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.

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.

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.

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.

Sodium-potassium-activated adenosine triphosphatase of brain microsomes: modification of sodium inhibition by diphenylhydantoins.

Effects of diphenylhydantoins on (Na(+) + K(+))-ATPase activity in rat and cat brain microsomes were studied. 5,5-diphenylhydantoin (DPH) in concentrations of 5-20 mug ml(-1) produces an apparent stimulation of the rat brain (Na(+) + K(+))-activated ATPase of 55-65% in media containing 50 mM Na(+), 0.15 mM K(+), 3 mM Mg(++), and 3 mM ATP. No effects are found on the Mg-ATPase. At constant K(+) levels of 0.05 mmole/liter and 0.15 mmole/liter, increasing the Na(+) concentration activates the enzyme similarly with and without DPH. However, Na(+) concentrations greater than 5 mmoles/liter and 10 mmoles/liter, respectively, which are inhibitory in these low K(+) media, produce less inhibition in the presence of DPH. In media containing 10 mM Na(+), the K(+) activation, on the other hand, is potentiated by DPH. In preparations from cat brain qualitatively similar results are obtained. No effect of DPH is seen on the inhibition produced by high K(+) in low Na(+) media. DPH produces an approximately constant apparent stimulation of 45% in the (Na(+) + K(+)) increments when these ions are varied simultaneously at a fixed ratio of 150 Na(+):1 K(+) with cat brain extracts. 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) has the same potency as DPH in reducing the Na(+) inhibition at high Na:K ratios. The hydantoins appear to act by decreasing the Na(+) inhibition that occurs at high Na:K ratios.

Receptor-mediated modulation of human monocyte, neutrophil, lymphocyte, and platelet function by phorbol diesters.

The tumor promoting phorbol diesters elicit a variety of responses from normal and leukemic blood cells in vitro by apparently interacting with cellular receptors. The biologically active ligand [20-(3)H] phorbol 12,13-dibutyrate ([(3)H]PDBu) bound specifically to intact human lymphocytes, monocytes, polymorphonuclear leukocytes (PMN), and platelets, but not to erythrocytes. Binding, which was comparable for all four blood cell types, occurred rapidly at 23 degrees and 37 degrees C, reaching a maximum by 20-30 min usually followed by a 30-40% decrease in cell associated radioactivity over the next 30-60 min. The time course for binding was temperature dependent with equilibrium binding occurring after 120-150 min at 4 degrees C, with no subsequent loss of cell-associated radioactivity at this temperature. Bound [(3)H]PDBu could be eluted by addition of unlabeled PDBu. Scatchard analysis of data from 4 degrees C binding studies revealed linear plots with high affinity receptors in these cell types with dissociation constants and receptors per cell of 60 nM and 7.8 x 10(5)/cell for lymphocytes, 51 nM and 15.5 x 10(5)/cell for monocytes, 38 nM and 4.0 x 10(5)/cell for PMN, and 19 nM and 2.9 x 10(4)/cell for platelets. Structure-activity studies using unlabeled phorbol-related compounds demonstrated a close correlation between their abilities to inhibit binding of [(3)H]PDBu to cells and their abilities to induce cellular responses (monocyte and PMN H(2)O(2) secretion, lymphocyte (3)HTdR incorporation, and platelet tritiated serotonin release); phorbol and 4-alpha phorbol were inactive while phorbol 12-myristate 13-acetate (PMA), PDBu, mezerein, and phorbol 12,13-diacetate (in decreasing order of potency) inhibited [(3)H]PDBu binding and elicited the various responses. Thus, these high affinity, specific receptors for the phorbol diesters, present on monocytes, lymphocytes, PMN, and platelets, mediate the pleiotypic effects induced by these ligands.

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.

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.

Human leukemia cell lines with comparable receptor binding characteristics but different phenotypic responses to phorbol diesters.

Phorbol diester (PDE) tumor promoters have differing effects on normal and neoplastic hematopoietic cells in vitro. The effects of PDEs on cells are apparently mediated by specific cellular receptors for these ligands. The purpose of this study was to determine if the different phenotypic responses of cells of different human leukemia cell lines were due to differences in the PDE receptors in these cells. All cells of the different lines studied [HL-60 (promyelocytic), HL-60Bll (undifferentiated blastic), U-937 (monoblastic), H-SB2 (T-lymphoblastoid), and SB (B-lymphoblastoid) bound the [20-3H]phorbol-12,13-dibutyrate in a specific manner. The ligand bound to the cells rapidly, reaching a maximum by 10 to 20 min at 37 degrees or by 60 min at 4 degrees. The bound [20-3H]phorbol-12,13-dibutyrate could be fully dissociated from the cells by adding unlabeled phorbol-12,13-dibutyrate; the kinetics of this dissociation paralleled association kinetics. Scatchard analysis of the binding data, derived from experiments done at 4 degrees, revealed linear plots, indicating, most likely, that only single classes of receptors existed on all of these lines. The dissociation constants for binding were all comparable (46 to 152 nM), and the calculated numbers of binding sites were comparable (4.8 to 8.1 X 10(5)/cell). None of the cells could degrade [20-3H]phorbol-12-myristate-13-acetate or [20-3H]phorbol-12,13-dibutyrate as determined by thin-layer chromatographic analysis of cells or supernatants of the cell cultures. PDEs inhibited the proliferation of U-937 and HL-60 cells but not that of the HL-60Bll, SB, or H-SB2 cells. The incorporation of tritiated thymidine into HL-60 cells (but not HL-60Bll cells) was dramatically inhibited by various PDEs, and the potency in causing this inhibition paralleled that known for the potency of the phorbol analogues to cause tumor promotion in vivo or to elicit other in vitro responses from hematopoietic cells. [20-3H]Phorbol-12-myristate-13-acetate caused the HL-60 and U-937 cells to adhere to the plastic, spread, and develop vacuoles, but the other cells displayed no changes. These results suggest that the differing phenotypic responses to PDEs are most likely related to postreceptor factors.

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.

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.

Separate and interactive regulation of cytochrome P450 3A4 by triiodothyronine, dexamethasone, and growth hormone in cultured hepatocytes.

CYP3A4, the predominant cytochrome P450 expressed in human liver, is responsible for the metabolism of endogenous steroids and many drugs. On the basis of pharmacokinetic studies in patients with hormonal derangements and the effects of replacement therapy, it has been suggested that iodothyronines decrease CYP3A4-mediated drug metabolism, whereas glucocorticoids and GH enhance CYP3A4 activity. The aim of the present study, using well differentiated human hepatocytes in primary culture, was to examine directly whether hormonal factors regulate CYP3A4 gene expression. Addition of T3 to primary hepatocytes resulted in a marked reduction of CYP3A4-catalyzed testosterone 6 beta-hydroxylase activity and corresponding levels of CYP3A4 protein and messenger ribonucleic acid compared to those in untreated cells. Conversely, both dexamethasone and GH treatment substantially increased CYP3A4 gene expression. None of the hormones studied consistently altered the expression of other human cytochrome P450 genes. We conclude that iodothyronines, glucocorticoids, and GH act directly on human hepatocytes to regulate the expression of CYP3A4, and these effects appear to be exerted at a pretranslational level. Altered regulation of hepatic CYP3A4 is, therefore, likely to account for previous observations concerning the effects of endocrine diseases and hormonal treatments on human cytochrome P450-mediated drug and steroid metabolism.

The current status of neurology of family practice residency programs.

The status of neurology in family practice residency programs was determined. Of 373 programs surveyed by questionnaire, 266 responded (71.3%). Neurology is a required rotation in 48% of the programs, most frequently done during the second year of residency. Preceptors are mainly neurologists in private practice. There is a need for cooperation between neurologists and family practitioners to develop appropriate educational experiences for family practice residents.

Gut flora and the origin of some urinary aromatic phenolic compounds.

The concentration of several phenolic acids and alcohols was measured in urine from germ-free and specific pathogen-free (SPF) rats before and after inoculation with faecal microorganisms, and from conventional rats before and after gut sterilization. The rate of excretion of benzoic acid, phenylacetic acid, and m- and p-hydroxyphenylpropionic acid in the germ-free animals was markedly increased after inoculation. Some acids showed no increase, including the endogenously generated homovanillic, vanilmandelic and p-hydroxyphenyllactic acids. Most others sought showed a small but significant increase. Some of the compounds excreted by the germ-free animals may have been in the food pellets, either as such or as precursors. The pattern was somewhat different in the SPF rats. The excretion of p-hydroxyphenylpropionic, p-hydroxyphenylacetic and m-hydroxyphenylacetic acids was initially much higher than in the germ-free animals and their excretion decreased after inoculation, presumably because of an altered pattern of gut flora. This work quantifies the effect of gut flora in the formation of some of the more important phenolic acids found in rat urine.

Efficacy of isatin analogues as antagonists of rat brain and heart atrial natriuretic peptide receptors coupled to particulate guanylyl cyclase.

Isatin is an endogenous indole and an inhibitor of atrial natriuretic peptide (ANP) receptors coupled with particulate guanylyl cyclase (GC). In this study, several isatin analogues were tested as inhibitors of ANP-stimulated GC in rat brain and heart membranes. None of these analogues affected activity in the absence of ANP, or stimulated ANP-induced activity. In both tissues, some 5-substituted isatins (5-hydroxyisatin, 5-methylisatin, and 5-aminoisatin) exhibited more effective inhibitory activity than isatin itself, with IC50 values in the range 1.3-20 microM. The efficacy of other analogues varied and was not consistent between the two tissues, raising the possibility of receptor heterogeneity and relative selectivity of inhibition. Some substituted isatins may have a role as pharmacological tools for investigating the physiological roles of natriuretic peptides and their receptors.

Excretion of catecholamines and their metabolites in transplantable rat phaeochromocytoma.

The urinary excretion pattern of catecholamines and their metabolites was studied in rats bearing a subcutaneous transplantable phaeochromocytoma. Compared with normal rats, tumour-bearing animals showed a markedly raised excretion of dopamine, noradrenaline and adrenaline, together with certain of their major acidic and alcoholic metabolites. No evidence of increased octopamine production could be obtained. There was a significant correlation between the output of dopamine and its metabolites, allowing accurate assessment of dopamine turnover rates which were comparable with those observed in human phaeochromocytoma. Tumour development, as determined by tumour weight, also correlated significantly with urinary excretion of noradrenaline and dopamine. Rat phaeochromocytoma appears to be a useful model for the human tumour.

Inhibitory potency of some isatin analogues on human monoamine oxidase A and B.

Isatin is an endogenous compound which acts as a selective inhibitor of monoamine oxidase (MAO) B. In this study a range of isatin analogues were tested for their in vitro inhibition of human MAO A and B. Most of the analogues were less potent than isatin. Hydroxylation of the aromatic ring changed the inhibitory potency in favour of MAO A, with 5-hydroxyisatin being a potent and selective MAO A inhibitor (IC50 8 microM). Isatinic acid, which is formed reversibly from isatin at alkaline pH, showed no inhibition.

Effects of metyrapone on expression of CYPs 2C11, 3A2, and other 3A genes in rat hepatocytes cultured on matrigel.

Hepatocytes cultured on matrigel express many liver-specific functions, but the levels and activities of the predominant male-specific rat hepatic CYPs, 3A2 and 2C11, decline rapidly in culture. Metyrapone maintains the level of total cytochrome P450 of rat hepatocytes in primary culture, but the mechanism underlying this effect has not been completely elucidated. The present study sought to determine whether metyrapone acts solely to stabilise CYP proteins in rat hepatocytes cultured on matrigel, or whether it also influences mRNA levels of the encoding genes. Metyrapone maintained the level of total cytochrome P450 in cultured hepatocytes so that values were > 200% of those found in untreated control cells 24 hr after isolation. At this time, CYP3A2-mediated testosterone 6 beta-hydroxylation was approximately 7-fold higher in hepatocytes cultured in the presence of metyrapone than in control cells, and CYP2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylation activities were between 2 and 3-fold greater. The results inferred from catalytic activities were supported by immunoquantitation of CYP3A and 2C11 proteins. The trend of increased CYP protein levels in metyrapone-treated cells continued throughout the 48-hr culture period. In control cells, CYP3A2 and 2C11 mRNA levels fell abruptly in culture to reach values at 24 hr that were < 30% of those in freshly isolated cells; addition of metyrapone failed to arrest this fall. However, treatment of cells with metyrapone considerably elevated levels of one or more CYP3A subfamily mRNA species, as detected by a riboprobe based on the cDNA for CYP3A1 ("CYP3A1-like mRNA') that were demonstrated, by another riboprobe, not to be CYP3A2 or RNCYP3AM. RT-PCR of mRNA prepared from cultured hepatocytes, followed by restriction mapping of the cloned cDNAs was used to characterise the CYP3A induced by metyrapone. This revealed that elevated levels of the CYP3A1-like mRNA were attributable to induction of RL33/cDEX mRNA; there were no CYP3A1 cDNAs isolated from these cells. These data are interpreted as indicating that metyrapone stabilises the expression of cytochrome P450 in culture by both pre- and posttranslational mechanisms. The particular mechanism employed is gene-specific, whereby even the highly homologous genes CYP3A2, RL33/cDEX and, possibly, RNCYP3AM are subject to different types of regulation in the presence of metyrapone.