control values post-resection (P < 0.001). Nuclear factor kappa-B, an inflammatory marker, was higher in CC patients pre-surgery compared to controls (P < 0.01), returning to control levels post-resection.
Muscle mass was affected by surgery rather than cancer per se. PDH activity was however lower in cancer patients, suggesting that muscle mass and mitochondrial enzyme activity are not inextricably linked. This reduction in mitochondrial enzyme activity may well contribute to the significant risks of major surgery to which CC patients are exposed.
PMCID: PMC3581615  PMID: 22648738
Cancer; Muscle; Mitochondria; Pyruvate dehydrogenase
19.  Left inguinal appendix in an HIV patient: A case report and review of literature 
The presence of the appendix in an inguinal hernia sac is rare, with an estimated incidence of 0.51–1% of all inguinal hernias. An inguinal appendix is most commonly referred to as Amyand's hernia.
A 59-year-old HIV positive male presented to our center with a left painful inguinal mass. The preoperative diagnosis was a left inguinal hernia. Intraoperatively, the sac was found to contain a non inflamed appendix; the appendix was reduced back to the peritoneal cavity and the patient underwent a tension free prosthetic left inguinal hernia repair.
Most cases of inguinal appendices are right-sided and are diagnosed intraoperatively; left-sided cases as we encountered are rare and most likely the result of cecal mobility. Preoperative diagnosis of the entity is difficult and most cases are diagnosed intraoperatively. A CT scan is not necessary unless other pressing differentials need to be ruled out. Most authors agree that if the appendix is not inflamed, appendectomy, concurrently with herniorrhaphy, should not be performed to avoid perioperative septic complications.
Surgical management of inguinal appendices carries a risk of septic complications. This is especially pertinent to our case, considering the immunocompromised status of our patient. The decisions in the operating room were geared toward limiting septic potential.
PMCID: PMC3604666  PMID: 23380372
Amyand hernia; Inguinal appendix
20.  Prevalence, risk factors and co-morbidities of diabetes among adults in rural Saskatchewan: the influence of farm residence and agriculture-related exposures 
BMC Public Health  2013;13:7.
Although rural Canadians are reported to have higher rates of diabetes than others, little is known about the relative influence of known versus agriculture-related risk factors. The purpose of this research was to carry out a comprehensive study of prevalence, risk factors and co-morbidities of diabetes among adults in rural Saskatchewan and to determine possible differences between those living on and off farms.
In 2010, we conducted a baseline mail-out survey (Saskatchewan Rural Health Study) of 11,982 households located in the province′s four agricultural quadrants. In addition to self-reported physician-diagnosed diabetes, the questionnaire collected information from farm and small town cohorts on possible diabetes determinants including lifestyle, family history, early life factors and environmental/agricultural-related exposures. Clustering effect within households was adjusted using Generalized Estimating Equations approach.
Responses were obtained from 4624 (42%) households comprising 8208 males and females aged 18 years or older and 7847 self-described Caucasian participants (7708 with complete information). The overall age-standardized diabetes prevalence for the latter was 6.35% but people whose primary residence was on farms had significantly lower diabetes prevalence than those living in non-farm locations (5.11% versus 7.33% respectively; p<0.0001). Diabetes risk increased with age and affected almost 17% of those older than 65 (OR 2.57; CI′ 1.63, 4.04 compared to those aged 18–45). Other known independent risk factors included family history of diabetes (OR 2.50 [CI′s 1.94, 3.23] if father; OR 3.11 [CI′s 2.44, 3.98] if mother), obesity (OR 2.66; CI′s 1.86, 3.78), as well as lower socioeconomic status, minimal/no alcohol intake and smoking. The most original finding was that exposure to insecticides conferred an increased risk for diabetes among males (OR 1.83; CI′s 1.15, 2.91). Finally, the co-morbidities with the strongest independent association with diabetes were heart disease and hypertension.
While known diabetes risk factors are important determinants of diabetes in the agricultural zones of Saskatchewan, on-farm residence is protective and appears related to increased outdoor activities. In contrast, we have now shown for the first time that exposure to insecticides is an independent risk factor for diabetes among men in rural Canada.
PMCID: PMC3552674  PMID: 23289729
Diabetes; Rural; Agriculture; Insecticides; Farm; Exposures
21.  Don't it make my blue eyes brown: heterochromia and other abnormalities of the iris 
Eye  2011;26(1):29-50.
Eye colour is one of the most important characteristics in determining facial appearance. In this paper I shall discuss the anatomy and genetics of normal eye colour, together with a wide and diverse range of conditions that may produce an alteration in normal iris pigmentation or form.
PMCID: PMC3259577  PMID: 21979861
eye colour; heterochromia; neoplasm; iris; melanoma; melanocyte
22.  Can genetic risk information for age-related macular degeneration influence motivation to stop smoking? A pilot study 
Eye  2011;26(1):109-118.
Smoking can increase the risk of macular degeneration and this is more than additive if a person also has a genetic risk. The purpose of this study was to examine whether knowledge of genetic risk for age-related macular degeneration (AMD) could influence motivation to quit smoking.
A questionnaire-based study of hypothetical case scenarios given to 49 smokers without AMD. Participants were randomly allocated to a generic risk, high genetic risk, or low genetic risk of developing AMD scenario.
Forty-seven percent knew of the link between smoking and eye disease. In all, 76%, 67%, and 46% for the high risk, generic, and low risk groups, respectively, would rethink quitting (Pfor trend=0.082). In all, 67%, 40%, and 38.5%, respectively, would be likely, very likely, or would definitely quit in the following month (Pfor trend=0.023). Few participants (<16% of any group) were very likely to or would definitely attend a quit smoking session with no difference across groups. In all, 75.5% of participants would consider taking a genetic test for AMD.
In this pilot study, a trend was seen for the group given high genetic risk information to be more likely to quit than the generic or low genetic risk groups. Participants were willing to take a genetic test but further work is needed to address the cost benefits of routine genetic testing for risk of AMD. More generic risk information should be given to the public, and health warnings on cigarette packets that ‘smoking causes blindness' is a good way to achieve this.
PMCID: PMC3259589  PMID: 22037055
macular degeneration; smoking; risk factors; smoking cessation; risk
23.  Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperaminoacidemia-hyperinsulinemia in healthy young and middle aged men and women 
Increased dietary long-chain n-3 polyunsaturated fatty acid (LCn-3PUFA) intake stimulates muscle protein anabolism in individuals who experience muscle loss due to aging or cancer cachexia. However, it is not known whether LCn-3PUFA elicit similar anabolic effects in healthy individuals. To answer this question we evaluated the effect of 8 weeks of LCn-3PUFA supplementation (4 g·d−1 of Lovaza®) in nine 25–45 y old healthy subjects on the rate of muscle protein synthesis (by using stable isotope labelled tracer techniques) and the activation (phosphorylation) of elements of the mTOR-p70s6k pathway during basal, postabsorptive conditions and during a hyperinsulinemic-hyperaminoacidemic clamp. We also measured the concentrations of protein, RNA, and DNA in muscle to obtain indices of the protein synthetic capacity, translational efficiency and cell size. Neither the basal muscle protein fractional synthesis rate nor basal signalling element phosphorylation changed in response to LCn-3PUFA supplementation but the anabolic response to insulin and amino acid infusion was greater after LCn-3PUFA (i.e., the muscle protein fractional synthesis rate during insulin and amino acid infusion increased from 0.062 ± 0.004 to 0.083 ± 0.007 %·h−1 and the phospho mTORSer2448 and p70s6kThr389 concentrations increased by ~50%; all P < 0.05). In addition, the muscle protein concentration and the protein-to-DNA ratio (i.e., muscle cell size) were both greater (P < 0.05) after LCn-3PUFA supplementation. We conclude that LCn-3PUFA have anabolic properties in healthy young and middle aged adults.
PMCID: PMC3499967  PMID: 21501117
n-3 PUFA; fish oil; muscle protein synthesis
24.  Postnatal expression of an apamin-sensitive K(Ca) current in vestibular calyx terminals 
The Journal of membrane biology  2011;244(2):81-91.
Afferent innervation patterns in the vestibular periphery are complex and vestibular afferents show a large variation in their regularity of firing. Calyx fibers terminate on type I vestibular hair cells and have firing characteristics distinct from bouton fibers that innervate type II hair cells. Whole cell patch clamp was used to investigate ionic currents that could influence firing patterns in calyx terminals. Underlying K(Ca) conductances have been described in vestibular ganglion cells, but their presence in afferent terminals has not been investigated previously. Apamin, a selective blocker of SK-type calcium-activated K+ channels, was tested on calyx afferent terminals isolated from gerbil semicircular canals during postnatal days 1 to 50. Lowering extracellular calcium or application of apamin (20–500 nM) reduced slowly activating outward currents in voltage clamp. Apamin also reduced the action potential after-hyperpolarization (AHP) in whole cell current clamp, but only after the first two postnatal weeks. K+ channel expression increased during the first postnatal month and SK channels were found to contribute to the AHP, which may in turn influence discharge regularity in calyx vestibular afferents.
PMCID: PMC3242503  PMID: 22057903
Afferent; After-hyperpolarization; Crista; Hair cell; Inner ear; Development
25.  The association between endotoxin and lung function among children and adolescents living in a rural area 
Increased levels of endotoxin found in rural and agricultural areas are an environmental exposure believed to cause a paradoxical proinflammatory effect on respiratory health that can exacerbate asthma. Previous studies involving adults have demonstrated an association between high endotoxin levels and lower lung function. Apart from occupational settings, however, few studies have investigated the relationship between lung function and endotoxin exposure, such as environmental tobacco smoke, especially in children. This study examined the modifying effects of sex, pre-existing asthma and other environmental exposures, including tobacco smoke, in children living in rural communities in Saskatchewan.
Knowledge of the effects of domestic endotoxin on children’s lung function is limited. The association between domestic endotoxin and asthma or wheeze and lung function among school-age children (six to 18 years of age) was examined. The interaction between endotoxin and other personal and environmental characteristics and lung function was also assessed.
A case-control study was conducted in and around the rural community of Humboldt, Saskatchewan, between 2005 and 2007. Parents of cases reported either doctor-diagnosed asthma or wheeze in the previous year. Controls were randomly selected from those not reporting these conditions. Data were collected by questionnaire to ascertain symptoms and conditions, while spirometry was used to measure lung function including forced vital capacity and forced expiratory volume in 1 s. Dust collected from the child’s play area floor and the child’s mattress was used to quantify endotoxin, and saliva was collected to quantify cotinine levels and assess tobacco smoke exposure.
There were 102 cases and 207 controls included in the present study. Lower forced expiratory volume in 1 s was associated with higher mattress endotoxin load among female cases (beta=−0.25, SE=0.07 [P<0.01]). There was a trend toward lower forced vital capacity, which was associated with higher play area endotoxin load among cases with high tobacco smoke exposure (beta=−0.17, SE=0.09 [P<0.10]).
Findings indicated that high endotoxin levels present in common household areas of rural children with asthma or wheeze may also affect their lung function. These associations may be potentiated by tobacco smoke exposure and female sex.
PMCID: PMC3267627  PMID: 22187693
Asthma; Endotoxin; Lung function; Rural; Tobacco smoke; Wheeze

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