Remote regulation of type 2 immunity by intestinal parasites.

The intestinal tract is the target organ of most parasitic infections, including those by helminths and protozoa. These parasites elicit prototypical type 2 immune activation in the host's immune system with striking impact on the local tissue microenvironment. Despite local containment of these parasites within the intestinal tract, parasitic infections also mediate immune adaptation in peripheral organs. In this review, we summarize the current knowledge on how such gut-tissue axes influence important immune-mediated resistance and disease tolerance in the context of coinfections, and elaborate on the implications of parasite-regulated gut-lung and gut-brain axes on the development and severity of airway inflammation and central nervous system diseases.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Information Gathering in Investigative and Medical Interviewing: Drawing Parallels Across Contexts.

Information gleaned from a patients' medical history is a core determinant of a medical diagnosis. Accurate and effective history-taking is, therefore, a foundational skill for medical practitioners and is introduced early in medical training. Recognizing and developing the skills of effective medical interviewing is an ongoing challenge for medical students and experienced clinicians alike. Important parallels exist between the information gathering skills required in medicine and health, and those required in investigative interviewing. Qualitative interviews were conducted with 19 experienced medical professionals from a range of specialty areas. They were asked about the role of the medical interview in their discipline, and about challenges they experience when gathering information from patients. Both theory-driven and grounded-theory approaches were used in combination to identify common themes. The interviews were rich with themes including approaches to introductory phases of the interview, eliciting a narrative account, and several topics that specifically paralleled issues in interviewing of vulnerable witnesses. We explore these themes through a lens of investigative interviewing by applying the knowledge of effective interviewing skills and structures to the data gained from the medical context. In general, themes indicated that there are numerous parallels to information gathering approaches in both contexts. As such, there may be scope for medical education to adopt some of the training techniques employed in the investigative interviewing field. Further, it is hoped that the present findings be used to spark an interdisciplinary conversation about communication from which both sides can learn.

"Strong Teeth": an early-phase study to assess the feasibility of an oral health intervention delivered by dental teams to parents of young children.

BACKGROUND: Tooth decay (caries) is a significant health burden in young children. There is strong evidence for the benefits of establishing appropriate home-based oral health behaviours in early childhood. Dental teams are well placed to provide this information and there is clear advice on what oral health information should be given to parents. However, research has shown that there is limited guidance, training and resources on how dental teams should deliver this advice. "Strong Teeth" is a complex oral health intervention, using evidence-based resources and training underpinned by behaviour change psychology, to support behaviour change conversations in dental practice. This early phase evaluation aims to assess the feasibility of this intervention, prior to a full-scale trial. METHODS: The study recruited 15 parents of children aged 0-2-years-old and 21 parents of children aged 3-5 years old, from five NHS dental practices across West Yorkshire. Participant demographics, self-reported brushing behaviours, dietary habits, a dental examination and three objective measures of toothbrushing were collected in a home-setting at baseline, then at 2-weeks and 2-months post-intervention. Recruitment, retention and intervention delivery were analysed as key process outcomes. Brushing habits were compared to national toothbrushing guidelines - the Delivering Better Oral Health toolkit (Public Health England). RESULTS: Strong Teeth was feasible to deliver in a General Dental Practice setting in 94% of cases. Feasibility of recruitment (37%) exceeded progression criterion, however retention of participants (75%) was below the progression criterion for the 0-2 age group. More than half of children recruited aged 3-5-years had caries experience (52%). Total compliance to toothbrushing guidance at baseline was low (28%) and increased after the intervention (52%), an improvement that was statistically significant. Dietary habits remained largely unchanged. Plaque scores significantly decreased in the 3-5-year-olds and toothbrushing duration increased in all age groups. CONCLUSION: "Strong Teeth" intervention delivery and data collection in the home setting was feasible. There was a positive indication of impact on reported toothbrushing behaviours. Some amendments to study design, particularly relating to the inclusion of the 0-2-year-old group, should be considered before progression to a full trial. Trial registration ISRCTN Register: ISRCTN10709150. Registered retrospectively 24/7/2019.

Health disparities among older adults following tropical cyclone exposure in Florida.

Tropical cyclones (TCs) pose a significant threat to human health, and research is needed to identify high-risk subpopulations. We investigated whether hospitalization risks from TCs in Florida (FL), United States, varied across individuals and communities. We modeled the associations between all storms in FL from 1999 to 2016 and over 3.5 million Medicare hospitalizations for respiratory (RD) and cardiovascular disease (CVD). We estimated the relative risk (RR), comparing hospitalizations during TC-periods (2 days before to 7 days after) to matched non-TC-periods. We then separately modeled the associations in relation to individual and community characteristics. TCs were associated with elevated risk of RD hospitalizations (RR: 4.37, 95% CI: 3.08, 6.19), but not CVD (RR: 1.04, 95% CI: 0.87, 1.24). There was limited evidence of modification by individual characteristics (age, sex, or Medicaid eligibility); however, risks were elevated in communities with higher poverty or lower homeownership (for CVD hospitalizations) and in denser or more urban communities (for RD hospitalizations). More research is needed to understand the potential mechanisms and causal pathways that might account for the observed differences in the association between tropical cyclones and hospitalizations across communities.

Optical interferometry-based array of seafloor environmental sensors using a transoceanic submarine cable.

Optical fiber-based sensing technology can drastically improve Earth observations by enabling the use of existing submarine communication cables as seafloor sensors. Previous interferometric and polarization-based techniques demonstrated environmental sensing over cable lengths up to 10,500 kilometers. However, measurements were limited to the integrated changes over the entire length of the cable. We demonstrate the detection of earthquakes and ocean signals on individual spans between repeaters of a 5860-kilometer-long transatlantic cable rather than the whole cable. By applying this technique to the existing undersea communication cables, which have a repeater-to-repeater span length of 45 to 90 kilometers, the largely unmonitored ocean floor could be instrumented with thousands of permanent real-time environmental sensors without changes to the underwater infrastructure.

Using process drama to explore the causes of dental anxiety in primary-school children.

BACKGROUND: Drama and role play can be unlisted as methods to allow children to view problems from a range of different perspectives that may differ from their own experience. Application of drama technique to assess the cause of dental fear and anxiety in a school setting is novel. AIM: The aim of this study was to engage primary school children in the core investigation via participatory arts methodologies, namely, process drama to gain understanding of the causes of dental anxiety. DESIGN: Sixty-three children, aged 7-10 years from three primary schools participated in this study. A 90-min drama workshop was carried in each school. The children were encouraged to identify the causes of dental anxiety using key concepts from process drama. The sessions were audio-recorded and transcribed. RESULTS: Four key concepts emerged: (1) fear of the unknown; (2) unpleasant sensory experience; (3) society's perception and portrayal of the dentist; and (4) learnt negative associations with the dentist. Within each four key concepts, two sub-themes were identified. CONCLUSIONS: Role-playing and use of drama are a novel application and can reveal a considerable amount of information from the child's perspective on the cause of dental fear and anxiety.

Epidemiology of community-acquired meticillin-resistant Staphylococcus aureus obtained from the UK West Midlands region.

SUMMARY: Between January 2005 and December 2005, 199 meticillin-resistant Staphylococcus aureus (MRSA) isolates were obtained from non-hospitalised patients presenting skin and soft tissue infections to local general practitioners. The study area incorporated 57 surgeries from three Primary Care Trusts in the Lichfield, Tamworth, Burntwood, North and East Birmingham regions of Central England, UK. Following antibiotic susceptibility testing, pulsed-field gel electrophoresis, Panton-Valentine leukocidin gene detection and SCCmec element assignment, 95% of the isolates were shown to be related to hospital epidemic strains EMRSA-15 and EMRSA-16. In total 87% of the isolate population harboured SCCmec IV, 9% had SCCmec II and 4% were identified as carrying novel SCCmec IIIa(-mecI). When mapped to patient home postcode, a diverse distribution of isolates harbouring SCCmec II and SCCmec IV was observed; however, the majority of isolates harbouring SCCmec IIIa(-mecI) were from patients residing in the north-west of the study region, highlighting a possible localised clonal group. Transmission of MRSA from the hospital setting into the surrounding community population, as demonstrated by this study, warrants the need for targeted patient screening and decolonisation in both the clinical and community environments.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis.

The intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T-cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T-cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

Learning from good practice: a review of current oral health promotion materials for parents of young children.

Objectives To examine the quality of UK-based oral health promotion materials (OHPM) for parents of young children aged 0-5 years old.Data sources OHPM were obtained via email request to dental public health consultants and oral health promotion teams in the UK, structured web-based searches or collected from oral health events.Data selection Materials were included if: they were freely available; they were in English; they were parent facing and included oral health advice aimed at children aged 0-5-years-old.Data extraction Quality assessment was based on: whether the oral health messages were consistent with Public Health England's Delivering better oral health guidance, and what barriers to good oral health were addressed by the OHPM using the Theoretical Domains Framework (TDF).Data synthesis A wide range of printed and digital OHPM were identified (n = 111). However, only one piece of material covered all 16 guidance points identified in Public Health England's Delivering better oral health (mean 6, SD 4), and one other material addressed all 12 domains of the TDF (mean 6, SD 2).Conclusions Although there were examples of high quality, further development is required to ensure OHPM are clear, consistent and address a wider range of barriers to good oral health behaviours.

Using intervention mapping to develop a home-based parental-supervised toothbrushing intervention for young children.

BACKGROUND: Dental caries in young children is a major public health problem impacting on the child and their family in terms of pain, infection and substantial financial burden on healthcare funders. In the UK, national guidance on the prevention of dental caries advises parents to supervise their child's brushing with fluoride toothpaste until age 7. However, there is a dearth of evidence-based interventions to encourage this practice in parents. The current study used intervention mapping (IM) to develop a home-based parental-supervised toothbrushing intervention to reduce dental caries in young children. METHODS: The intervention was developed using the six key stages of the IM protocol: (1) needs assessment, including a systematic review, qualitative interviews, and meetings with a multi-disciplinary intervention development group; (2) identification of outcomes and change objectives following identification of the barriers to parental-supervised toothbrushing (PSB), mapped alongside psychological determinants outlined in the Theoretical Domains Framework (TDF); (3) selection of methods and practical strategies; (4) production of a programme plan; (5) adoption and implementation and (6) Evaluation. RESULTS: The comprehensive needs assessment highlighted key barriers to PSB, such as knowledge, skills, self-efficacy, routine setting and behaviour regulation and underlined the importance of individual, social and structural influences. Parenting skills (routine setting and the ability to manage the behaviour of a reluctant child) were emphasised as critical to the success of PSB. The multi-disciplinary intervention development group highlighted the need for both universal and targeted programmes, which could be implemented within current provision. Two intervention pathways were developed: a lower cost universal pathway utilising an existing national programme and an intensive targeted programme delivered via existing parenting programmes. A training manual was created to accompany each intervention to ensure knowledge and standardise implementation procedures. CONCLUSIONS: PSB is a complex behaviour and requires intervention across individual, social and structural levels. IM, although a time-consuming process, allowed us to capture this complexity and allowed us to develop two community-based intervention pathways covering both universal and targeted approaches, which can be integrated into current provision. Further research is needed to evaluate the acceptability and sustainability of these interventions.

Parents' Experiences of Toothbrushing with Children: A Qualitative Study.

Globally, dental caries is one of the most prevalent diseases and is more common in children living in deprived areas. Dental caries is preventable, and guidance in the United Kingdom recommends parental supervised brushing (PSB): a collection of behaviors-including twice-daily toothbrushing with fluoridated toothpaste-that should begin upon eruption of the first tooth (approximately 6 to 12 mo of age) and for which children need to be helped or supervised by an adult until at least 7 y of age. The aim of this study was to explore parents' experiences of toothbrushing with their young children and to establish barriers and facilitators to PSB at individual, interpersonal, and environmental levels according to the theoretical domains framework. Qualitative semistructured interviews guided by the framework were conducted with 27 parents of young children (<7 y) in 2 deprived areas of the United Kingdom. Framework analysis was used. Parents were not aware of national guidance concerning their active involvement in toothbrushing; however, they did have detailed knowledge of toothbrushing practices for children, and their intentions were to brush their children's teeth themselves twice every day as part of a family routine. Nonetheless, parents' difficulties experienced in managing their children's challenging behavior and the environmental context of their stressful lives meant that many parents adopted a role of simply reminding their children to brush or watching them brush. As such, the main barriers to PSB among parents living in deprived areas were skills in managing their children's behavior and environmental influences on family life. The results of our study have clear implications for the development of appropriate interventions to address the modifiable barriers to improve parental adoption of PSB. Knowledge Transfer Statement: The results of this study will be used to develop a behavior change intervention to encourage parental supervised brushing. The intervention-which is likely to be delivered through health practitioners rather than dental teams-will be developed to reduce dental caries among young children and will require evaluation in terms of its clinical and cost effectiveness.

Quinoline antifolate thymidylate synthase inhibitors: variation of the C2- and C4-substituents.

Modifications to the bicyclic ring system of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (1, CB3717) have led to the synthesis of a series of quinoline antifolates bearing a variety of substituents at the C2 and C4 positions. In general the synthetic route involved the coupling of the appropriate diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate with a disubstituted 6-(bromomethyl)quinoline followed by deprotection using mild alkali. The compounds were tested as inhibitors of partially purified L1210 TS. As a measure of cytotoxicity, the compounds were tested for their inhibition of the growth of L1210 cells in culture. Good enzyme inhibition and cytotoxicity were found for compounds containing chloro, amino, or methyl substituents at the C2 position with chloro or bromo substituents at C4. The effect on enzyme inhibition of varying the N10 substituent of 2h was similar to that observed in the quinazolinone-containing antifolates, indicating that the quinoline compounds may be interacting with the enzyme in a similar way to the quinazolinones. Also, the introduction of a 2'-fluoro substituent into the benzoyl ring of several of the quinoline antifolates led to an increase in both TS inhibition and the inhibition of L1210 cell growth. These data demonstrate that the N3-H of the pyrimidine ring of the quinazolinone antifolates is not required for binding to TS if appropriate substituents are placed at the C2 and C4 positions of the bicyclic ring system.

Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C2 position.

Modification of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-N-prop-2- ynylamino]benzoyl]-L-glutamic acid (1a) has led to the synthesis of quinazoline antifolates bearing alkyl, substituted alkyl, and aryl substituents at C2. In general the synthetic route involved the coupling of the appropriate diethyl N-[4-(alkylamino)benzoyl]-L-glutamate with a C2-substituted 6-(bromo-methyl)-3,4-dihydro-4-oxoquinazoline followed by deprotection using mild alkali. Good enzyme inhibition and cytotoxicity were found with compounds containing small nonpolar groups in the C2 position with the 2-desamino-2-methyl analogue 3a being the most potent. Larger C2 substituents were tolerated by the enzyme, but cytotoxicity was reduced. Highly potent series were followed up by the synthesis of a number of analogues in which the N10 substituent was varied. In this manner a number of interesting TS inhibitors have been prepared. Although none of these was more potent than 1a against the isolated enzyme, over half of the compounds prepared were more potent as cytotoxic agents against L1210 cells in culture. The potential of such compounds as useful antitumor agents was further enhanced by the finding that the improved aqueous solubilities of compounds such as 3a over 1a were reflected in vivo in that 3a was at least 5 times less toxic to mice than 1a.

High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity.

The goal of this study was to determine if high-dose methamphetamine treatment altered presynaptic immunoreactivity for the amino acid neurotransmitters GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg every 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynaptic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immunoreactivity, there was a significant increase in the percentage of glutamate-immuno-positive terminals associated with perforated postsynaptic densities. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastructural or immunocytochemical changes. In addition, induction of hyperthermia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreactivity. Altered presynaptic GABA immunolabeling and terminal size were found in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dopamine loss. In addition, ultrastructural changes in glutamate-positive synapses which have been correlated with increased synaptic activity were found. These results are similar to changes in GABA and glutamate synapses that follow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamphetamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mitochondrial Immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores.

A case of coccidioidomycosis diagnosed by exoantigen testing.

A case of coccidioidomycosis is described which was caused by a pigmented fungus that failed to produce arthroconidia. Exoantigen testing showed that the isolate produced an antigen that gave a line of identity with Coccidioides (C.) immitis. The formation of spherules in a guinea pig testis confirmed the identity of the isolate as C. immitis. The patient's serum was found to have antibodies that reacted in complement fixation and immunodiffusion tests to C. immitis antigens. The exoantigen test results were responsible for the diagnosis of coccidioidomycosis in this case.

A peptidergic circuit for reproductive behavior.

A projection from the medial amygdaloid nucleus to the hippocampus and septum probably uses vasopressin as a transmitter. The nucleus synthesizes vasopressin and activation of the nucleus has a hippocampal effect that is completely blocked by a vasopressin antagonist. The afferent and efferent projections of this peptidergic nucleus suggest a possible role for the system in sexual behavior. Stimulation of the nucleus inhibits the output of the hippocampus in both genders and reorganizes behavior for a period of 15-20 min. In males, the effect of peptidergic activation is to produce a behavior that resembles the post-ejaculatory interval in coitus. This state is characterized by an EEG that resembles slow-wave sleep and by ultrasonic vocalizations at a characteristic frequency of 22 kHz. Castration in either gender causes depletion of the peptide from the target fields and eliminates the peptidergic signal in the hippocampus after about 15 weeks. The effects of castration in males can be reversed by testosterone replacement. The fluctuation of estrogen levels in rat plasma during the estrus cycle happens too quickly to impact the peptidergic system, and thus there is no significant change in the strength of the peptidergic signal among the proestrus, estrus, metestrus and diestrus stages. This fact permits study of the physiology of the system without concern for stage of estrus but does not permit conclusions regarding its function in females.

Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration.

Metabolic mapping of discrete brain regions using cytochrome oxidase histochemistry was used as a marker for alterations in mitochondrial function and cytochrome oxidase enzymatic activity in response to high doses of amphetamine derivatives. The activity of cytochrome oxidase, complex IV of the electron transport chain, was determined at three different time-points following administration of high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) (four injections of 10-15 mg/kg administered over 8 h). There was a rapid decrease in cytochrome oxidase staining in the striatum (23-29%), nucleus accumbens (29-30%) and substantia nigra (31-43%), 2 h following administration of either methamphetamine and MDMA. This decrease in cytochrome oxidase activity was transient and returned to control levels within 24 h. Since the methamphetamine and MDMA-induced decrease in cytochrome oxidase activity was localized to dopamine-rich regions, increased extracellular concentrations of dopamine may contribute to the inhibition of metabolic function via its metabolism to form quinones or other reactive oxygen species. These results support previous studies demonstrating that psychostimulants induce a rapid and transient decrease in striatal ATP stores and provide further evidence that these drugs of abuse can disrupt mitochondrial function.

Harnessing the heightened public awareness of celebrity HIV disclosures: "Magic" and "Cookie" Johnson and HIV testing.

This article investigates the impact NBA basketball star Earvin ("Magic") Johnson's HIV disclosure had on changes in demand for HIV counseling and testing services in New York State's 61 Anonymous HIV Counseling and Testing sites. Interrupted time-series analyses were conducted on weekly data from over 34,000 clients seeking anonymous HIV counseling and testing services from January 1991 to June 1992, to determine whether demand for these services changed as a result of the disclosure. Results indicated that immediately following the HIV disclosure, there was a substantial increase in service demand, which transcended all sex, race, age, and most HIV risk-related boundaries. Seven months later, demand had not returned to pre-disclosure levels. The strong impact on females, coupled with additional data analyses in obstetrical settings, suggests that previous research has been too narrow in focus, and that the effect of Johnson's HIV disclosure has been enhanced, in part, by the publicity surrounding his wife and baby. The importance of harnessing the heightened public awareness of celebrity HIV disclosures is discussed.

Parental interrater reliability as a function of situational specificity and familiarity of target child.

Child behavior ratings were made by 17 mothers and fathers of the same child. Agreement was computed for each parent pair under the following experimental conditions: (1) Ratings of their own child's behavior in general (CBC); (2) ratings of own child based on observations of him/her in a videotaped sample; (3) ratings of an unknown child based on observations of him/her in a videotaped sample; and (4) ratings of the videotaped sample of own child and unknown child using a one minute time-sampling procedure. Parents achieved higher rates of agreement (X = .81) than have previously been reported. Increasing the specificity of the behavior being rated did not significantly affect agreement. Those parent pairs who agreed the most did not necessarily spend a large amount of time in the same kind of situations with their child. Agreement was significantly greater when parents rated their own children's videotaped behavior sample as opposed to that of an unknown child.