Evaluating changes to home bowel cancer screening kits: an end-user perspective study.

PURPOSE: Many people do not participate in mail-out bowel cancer screening programs due to difficulties using the screening kit. The current study investigated the ways the screening kit could be modified to improve usability. METHODS: 1,109 people evaluated 15 different screening kit modifications. Participants reported on how these kit modifications would affect their screening barriers, their future screening intentions, and how much they would recommend that the modification is made to the current screening kit used the program. All responses were given via an online survey conducted between April and December of 2021. RESULTS: Seventeen percent of previous NBCSP non-participators indicated that a one-sample test would increase their intention to participate. Recommendation ratings demonstrated higher levels of support for modifications that included providing a barcode naming label (M = 9.06, 95% CI [8.81, 9.31]), having a larger diameter opening of the collection tube (M = 8.42, 95% CI [8.10, 8.74]), and highlighting the expiry date on the kit packaging (M = 8.59, 95% CI [8.29, 8.89]). There were lower levels of support for modifications that reduced the size of the packaging the kit is sent in (M = 6.47, 95% CI [6.09, 6.85]), removed branding from kit packaging (M = 5.98, 95% CI [5.57, 6.39]), and removed the information booklet that comes with the screening kit (M = 5.25, 95% CI [4.78, 5.72]). CONCLUSION: These findings highlight multiple ways in which bowel cancer screening kits can be changed to increase usability for invitees of national bowel cancer screening programs. Findings have implications for all screening programs that use immunochemical-based bowel cancer screening kits.

A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report.

BACKGROUND: Congenital hypothyroidism (CH) has an incidence of approximately 1:3000, but only 15% have mutations in the thyroid hormone synthesis pathways. Genetic analysis allows for the precise diagnosis. CASE PRESENTATION: A 3-week old girl presented with a large goiter, serum TSH > 100 mIU/L (reference range: 0.7-5.9 mIU/L); free T4 < 3.2 pmol/L (reference range: 8.7-16 pmol/L); thyroglobulin (TG) 101 µg/L. Thyroid Tc-99 m scan showed increased radiotracer uptake. One brother had CH and both affected siblings have been clinically and biochemically euthyroid on levothyroxine replacement. Another sibling had normal thyroid function. Both Sudanese parents reported non-consanguinity. Peripheral blood DNA from the proposita was subjected to whole exome sequencing (WES). WES identified a novel homozygous missense mutation of the TG gene: c.7021G > A, p.Gly2322Ser, which was subsequently confirmed by Sanger sequencing and present in one allele of both parents. DNA samples from 354 alleles in four Sudanese ethnic groups (Nilotes, Darfurians, Nuba, and Halfawien) failed to demonstrate the presence of the mutant allele. Haplotyping showed a 1.71 centiMorgans stretch of homozygosity in the TG locus suggesting that this mutation occurred identical by descent and the possibility of common ancestry of the parents. The mutation is located in the cholinesterase-like (ChEL) domain of TG. CONCLUSIONS: A novel rare missense mutation in the TG gene was identified. The ChEL domain is critical for protein folding and patients with CH due to misfolded TG may present without low serum TG despite the TG gene mutations.

Whole-Genome Sequences of Variants of Bacillus anthracis Sterne and Their Toxin Gene Deletion Mutants.

Here, we report the draft genome sequences of three laboratory variants of Bacillus anthracis Sterne and their double (Δlef Δcya) and triple (Δpag Δlef Δcya) toxin gene deletion derivatives.

Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Measuring Preference for Supernormal Over Natural Rewards : A Two-Dimensional Anticipatory Pleasure Scale.

Supernormal (SN) stimuli are artificial products that activate reward pathways and approach behavior more so than naturally occurring stimuli for which these systems were intended. Many modern consumer products (e.g., snack foods, alcohol, and pornography) appear to incorporate SN features, leading to excessive consumption, in preference to naturally occurring alternatives. No measure currently exists for the self-report assessment of individual differences or changes in susceptibility to such stimuli. Therefore, an anticipatory pleasure scale was modified to include items that represented both SN and natural (N) classes of rewarding stimuli. Exploratory factor analysis yielded a two-factor solution, and as predicted, N and SN items reliably loaded on separate dimensions. Internal reliability for the two scales was high, ρ =.93 and ρ =.90, respectively. The two-dimensional measure was evaluated via regression using the N and SN scale means as predictors and self-reports of daily consumption of 21 products with SN features as outcomes. As expected, SN pleasure ratings were related to higher SN product consumption, while N pleasure ratings had either negative or neutral associations to consumption of these products. We conclude that the resulting two-dimensional measure is a potentially reliable and valid self-report measure of differential preference for SN stimuli. While further evaluation is needed (e.g., using experimental measures), the proposed scale may play a useful role in the study of both trait- and state-based variation in human susceptibility to SN stimuli.

Whole transcriptome organisation in the dehydrated supraoptic nucleus.

The supraoptic nucleus (SON) is part of the central osmotic circuitry that synthesises the hormone vasopressin (Avp) and transports it to terminals in the posterior lobe of the pituitary. Following osmotic stress such as dehydration, this tissue undergoes morphological, electrical and transcriptional changes to facilitate the appropriate regulation and release of Avp into the circulation where it conserves water at the level of the kidney. Here, the organisation of the whole transcriptome following dehydration is modelled to fit Zipf's law, a natural power law that holds true for all natural languages, that states if the frequency of word usage is plotted against its rank, then the log linear regression of this is -1. We have applied this model to our previously published euhydrated and dehydrated SON data to observe this trend and how it changes following dehydration. In accordance with other studies, our whole transcriptome data fit well with this model in the euhydrated SON microarrays, but interestingly, fit better in the dehydrated arrays. This trend was observed in a subset of differentially regulated genes and also following network reconstruction using a third-party database that mines public data. We make use of language as a metaphor that helps us philosophise about the role of the whole transcriptome in providing a suitable environment for the delivery of Avp following a survival threat like dehydration.

Whole transcriptome organisation in the dehydrated supraoptic nucleus

The supraoptic nucleus (SON) is part of the central osmotic circuitry that synthesises the hormone vasopressin (Avp) and transports it to terminals in the posterior lobe of the pituitary. Following osmotic stress such as dehydration, this tissue undergoes morphological, electrical and transcriptional changes to facilitate the appropriate regulation and release of Avp into the circulation where it conserves water at the level of the kidney. Here, the organisation of the whole transcriptome following dehydration is modelled to fit Zipf's law, a natural power law that holds true for all natural languages, that states if the frequency of word usage is plotted against its rank, then the log linear regression of this is -1. We have applied this model to our previously published euhydrated and dehydrated SON data to observe this trend and how it changes following dehydration. In accordance with other studies, our whole transcriptome data fit well with this model in the euhydrated SON microarrays, but interestingly, fit better in the dehydrated arrays. This trend was observed in a subset of differentially regulated genes and also following network reconstruction using a third-party database that mines public data. We make use of language as a metaphor that helps us philosophise about the role of the whole transcriptome in providing a suitable environment for the delivery of Avp following a survival threat like dehydration.

2005 hurricane surveillance: measures to reduce carbon monoxide poisoning in all Floridians.

The 2005 Florida hurricanes caused widespread power outages, increasing generator use that directly resulted in a surge in carbon monoxide (CO) poisonings. Of the 126 CO poisonings documented, 77% were related to generator use and 43% of these generators were placed outside but near a window. African-Americans and Latinos had a higher incidence of CO poisoning. The strength of the authors' study described here was the inclusion of the first responder network in one surveillance system for hurricane response. Notable advances have occurred since the authors' study, including CO poisoning listed as a reportable condition, regulation requiring CO detectors, CO generator warning labeling, and the development of a local surveillance and classification program for the county health departments. To prepare for future multiple hurricane seasons, comprehensive outreach should be focused at the local level through the first responder network and community groups to reduce CO poisonings in all populations.

The life of form: emergent patterns of morphological transformation.

The inherent logical difficulties of understanding biological form in terms of historical narratives and genetic programmes are considered. It is concluded that neither of these approaches can resolve the problems presented by the evidence of parallel and convergent evolution, and for intrinsic constraints on morphogenesis such as the occurrence of phylotypic stages in the developments of members of different phyla. An alternative approach which could resolve the conflicts of historical and structural analysis is described in terms of the complex dynamics of genetic networks acting within the context of morphogenetic fields, from which emergent biological forms arise. This is described as the life of form within the biological realm.

Prevalence of anaemia in patients with diabetes mellitus.

BACKGROUND: Anaemia is an increasingly recognised entity in patients with diabetes mellitus. AIMS: We aimed to determine the prevalence of anaemia in our population of patients with diabetes, and to examine the factors associated with anaemia. METHODS: The haemoglobin (Hb) levels in a consecutive series of patients attending for annual review of their diabetes over a three-month period were measured. Patients were classified as anaemic as per the WHO criteria. RESULTS: During the period of study, 270 patients attended for review. Eleven per cent of males and 16% of females were anaemic. Seventy four per cent of anaemic patients had a serum creatinine <110micromol/l and 72% of anaemic patients had a calculated creatinine clearance of >60ml/min. CONCLUSIONS: Anaemia was relatively common in patients attending for routine outpatient diabetes clinic review. The high prevalence of anaemia supports the routine screening for anaemia in the diabetes out-patient clinic, including in those without overt nephropathy.

Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages.

The nuclear oxysterol receptors LXRalpha (NR1H3) and LXRbeta (NR1H2) coordinately regulate the expression of genes involved in the transport and catabolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limit the transformation of these cells into foam cells in response to lipid loading. Here, we report that natural and synthetic LXR ligands induce the expression of the LXRalpha gene in primary human macrophages and differentiated THP-1 macrophages. This regulation was not observed in primary human adipocytes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXRalpha gene was isolated, and the transcription initiation site delineated. Analysis of the LXRalpha promoter revealed a functional LXR/RXR binding site approximately 2.9 kb upstream of the transcription initiation site. We conclude that LXRalpha regulates its own expression in human macrophages and that this response is likely to amplify the effects of oxysterols on reverse cholesterol transport. These findings underscore the importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.

Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor.

Cytochromes P450 (P450s) are involved in the oxidative metabolism of a plethora of structurally unrelated compounds, including therapeutic drugs. Two orphan members of the nuclear receptor superfamily, the pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) have been implicated in this phenomenon. In the present study, we examined the transcriptional regulation of the human CYP2B6 gene. In primary cultures of human hepatocytes, CYP2B6 was highly inducible by a number of compounds known to be human PXR ligands, including rifampicin and hyperforin. PXR was shown to be capable of activating the phenobarbital-responsive enhancer module (PBREM) region of the CYP2B6 gene, a 51-base-pair enhancer element that mediates induction of CYP2B6 expression by CAR. The two nuclear receptor-binding motifs within the PBREM effectively bound PXR as a heterodimer with the 9-cis retinoic acid receptor alpha (NR2B1). Taken together, these observations demonstrate that the CYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s.

Varying functions of specific major histocompatibility class II transactivator promoter III and IV elements in melanoma cell lines.

Melanoma cells commonly express MHC class II molecules constitutively. This is a rare, or possibly unique, phenotype for a nonprofessional antigen-presenting cell, where MHC class II expression ordinarily occurs only after IFN-gamma treatment. Despite the fact that constitutive expression of MHC class II on melanoma cells has been observed for decades and that the regulation of the MHC class II genes is well understood for many different cell types, there is no data regarding the basis for constitutive MHC class II expression in melanoma cells. Here we report that MHC class II expression in melanoma cells can be traced to constitutive expression of the class II transactivator protein (CIITA), which mediates both IFN-gamma-inducible and -constitutive MHC class II expression in all other cell types. In addition, we determined that constitutive CIITA expression is the result of the activation of both the B cell-specific CIITA promoter III and the IFN-gamma-inducible CIITA promoter IV, the latter of which previously has never been known to function as a constitutive promoter in any cell type. The recently described B cell-related ARE-1 activity is important for promoter III activation in the melanoma cells. Constitutive promoter IV activation involves the IFN regulatory factor element (IRF-E), which binds members of the IRF family of proteins, although the major, IFN-gamma inducible member of this family, IRF-1, is not constitutively expressed in these cells. In cells with constitutively active promoter IV, the promoter IV IRF-E is most likely activated by IRF-2. The relevance of these results to the pathway of melanoma development is discussed.

Impaired class II transactivator expression in mice lacking interferon regulatory factor-2.

Class II transactivator (CIITA) is required for both constitutive and inducible expression of MHC class II genes. IFN-gamma induced expression of CIITA in various cell types is directed by CIITA type IV promoter. The two transactivators, STAT1 and IRF-1, mediate the IFN-gamma activation of the type IV promoter by binding to the GAS and IRF-E of the promoter, respectively. In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. IRF-1 and IRF-2 can co-occupy the IRF-E of the human CIITA type IV promoter. To understand the effect of loss of IRF-2 on the endogenous CIITA expression, we assayed for CIITA expression in IRF-2 knock-out mice. Both basal and IFN-gamma induced CIITA expression were reduced in IRF-2 knock-out mice. At least half of the amount of inducible CIITA mRNA depends on IRF-2. The reduction of IFN-gamma induced CIITA mRNA in IRF-2 knock-out mice was due to the reduction of the type IV CIITA mRNA induction. The reduction of basal CIITA mRNA was apparently due to the reduction of CIITA mRNA originating from other promoters. These data indicate that IRF-2, like IRF-1, plays a critical role in the regulation of the endogenous CIITA gene. The implications in understanding the previously described phenotypes of IRF-2 defective mice are discussed.

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

A cellular oscillator model for periodic pattern formation.

In this paper, we present a model for pattern formation in developing organisms that is based on cellular oscillators (CO). An oscillatory process within cells serves as a developmental clock whose period is tightly regulated by cell autonomous or non-autonomous mechanisms. A spatial pattern is generated as a result of an initial temporal ordering of the cell oscillators freezing into spatial order as the clocks slow down and stop at different times or phases in their cycles. We apply a CO model to vertebrate somitogenesis and show that we can reproduce the dynamics of periodic gene expression patterns observed in the pre-somitic mesoderm. We also show how varying somite lengths can be generated with the CO model. We then discuss the model in view of experimental evidence and its relevance to other instances of biological pattern formation, showing its versatility as a pattern generator.

Spatiotemporal variation in a Lyme disease host and vector: black-legged ticks on white-footed mice.

We monitored population density of white-footed mice (Peromyscus leucopus), burdens of immature black-legged ticks (Ixodes scapularis) on mice, and infection prevalence of host-seeking ticks on six forest plots in southeastern New York State from 1995 through 1999. Despite densities of mice that fluctuated two orders of magnitude, average larval and nymphal tick burdens per mouse remained remarkably constant. Spatial variability in mouse density and tick burdens was modest. The total number of larval and nymphal ticks that fed on the mouse population each year depended strongly on population density of mice; a steady increase was observed in both mouse density and total tick meals on mice from 1996 through 1999. The result was a steady increase in the infection prevalence of nymphal and adult ticks with the etiological agent of Lyme disease, Borrelia burgdorferi, over this time. We suggest that fluctuations in population density of mice, combined with possible regulation of tick burdens on mice, may influence risk of human exposure to Lyme disease.

Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.

Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.

A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.

New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome.

Opitz syndrome (OS) is a genetically heterogeneous malformation disorder. Patients with OS may present with a variable array of malformations that are indicative of a disturbance of the primary midline developmental field. Mutations in the C-terminal half of MID1, an RBCC (RING, B-box and coiled-coil) protein, have recently been shown to underlie the X-linked form of OS. Here we show that the MID1 gene spans at least 400 kb, almost twice the distance originally reported and has a minimum of six mRNA isoforms as a result of the alternative use of 5' untranslated exons. In addition, our detailed mutational analysis of MID1 in a cohort of 15 patients with OS has resulted in the identification of seven novel mutations, two of which disrupt the N-terminus of the protein. The most severe of these (E115X) is predicted to truncate the protein before the B-box motifs. In a separate patient, a missense change (L626P) was found that also represents the most C-terminal alteration reported to date. As noted with other C-terminal mutations, GFP fusion constructs demonstrated that the L626P mutant formed cytoplasmic clumps in contrast to the microtubular distribution seen with the wild-type sequence. Notably, however, both N-terminal mutants showed no evidence of cytoplasmic aggregation, inferring that this feature is not pathognomonic for X-linked OS. These new data and the finding of linkage to MID1 in the absence of a demonstrable open reading frame mutation in a further family support the conclusion that X-linked OS results from loss of function of MID1.