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1.  A multidimensional approach to pain assessment in critically ill infants during a painful procedure 
The Clinical journal of pain  2013;29(7):613-620.
Objectives
Inferring the pain level of a critically ill infant is complex. The ability to accurately extract the appropriate pain cues from observations is often jeopardized when heavy sedation and muscular blocking agents are administered. Near-infrared spectroscopy (NIRS) is a noninvasive method that may provide the bridge between behavioral observational indicators and cortical pain processing. We aimed to describe regional cerebral and systemic hemodynamic changes, as well as behavioral reactions in critically ill infants with congenital heart defects (CHD) during chest drain removal following cardiac surgery.
Methods
Our sample included 20 critically ill infants with CHD less than 12 months of age admitted to the cardiac intensive care unit following surgery.
Results
Cerebral deoxygenated hemoglobin concentrations significantly differed across the epochs (i.e. Baseline, Tactile stimulus, Noxious stimulus) (p = .01). Physiological systemic responses and FLACC pain scores differed significantly across the events (p < .01). The three outcome measures were not found to be associated with each other. Mean FLACC pain scores during the painful procedure was 7/10 despite administration of morphine. Midazolam administration accounted for 36% of the variance in pain scores.
Discussion
We demonstrated with a multidimensional pain assessment approach that significant cerebral, physiological and behavioral activity was present in response to a noxious procedure in critically ill infants despite the administration of analgesic treatment. Considering that the sedating agent significantly dampened pain behaviors, assessment of cerebral hemodynamic in the context of pain seems to be an important addition.
doi:10.1097/AJP.0b013e31826dfb13
PMCID: PMC3640737  PMID: 23328334
2.  An initial evaluation of analyser-based phase-contrast X-ray imaging of carotid plaque microstructure 
The British Journal of Radiology  2013;86(1021):20120318.
ABSTRACT.
Carotid artery plaque instability can result in rupture and lead to ischaemic stroke. Stability of plaques appears to be a function of composition. Current non-invasive imaging techniques are limited in their ability to classify distinct histological regions within plaques. Phase-contrast (PC) X-ray imaging methods are an emerging class of techniques that have shown promise for identifying soft-tissue features without use of exogenous contrast agents. This is the first study to apply analyser-based X-ray PC imaging in CT mode to provide three-dimensional (3D) images of excised atherosclerotic plaques. The results provide proof of principle for this technique as a promising method for analysis of carotid plaque microstructure. Multiple image radiography CT (MIR-CT), a tomographic implementation of X-ray PC imaging that employs crystal optics, was employed to image excised carotid plaques. MIR-CT imaging yields three complementary images of the plaque's 3D X-ray absorption, refraction and scatter properties. These images were compared with histological sections of the tissue. X-ray PC images were able to identify the interface between the plaque and the medial wall. In addition, lipid-rich and highly vascularized regions were visible in the images as well as features depicting inflammation. This preliminary research shows MIR-CT imaging can reveal details about plaque structure not provided by traditional absorption-based X-ray imaging and appears to identify specific histological regions within plaques. This is the first study to apply analyser-based X-ray PC imaging to human carotid artery plaques to identify distinct soft-tissue regions.
doi:10.1259/bjr.20120318
PMCID: PMC3615397  PMID: 23239697
3.  HIV knowledge and perceptions of risk in a young, urban, drug-using population 
Public health  2011;125(11):791-794.
doi:10.1016/j.puhe.2011.09.008
PMCID: PMC3220754  PMID: 21996528
4.  A randomized trial of hypothesis-driven vs screening neurologic examination 
Neurology  2011;77(14):1395-1400.
Objective:
We hypothesized that trainees would perform better using a hypothesis-driven rather than a traditional screening approach to the neurologic examination.
Methods:
We randomly assigned 16 medical students to perform screening examinations of all major aspects of neurologic function or hypothesis-driven examinations focused on aspects suggested by the history. Each student examined 4 patients, 2 of whom had focal deficits. Outcomes of interest were the correct identification of patients with focal deficits, number of specific deficits detected, and examination duration. Outcomes were assessed by an investigator blinded to group assignments. The McNemar test was used to compare the sensitivity and specificity of the 2 examination methods.
Results:
Sensitivity was higher with hypothesis-driven examinations than with screening examinations (78% vs 56%; p = 0.046), although specificity was lower (71% vs 100%; p = 0.046). The hypothesis-driven group identified 61% of specific examination abnormalities, whereas the screening group identified 53% (p = 0.008). Median examination duration was 1 minute shorter in the hypothesis-driven group (7.0 minutes vs 8.0 minutes; p = 0.13).
Conclusions:
In this randomized trial comparing 2 methods of neurologic examination, a hypothesis-driven approach resulted in greater sensitivity and a trend toward faster examinations, at the cost of lower specificity, compared with the traditional screening approach. Our findings suggest that a hypothesis-driven approach may be superior when the history is concerning for an acute focal neurologic process.
doi:10.1212/WNL.0b013e3182315249
PMCID: PMC3182756  PMID: 21900631
5.  Secondary preventive medication persistence and adherence 1 year after stroke 
Neurology  2011;77(12):1182-1190.
Objective:
Data on long-term use of secondary prevention medications following stroke are limited. The Adherence eValuation After Ischemic stroke–Longitudinal (AVAIL) Registry assessed patient, provider, and system-level factors influencing continuation of prevention medications for 1 year following stroke hospitalization discharge.
Methods:
Patients with ischemic stroke or TIA discharged from 106 hospitals participating in the American Heart Association Get With The Guidelines–Stroke program were surveyed to determine their use of warfarin, antiplatelet, antihypertensive, lipid-lowering, and diabetes medications from discharge to 12 months. Reasons for stopping medications were ascertained. Persistence was defined as continuation of all secondary preventive medications prescribed at hospital discharge, and adherence as continuation of prescribed medications except those stopped according to health care provider instructions.
Results:
Of the 2,880 patients enrolled in AVAIL, 88.4% (2,457 patients) completed 1-year interviews. Of these, 65.9% were regimen persistent and 86.6% were regimen adherent. Independent predictors of 1-year medication persistence included fewer medications prescribed at discharge, having an adequate income, having an appointment with a primary care provider, and greater understanding of why medications were prescribed and their side effects. Independent predictors of adherence were similar to those for persistence.
Conclusions:
Although up to one-third of stroke patients discontinued one or more secondary prevention medications within 1 year of hospital discharge, self-discontinuation of these medications is uncommon. Several potentially modifiable patient, provider, and system-level factors associated with persistence and adherence may be targets for future interventions.
doi:10.1212/WNL.0b013e31822f0423
PMCID: PMC3265047  PMID: 21900638
6.  Transient ischemic attacks characterized by RNA profiles in blood 
Neurology  2011;77(19):1718-1724.
Objective:
Transient ischemic attacks (TIA) are common. Though systemic inflammation and thrombosis are associated with TIA, further study may provide insight into TIA pathophysiology and possibly lead to the development of treatments specifically targeted to TIA. We sought to determine whether gene expression profiles in blood could better characterize the proinflammatory and procoagulant states in TIA patients.
Methods:
RNA expression in blood of TIA patients (n = 26) was compared to vascular risk factor control subjects without symptomatic cardiovascular disease (n = 26) using Affymetrix U133 Plus 2.0 microarrays. Differentially expressed genes in TIA were identified by analysis of covariance and evaluated with cross-validation and functional analyses.
Results:
Patients with TIA had different patterns of gene expression compared to controls. There were 480 probe sets, corresponding to 449 genes, differentially expressed between TIA and controls (false discovery rate correction for multiple comparisons, p ≤ 0.05, absolute fold change ≥1.2). These genes were associated with systemic inflammation, platelet activation, and prothrombin activation. Hierarchical cluster analysis of the identified genes suggested the presence of 2 patterns of RNA expression in patients with TIA. Prediction analysis identified a set of 34 genes that discriminated TIA from controls with 100% sensitivity and 100% specificity.
Conclusion:
Patients with recent TIA have differences of gene expression in blood compared to controls. The 2 gene expression profiles associated with TIA suggests heterogeneous responses between subjects with TIA that may provide insight into cause, risk of stroke, and other TIA pathophysiology.
doi:10.1212/WNL.0b013e318236eee6
PMCID: PMC3208953  PMID: 21998319
7.  Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA 
Neurology  2011;77(13):1222-1228.
Objectives:
Stroke risk immediately after TIA defined by time-based criteria is high, and prognostic scores (ABCD2 and ABCD3-I) have been developed to assist management. The American Stroke Association has proposed changing the criteria for the distinction between TIA and stroke from time-based to tissue-based. Research using these definitions is lacking. In a multicenter observational cohort study, we have investigated prognosis and performance of the ABCD2 score in TIA, subcategorized as tissue-positive or tissue-negative on diffusion-weighted imaging (DWI) or CT imaging according to the newly proposed criteria.
Methods:
Twelve centers provided data on ABCD2 scores, DWI or CT brain imaging, and follow-up in cohorts of patients with TIA diagnosed by time-based criteria. Stroke rates at 7 and 90 days were studied in relation to tissue-positive or tissue-negative subcategorization, according to the presence or absence of brain infarction. The predictive power of the ABCD2 score was determined using area under receiver operator characteristic curve (AUC) analyses.
Results:
A total of 4,574 patients were included. Among DWI patients (n = 3,206), recurrent stroke rates at 7 days were 7.1%(95% confidence interval 5.5–9.1) after tissue-positive and 0.4% (0.2–0.7) after tissue-negative events (p diff < 0.0001). Corresponding rates in CT-imaged patients were 12.8% (9.3–17.4) and 3.0% (2.0–4.2), respectively (p diff < 0.0001). The ABCD2 score had predictive value in tissue-positive and tissue-negative events (AUC = 0.68 [95% confidence interval 0.63–0.73] and 0.73 [0.67–0.80], respectively; p sig < 0.0001 for both results, p diff = 0.17). Tissue-positive events with low ABCD2 scores and tissue-negative events with high ABCD2 scores had similar stroke risks, especially after a 90-day follow-up.
Conclusions:
Our findings support the concept of a tissue-based definition of TIA and stroke, at least on prognostic grounds.
doi:10.1212/WNL.0b013e3182309f91
PMCID: PMC3179650  PMID: 21865578
8.  Prediction of Cell Penetrating Peptides by Support Vector Machines 
PLoS Computational Biology  2011;7(7):e1002101.
Cell penetrating peptides (CPPs) are those peptides that can transverse cell membranes to enter cells. Once inside the cell, different CPPs can localize to different cellular components and perform different roles. Some generate pore-forming complexes resulting in the destruction of cells while others localize to various organelles. Use of machine learning methods to predict potential new CPPs will enable more rapid screening for applications such as drug delivery. We have investigated the influence of the composition of training datasets on the ability to classify peptides as cell penetrating using support vector machines (SVMs). We identified 111 known CPPs and 34 known non-penetrating peptides from the literature and commercial vendors and used several approaches to build training data sets for the classifiers. Features were calculated from the datasets using a set of basic biochemical properties combined with features from the literature determined to be relevant in the prediction of CPPs. Our results using different training datasets confirm the importance of a balanced training set with approximately equal number of positive and negative examples. The SVM based classifiers have greater classification accuracy than previously reported methods for the prediction of CPPs, and because they use primary biochemical properties of the peptides as features, these classifiers provide insight into the properties needed for cell-penetration. To confirm our SVM classifications, a subset of peptides classified as either penetrating or non-penetrating was selected for synthesis and experimental validation. Of the synthesized peptides predicted to be CPPs, 100% of these peptides were shown to be penetrating.
Author Summary
Cell penetrating peptides (CPPs) are peptides that can potentially transport other functional molecules across cellular membranes and therefore serve a role as drug delivery vehicles. The properties of a given peptide that make it cell penetrating are unclear, and the rapid screening of potential CPPs aids researchers by allowing focus on those peptides most likely to be utilized in a therapeutic capacity. This paper shows that basic features representing primary biochemical properties of these peptides can be used to train a classifier that can accurately predict cell penetrating potential of peptides and provide insight into the biochemical properties associated with cell penetration.
doi:10.1371/journal.pcbi.1002101
PMCID: PMC3136433  PMID: 21779156
9.  Velocities of Bone Mineral Accrual in Black and White American Children 
Journal of Bone and Mineral Research  2010;25(7):1527-1535.
Black adults have higher bone mass than whites in the United States, but it is not clear when black children gain bone mineral faster than white children. We performed a cohort study to compare the growth velocity of total-body bone mineral content (TBMC) between black and white children of the same sex at different ages and stages of sexual maturity. TBMC and total-body area were measured in a cohort of 188 black and white boys and girls aged 5 to 15 years annually for up to 4 years. Rates of change in TBMC and area were found to vary with age and with Tanner stage. For both TBMC and area, growth velocities between black and white children differed significantly across Tanner stages. Age-specific velocities were higher in black children during prepuberty and initial entry into puberty but reversed in subsequent Tanner stages. Despite earlier entry into each Tanner stage, black children spent only an average of only 0.2 year longer in Tanner stages II through IV, and total gain in TBMC from age 5 to 15 was not higher in whites. In conclusion, the higher bone mass in black adults compared with whites cannot be attributed to faster accrual during puberty. It is due to black children's higher rate of bone mineral accrual in prepuberty and plausibly in postpuberty. Most of the racial difference in TBMC velocity can be explained by growth in size. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.43
PMCID: PMC3153996  PMID: 20200959
racial; bone density; growth
10.  The 5-year direct medical cost of neonatal and childhood stroke in a population-based cohort 
Neurology  2010;74(5):372-378.
Background:
Despite increasing awareness of the long-term impact of pediatric stroke, there are few estimates of the costs of care. We examined acute and 5-year direct costs of neonatal and childhood stroke in a population-based cohort in Northern California.
Methods:
We obtained electronic cost data for 266 children with neurologist-confirmed strokes, and 786 age-matched stroke-free controls, within the population of all children (<20 years) enrolled in a large managed care plan from 1996 through 2003. Cost data included all inpatient and outpatient health service costs including care at out-of-plan facilities. Costs were assessed for 5 years after stroke, expressed in 2003 US dollars, and stratified by age at stroke onset (neonatal, defined as <29 days of life, vs childhood). Stroke costs were adjusted for costs in stroke-free age-matched controls.
Results:
Average adjusted 5-year costs for pediatric stroke are substantial: $51,719 for neonatal stroke and $135,161 for childhood stroke. The average cost of a childhood stroke admission was $81,869. The average birth admission cost for a neonatal stroke was $39,613; adjustment for control birth admission costs reduced this by only $4,792, suggesting the stroke accounted for 88% of costs. Even among neonates whose strokes were not recognized until later in childhood (“presumed perinatal strokes”), admission costs exceeded those of controls. Chronic costs were highest in the first year poststroke, but continued to exceed control costs even in the fifth year by an average of $2,016.
Conclusions:
The economic burden of neonatal and childhood stroke is both large and sustained.
GLOSSARY
= interquartile range;
= intraventricular hemorrhage;
= Kaiser Permanente Medical Care Program;
= Kaiser Pediatric Stroke Study;
= length of stay.
doi:10.1212/WNL.0b013e3181cbcd48
PMCID: PMC2816005  PMID: 20054007
11.  A survey of prelicensure pain curricula in health science faculties in Canadian universities 
OBJECTIVE:
The present exploratory, descriptive study aimed to determine the designated time for mandatory pain content in curricula of major Canadian universities for students in health science and veterinary programs before being licensed.
METHOD:
Major Canadian university sites (n=10) were chosen where health science faculties included at least medicine (n=10) and nursing (n=10); many also included dentistry (n=8), pharmacy (n=7), physical therapy (n=8) and/or occupational therapy (n=6). These disciplines provide the largest number of students entering the workforce but are not the only ones contributing to the health professional team. Veterinary programs (n=4) were also surveyed as a comparison. The Pain Education Survey, developed from previous research and piloted, was used to determine total mandatory pain hours.
RESULTS:
The majority of health science programs (67.5%) were unable to specify designated hours for pain. Only 32.5% respondents could identify specific hours allotted for pain course content and/or additional clinical conferences. The average total time per discipline across all years varied from 13 h to 41 h (range 0 h to 109 h). All veterinary respondents identified mandatory designated pain content time (mean 87 h, range 27 h to 200 h). The proportion allotted to the eight content categories varied, but time was least for pain misbeliefs, assessment and monitoring/follow-up planning.
CONCLUSIONS:
Only one-third of the present sample could identify time designated for teaching mandatory pain content. Two-thirds reported ‘integrated’ content that was not quantifiable or able to be determined, which may suggest it is not a priority at that site. Many expressed a need for pain-related curriculum resources.
PMCID: PMC2807771  PMID: 20011714
Canadian health science universities; Prelicensure pain curricula
12.  Inhibition of Multidrug-Resistant Acinetobacter baumannii by Non-Viral Expression of hCAP-18 in a Bioengineered Human Skin Tissue 
When skin is compromised, a cascade of signals initiates the rapid repair of the epidermis to prevent fluid loss and provide defense against invading microbes. During this response, keratinocytes produce host defense peptides that have antimicrobial activity against a diverse set of pathogens. Using non-viral vectors we have genetically modified the novel, non-tumorigenic, pathogen-free human keratinocyte progenitor cell line (NIKS) to express the human cathelicidin host defense peptide in a tissue-specific manner. NIKS skin tissue that expresses elevated levels of cathelicidin possesses key histological features of normal epidermis and displays enhanced antimicrobial activity against bacteria in vitro. Moreover, in an in vivo infected burn wound model, this tissue results in a two log reduction in a clinical isolate of multidrug-resistant Acinetobacter baumannii. Taken together, these results suggest this genetically engineered human tissue could be applied to burns and ulcers to counteract bacterial contamination and prevent infection.
doi:10.1038/mt.2008.289
PMCID: PMC2736055  PMID: 19190595
antimicrobial peptide; cathelicidin; LL-37; engineered skin substitute; Acinetobacter baumannii
13.  Co-bedding as a Comfort measure For Twins undergoing painful procedures (CComForT Trial) 
BMC Pediatrics  2009;9:76.
Background
Co-bedding, a developmental care strategy, is the practice of caring for diaper clad twins in one incubator (versus separating and caring for each infant in separate incubators), thus creating the opportunity for skin-to-skin contact and touch between the twins. In studies of mothers and their infants, maternal skin-to-skin contact has been shown to decrease procedural pain response according to both behavioral and physiological indicators in very preterm neonates. It is uncertain if this comfort is derived solely from maternal presence or from stabilization of regulatory processes from direct skin contact. The intent of this study is to compare the comfort effect of co-bedding (between twin infants who are co-bedding and those who are not) on infant pain response and physiologic stability during a tissue breaking procedure (heelstick).
Methods/Design
Medically stable preterm twin infants admitted to the Neonatal Intensive Care Unit will be randomly assigned to a co-bedding group or a standard care group. Pain response will be measured by physiological and videotaped facial reaction using the Premature Infant Pain Profile scale (PIPP). Recovery from the tissue breaking procedure will be determined by the length of time for heart rate and oxygen saturation to return to baseline. Sixty four sets of twins (n = 128) will be recruited into the study. Analysis and inference will be based on the intention-to-treat principle.
Discussion
If twin contact while co-bedding is determined to have a comforting effect for painful procedures, then changes in current neonatal care practices to include co-bedding may be an inexpensive, non invasive method to help maintain physiologic stability and decrease the long term psychological impact of procedural pain in this high risk population. Knowledge obtained from this study will also add to existing theoretical models with respect to the exact mechanism of comfort through touch.
Trial registration
NCT00917631
doi:10.1186/1471-2431-9-76
PMCID: PMC2804568  PMID: 20003351
14.  Development of a novel oral vaccine against Mycobacterium avium paratuberculosis and Johne disease 
Bioengineered Bugs  2009;1(3):155-163.
Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne disease, a granulomatous enteritis of cattle and other domesticated and wild ruminant species. Johne disease is prevalent worldwide and has a significant impact on the global agricultural economy. Current vaccines against Johne are insufficient in stemming its spread, and associated side-effects prevent their widespread use in control programs. Effective and safe vaccine strategies are needed. The main purpose of this paper is to propose and evaluate the development of a novel oral subunit-vaccine using a patho-biotechnological approach. This novel strategy, which harnesses patho-genetic elements from the intracellular pathogen Listeria monocytogenes, may provide a realistic route towards developing an effective next generation subunit vaccine against Johne disease and paratuberculosis.
doi:10.4161/bbug.1.3.10408
PMCID: PMC3026420  PMID: 21326921
vaccine; paratuberculosis; Johne disease; patho-biotechnology; Listeria monocytogenes
15.  Mutations responsible for Larsen syndrome cluster in the FLNB protein 
Journal of Medical Genetics  2006;43(5):e24.
Background
A gene for Larsen syndrome was recently described, and mutations were reported in five cases.
Objective
To test whether mutations in this gene, FLNB, could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non‐random pattern.
Results
Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected.
Conclusions
Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.
doi:10.1136/jmg.2005.038695
PMCID: PMC2564529  PMID: 16648377
Larsen syndrome; skeletal/craniofacial development; genetic heterogeneity; mutation detection
16.  Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study 
Gut  2005;54(12):1693-1698.
Background: Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis.
Methods: Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3).
Results: Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p<0.05) but did not correlate with GER.
Conclusions: Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.
doi:10.1136/gut.2005.069088
PMCID: PMC1774813  PMID: 16085693
ghrelin; diabetic gastroparesis; pancreatic polypeptide
17.  Kangaroo mother care diminishes pain from heel lance in very preterm neonates: A crossover trial 
BMC Pediatrics  2008;8:13.
Background
Skin-to-skin contact, or kangaroo mother care (KMC) has been shown to be efficacious in diminishing pain response to heel lance in full term and moderately preterm neonates. The purpose of this study was to determine if KMC would also be efficacious in very preterm neonates.
Methods
Preterm neonates (n = 61) between 28 0/7 and 31 6/7 weeks gestational age in three Level III NICU's in Canada comprised the sample. A single-blind randomized crossover design was employed. In the experimental condition, the infant was held in KMC for 15 minutes prior to and throughout heel lance procedure. In the control condition, the infant was in prone position swaddled in a blanket in the incubator. The primary outcome was the Premature Infant Pain Profile (PIPP), which is comprised of three facial actions, maximum heart rate, minimum oxygen saturation levels from baseline in 30-second blocks from heel lance. The secondary outcome was time to recover, defined as heart rate return to baseline. Continuous video, heart rate and oxygen saturation monitoring were recorded with event markers during the procedure and were subsequently analyzed. Repeated measures analysis-of-variance was employed to generate results.
Results
PIPP scores at 90 seconds post lance were significantly lower in the KMC condition (8.871 (95%CI 7.852–9.889) versus 10.677 (95%CI 9.563–11.792) p < .001) and non-significant mean differences ranging from 1.2 to1.8. favoring KMC condition at 30, 60 and 120 seconds. Time to recovery was significantly shorter, by a minute(123 seconds (95%CI 103–142) versus 193 seconds (95%CI 158–227). Facial actions were highly significantly lower across all points in time reaching a two-fold difference by 120 seconds post-lance and heart rate was significantly lower across the first 90 seconds in the KMC condition.
Conclusion
Very preterm neonates appear to have endogenous mechanisms elicited through skin-to-skin maternal contact that decrease pain response, but not as powerfully as in older preterm neonates. The shorter recovery time in KMC is clinically important in helping maintain homeostasis.
Trial Registration
(Current Controlled Trials) ISRCTN63551708
doi:10.1186/1471-2431-8-13
PMCID: PMC2383886  PMID: 18435837
18.  Polymorphisms in the Estrogen Receptor β (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women 
Context
A major determinant of osteoporotic fractures is peak bone mineral density (BMD), which is a highly heritable trait. Recently, we identified significant linkage for hip BMD in premenopausal sister pairs at chromosome 14q (LOD score = 3.5), where the estrogen receptor β gene (ESR2) is located.
Objective
The objective of the study was to determine whether ESR2 polymorphisms are associated with normal BMD variation.
Design
This was a population‐based genetic association study, using 11 single nucleotide polymorphisms (SNPs) distributed across the ESR2 gene.
Setting
The study was conducted at an academic research laboratory and medical center.
Patients and Other Participants
A total of 411 healthy men (aged 18–61 yr) and 1291 healthy premenopausal women (aged 20–50 yr) living in Indiana participated in the study.
Intervention(s)
There were no interventions.
Main Outcome Measure(s)
The main outcome measures were SNP genotype distributions and their association with BMD at the femoral neck and lumbar spine.
Results
Significant association of spine BMD was found with three SNPs in men and one SNP in women (P ≤ 0.05). The conditional linkage analysis using the ESR2 haplotypes showed that the ESR2 gene accounts for, at most, 18% of the original linkage.
Conclusions
ESR2 polymorphisms are significantly associated with bone mass in both men and women. However, the ESR2 gene is not entirely responsible for our original linkage, and an additional gene(s) in chromosome 14q contributes to the determination of BMD.
doi:10.1210/jc.2004-2253
PMCID: PMC1948071  PMID: 16118344
19.  Breast cancer outcomes in South Asian population of West Yorkshire 
British Journal of Cancer  2004;90(10):1926-1932.
doi:10.1038/sj.bjc.6601795
PMCID: PMC2410283  PMID: 15138473
breast cancer; survival; ethnicity; South Asian; treatment delays
20.  Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery 
British Journal of Cancer  2004;90(7):1343-1348.
doi:10.1038/sj.bjc.6601693
PMCID: PMC2409668  PMID: 15054452
breast neoplasms; radiotherapy; adjuvant treatment; treatment delay; survival
21.  Surgeon workload and survival from breast cancer 
British Journal of Cancer  2003;89(3):487-491.
doi:10.1038/sj.bjc.6601148
PMCID: PMC2394379  PMID: 12888817
Breast neoplasms; workload; surgery; survival
22.  Preventing running injuries. Practical approach for family doctors. 
Canadian Family Physician  2003;49:1101-1109.
OBJECTIVE: To present a practical approach for preventing running injuries. QUALITY OF EVIDENCE: Much of the research on running injuries is in the form of expert opinion and comparison trials. Recent systematic reviews have summarized research in orthotics, stretching before running, and interventions to prevent soft tissue injuries. MAIN MESSAGE: The most common factors implicated in running injuries are errors in training methods, inappropriate training surfaces and running shoes, malalignment of the leg, and muscle weakness and inflexibility. Runners can reduce risk of injury by using established training programs that gradually increase distance or time of running and provide appropriate rest. Orthoses and heel lifts can correct malalignments of the leg. Running shoes appropriate for runners' foot types should be selected. Lower-extremity strength and flexibility programs should be added to training. Select appropriate surfaces for training and introduce changes gradually. CONCLUSION: Prevention addresses factors proven to cause running injuries. Unfortunately, injury is often the first sign of fault in running programs, so patients should be taught to recognize early symptoms of injury.
PMCID: PMC2214294  PMID: 14526862
23.  Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer 
British Journal of Cancer  2002;86(7):1097-1103.
Fibroblast growth factor 8 can transform NIH3T3 cells and its expression has been found to be associated with breast and prostate cancer. Following our finding that fibroblast growth factor 8 mRNA expression is increased in breast cancer, we have undertaken an immunohistochemistry study of fibroblast growth factor 8 expression in a series of human breast tissues and other normal tissues. Our findings confirm increased expression of fibroblast growth factor 8 in malignant breast tissue but also show significant fibroblast growth factor 8 expression in non-malignant breast epithelial cells. No significant difference in fibroblast growth factor 8 expression was found between different grades of ductal carcinoma, lobular carcinoma and ductal carcinoma in-situ or cancer of different oestrogen receptor, progesterone receptor or nodal status. The highest levels of fibroblast growth factor 8 expression were found in lactating breast tissues and fibroblast growth factor 8 was also detected in human milk. A survey of other normal tissues showed that fibroblast growth factor 8 is expressed in the proliferative cells of the dermis and epithelial cells in colon, ovary fallopian tube and uterus. Fibroblast growth factor 8 appears to be expressed in several organs in man and appears to have an importance in lactation.
British Journal of Cancer (2002) 86, 1097–1103. DOI: 10.1038/sj/bjc/6600213 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600213
PMCID: PMC2364190  PMID: 11953856
fibroblast growth factor 8; human breast cancer; lactation
24.  Comparison of the RNA-amplification based methods RT–PCR and NASBA for the detection of circulating tumour cells 
British Journal of Cancer  2002;86(1):102-109.
Increasingly, reverse transcriptase polymerase chain reaction (RT–PCR) is used to detect clinically significant tumour cells in blood or bone marrow. This may result in a redefinition of disease-free and clinical relapse. However, its clinical utility may be limited by lack of automation or reproducibility. Recent studies have suggested nucleic acid sequence-based amplification of target RNA may be more robust. In this study, nucleic acid sequence-based amplification was established to detect melanoma, colorectal and prostate cancer cells. Nucleic acid sequence-based amplification and RT–PCR both successfully amplified target RNA in peripheral blood samples from patients with melanoma and colorectal cancer, but only RT–PCR detected PSA in blood samples from patients with prostate cancer. There was relatively good agreement between sample replicates analyzed by RT–PCR (Kappa values of one for tyrosinase, 0.67 for CK-20 and one for PSA), but less agreement when analyzed by nucleic acid sequence-based amplification. This may limit the routine use of NASBA for the detection of clinically significant disease. In summary, RT–PCR appears at present to be the most reliable and reproducible method for the detection of low-level disease in cancer patients, although prospective studies are warranted to assess the clinical utility of different molecular diagnostic methods.
British Journal of Cancer (2002) 86, 102–109. DOI: 10.1038/sj/bjc/6600014 www.bjcancer.com
© 2002 The Cancer Research Campaign
doi:10.1038/sj.bjc.6600014
PMCID: PMC2746547  PMID: 11857020
RT–PCR; NASBA; minimal-disease; prostate; melanoma; colorectal
25.  Unsuspected thyrotoxicosis and hyperemesis gravidarum in Asian women. 
Postgraduate Medical Journal  1997;73(858):234-236.
This report describes three women with hyperemesis gravidarum caused by previously undiagnosed thyrotoxicosis. All three women were eight weeks pregnant and only one woman had typical features of thyrotoxicosis. Hyperemesis could not be controlled by anti-emetics. The patients were successfully treated with antithyroid drugs. Anti-thyroid treatment does not need to be continued once resolution of symptoms and thyrotoxicosis have occurred.
PMCID: PMC2431283  PMID: 9156127

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