Pruritic urticarial papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy
Thirty women who were seen at our institution between 1984 and 1988 for pruritic urticarial papules and plaques of pregnancy (PUPPP) were retrospectively evaluated and interviewed. We found a significantly increased maternal weight gain and newborn birth weight in patients with PUPPP, compared with age and parity-matched controls. The average weight gain during pregnancy was 18.1 +/- 0.9 (SEM) kg for the patients with PUPPP (excluding twin gestations) and 14.6 +/- 1.0 kg for the controls. The mean newborn birth weight was 3.6 +/- 0.09 kg for the PUPPP group and 3.3 +/- 0.08 kg for the control group. There were three twin pregnancies (10%), compared with the twin gestation rate at our institution of 1.6%. Therefore, based on our findings of an increased maternal weight gain and neonatal birth weight, an increased twin rate, and an abdominal eruption that occurs in primigravidas in their third trimester of pregnancy, we suggest that abdominal distention or a reaction to it may play a role in the development of PUPPP.
Lipids in the pathogenesis of ichthyosis: topical cholesterol sulfate-induced scaling in hairless mice
Although several abnormalities of lipid metabolism have been associated with abnormal cornification in humans, evidence that these lipids directly provoke abnormal scale is lacking. One recently described example of a lipid abnormality in ichthyosis is absence of the enzyme steroid sulfatase in recessive X-linked ichthyosis (RXLI). This enzyme normally desulfates cholesterol sulfate (CS) and sulfated steroid hormones, including dehydroepiandrosterone sulfate (DHEAS). As a result of this enzyme deficiency, patients with RXLI accumulate CS in their blood and skin. To determine whether sulfated sterols are the specific cause of increased scale, we applied CS, DHEAS, cholesterol, or vehicle alone to the backs of hairless mice. In animals treated with CS, but not with DHEAS or with vehicle, visible scale without erythema appeared after 1 week, peaked at 2 weeks, and then diminished. When the dose of CS was doubled, abnormal scale reappeared and then decreased again. CS-induced scale was reversible, clearing within 3 days of discontinuation of treatment. Because there was no acanthosis, dermal inflammation, abnormal transepidermal water loss, or increased labeling index, it appears that the 3-fold increase in thickness of the stratum corneum in CS-treated animals is due to a direct effect on this layer.
A patient with febrile ulceronecrotic Mucha-Habermann's disease manifested the characteristic features of this entity. These include a polymorphous eruption with histopathologic findings of Mucha-Habermann's disease, large ulceronecrotic skin lesions, intermittent high fever, and constitutional symptoms. The patient was unique in that he also had malabsorption and eosinophilia. This disease may represent a hypersensitivity reaction. To our knowledge, there are five previous cases of febrile ulceronecrotic Mucha-Habermann's disease reported in the world literature.
Syringomas pose a cosmetic problem in some patients. In the past, surgical removal of large portions of the lower lid or electrodesiccation have been the usual methods of removal. This report describes a technique for individual excision of these tumors that is easily performed as an office procedure using a pair of fine ophthalmologic spring-action scissors and gives excellent cosmetic results.
Adverse event (AE) detection and reporting practices were compared during the first phase of the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE), a suicide intervention study. Data were collected using a combination of chart reviews and structured telephone follow-up assessments postenrollment. Beyond chart reviews, structured telephone follow-up assessments identified 45% of the total AEs in our study. Notably, detection of suicide attempts significantly varied by approach with 53 (18%) detected by chart review, 173 (59%) by structured telephone follow-up assessments, and 69 (23%) marked as duplicates. Findings provide support for utilizing multiple methods for more robust AE detection in suicide research.
Starting and keeping a new job can be stressful for anyone. However, there are healthy ways to deal with this stress. This tip sheet has some tips to help you be more prepared to start and keep a new job, and hopefully be a little less stressed.
Describes how an institutional repository of scholarly publications and other library services can be utilized to support the dissemination of translational science research by providing access to an institution's published research, collecting and archiving grey literature, publicizing individual and department collections, and measuring research impact via usage statistics.
Presentation during the National Program Committee Section on Translational Research, Medical Library Association Annual Meeting, May 2012, Seattle, WA.
Evening Snacking in Relation to Self-reported Declines in Sleep Quality during Pregnancy: Preliminary Results from the Decision-Making, Eating, and Weight Gain during Pregnancy (DEW) Study
Background: Poor sleep in non-pregnant adults has been associated with increased evening snacking, which may contribute to weight gain. Sleep disturbances are common during pregnancy.
Objective: To examine the association between changes in sleep quality from pre-pregnancy and evening snacking.
Methods: In an ongoing prospective cohort study, pregnant women were recruited from UMMHC obstetric practices and the community. Participants are 18+ years, with singleton gestation <36 weeks, pre-pregnancy BMI 18.5-40 kg/m2, English-speaking, and with plans to deliver at UMMHC. Participants were asked “compared to the three months before you became pregnant, how is your sleep quality now?”; we combined responses of “about the same”/“a little better”/“a lot better” versus “a little worse”/“much worse”. Participants completed three 24-hour dietary recalls (2 weekdays, 1 weekend day). Evening snacks were defined as eating occasions after dinner but before bedtime during which food items other than water was consumed. Fisher’s Exact tests and t-tests provided comparisons for evening snacking (yes/no), number of snacks, and energy intake.
Results: Women with complete data (n=55) were 58% non-Hispanic White and aged 30.0 (SD: 4.3) years; gestational age at study visit was 23.0 (SD: 5.9) weeks. Of 866 meals reported, 94 were evening snacks. 71% (n=39) reported that their current sleep quality was worse than before pregnancy. Evening snacks were reported by 90% of women reporting worse sleep and 69% same/better (p=0.1028). While the number of snacks among snackers did not differ by change in sleep quality (M[SD]: 2.2[1.2] versus 1.6[0.8], p=0.2372), energy intake from these snacks was higher among women whose sleep quality had declined (M[SD]: 630 versus 309 kcal, p=0.0480).
Conclusions: Declines in sleep quality during pregnancy may be linked to evening snacking. More research is needed to understand the role of sleep quality, eating behavior, and weight gain during pregnancy.
This data set is the primary data source for the study that investigated the status of Vitamin D in children with inflammatory bowel disease (IBD). Manuscript has been submitted for publication by the authors.
Context: There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).
Aim: To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.
Hypothesis: Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.
Subjects and Methods: A case-controlled retrospective study of subjects with IBD (n=58) of 2-20 years (male n=31, age 16.38 ± 2.21 years; female n=27, age16.56 ± 2.08 years) and healthy controls (n=116; male n=49, age 13.90 ± 4.59 years; female n=67, age 15.04 ± 4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (/mL) ( /L), overweight as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Data were expressed as mean ± SD.
Results: Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69 ± 24.43 nmol/L, 53.26 ± 25.51, and 65.32 ± 27.97 respectively (ANOVA, p=0.196).
The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p=0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p=0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls.
However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p=0.025), as well as controls (65.3 ± 28.0 nmol/L vs. 49.5 ± 25.23, p = 0.045).
Conclusion: There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.
Antigen presented to CD4+ T cells by major histocompatibility complex class II molecules (MHCII) plays a key role in adaptive immunity. Antigen presentation is initiated by the proteolytic cleavage of pathogenic or self proteins and loading of resultant peptides to MHCII. The loading and exchange of peptides to MHCII is catalyzed by a nonclassical MHCII molecule, HLA-DM (DM). It is well established that DM promotes peptide exchange in vitro and in vivo. However, the mechanism of DM-catalyzed peptide association and dissociation, and how this would affect epitope selection in human responses to infectious disease remain unclear. The work presented in this thesis was directed towards the understanding of mechanism of DM-mediated peptide exchange and its role in epitope selection.
In Chapter II, I measured the binding affinity, intrinsic dissociation half-life and DM-mediated dissociation half-life for a large set of peptides derived from vaccinia virus and compared these properties to the peptide-specific CD4+ T cell responses. These data indicated that DM shapes the peptide repertoire during epitope selection by favoring the presentation of peptides with greater DM-mediated kinetic stability, and DM-susceptibility is a strong and independent factor governing peptide immunogenicity.
In Chapter III, I computationally simulated peptide binding competition reactions and found that DM influences the IC50 (50% inhibition concentration) of peptides based on their susceptibility to DM, which was confirmed by experimental data. Therefore, I developed a novel fluorescence polarization-based method to measure DM-susceptibility, reported as a IC50 (change in IC50 in the absence and presence of DM). Traditional assays to measure DM-susceptibility based on differential peptide dissociation rates are cumbersome because each test peptide has to be individually labeled and multiple time point samples have to be collected. However, in this method developed here only single probe peptide has to be labeled and only single reading have to be done, which allows for fast and high throughput measure of DM-susceptibility for a large set of peptides.
In Chapter IV, we generated a series of peptide and MHCII mutants, and investigated their interactions with DM. We found that peptides with non-optimal P1 pocket residues exhibit low MHCII affinity, low kinetic stability and high DM-susceptibility. These changes were accompanied with conformational alterations detected by surface plasmon resonance, gel filtration, dynamic light scattering, small-angle X-ray light scattering, antibody-binding, and nuclear magnetic resonance assays. Surprisingly, all these kinetic and conformational changes could be reversed by reconstitution with a more optimal P9 pocket residue. Taken together, our data demonstrated that conformation of MHCII-peptide complex constrained by interactions throughout the peptide binding groove is a key determinant of DM-susceptibility.
B cells recognizing cognate antigen on the virion can internalize and process the whole virion for antigen presentation to CD4+ T cells specific for an epitope from any of the virion proteins. In turn, the epitope-specific CD4+ T cells provide intermolecular (also known as noncognate or heterotypic) help to B cells to generate antibody responses against any protein from the whole virion. This viral intermolecular help model in which CD4+ T cells provide help to B cells with different protein specificities was established in small size influenza virus, hepatitis B virus and viral particle systems. For large and complex pathogens such as vaccinia virus and bacteria, the CD4+ T cell-B cell interaction model may be complicated because B cells might not be able to internalize the large whole pathogen. Recently, a study in mice observed that CD4+ T cell help is preferentially provided to B cells with the same protein specificity to generate antibody responses against vaccinia virus. However, for larger pathogens such as vaccinia virus and bacteria the CD4+ T cell-B cell interaction model has yet to be tested in humans. In Chapter V, I measured in 90 recently vaccinated and 7 long-term vaccinia-immunized human donors the CD4+ T cell responses and antibody responses against four vaccinia viral proteins (A27L, A33R, B5R and L1R) known to be strongly targeted by cellular and humoral responses. We found that there is no direct linkage between antibody and CD4+ T cell responses against each protein. However, the presence of immune responses against these four proteins is linked together within donors. Taken together, our data indicated that individual viral proteins are not the primary recognition unit and CD4+ T cells provide intermolecular help to B cells to generate robust antibody responses against large and complicated vaccinia virus in humans.
Depression in Rheumatoid Arthritis and an Estimation of the Bi-directional Association of Depression and Disease Burden: A Dissertation
Depression is a common comorbidity in rheumatoid arthritis (RA), yet it may not be adequately recognized during routine clinical care. RA symptoms may confer a risk for depression, and vice versa; depression may affect RA disease activity and response to treatment. The study aims were to compare patient- and physician-reported depression measures, evaluate the temporal bi-directional association between RA disease activity and depressive symptomology, and assess depression as a moderator of RA treatment.
Patients were identified using a national RA registry sample (Consortium of Rheumatology Researchers of North America; CORRONA). Depression prevalence and incidence rates were estimated, and concordance and disagreement using measures reported separately by patients and physicians, as well as baseline cross-sectional associations between RA disease and a history of depression. A survival analysis was conducted to temporally predict the incident onset of self-reported depressive symptoms using the different metrics of RA disease activity. Also, mixed effects models were used to assess prospective changes in RA disease activity by prevalent and incident depressive symptom status. Lastly, logistic regression models compared the likelihood of clinical response to RA treatment during follow-up in those with and without depression when starting biologic disease modifying anti-rheumatic drug (DMARD) therapy.
Patient-reported depression rates were much higher and significantly different from physician based comorbidity estimates. Patient and physician RA disease activity measures were associated with an increased risk for depression onset, but not laboratory-reported serum biomarkers. Similarly, depression was temporally associated with significantly slower rates of decline regarding every patient-reported disease activity measure, some physician-reported metrics, but not acute phase reactants. Moreover, there was a significantly lower probability of achieving clinical remission among those with depression on a biologic DMARD after 6 months and an analogous effect at 12-months that was slightly lower in magnitude, which did not reach statistical significance.
Rheumatologists under-reported the occurrence of prevalent and incident depressive symptoms, and thus are likely unaware of its presence in their RA patients. Further, the results suggest the bi-directional effects between these conditions are related to the cognitive and behavioral aspects of depression and their interactions with disease activity, rather than shared immunological mechanisms in the context of cell-mediated immunity. When also considering the impact on clinical response to biologic DMARDS, the findings collectively imply that rheumatologists must address any challenges due to depression to provide the best care to their patients.
Secular trends in occurrence of acute venous thromboembolism: the Worcester venous thromboembolism study (1985 to 2009)
BACKGROUND: The clinical epidemiology of venous thromboembolism has changed recently due to advances in identification, prophylaxis, and treatment. We sought to describe secular trends in occurrence of venous thromboembolism among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA).
METHODS: Population-based methods were used to monitor trends in event rates of first-time or recurrent venous thromboembolism in 5025 WMSA residents diagnosed with acute pulmonary embolism and/or lower-extremity deep vein thrombosis during 9 annual periods between 1985 and 2009. Medical records were reviewed by abstractors and validated by clinicians.
RESULTS: Age- and sex-adjusted annual event rates for first-time venous thromboembolism increased from 73 (95% CI 64-82) per 100,000 in 1985/1986 to 133 (122-143) in 2009, due mostly to an increase in pulmonary embolism. The rate of recurrent venous thromboembolism decreased from 39 (32-45) in 1985/1986 to 19 (15-23) in 2003, and then increased to 35 (29-40) in 2009. There was an increasing trend in using non-invasive diagnostic testing, with about half of tests being invasive in 1985/1986 and almost all non-invasive by 2009.
CONCLUSIONS: Despite advances in identification, prophylaxis, and treatment between 1985 and 2009, the annual event rate of venous thromboembolism has increased and remains high. While these increases may be partially due to increased sensitivity of diagnostic methods, especially for pulmonary embolism, it may also imply that current prevention and treatment strategies are less than optimal.
Recent breakthroughs in creating induced pluripotent stem cells (iPS cells) provide alternative means to obtain embryonic stem (ES) cell-like cells without destroying embryos by introducing four reprogramming factors (Oct3/4, Sox2, and Klf4/c-Myc or Nanog/Lin28) into somatic cells. However, the molecular basis of reprogramming is largely unknown. To address this question, we employed microRNAs, small molecules, and conducted genome-wide RNAi screen, to investigate the regulatory mechanisms of reprogramming.
First we showed that depleting miR-21 and miR-29a enhances reprogramming in mouse embryonic fibroblasts (MEFs). We also showed that p53 and ERK1/2 pathways are regulated by miR-21 and miR-29a and function in reprogramming.
Second, we showed that computational chemical biology combined with genomic analysis can be used to identify small molecules regulating reprogramming. We discovered that the NSAID Nabumetone and the anti-cancer drug OHTM could replace Sox2 during reprogramming. Nabumetone could also replace c-Myc or Sox2 without compromising self-renewal and pluripotency of derived iPS cells.
To identify the cell-fate determinants during reprogramming, we integrated a genome-wide RNAi screen with transcriptome analysis to dissect the molecular requirements in reprogramming. We found that extensive interactions of embryonic stem cell core circuitry regulators are established in mature iPS cells, including Utf1, Nr6a1, Tdgf1, Gsc, Fgf10, T, Chrd, Dppa3, Fgf17, Eomes, Foxa2. Remarkably, genes with non-differential change play the most critical roles in the transitions of reprogramming. Functional validation showed that some genes act as essential or barrier roles to reprogramming. We also identified several genes required for maintaining ES cell properties. Altogether, our results demonstrate the significance of miRNA function in regulating multiple signaling networks involved in reprogramming. And our work further advanced the reprogramming field by identifying several new key modulators.
The recurrent nature of the 3 most common vestibulopathies suggests a recurrent cause. Histopathology in temporal bones from patients with these syndromes - vestibular neuronitis (VN, n = 7), Meniere's disease (MD, n = 8) and benign paroxysmal positional vertigo (BPPV, n = 5) - shows focal degeneration of vestibular nerve axons and degenerated nearby facial nerve meatal ganglion cells. Transmission electron microscopic confirmation of intracytoplasmic viral particles in surgically excised vestibular nerves from patients with VN and MD support a viral etiology in these vestibulopathies. Antiviral treatment of these syndromes in a series of 211 patients with a 3- to 8-year follow-up resulted in complete control of vertigo in VN (88%), MD (90%) and BPPV (60%).
Currently, most preclinical models to validate thrombectomy technologies have not directly translated to the clinical arena. Herein, we review our strategy that combines in vitro and in vivo modeling to assess thrombectomy device safety and efficacy quantitatively.
OBJECTIVES: To evaluate the validity and participants' acceptance of an online assessment of role function using computer adaptive test (RF-CAT).
METHODS: The RF-CAT and a set of established quality of life instruments were administered in a cross-sectional study in a panel sample (n = 444) recruited from the general population with over-selection of participants with selected self-report chronic conditions (n = 225). The efficiency, score accuracy, validity, and acceptability of the RF-CAT were evaluated and compared to existing measures.
RESULTS: The RF-CAT with a stopping rule of six items with content balancing used 25 of the available bank items and was completed on average in 66 s. RF-CAT and the legacy tools scores were highly correlated (.64-.84) and successfully discriminated across known groups. The RF-CAT produced a more precise assessment over a wider range than the SF-36 Role Physical scale. Patients' evaluations of the RF-CAT system were positive overall, with no differences in ratings observed between the CAT and static assessments.
CONCLUSIONS: The RF-CAT was feasible, more precise than the static SF-36 RP and equally acceptable to participants as legacy measures. In empirical tests of validity, the better performance of the CAT was not uniformly statistically significant. Further research exploring the relationship between gained precision and discriminant power of the CAT assessment is needed.
Translational stroke research occurs at the interface between basic science and clinical research, and encompasses contributors with varied backgrounds and areas of expertise. The traditional approach to translational stroke research is to take novel discoveries of basic researchers about the mechanisms and consequences of ischemic brain injury and evaluate the potential of these discoveries to enhance clinical stroke diagnostics and therapeutics. Animal stroke modeling and imaging are key steps in this traditional bench-to-bedside paradigm for translational stroke research. Newer approaches to translational research include reverse and lateral translation. With these paradigms, basic researchers are stimulated to improve our understanding of the pathophysiological mechanisms that underlie a clinically observed phenomenon or treatment effect or improve upon an observed treatment effect by determining if drug modification can enhance a clinically beneficial effect. No matter how translational stroke research is conducted, this type of research is critical for the future and involves multidisciplinary teams that need to have productive and insightful ideas and communications.
Frequency and impact of intensive care unit complications on moderate-severe traumatic brain injury: early results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study
BACKGROUND: Known predictors of adverse outcomes in patients with moderate-severe TBI (msTBI) explain only a relatively small proportion of patient-related outcomes. The frequency and impact of intensive care unit complications (ICU-COMPL) on msTBI-associated outcomes are poorly understood.
METHODS: In 213 consecutive msTBI patients admitted to a Level I Trauma Center neuro trauma ICU, twenty-eight ICU-COMPL (21 medical and 7 neurological) were prospectively collected and adjudicated by group consensus, using pre-defined criteria. We determined frequencies, and explored associations of ICU-COMPL and hospital discharge outcomes using multivariable logistic regression.
RESULTS: The average age of the study sample was 53 years, and the median presenting Glasgow Coma Scale and Injury Severity Scores were 5 and 27, respectively. Hyperglycemia (79%), fever (62%), systemic inflammatory response syndrome (60%), and hypotension requiring vasopressors (42%) were the four most common medical ICU-COMPL. Herniation (39%), intracranial rebleed (39%), and brain edema requiring osmotherapy (37%) were the three most common neurological ICU-COMPL. After adjusting for admission variables, duration of ventilation, and ICU length-of-stay, patients with brain edema (OR 5.8; 95% CI 2, 16.7) had a significantly increased odds for dying during hospitalization whereas patients with hospital-acquired urinary tract infection (UTI) had a decreased odds (OR 0.05; 95% CI 0.005, 0.6). Sensitivity analysis revealed that UTI occurred later, suggesting a non-causal association with survival. Brain herniation (OR 15.7; 95% CI 2.6, 95.4) was associated with an unfavorable functional status (GOS 1-3).
CONCLUSION: ICU-COMPL are very common after msTBI, have a considerable impact on short-term outcomes, and should be considered in the prognostication of these high risk patients. Survival associations of time-dependent complications warrant cautious interpretation.
BACKGROUND: Point-of-care (POC) HbA1c testing allows for timely treatment changes, improved glycemic control, and patient and provider satisfaction. Substantial variation between POC and laboratory HbA1c results has been reported. At our university hospital diabetes clinic, we observed significant negative bias in HbA1c with the DCA Vantage (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) compared with the Tosoh G8 HPLC laboratory analyzer (Tosoh Bioscience, San Francisco, CA, USA). This led us to systematically analyze the bias with the goal of recalibrating the DCA to minimize bias.
METHODS: We analyzed 45 patient samples, with HbA1c ranging between 5% and 10.8%, concurrently on two DCA analyzers and on the Tosoh G8 machine. The bias for each sample was the difference between the value on the DCA and the Tosoh G8 analyzer. Based on regression equations derived from the data, a correction factor for each DCA analyzer was calculated. The analyzers were recalibrated and retested for bias.
RESULTS: At baseline, the mean bias (range) was -0.5229 (+0.1 to -1.3) for Analyzer 1 and -0.5348 (0.0 to -1.6) for Analyzer 2. After recalibration, the mean bias (range) was 0.000 (+0.6 to -0.6) and 0.0003 (+0.5 to -0.5) for Analyzers 1 and 2, respectively, and the systematic negative bias seen prior to the calibration was almost eliminated.
CONCLUSIONS: We recommend periodic recalibration of POC analyzers to eliminate systematic unidirectional bias and to harmonize results between the POC and central laboratory analyzers within a healthcare system. Calibration may need to be repeated with any change in the reagent lot. University School of Medicine.