Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients

<p>Abstract</p> <p>Background</p> <p>There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses.</p> <p>Methods</p> <p>We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 μmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica.</p> <p>Results</p> <p>There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low.</p> <p>Conclusions</p> <p>In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.</p

Increasing efficacy of primary care-based counseling for diabetes prevention: Rationale and design of the ADAPT (Avoiding Diabetes Thru Action Plan Targeting) trial

<p>Abstract</p> <p>Background</p> <p>Studies have shown that lifestyle behavior changes are most effective to prevent onset of diabetes in high-risk patients. Primary care providers are charged with encouraging behavior change among their patients at risk for diabetes, yet the practice environment and training in primary care often do not support effective provider counseling. The goal of this study is to develop an electronic health record-embedded tool to facilitate shared patient-provider goal setting to promote behavioral change and prevent diabetes.</p> <p>Methods</p> <p>The ADAPT (Avoiding Diabetes Thru Action Plan Targeting) trial leverages an innovative system that integrates evidence-based interventions for behavioral change with already-existing technology to enhance primary care providers' effectiveness to counsel about lifestyle behavior changes. Using principles of behavior change theory, the multidisciplinary design team utilized in-depth interviews and <it>in vivo </it>usability testing to produce a prototype diabetes prevention counseling system embedded in the electronic health record.</p> <p>Results</p> <p>The core element of the tool is a streamlined, shared goal-setting module within the electronic health record system. The team then conducted a series of innovative, "near-live" usability testing simulations to refine the tool and enhance workflow integration. The system also incorporates a pre-encounter survey to elicit patients' behavior-change goals to help tailor patient-provider goal setting during the clinical encounter and to encourage shared decision making. Lastly, the patients interact with a website that collects their longitudinal behavior data and allows them to visualize their progress over time and compare their progress with other study members. The finalized ADAPT system is now being piloted in a small randomized control trial of providers using the system with prediabetes patients over a six-month period.</p> <p>Conclusions</p> <p>The ADAPT system combines the influential powers of shared goal setting and feedback, tailoring, modeling, contracting, reminders, and social comparisons to integrate evidence-based behavior-change principles into the electronic health record to maximize provider counseling efficacy during routine primary care clinical encounters. If successful, the ADAPT system may represent an adaptable and scalable technology-enabled behavior-change tool for all primary care providers.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01473654">NCT01473654</a></p

A Unique Role for the Host ESCRT Proteins in Replication of Tomato bushy stunt virus

Plus-stranded RNA viruses replicate in infected cells by assembling viral replicase complexes consisting of viral- and host-coded proteins. Previous genome-wide screens with Tomato bushy stunt tombusvirus (TBSV) in a yeast model host revealed the involvement of seven ESCRT (endosomal sorting complexes required for transport) proteins in viral replication. In this paper, we show that the expression of dominant negative Vps23p, Vps24p, Snf7p, and Vps4p ESCRT factors inhibited virus replication in the plant host, suggesting that tombusviruses co-opt selected ESCRT proteins for the assembly of the viral replicase complex. We also show that TBSV p33 replication protein interacts with Vps23p ESCRT-I and Bro1p accessory ESCRT factors. The interaction with p33 leads to the recruitment of Vps23p to the peroxisomes, the sites of TBSV replication. The viral replicase showed reduced activity and the minus-stranded viral RNA in the replicase became more accessible to ribonuclease when derived from vps23Δ or vps24Δ yeast, suggesting that the protection of the viral RNA is compromised within the replicase complex assembled in the absence of ESCRT proteins. The recruitment of ESCRT proteins is needed for the precise assembly of the replicase complex, which might help the virus evade recognition by the host defense surveillance system and/or prevent viral RNA destruction by the gene silencing machinery

A Host Small GTP-binding Protein ARL8 Plays Crucial Roles in Tobamovirus RNA Replication

Tomato mosaic virus (ToMV), like other eukaryotic positive-strand RNA viruses, replicates its genomic RNA in replication complexes formed on intracellular membranes. Previous studies showed that a host seven-pass transmembrane protein TOM1 is necessary for efficient ToMV multiplication. Here, we show that a small GTP-binding protein ARL8, along with TOM1, is co-purified with a FLAG epitope-tagged ToMV 180K replication protein from solubilized membranes of ToMV-infected tobacco (Nicotiana tabacum) cells. When solubilized membranes of ToMV-infected tobacco cells that expressed FLAG-tagged ARL8 were subjected to immunopurification with anti-FLAG antibody, ToMV 130K and 180K replication proteins and TOM1 were co-purified and the purified fraction showed RNA-dependent RNA polymerase activity that transcribed ToMV RNA. From uninfected cells, TOM1 co-purified with FLAG-tagged ARL8 less efficiently, suggesting that a complex containing ToMV replication proteins, TOM1, and ARL8 are formed on membranes in infected cells. In Arabidopsis thaliana, ARL8 consists of four family members. Simultaneous mutations in two specific ARL8 genes completely inhibited tobamovirus multiplication. In an in vitro ToMV RNA translation-replication system, the lack of either TOM1 or ARL8 proteins inhibited the production of replicative-form RNA, indicating that TOM1 and ARL8 are required for efficient negative-strand RNA synthesis. When ToMV 130K protein was co-expressed with TOM1 and ARL8 in yeast, RNA 5′-capping activity was detected in the membrane fraction. This activity was undetectable or very weak when the 130K protein was expressed alone or with either TOM1 or ARL8. Taken together, these results suggest that TOM1 and ARL8 are components of ToMV RNA replication complexes and play crucial roles in a process toward activation of the replication proteins' RNA synthesizing and capping functions

The TPR Domain in the Host Cyp40-like Cyclophilin Binds to the Viral Replication Protein and Inhibits the Assembly of the Tombusviral Replicase

Replication of plus-stranded RNA viruses is greatly affected by numerous host-coded proteins acting either as susceptibility or resistance factors. Previous genome-wide screens and global proteomics approaches with Tomato bushy stunt tombusvirus (TBSV) in a yeast model host revealed the involvement of cyclophilins, which are a large family of host prolyl isomerases, in TBSV replication. In this paper, we identified those members of the large cyclophilin family that interacted with the viral replication proteins and inhibited TBSV replication. Further characterization of the most effective cyclophilin, the Cyp40-like Cpr7p, revealed that it strongly inhibits many steps during TBSV replication in a cell-free replication assay. These steps include viral RNA recruitment inhibited via binding of Cpr7p to the RNA-binding region of the viral replication protein; the assembly of the viral replicase complex and viral RNA synthesis. Since the TPR (tetratricopeptide repeats) domain, but not the catalytic domain of Cpr7p is needed for the inhibitory effect on TBSV replication, it seems that the chaperone activity of Cpr7p provides the negative regulatory function. We also show that three Cyp40-like proteins from plants can inhibit TBSV replication in vitro and Cpr7p is also effective against Nodamura virus, an insect pathogen. Overall, the current work revealed a role for Cyp40-like proteins and their TPR domains as regulators of RNA virus replication

Heterogeneity of mammary lesions represent molecular differences

BACKGROUND: Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. METHODS: We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. RESULTS: We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype. CONCLUSION: We propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype

Management of nystagmus in children: A review of the literature and current practice in UK specialist services

Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillations of one or both eyes, initiated by a slow phase. It is not uncommon in the UK and regularly seen in paediatric ophthalmology and adult general/strabismus clinics. In some cases, it occurs in isolation, and in others, it occurs as part of a multisystem disorder, severe visual impairment or neurological disorder. Similarly, in some cases, visual acuity can be normal and in others can be severely degraded. Furthermore, the impact on vision goes well beyond static acuity alone, is rarely measured and may vary on a minute-to-minute, day-to-day or month-to-month basis. For these reasons, management of children with nystagmus in the UK is varied, and patients report hugely different experiences and investigations. In this review, we hope to shine a light on the current management of children with nystagmus across five specialist centres in the UK in order to present, for the first time, a consensus on investigation and clinical management