Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Applicants' Self-Reported Priorities in Selecting a Residency Program.

BACKGROUND: Residency recruitment is a high-stakes activity for all participants, yet there is limited information about how applicants choose among programs. OBJECTIVE: This study evaluated the importance applicants place on various residency program attributes; whether applicant priorities vary by sex, race/ethnicity, or specialty choice; and whether the importance of these factors changes over time. METHODS: Highly ranked applicants to residency programs at 2 academic medical centers were surveyed annually from 2004 to 2012 regarding the importance of 26 characteristics in selecting a program. Mean ratings of importance for each factor were analyzed to assess priority for the overall applicant group, and whether priorities differed for subgroups (by sex, race/ethnicity, and specialty). RESULTS: Of 9669 applicants surveyed, 6285 (65%) responded. The 5 factors with highest rating of importance (overall and across all subgroups) were the program's ability to prepare residents for future training or position, resident esprit de corps, faculty availability and involvement in teaching, depth and breadth of faculty, and variety of patients and clinical resources. Small but significant differences in the ratings of some factors by sex and/or specialty group were identified. Institution-level characteristics, such as call rooms, salary, and benefits, were relatively unimportant. Applicant priorities were stable over the 9-year study period. CONCLUSIONS: Highly ranked applicants to competitive residency programs value educational aspects of the program most highly, along with resident morale. Top factors were consistent across subgroups and over the 9 years of the study. These findings have implications for resident recruitment strategies.

A novel biosensor for quantitative monitoring of on-target activity of paclitaxel.

This study describes a system for quantifying paclitaxel activity using the C-terminus of α-tubulin as a biomarker. Following stabilization of microtubules with paclitaxel, a specific detyrosination reaction occurs at the C-terminus of α-tubulin which could be used to assess efficacy. A fluorescence resonance energy transfer (FRET) based biosensor was synthesized comprising a short peptide that corresponded to the C-terminus of α-tubulin, a fluorophore (Abz), and a quencher (Dnp). The fluorophore added to the end of the peptide can be released upon enzymatic detyrosination. In addition, a single fluorophore-tagged peptide was also conjugated to mesoporous silica nanoparticles to examine the feasibility of combining the drug with the peptide biomarker. As a proof of concept, we found that the degree of peptide cleavage, and therefore enzymatic activity, was directly correlated with exogenous bovine carboxypeptidase (CPA) an enzyme that mimics endogenous detyrosination. In addition, we show that cell lysates obtained from paclitaxel-treated cancer cells competed with exogenous CPA for biosensor cleavage in a paclitaxel dose-dependent manner. Our work provides strong evidence for the feasibility of combining paclitaxel with a novel biosensor in a multi-load nanoparticle.

Lactobacillus acidophilus NCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain - a randomised clinical study.

BACKGROUND: In a recent double-blinded clinical trial, the probiotic combination of Lactobacillus acidophilus NCFM (L-NCFM) and B-LBi07 reduced bloating symptoms in patients with functional bowel disorders; an effect more evident in those who reported abdominal pain. In mice, L-NCFM but not B-LBi07 induced colonic mu-opioid receptor (MOR) and cannabinoid receptor 2 (CB2) expression, and reduced visceral sensitivity. AIMS: To determine if L-NCFM was the active component in the clinical trial and to investigate the mechanism of action in humans with mild to moderate abdominal pain. METHODS: Caucasian women (n = 20) 18-70 years with mild to moderate abdominal pain were enrolled in a double-blind, two-armed, single-centre study. Patients were given either L-NCFM alone or in combination with B-LBi07 for 21 days at a total dose of 2 × 10(10) CFU b.d. Colonic biopsies were collected during unsedated, unprepped flexible sigmoidoscopy before and at the end of probiotic consumption. mRNA and immunostaining were then performed on these biopsies. Patients kept symptom diaries for the 7 days prior to starting probiotic therapy and for the last 7 days of therapy. RESULTS: L-NCFM alone, but not with B-LBi07, induced colonic MOR mRNA and protein expression, as well as downstream signalling, as measured by enterocyte STAT3-phosphorylation. In contrast, CB2 expression was decreased. Both treatment groups trended towards improvement in symptoms, but the study was insufficiently powered to draw meaningful conclusions. CONCLUSIONS: Lactobacillus acidophilus NCFM modulates mu-opioid receptor expression and activity, while the combination of L-NCFM and B-LBi07 does not. This study provides a possible mechanism for action by which probiotics modulates pain sensation in humans (Clinical Trial Number: NCT01064661).

Corrected confidence bands for functional data using principal components.

Functional principal components (FPC) analysis is widely used to decompose and express functional observations. Curve estimates implicitly condition on basis functions and other quantities derived from FPC decompositions; however these objects are unknown in practice. In this article, we propose a method for obtaining correct curve estimates by accounting for uncertainty in FPC decompositions. Additionally, pointwise and simultaneous confidence intervals that account for both model- and decomposition-based variability are constructed. Standard mixed model representations of functional expansions are used to construct curve estimates and variances conditional on a specific decomposition. Iterated expectation and variance formulas combine model-based conditional estimates across the distribution of decompositions. A bootstrap procedure is implemented to understand the uncertainty in principal component decomposition quantities. Our method compares favorably to competing approaches in simulation studies that include both densely and sparsely observed functions. We apply our method to sparse observations of CD4 cell counts and to dense white-matter tract profiles. Code for the analyses and simulations is publicly available, and our method is implemented in the R package refund on CRAN.

Think small: zebrafish as a model system of human pathology.

Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed.

Predicting breakdown of the blood-brain barrier in multiple sclerosis without contrast agents.

BACKGROUND AND PURPOSE: Disruption of the BBB in MS is associated with the development of new lesions and clinical relapses and signifies the presence of active inflammation. It is most commonly detected as enhancement on MR imaging performed with contrast agents that are costly and occasionally toxic. We investigated whether the BBB status in white matter lesions may be indirectly ascertained via examination of features on T1- and T2-weighted images obtained before the injection of a contrast agent. MATERIALS AND METHODS: We considered 93 brain MR imaging studies on 16 patients that included T1-, T2-, and T2-weighted FLAIR images and predicted voxel wise enhancement after intravenous injection of a gadolinium chelate. We then used these voxel-level predictions to determine the presence or absence of abnormal enhancement anywhere in the brain. RESULTS: On a voxel-by-voxel basis, enhancement can be predicted by using contrast-free measures with an AUC of 0.83 (95% CI, 0.80-0.87). At the whole-brain level, enhancement can be predicted with an AUC of 0.72 (95% CI, 0.62-0.82). CONCLUSIONS: In many cases, breakdown of the BBB in acute MS lesions may be inferred without the need to inject an MR imaging contrast agent. The inference relies on intrinsic properties of tissue damage in acute lesions. Although contrast studies are more accurate, they may sometimes be unnecessary.

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants < 1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself. Journal of Perinatology (2007) 27, S45-S47. doi:10.1038/sj.jp.7211842.

Heterotopic pancreas: typical and atypical imaging findings.

Heterotopic pancreas is a common condition often encountered during laporotomy or autopsy. Prospective radiographic diagnosis is challenging because of the variable imaging appearances. The purpose of this review is to present the typical and atypical appearances of heterotopic pancreas on imaging studies. Familiarity with the spectrum of radiological findings in conjunction with biochemical markers is helpful to improve diagnostic accuracy.

Continuous positive airway pressure and conventional mechanical ventilation in the treatment of meconium aspiration syndrome.

Meconium aspiration syndrome (MAS) is a complex syndrome that ranges in severity from mild respiratory distress to severe respiratory failure, persistent pulmonary hypertension of the newborn and sometimes death. Understanding of the syndrome's complicated pathophysiology will help determine the appropriate treatment strategy, including the use of continuous positive airway pressure (CPAP), conventional mechanical ventilation (CMV) and other therapies. Approximately 30 to 50% of infants diagnosed with MAS will require CPAP or mechanical ventilation. The optimum modes of ventilation for MAS are not known. Very few studies have been conducted to determine 'best' ventilatory strategies. Despite the introduction, over the last two decades, of innovative ventilatory treatments for this disease (for example, surfactant, high-frequency ventilation, inhaled nitric oxide, extracorporeal membrane oxygenation), the majority of infants can be successfully managed with CPAP or mechanical ventilation alone.

PCO2 and room air saturation values in premature infants at risk for bronchopulmonary dysplasia.

OBJECTIVE: To determine the capillary partial pressure of carbon dioxide (PCO(2)) and room air transcutaneous hemoglobin saturation (RA SAT) at 36 weeks' postmenstrual age (PMA) in infants born with weight between 501 and 1250 g. STUDY DESIGN: Multicenter, prospective investigation with primary data collection within 72 h of 36 weeks PMA or discharge, whichever first. PCO(2) and RA SAT determinations were done at rest on infants not requiring mechanical ventilation or nasal continuous positive airway pressure (NCPAP). RESULT: A total of 220 infants were enrolled (mean gestational age 27.7 weeks, mean birthweight 951 g). In infants with traditionally defined chronic lung disease (CLD) compared to those without CLD, the mean PCO(2) was significantly higher (54 versus 45 mm Hg) and the median RA SAT significantly lower (<80 versus 97%). In infants with the new classification of bronchopulmonary dysplasia (BPD), there was a significant linear trend toward increasing PCO(2) with increasing severity of BPD (45, 47, 54 and 62 mm Hg in No, Mild, Moderate and Severe BPD). There was a significant linear trend toward decreasing RA SAT with increasing severity of BPD (97, 95 <80, <80% in No, Mild, Moderate and Severe BPD). CONCLUSION: Defining CLD as BPD based upon a RA SAT test is a more discriminate, objective method to categorize lung injury. PCO(2) is an objective measure of lung function that inversely correlates with RA SAT. These determinations done together at 36 weeks PMA may provide more precise and accurate estimates of lung injury that might allow for better understanding of pulmonary therapies and clearer comparison of BPD rates and severities among NICUs.

Transitional hypothermia in preterm newborns.

Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants <1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself.

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia.

AIMS/HYPOTHESIS: Postprandial hypoglycaemia following gastric bypass for obesity is considered a late manifestation of the dumping syndrome and can usually be managed with dietary modification. We investigated three patients with severe postprandial hypoglycaemia and hyperinsulinaemia unresponsive to diet, octreotide and diazoxide with the aim of elucidating the pathological mechanisms involved. METHODS: Glucose, insulin, and C-peptide were measured in the fasting and postprandial state, and insulin secretion was assessed following selective intra-arterial calcium injection. Pancreas histopathology was assessed in all three patients. RESULTS: All three patients had evidence of severe postprandial hyperinsulinaemia and hypoglycaemia. In one patient, reversal of gastric bypass was ineffective in reversing hypoglycaemia. All three patients ultimately required partial pancreatectomy for control of neuroglycopenia; pancreas pathology of all patients revealed diffuse islet hyperplasia and expansion of beta cell mass. CONCLUSIONS/INTERPRETATION: These findings suggest that gastric bypass-induced weight loss may unmask an underlying beta cell defect or contribute to pathological islet hyperplasia, perhaps via glucagon-like peptide 1-mediated pathways.

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans.

BACKGROUND: As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans. MATERIAL AND METHODS: We assessed the effect of simvastatin on left ventricular function and coenzyme Q10 levels in 21 (11 male, 10 female) hypercholesterolaemic subjects (mean age = 56 years) with normal LVF, over a period of 6 months. Subjects were re-tested after a 1-month wash-out period (7 months). Echocardiography was performed on all subjects before commencement of simvastatin (20 mg day(-1)), and at 1, 3, 6 and 7 months after initiation of treatment. Fasting blood samples were also collected at these intervals to assess lipids, apoproteins, vitamin E and coenzyme Q10. RESULTS: Serum lipids showed the expected reductions. Plasma vitamin E and coenzyme Q10 levels were reduced by 17 +/- 4% (P < 0.01) and 12 +/- 4% (P < 0.03) at 6 months. However, the coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio increased significantly. Left ventricular ejection fraction (EF) decreased transiently after 1 month, while no significant change was observed at 3 and 6 months. Other markers of left ventricular function did not change significantly at any time point. CONCLUSION: Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.

Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.

BACKGROUND AND OBJECTIVES: Individuals with primary or secondary immune-deficiency diseases may be at risk for vaccinia infection if widespread smallpox-immunization programmes are implemented in the United States of America (USA) for bioterrorism preparedness. The objective of this study was to determine whether commercial immune globulin (intravenous, human) products contain biologically active antibodies to vaccinia that have the potential to protect people, with immune deficiencies, from complications of vaccinia. MATERIALS AND METHODS: Eight currently United States (US)-licensed and two European intravenous immunoglobulin (IVIG) products were tested in a vaccinia plaque-reduction neutralization assay. The in vivo activity of five of these lots was assessed in severely immune-deficient mice. RESULTS: All tested products contained neutralizing anti-vaccinia activity, in vitro and in vivo. CONCLUSIONS: The use of IVIG by individuals with inherited or acquired humoral immune deficiencies may provide some protection if they are inadvertently exposed to vaccinia.

Are cardiac transplant patients more likely to have periodontitis? A case record study.

In several large epidemiological studies chronic periodontitis has been implicated as an additional risk factor, independent of other risk factors, for the development of ischaemic heart disease. The underlying mechanism is thought to be a localised infection giving rise to an inflammatory host response, and some experimental data agree with this hypothesis. Recently, however, some studies have questioned the post dated relationship between the two diseases. The current case-record study was undertaken to evaluate the prevalence of chronic periodontitis and the severity of such periodontal disease in a heart transplant population, assuming the latter represented a relatively severely compromised cardiovascular patient population. The study demonstrated that 76% of the patients had various degrees of periodontal disease prior to undergoing a heart transplant. Thus, it is possible that a relationship between cardiovascular disease and periodontal disease exists, but further, large intervention studies will be needed to confirm such a conclusion.

Dietary and clastogenic factors in children who immigrated to Israel from regions contaminated by the Chernobyl accident.

The authors evaluated the possible association between dietary history and plasma clastogenic factors in children who immigrated to Israel between 1989 and 1993 from regions contaminated by the Chernobyl accident. The authors compared questionnaire data about demographic variables, dietary histories before and after immigration occurred, and health status with clastogenic factor scores for 162 immigrants. Logistic regression analysis revealed a negative association between clastogenic factor scores and frequency of consumption of fresh vegetables and fruit among children < or = 7 yr of age during the postimmigration period. Intake of eggs and fish by boys who were < or = 7 yr of age prior to immigration was associated positively with clastogenic factor scores. Consumption of fresh vegetables and fruits afforded protection to the immune systems of children who were < or = 7 yr of age.

Precise adjustment of nanometric-scale diffusion layers within a redox dendrimer molecule by ultrafast cyclic voltammetry: an electrochemical nanometric microtome.

Performing cyclic voltammetry at scan rates into the megavolt per second range allows the exploration of the nanosecond time scale as well as the creation of nanometric diffusion layers adjacent to the electrode surface. This latter property is used here to adjust precisely the diffusion layer width within the outer shell of a fourth-generation dendrimer molecule decorated by 64 [Ru(II)(tpy)2] redox centers (tpy = terpyridine). Thus the shape of the dendrimer molecule adsorbed onto the ultramicroelectrode surface can be explored voltammetrically in a way reminiscent of an analysis with a nanometric microtome. The quantitative analysis developed here applied to the experimental voltammograms demonstrates that in agreement with previous scanning tunneling microscopy (STM) studies the adsorbed dendrimer molecules are no more spherical as they are in solution but resemble more closely hemispheres resting onto the electrode surface on their diametrical planes. The same quantitative analysis gives access to the apparent diffusion coefficient featuring electron hopping between the [Ru(II)/ Ru(III)(tpy)2] redox centers distributed on the dendrimer surface. Based on the electron hopping rate constant thus measured and on a Smoluchowski-type model developed here to take into account viscosity effects during the displacement of the [Ru(II)/Ru(III)(tpy)2] redox centers around their equilibrium positions, it is shown that the [Ru(II)/Ru(III)(tpy)2] redox centers are extremely labile in their potential wells so that they may cross-talk considerably more easily than they would do in solution at an equivalent concentration.