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1.  Prevention of respiratory complications after abdominal surgery: a randomised clinical trial. 
BMJ : British Medical Journal  1996;312(7024):148-153.
OBJECTIVE--To evaluate the prevention of respiratory complications after abdominal surgery by a comparison of a global policy of incentive spirometry with a regimen consisting of deep breathing exercises for low risk patients and incentive spirometry plus physiotherapy for high risk patients. DESIGN--Stratified randomised trial. SETTING--General surgical service of an urban teaching hospital. PATIENTS--456 patients undergoing abdominal surgery. Patients less than 60 years of age with an American Society of Anesthesia classification of 1 were considered to be at low risk. OUTCOME MEASURES--Respiratory complications were defined as clinical features consistent with collapse or consolidation, a temperature above 38 degrees C, plus either confirmatory chest radiology or positive results on sputum microbiology. We also recorded the time that staff devoted to prophylactic respiratory therapy. RESULTS--There was good baseline equivalence between the groups. The incidence of respiratory complications was 15% (35/231) for patients in the incentive spirometry group and 12% (28/225) for patients in the mixed therapy group (P = 0.40; 95% confidence interval -3.6% to 9.0%). It required similar amounts of staff time to provide incentive spirometry and deep breathing exercises for low risk patients. The inclusion of physiotherapy for high risk patients, however, resulted in the utilisation of an extra 30 minutes of staff time per patient. CONCLUSIONS--When the use of resources is taken into account, the most efficient regimen of prophylaxis against respiratory complications after abdominal surgery is deep breathing exercises for low risk patients and incentive spirometry for high risk patients.
PMCID: PMC2349849  PMID: 8563533
2.  Delirium in the Cardiovascular Intensive Care Unit: Exploring Modifiable Risk Factors 
Critical care medicine  2013;41(2):405-413.
Delirium, an acute organ dysfunction, is common among critically ill patients leading to significant morbidity and mortality; its epidemiology in a mixed cardiology and cardiac surgery intensive care unit (CVICU) is not well established. We sought to determine the prevalence and risk factors for delirium among CVICU patients.
Prospective observational study.
27-bed medical-surgical CVICU.
200 consecutive patients with an expected CVICU length of stay >24 hours.
Baseline demographic data and daily assessments for delirium using the validated and reliable Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) were recorded, and quantitative tracking of delirium risk factors were conducted. Separate analyses studied the role of admission risk factors for occurrence of delirium during the CVICU stay and identified daily occurring risk factors for the development of delirium on a subsequent CVICU day.
Main Results
Prevalence of delirium was 26%, similar among cardiology and cardiac surgical patients. Nearly all (92%) exhibited the hypoactive subtype of delirium. Benzodiazepine use on admission was independently predictive of a 3-fold increased risk of delirium [Odds Ratio 3.1 (1, 9.4), p=0.04] during the CVICU stay. Of the daily occurring risk factors, patients who received benzodiazepines [2.6 (1.2, 5.7), p=0.02] or had restraints or devices that precluded mobilization [2.9 (1.3, 6.5), p<0.01] were more likely to have delirium the following day. Hemodynamic status was not associated with delirium.
Delirium occurred in 1 in 4 patients in the CVICU and was predominately hypoactive in subtype. Chemical restraints via use of benzodiazepines or the use of physical restraints/restraining devices predisposed patients to a greater risk of delirium, pointing to areas of quality improvement that would be new to the vast majority of CVICUs.
PMCID: PMC3557701  PMID: 23263581
delirium; cardiovascular intensive care unit; acute coronary syndrome; cardiac surgery; benzodiazepines; restraints
3.  A Rare Presentation of Community Acquired Methicillin Resistant Staphylococcus aureus 
Prostatic abscess is a rarely described condition and is commonly caused by gram-negative organisms such as enterobacteria. However, as the prevalence of methicillin resistant Staphylococcus aureus (MRSA) increases in the community, unusual infections due to this organism have been recently published. In this report, we describe a patient with diabetes mellitus type 2, who presents with diabetic ketoacidosis—later found to be due to a prostatic abscess from which MRSA was cultured.
PMCID: PMC3888670  PMID: 24459592
4.  Digital music exposure reliably induces temporary threshold shift (TTS) in normal hearing human subjects 
Ear and hearing  2012;33(6):e44-e58.
One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is availability of an established clinical paradigm with real world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal hearing human subjects.
Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93–95 (n=10), 98–100 (n=11), or 100–102 (n=12) dBA in-ear exposure level for a period of four hours. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured prior to and after music exposure. Post-music tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and one week later.
Changes in thresholds after the lowest level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a “notch” configuration, with the largest changes observed at 4 kHz (mean=6.3±3.9dB; range=0–13 dB). Recovery was largely complete within the first 4 hours post-exposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1-week post-exposure.
These data provide insight into the variability of TTS induced by music player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function following digital music player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in future TTS studies, including protective agent evaluations, that some noise exposures have resulted in neural degeneration in animal models, even when both audiometric thresholds and DPOAE levels returned to pre-exposure values.
PMCID: PMC3480981  PMID: 22885407
music; hearing loss; digital audio player; MP3; distortion product otoacoustic emission; temporary threshold shift; TTS
5.  Enhanced stability of microRNA expression facilitates classification of FFPE tumour samples exhibiting near total mRNA degradation 
British Journal of Cancer  2012;107(4):684-694.
As degradation of formalin-fixed paraffin-embedded (FFPE) samples limits the ability to profile mRNA expression, we explored factors predicting the success of mRNA expression profiling of FFPE material and investigated an approach to overcome the limitation.
Bladder (n=140, stored 3–8 years) and cervix (n=160, stored 8–23 years) carcinoma FFPE samples were hybridised to Affymetrix Exon 1.0ST arrays. Percentage detection above background (%DABG) measured technical success. Biological signal was assessed by distinguishing cervix squamous cell carcinoma (SCC) and adenocarcinoma (AC) using a gene signature. As miR-205 had been identified as a marker of SCC, precursor mir-205 was measured by Exon array and mature miR-205 by qRT–PCR. Genome-wide microRNA (miRNA) expression (Affymetrix miRNA v2.0 arrays) was compared in eight newer FFPE samples with biological signal and eight older samples without.
RNA quality controls (QCs) (e.g., RNA integrity (RIN) number) failed to predict profiling success, but sample age correlated with %DABG in bladder (R=−0.30, P<0.01) and cervix (R=−0.69, P<0.01). Biological signal was lost in older samples and neither a signature nor precursor mir-205 separated samples by histology. miR-205 qRT–PCR discriminated SCC from AC, validated by miRNA profiling (26-fold higher in SCC; P=1.10 × 10−5). Genome-wide miRNA (R=0.95) and small nucleolar RNA (R=0.97) expression correlated well in the eight newer vs older FFPE samples and better than mRNA expression (R=0.72).
Sample age is the best predictor of successful mRNA profiling of FFPE material, and miRNA profiling overcomes the limitation of age and copes well with older samples.
PMCID: PMC3419950  PMID: 22805332
microRNA; FFPE; degradation; microarray; snoRNA; profiling
6.  In Vivo Neutralization of α-Cobratoxin with High-Affinity Llama Single-Domain Antibodies (VHHs) and a VHH-Fc Antibody 
PLoS ONE  2013;8(7):e69495.
Small recombinant antibody fragments (e.g. scFvs and VHHs), which are highly tissue permeable, are being investigated for antivenom production as conventional antivenoms consisting of IgG or F(ab’)2 antibody fragments do not effectively neutralize venom toxins located in deep tissues. However, antivenoms composed entirely of small antibody fragments may have poor therapeutic efficacy due to their short serum half-lives. To increase serum persistence and maintain tissue penetration, we prepared low and high molecular mass antivenom antibodies. Four llama VHHs were isolated from an immune VHH-displayed phage library and were shown to have high affinity, in the low nM range, for α-cobratoxin (α–Cbtx), the most lethal component of Naja kaouthia venom. Subsequently, our highest affinity VHH (C2) was fused to a human Fc fragment to create a VHH2-Fc antibody that would offer prolonged serum persistence. After in planta (Nicotiana benthamiana) expression and purification, we show that our VHH2-Fc antibody retained high affinity binding to α–Cbtx. Mouse α–Cbtx challenge studies showed that our highest affinity VHHs (C2 and C20) and the VHH2-Fc antibody effectively neutralized lethality induced by α–Cbtx at an antibody:toxin molar ratio as low as ca. 0.75×:1. Further research towards the development of an antivenom therapeutic involving these anti-α-Cbtx VHHs and VHH2-Fc antibody molecules should involve testing them as a combination, to determine whether they maintain tissue penetration capability and low immunogenicity, and whether they exhibit improved serum persistence and therapeutic efficacy.
PMCID: PMC3718736  PMID: 23894495
7.  Regulatory role of suppressive motifs from commensal DNA 
Mucosal immunology  2012;5(6):623-634.
The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, are enriched in suppressive motifs able to inhibit lamina propria DC activation. In addition, immunosuppressive oligonucleotides sustain Treg cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes.
PMCID: PMC3427718  PMID: 22617839
8.  Transfer of auxinic herbicide resistance from Brassica kaber to Brassica juncea and Brassica rapa through embryo rescue 
Auxinic herbicides are widely used in agriculture to selectively control broadleaf weeds. Prolonged use of auxinic herbicides has resulted in the evolution of resistance to these herbicides in some biotypes of Brassica kaber (wild mustard), a common weed in agricultural crops. In this study, auxinic herbicide resistance from B. kaber was transferred to Brassica juncea and Brassica rapa, two commercially important Brassica crops, by traditional breeding coupled with in vitro embryo rescue. A high frequency of embryo regeneration and hybrid plant establishment was achieved. Transfer of auxinic herbicide resistance from B. kaber to the hybrids was assessed by whole-plant screening of hybrids with dicamba, a widely used auxinic herbicide. Furthermore, the hybrids were tested for fertility (both pollen and pistil) and their ability to produce backcross progeny. The auxinic herbicide-resistant trait was introgressed into B. juncea by backcross breeding. DNA ploidy of the hybrids as well as of the backcross progeny was estimated by flow cytometry. Creation of auxinic herbicide-resistant Brassica crops by non-transgenic approaches should facilitate effective weed control, encourage less tillage, provide herbicide rotation options, minimize occurrence of herbicide resistance, and increase acceptance of these crops.
PMCID: PMC3751267  PMID: 23990700
Auxinic herbicides; Embryo rescue; Dicamba; Introgression
9.  Evaluation of surveillance for surgical site infections in Thika Hospital, Kenya 
The Journal of Hospital Infection  2013;83(2):140-145.
In low-income countries, surgical site infections (SSIs) are a very frequent form of hospital-acquired infection. Surveillance is an important method for controlling SSI but it is unclear how this can best be performed in low-income settings.
To examine the epidemiological characteristics of various components of an SSI surveillance programme in a single Kenyan hospital.
The study assessed the inter-observer consistency of the surgical wound class (SWC) and American Society of Anesthesiologists (ASA) scores using the kappa statistic. Post-discharge telephone calls were evaluated against an outpatient clinician review ‘gold standard’. The predictive value of components of the Centers for Disease Control and Prevention – National Healthcare Safety Network (CDC-NHNS) risk index was examined in patients having major obstetric or gynaecological surgery (O&G) between August 2010 and February 2011.
After appropriate training, surgeons and anaesthetists were found to be consistent in their use of the SWC and ASA scores respectively. Telephone calls were found to have a sensitivity of 70% [95% confidence interval (CI): 47–87] and a specificity of 100% (95% CI: 95–100) for detection of post-discharge SSI in this setting. In 954 patients undergoing major O&G operations, the SWC score was the only parameter in the CDC-NHNS risk index model associated with the risk of SSI (odds ratio: 4.00; 95% CI: 1.21–13.2; P = 0.02).
Surveillance for SSI can be conducted in a low-income hospital setting, although dedicated staff, intensive training and local modifications to surveillance methods are necessary. Surveillance for post-discharge SSI using telephone calls is imperfect but provides a practical alternative to clinic-based diagnosis. The SWC score was the only predictor of SSI risk in O&G surgery in this context.
PMCID: PMC3580288  PMID: 23332563
Epidemiology; Kenya; Sub-Saharan Africa; Surgical site infection; Surveillance
10.  A meta-analysis of cancer risk associated with the TP53 intron 3 duplication polymorphism (rs17878362): geographic and tumor-specific effects 
Cell Death & Disease  2013;4(2):e492-.
We have performed a meta-analysis of cancer risk associated with the rs17878362 polymorphism of the TP53 suppressor gene (PIN3, (polymorphism in intron 3), 16 bp sequence insertion/duplication in intron 3), using a compilation of a total of 25 published studies with 10 786 cases and 11 760 controls. Homozygote carriers of the duplicated allele (A2A2) had a significantly increased cancer risk compared with A1A1 carriers (aggregated odds ratio (OR)=1.45, 95% confidence interval (CI)=1.22–1.74). However, there was no significant effect for the A1A2 heterozygotes (A1A2 versus A1A1 aggregated OR=1.08, 95% CI=0.99–1.18). No significant heterogeneity or publication bias was detected in the data set analysed. When comparing populations groups, increased cancer risk was associated with A2A2 carriage in Indian, Mediterranean and Northern Europe populations but not in the Caucasian population of the United States. Analysis by cancer site showed an increased risk for A2A2 carriers for breast and colorectal, but not for lung cancers. These results support that the A2A2 genotype of rs17878362 is associated with increased cancer risk, with population and tumour-specific effects.
PMCID: PMC3734845  PMID: 23412385
TP53; rs17878362; intron3; PIN3
11.  Biological functions of p53 isoforms through evolution: lessons from animal and cellular models 
Cell Death and Differentiation  2011;18(12):1815-1824.
The TP53 tumour-suppressor gene is expressed as several protein isoforms generated by different mechanisms, including use of alternative promoters, splicing sites and translational initiation sites, that are conserved through evolution and within the TP53 homologues, TP63 and TP73. Although first described in the eighties, the importance of p53 isoforms in regulating the suppressive functions of p53 has only become evident in the last 10 years, by analogy with observations that p63 and p73 isoforms appeared indispensable to fully understand the biological functions of TP63 and TP73. This review summarizes recent advances in the field of ‘p53 isoforms', including new data on p63 and p73 isoforms. Details of the alternative mechanisms that produce p53 isoforms and cis- and trans-regulators identified are provided. The main focus is on their biological functions (apoptosis, cell cycle, aging and so on) in cellular and animal models, including mouse, zebrafish and Drosophila. Finally, the deregulation of p53 isoform expression in human cancers is reviewed. Based on these latest results, several developments are expected in the future: the identification of drugs modulating p53 isoform expression; the generation of animal models and the evaluation of the use of p53 isoform as biomarkers in human cancers.
PMCID: PMC3214904  PMID: 21941372
tumour suppressor; p53; p63; p73; p53 family; isoforms
12.  Is pre-operative imaging essential prior to ureteric stone surgery? 
The aim of this study was to identify patients not requiring ureteric stone surgery based on pre-operative imaging (within 24 hours) prior to embarking on semirigid ureteroscopy (R-URS) for urolithiasis.
The imaging of all consecutive patients on whom R-URS for urolithiasis was performed over a 12-month period was reviewed. All patients had undergone a plain x-ray of the kidney, ureters and bladder (KUB), abdominal non-contrast computed tomography (NCCT-KUB) or both on the day of surgery.
A total of 96 patients were identified for the study. Stone sizes ranged from 3mm to 20mm. Thirteen patients (14%) were cancelled as no stone(s) were identified on pre-operative imaging. Of the patients cancelled, 8 (62%) required NCCT-KUB to confirm spontaneous stone passage.
One in seven patients were stone free on the day of surgery. This negates the need for unnecessary anaesthetic and instrumentation of the urinary tract, with the associated morbidity. Up-to-date imaging prior to embarking on elective ureteric stone surgery is highly recommended.
PMCID: PMC3954325  PMID: 22943334
Urolithiasis; Ureteroscopy; Imaging
13.  A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models 
Toxicological Sciences  2012;130(2):416-426.
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing. We tested the hypothesis that the kidney safety liability of DB289 would be detected in a mouse diversity panel (MDP) comprised of 34 genetically diverse inbred mouse strains. MDP mice received 10 days of oral treatment with DB289 or vehicle and classical renal biomarkers blood urea nitrogen (BUN) and serum creatinine (sCr), as well as urine biomarkers of kidney injury were measured. While BUN and sCr remained within reference ranges, marked elevations were observed for kidney injury molecule-1 (KIM-1) in the urine of sensitive mouse strains. KIM-1 elevations were not always coincident with elevations in alanine aminotransferase (ALT), suggesting that renal injury was not linked to hepatic injury. Genome-wide association analyses of KIM-1 elevations indicated that genes participating in cholesterol and lipid biosynthesis and transport, oxidative stress, and cytokine release may play a role in DB289 renal injury. Taken together, the data resulting from this study highlight the utility of using an MDP to predict clinically relevant toxicities, to identify relevant toxicity biomarkers that may translate into the clinic, and to identify potential mechanisms underlying toxicities. In addition, the sensitive mouse strains identified in this study may be useful in screening next-in-class compounds for renal injury.
PMCID: PMC3498743  PMID: 22940726
pharmacogenetic; mouse diversity panel; DB289; human African trypanosomiasis; sleeping sickness
14.  Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome 
Immunity  2011;35(2):194-207.
Although Toll-like receptor 9 (TLR9) has been implicated in regulating cytokine and type I interferon (IFN) production during malaria in humans and mice, the high AT content of the Plasmodium falciparum genome prompted us to examine the possibility that malarial DNA triggered TLR9-independent DNA sensing pathways. Over 6000 ATTTTTAC (“AT-rich”) motifs are present in the genome of P. falciparum, which we show here potently induce type I IFNs. Parasite DNA, parasitized erythrocytes and oligonucleotides containing the AT-r motif induce type I IFNs via a pathway that did not involve previously described sensors including TLR9, DAI, RNA polymerase-III or IFI16/p204. Rather, AT-rich DNA sensing involved an unknown receptor that coupled to STING, TBK1 and IRF3-IRF7 signaling pathway. Mice lacking both IRF3 and IRF7, the kinase TBK1 or the type I IFN receptor were resistant to otherwise lethal cerebral malaria. Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria.
PMCID: PMC3162998  PMID: 21820332
15.  The Role of Retinoic Acid in Tolerance and Immunity 
Immunity  2011;35(1):13-22.
PMCID: PMC3418663  PMID: 21777796
16.  Muscle Invasive Bladder Cancer: From Diagnosis to Survivorship 
Advances in Urology  2012;2012:142135.
Bladder cancer is the fifth most commonly diagnosed cancer and the most expensive adult cancer in average healthcare costs incurred per patient in the USA. However, little is known about factors influencing patients' treatment decisions, quality of life, and responses to treatment impairments. The main focus of this paper is to better understand the impact of muscle invasive bladder cancer on patient quality of life and its added implications for primary caregivers and healthcare providers. In this paper, we discuss treatment options, side effects, and challenges that patients and family caregivers face in different phases along the disease trajectory and further identify crucial areas of needed research.
PMCID: PMC3424737  PMID: 22924038
17.  Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha 
Immunity  2011;34(3):435-447.
Vitamin A and its metabolite, retinoic acid (RA), have recently been implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we show that RA is also required to elicit proinflammatory CD4+ helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) is the critical mediator of these effects. Strikingly, antagonism of RAR signaling and deficiency in RARα(Rara−/−) results in a cell autonomous CD4+ T cell activation defect. Altogether, these findings reveal a fundamental role for the RA/RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses.
PMCID: PMC3415227  PMID: 21419664
18.  The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI 
Translational Psychiatry  2012;2(7):e130-.
Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.
PMCID: PMC3410628  PMID: 22760554
amygdala; anterior cingulate; bipolar disorder; fMRI; polygenic
19.  Air Pollution, Its Mortality Risk, and Economic Impacts in Tehran, Iran 
Air pollution in Tehran is widely recognized as a serious environmental challenge, posing significant threats to the health of the resident population. Improving air quality will be difficult for many reasons, including climate and topography, heavy dependence on motor vehicles for mobility, and limited resources to reduce polluting emissions. Consequently, it is useful to have information regarding the scale of the health threat and the economic value of reducing that threat.
This paper integrates information on air quality, population, economic valuation, and health science to assess the most serious impact of fine particle pollution on humans, which is increased mortality risk, and provides estimates of the costs of present pollution levels, both in terms of risk and in terms of economic value relative to attaining air quality standards.
Mid-range results indicate that mortality risk for the population aged 30 and over would be reduced from 8.2 per 1,000 residents annually to 7.4 per 1,000 and that the estimated annual economic benefits of this reduced risk would be $378.5 million, if health-based World Health Organization-recommended annual average PM2.5 standards were met.
The potential public health benefits of reducing particulate air pollution are significant, and will increase with growing population.
PMCID: PMC3468981  PMID: 23113175
Air pollution; Mortality; Iran
20.  Modifiable and fixed factors predicting quality of life in people with colorectal cancer 
British Journal of Cancer  2011;104(11):1697-1703.
People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it.
Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30).
Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R2=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R2=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors.
Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.
PMCID: PMC3111166  PMID: 21559017
quality of life; colorectal cancer; assessment
21.  Spectral integration and bandwidth effects on speech recognition in school-aged children and adults 
Ear and Hearing  2010;31(1):56-62.
Previous studies have shown that adult listeners are more adept than child listeners at identifying spectrally-degraded speech. However, the development of the ability to combine speech information from different frequency regions has received little previous attention. The purpose of the present study was to determine the effect of age on the bandwidth necessary to achieve a relatively low criterion level of speech recognition for two frequency bands, then to determine the improvement in speech recognition that resulted when both speech bands were present simultaneously.
Listeners in the present study included normal-hearing children (6–14 years old, n=18) and adults (n=11). In the first stage of testing, sentences were bandpass-filtered around either 500 or 2500 Hz, and the bandwidth of that filter was varied adaptively to determine the width required for approximately 15–25% correct speech recognition. In the second stage of testing, these criterion bandwidths were presented in fixed block trials with either one band or both bands, and percent correct performance was determined.
Results suggest that age is inversely associated with the bandwidth required to achieve a relatively low criterion level of speech recognition for speech bands centered at either 500 Hz or 2500 Hz. However, both adults and children show a similar, large improvement in performance when both bands are presented simultaneously.
Although younger children require more bandwidth to correctly recognize speech filtered around a single frequency, they appear to be relatively adept at integrating frequency-distributed information to recognize a composite stimulus.
PMCID: PMC3341940  PMID: 19816182
22.  Stimulation of TLR4 by recombinant HSP70 requires structural integrity of the HSP70 protein itself 
Toll-like receptor 4 (TLR4) is activated by bacterial endotoxin, a prototypical pathogen-associated molecular pattern (PAMP). It has been suggested that TLR4 can also be activated by damage-associated molecular pattern (DAMP) proteins such as HSP70. It remains a challenge to provide unequivocal evidence that DAMP proteins themselves play a role in TLR4 activation, as the DAMP proteins used are often contaminated with endotoxin and other TLR ligands introduced during protein expression and/or purification.
Here we report that the activation of TLR4 on primary human macrophage cultures by recombinant HSP70 is not solely due to contaminating endotoxin. Polymyxin B pretreatment of HSP70 preparations to neutralize contaminating endotoxin caused significant reductions in the amount of TNF-α induced by the recombinant protein as determined by ELISA. However, digestion of HSP70 with Proteinase K-agarose beads also dramatically reduced the TNF-α response of macrophages to HSP70, while leaving levels of contaminating endotoxin largely unchanged relative to controls.
These results indicate that the stimulatory effect of recombinant HSP70 requires both the presence of endotoxin and structural integrity of the heat shock protein itself.
PMCID: PMC3355006  PMID: 22448747
Endotoxin; Heat shock protein 70; Polymyxin B; Proteinase K; TLR4
23.  Exon-array profiling unlocks clinically and biologically relevant gene signatures from formalin-fixed paraffin-embedded tumour samples 
British Journal of Cancer  2011;104(6):971-981.
Degradation and chemical modification of RNA in formalin-fixed paraffin-embedded (FFPE) samples hamper their use in expression profiling studies. This study aimed to show that useful information can be obtained by Exon-array profiling archival FFPE tumour samples.
Nineteen cervical squamous cell carcinoma (SCC) and 9 adenocarcinoma (AC) FFPE samples (10–16-year-old) were profiled using Affymetrix Exon arrays. The gene signature derived was tested on a fresh-frozen non-small cell lung cancer (NSCLC) series. Exploration of biological networks involved gene set enrichment analysis (GSEA). Differential gene expression was confirmed using Quantigene, a multiplex bead-based alternative to qRT–PCR.
In all, 1062 genes were higher in SCC vs AC, and 155 genes higher in AC. The 1217-gene signature correctly separated 58 NSCLC into SCC and AC. A gene network centered on hepatic nuclear factor and GATA6 was identified in AC, suggesting a role in glandular cell differentiation of the cervix. Quantigene analysis of the top 26 differentially expressed genes correctly partitioned cervix samples as SCC or AC.
FFPE samples can be profiled using Exon arrays to derive gene expression signatures that are sufficiently robust to be applied to independent data sets, identify novel biology and design assays for independent platform validation.
PMCID: PMC3065290  PMID: 21407225
cervix cancer; exon array; expression profiling; FFPE; histology
24.  Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens 
Nature  2011;471(7337):220-224.
Under physiological conditions the gut associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens1,2. A notable counter-example is celiac disease, where genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T cell and antibody responses against dietary gluten, a protein present in wheat3. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, was shown to play a critical role in the induction of intestinal regulatory responses4–6. We found that in conjunction with IL-15, a cytokine greatly upregulated in the gut of celiac disease patients, retinoic acid rapidly activated dendritic cells to induce JNK phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings unveil an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.
PMCID: PMC3076739  PMID: 21307853
25.  Evidence of hearing loss in a “normally-hearing” college-student population 
International journal of audiology  2011;50(Suppl 1):S21-S31.
We report pure-tone hearing threshold findings in 56 college students. All subjects reported normal hearing during telephone interviews, yet not all subjects had normal sensitivity as defined by well-accepted criteria. At one or more test frequencies (0.25–8 kHz), 7% of ears had thresholds ≥25 dB HL and 12% had thresholds ≥20 dB HL. The proportion of ears with abnormal findings decreased when three-frequency pure-tone-averages were used. Low-frequency PTA hearing loss was detected in 2.7% of ears and high-frequency PTA hearing loss was detected in 7.1% of ears; however, there was little evidence for “notched” audiograms. There was a statistically reliable relationship in which personal music player use was correlated with decreased hearing status in male subjects. Routine screening and education regarding hearing loss risk factors are critical as college students do not always self-identify early changes in hearing. Large-scale systematic investigations of college students’ hearing status appear to be warranted; the current sample size was not adequate to precisely measure potential contributions of different sound sources to the elevated thresholds measured in some subjects.
PMCID: PMC3095511  PMID: 21288064
college student population; hearing loss; high frequency; noise

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