Zinc deficiency in low- and middle-income countries: prevalence and approaches for mitigation.

This review addresses the prevalence of zinc deficiency in Low- and Middle-income Countries (LMICs) and assesses the available strategies for its alleviation. The paucity of national-level data on the zinc deficiency in LMICs is partially a result of the lack of a reliable biomarker. Zinc deficiency appears to be a public health problem in almost all the LMICs, irrespective of the recommended indicators (plasma zinc concentration, dietary zinc adequacy and stunting prevalence) used. Based on plasma/serum zinc concentration (PZC), which is the most appropriate indicator at present, the prevalence of zinc deficiency in LMICs is of concern. Among the 25 countries for which national PZC data were available, 23 had a zinc deficiency prevalence of >20% for at least one physiological group. Zinc supplementation is largely restricted as an adjunct therapy for diarrhoea management in children, and the best platform and the most effective way of preventive zinc supplementation delivery remains to be established. Impact assessment for current zinc fortification programmes in LMICs and the effectiveness of zinc supplementation as part of a multi-micronutrient powder is to be determined. Dietary diversification, though promising for LMICs, is in the nascent stages of development at present. Inclusion of meat and animal products can be an important way of improving zinc status. Programmatic experience with the promotion of home processing techniques to increase absorbable zinc in the diet is lacking. Conventional biofortification techniques are gaining recognition in LMICs; however, transgenic biofortification as a strategy remains controversial.

Effect of Zinc Intake on Growth in Infants: A Meta-analysis.

A systematic review and meta-analysis of available randomized controlled trials (RCTs) was conducted to evaluate the effect of zinc (Zn) intake on growth in infants. Out of 5500 studies identified through electronic searches and reference lists, 19 RCTs were selected after applying the exclusion/inclusion criteria. The influence of Zn intake on growth was considered in the overall meta-analysis. Other variables were also taken into account as possible effect modifiers: doses of Zn intake, intervention duration, nutritional status, and risk of bias. From each select growth study, final measures of weight, length, mid upper arm circumference (MUAC), head circumference, weight for age z-score (WAZ), length for age z-score (LAZ), and weight for length z-score (WLZ) were assessed. Pooled ß and 95% confidence interval (CI) were calculated. Additionally, we carried out a sensitivity analysis. Zn intake was not associated with weight, length, MUAC, head circumference, and LAZ in the pooled analyses. However, Zn intake had a positive and statistically effect on WAZ (ß = 0.06; 95%CI 0.02 to 0.10) and WLZ (ß = 0.05; 95%CI 0.01 to 0.08). The dose-response relationship between Zn intake and these parameters indicated that a doubling of Zn intake increased WAZ and WLZ by approximately 4%. Substantial heterogeneity was present only in length analyses (I(2) = 45%; p = 0.03). Zn intake was positively associated with length values at short time (four to 20 weeks) (ß = 0.01; CI 95% 0 to 0.02) and at medium doses of Zn (4.1 to 8 mg/day) (ß = 0.003; CI 95% 0 to 0.01). Nevertheless, the effect magnitude was small. Our results indicate that Zn intake increases growth parameters of infants. Nonetheless, interpretation of these results should be carefully considered.

Vein imaging laser reduces bruising in bruise-prone botulinum toxin injected patients.

BACKGROUND: Injection-related bruising is a common complication of many injectable treatments including facial injections of botulinum toxin (BTX) for aesthetic use. OBJECTIVE: We have investigated the use of a vein imaging laser (VIL) to observe otherwise non-visible subcutaneous blood vessels in 40 patients who had a history of bruising with past BTX injections to the face during the previous 12 months. METHODS: Over a 4-month period 40 patients, who previously had developed bruising after injectable BTX to the face, were treated with further BTX to the same areas as previously, but using a VIL during the injections. Patients were evaluated for their severity of bruising. RESULTS: 40 patients out of 2400 patients had experienced bruising with a severity score total of 92 (mean per patient 2.3) with BTX injections before VIL use. On injection using the VIL 6 of the 40 patients had bruising with severity score total of 7 (mean 1.16). CONCLUSION: The use of a VIL significantly reduced the frequency and severity of bruising associated with BTX injections.

Chromosome specific paints from a high resolution flow karyotype of the mouse.

Chromosomes from antigen stimulated B-cells from spleens of inbred mice have been separated using flow cytometry into 18 distinguishable peaks. Using locus-specific oligonucleotides and fluorescence in situ hybridization to banded metaphase spreads, 15 individual chromosomes were identified: 1, 2, 3, 6, 7, 8, 9, 11, 12, 16, 17, 18, 19, X and Y. The remaining six chromosomes, occurring as pairs in three peaks, 4 with 5, 10 with 13, and 14 with 15, were resolved by flow sorting chromosomes from mice carrying an appropriate homozygous translocation and 4, 5 and 14 have been isolated in this way. This is the first demonstration of how a complete set of mouse chromosome paints can be produced.

Recurrent acute otitis media: a survey of current management in England.

OBJECTIVE: Recurrent acute otitis media is common in children. The preferred treatment measures for recurrent acute otitis media have a mixed evidence base. This study sought to assess baseline practice across ENT departments in England. METHODS: A national telephone survey of healthcare staff was conducted. Every ENT centre in England was contacted. A telephone script was used to ask about antibiotic and grommet use and duration in recurrent acute otitis media cases. RESULTS: Ninety-six centres (74 per cent) provided complete information. Recurrent acute otitis media treatment across England by ENT departments varied. The antibiotic first- and second-line prophylaxis offered varies, with trimethoprim used in 33 centres and 29 centres not offering any antibiotics. The timing or choice about when to use grommets also varies, but 87 centres (91 per cent) offer grommet surgery at one stage. CONCLUSION: The treatments received by children in England for recurrent acute otitis media vary by centre; collaborative research in this area is advised.

The negative impact of wearing personal protective equipment on communication during coronavirus disease 2019.

BACKGROUND: Coronavirus disease 2019 personal protective equipment has been reported to affect communication in healthcare settings. This study sought to identify those challenges experimentally. METHOD: Bamford-Kowal-Bench speech discrimination in noise performance of healthcare workers was tested under simulated background noise conditions from a variety of hospital environments. Candidates were assessed for ability to interpret speech with and without personal protective equipment, with both normal speech and raised voice. RESULTS: There was a significant difference in speech discrimination scores between normal and personal protective equipment wearing subjects in operating theatre simulated background noise levels (70 dB). CONCLUSION: Wearing personal protective equipment can impact communication in healthcare environments. Efforts should be made to remind staff about this burden and to seek alternative communication paradigms, particularly in operating theatre environments.

A small conserved domain in the yeast Spa2p is necessary and sufficient for its polarized localization.

SPA2 encodes a yeast protein that is one of the first proteins to localize to sites of polarized growth, such as the shmoo tip and the incipient bud. The dynamics and requirements for Spa2p localization in living cells are examined using Spa2p green fluorescent protein fusions. Spa2p localizes to one edge of unbudded cells and subsequently is observable in the bud tip. Finally, during cytokinesis Spa2p is present as a ring at the mother-daughter bud neck. The bud emergence mutants bem1 and bem2 and mutants defective in the septins do not affect Spa2p localization to the bud tip. Strikingly, a small domain of Spa2p comprised of 150 amino acids is necessary and sufficient for localization to sites of polarized growth. This localization domain and the amino terminus of Spa2p are essential for its function in mating. Searching the yeast genome database revealed a previously uncharacterized protein which we name, Sph1p (a2p omolog), with significant homology to the localization domain and amino terminus of Spa2p. This protein also localizes to sites of polarized growth in budding and mating cells. SPH1, which is similar to SPA2, is required for bipolar budding and plays a role in shmoo formation. Overexpression of either Spa2p or Sph1p can block the localization of either protein fused to green fluorescent protein, suggesting that both Spa2p and Sph1p bind to and are localized by the same component. The identification of a 150-amino acid domain necessary and sufficient for localization of Spa2p to sites of polarized growth and the existence of this domain in another yeast protein Sph1p suggest that the early localization of these proteins may be mediated by a receptor that recognizes this small domain.

The BiZiFED project: Biofortified zinc flour to eliminate deficiency in Pakistan.

Zinc deficiency is a global public health problem, affecting ~17% of the world's population, with the greatest burden in low- and middle-income countries. An increasing body of evidence suggests that biofortification may be a cost-effective and sustainable approach to reducing zinc and other micronutrient deficiencies. Biofortification enhances the nutritional quality of food crops through conventional plant breeding techniques and agronomic practices. This paper presents ongoing research on biofortification in Pakistan, where over 40% of women are zinc deficient. The Biofortified Zinc Flour to Eliminate Deficiency (BiZiFED) project aims to investigate the impact of biofortification as a strategy to alleviate zinc deficiency in Pakistan. The project is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Global Challenges Research Fund from May 2017 to April 2019. This paper outlines the four objectives and work packages within the BiZiFED project: (1) a double-blind, randomised controlled trial to examine the effect of consuming flour made from a high zinc variety of biofortified wheat (Zincol-2016/NR-421) on dietary zinc intake and status; (2) a cost-effectiveness study to assess the health and economic impact of agronomic biofortification of wheat; (3) a mixed methods study to explore the cultural acceptability and sustainability of biofortification in Pakistan; (4) capacity building and development of long-term research partnerships in Pakistan. The findings will contribute to the evidence base for the potential impact of biofortification to alleviate zinc deficiency among the poorest communities.

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

An overview of ultraviolet radiation, sunscreens, and photo-induced dermatoses.

The incidence of sunlight-induced skin aging and skin cancers, particularly melanoma skin cancer, has been increasing in many parts of the world. Authorities are recommending primary prevention programs to reduce cutaneous photodamage and skin carcinogenesis. An integral component of these programs is the use of protective clothing and effective sunscreens. Most modern sunscreens have highly efficient absorption or reflecting capabilities throughout ultraviolet B, partly ultraviolet A, and in some instances infrared wavelengths. Over the last several years, more efficient sunscreening ingredients have been developed for improved skin protection. More recently, direct evidence has demonstrated the effectiveness of sunscreens in their ability to reduce the incidence of solar keratoses. This article reviews the protectiveness of sunscreens and assays that predict their levels of protection.

Induction of ornithine decarboxylase activity and DNA synthesis in hairless mouse epidermis by retinoids.

The ability of all-trans-retinoic acid (RA) and other retinoid derivatives to enhance DNA synthesis and to induce ornithine decarboxylase [L-ornithine carboxylyase; EC 4.1.1.17 (ODC)] activity has been investigated in normal and tape-stripped hairless mouse epidermis. Initial studies showed that the retinoids could inhibit the induction of epidermal ODC activity found 4.5 hr after tape stripping. Ten nmol RA, 13-cis-retinoic acid (13-cis-RA), ethyl-all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6, 8-nonatetraenoate (aromatic retinoid), or ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8, 8,-tetramethyl-2-naphthyl)-1-propenyl]benzoate (arotinoid ethyl ester) applied topically to the skin at 1 hr before tape stripping inhibited the induction of ODC activity. Induction of epidermal ODC activity was inhibited by arotinoid ethyl ester but not by RA, 13-cis-RA, or aromatic retinoid when they were applied to the skin at 24 hr prior to tape stripping. RA applied topically to normal hairless mouse skin induced a dose-dependent increase in epidermal ODC activity, detectable 24 hr or more after treatment. RA induced epidermal ODC activity to levels only 15- to 30-fold less than found after treatment with the potent tumor promoter tetradecanoylphorbol-13-acetate. Epidermal ODC activity was also induced by topical 13-cis-RA, aromatic retinoid, and arotinoid ethyl ester at this time, although in lower amounts than after RA treatment. The induction of ODC activity by RA was itself inhibited by topical arotinoid ethyl ester treatment. RA, 13-cis-RA, and aromatic retinoid induced ODC activity at doses below those required to enhance epidermal DNA synthesis. In summary, we have shown that, in common with other proliferative stimuli, retinoids can induce ODC activity in hairless mouse epidermis per se. Our results suggest that, because of their ability to also inhibit the expression of ODC activity, the induced ODC activity is found only after the retinoids have been depleted. The ability both to inhibit and to induce ODC activity may be related to the action of RA as a weak tumor promoter under certain conditions and as an inhibitor of promotion under others.

Inhibition of ultraviolet-B skin carcinogenesis by all-trans-retinoic acid regimens that inhibit ornithine decarboxylase induction.

There is a correlation between the ability to induce the polyamine-biosynthetic enzyme ornithine decarboxylase (ODC) and the tumor-promoting ability of various carcinogens in mouse epidermis. Some agents which inhibit skin carcinogenesis also inhibit ODC induction. In this study, all-trans-retinoic acid (RA) regimens that inhibited the induction of epidermal ODC by ultraviolet-B (UVB) were tested for their ability to inhibit UVB skin carcinogenesis. Hairless mice were irradiated once daily with UVB for 20 days, receiving a total dose of UVB (17.1 kJ/sq m). Topical RA was applied immediately (RA, one dose) or applied 0, 1, 2, 3, and 4 hr (RA, five doses) after each irradiance. The mice were maintained for 52 weeks and then sacrificed. Groups treated with RA tended to have fewer mice with tumors, fewer tumors per mouse, smaller tumor diameters, and slower growing tumors than did appropriate irradiated control groups. RA given five times was more effective than was RA given one time at inhibiting UVB skin carcinogenesis. These results show that RA treatments that inhibit epidermal ODC induction may be effective in reducing the carcinogenicity of UVB.

Inhibition of ultraviolet-B epidermal ornithine decarboxylase induction and skin carcinogenesis in hairless mice by topical indomethacin and triamcinolone acetonide.

Modulation of ultraviolet-B (UVB) skin carcinogenesis by topical treatment with two antiinflammatory drugs expected to have different mechanisms of action has been studied in the hairless mouse. Indomethacin is a nonsteroidal antiinflammatory agent which may act by inhibiting prostaglandin biosynthesis. Triamcinolone acetonide is a steroidal antiinflammatory agent. Both of these drugs inhibited the induction of epidermal ornithine decarboxylase by UVB when applied topically in a acetone vehicle. A UVB skin tumor study was designed. Groups of mice were irradiated daily with UVB for 20 days, each mouse receiving a total of 17.1 kJ UVB per sq m. Group 1 was treated with acetone immediately after each irradiation; Group 2 received 700 nmol indomethacin in acetone immediately after each irradiation; Group 3 received 14.4 nmol triamcinolone acetonide in acetone immediately after each irradiation. Mice were killed after 52 weeks, and the tumors were excised and examined histologically. Both topical indomethacin and topical triamcinolone acetonide were effective in reducing the incidence and size of the skin tumors induced by UVB. This evidence supports the hypothesis that the induction of ornithine decarboxylase may be a critical component of UVB skin carcinogenesis and that inhibition of ornithine decarboxylase induction can be used as a screen for agents which will inhibit UVB skin carcinogenesis.

Homozygous deletions at 3p12 in breast and lung cancer.

We have constructed a physical map of the region homozygously deleted in the U2020 cell line at 3p12, including the location of putative CpG islands. Adjacent to one of these islands, we have identified and cloned a new gene (DUTT1) and used probes from this gene to detect two other homozygous deletions occurring in lung and breast carcinomas: the smallest deletion is within the gene itself and would result in a truncated protein. The DUTT1 gene is a member of the neural cell adhesion molecule family, although its widespread expression suggests it plays a less specialized role compared to other members of the family.

The recognition of distorted DNA structures by HMG-D: a footprinting and molecular modelling study.

The high mobility group (HMG) domain is a DNA binding motif found in some eukaryotic chromosomal proteins and transcription factors. This domain binds in the minor groove of DNA inducing a sharp bend and also preferentially binds to certain distorted DNA structures. Although structures of sequence-specific HMG domains with their cognate double-helical DNA binding sites have been solved, the nature of the interaction of the domain with distorted DNA remains to be established. In this study we have investigated the interaction of HMG-D, a Drosophila counterpart of the vertebrate HMG1, with a DNA oligomer containing a bulge of two adenine residues. We show by footprinting that HMG-D binds preferentially on one side of the bulged DNA. Based on these data and on the published NMR structures of the HMG domain of HMG-D and the LEF-1-DNA complex, we modelled the HMG-D - bulged DNA complex. This model predicts that two residues, Val32 and Thr33, in the loop between alpha-helices I and II are inserted deep into the "hole" in the DNA formed by the two missing bases on one strand of the DNA bulge. Mutation of these residues confirmed that both are required for the efficient binding and bending of DNA by HMG-D. We discuss both the role of this loop in the recognition of distorted DNA structures by non-sequence specific HMG domain proteins and that of the basic tail in stabilising the induced DNA bend.

The relationship between zinc intake and growth in children aged 1-8 years: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: It is estimated that zinc deficiency affects 17% of the world's population, and because of periods of rapid growth children are at an increased risk of deficiency, which may lead to stunting. This paper presents a systematic review and meta-analysis of the randomised controlled trials (RCTs) that assess zinc intake and growth in children aged 1-8 years. This review is part of a larger systematic review by the European Micronutrient Recommendations Aligned Network of Excellence that aims to harmonise the approach to setting micronutrient requirements for optimal health in European populations (www.eurreca.org). SUBJECT/METHODS: Searches were performed of literature published up to and including December 2013 using MEDLINE, Embase and the Cochrane Library databases. Included studies were RCTs in apparently healthy child populations aged from 1 to 8 years that supplied zinc supplements either as capsules or as part of a fortified meal. Pooled meta-analyses were performed when appropriate. RESULTS: Nine studies met the inclusion criteria. We found no significant effect of zinc supplementation of between 2 weeks and 12 months duration on weight gain, height for age, weight for age, length for age, weight for height (WHZ) or WHZ scores in children aged 1-8 years. CONCLUSIONS: Many of the children in the included studies were already stunted and may have been suffering from multiple micronutrient deficiencies, and therefore zinc supplementation alone may have only a limited effect on growth.

Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis.

In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult's studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) -0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, -0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI -0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta-analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further.

Ultraviolet light and epidermal polyamines.

Numerous studies have indicated that the activities of the polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAM.D) are increased in hyperplastic and neoplastic growth. The levels of the polyamines themselves, putrescine, spermidine, and spermine are also often altered in these situations. Epidermal ODC activity is greatly elevated in response to tumor promoting chemicals and also in response to irradiation with short-wave length and mid-wave length ultraviolet. In addition, the levels of the epidermal polyamines change after mid-wavelength ultraviolet irradiation, leading to elevation of putrescine and spermidine, but depression of the spermine level. The spermidine to spermine ratio was significantly elevated after chronic ultraviolet irradiation. Preliminary studies on human skin also shows that mid-wavelength ultraviolet light is capable of inducing ODC. Different pharmacological agents have been found to significantly inhibit the ultraviolet induction of epidermal ODC. Topical corticosteroids and indomethacin significantly inhibit ultraviolet induced opidermal ODC. In addition, retinoic acid inhibited the ultraviolet induction of this enzyme in some experimental situations. Long-wave length ultraviolet alone produced no significant induction of ODC, however, certain phototoxic drugs (8-methoxypsoralen and anthracene) in combination with long-wave length ultraviolet did induce epidermal ODC. It is possible that further studies of changing epidermal polyamine metabolism in response to ultraviolet and tumor promoting agents, may lead to a greater understanding of cutaneous carcinogenesis.

Epidermal pyridoxal 5'-phosphate depletion, inhibition of DNA synthesis, and inhibition of the expression of ornithine decarboxylase activity by the vitamin B-6 antagonist 4'-deoxypyridoxine.

The induction of ornithine decarboxylase (ODC) activity may be an essential component of skin tumor promotion. ODC requires pyridoxal 5'-phosphate (PLP) as a cofactor. We have measured the epidermal PLP concentration and investigated its relationship to DNA synthesis and ODC activity in the hairless mouse. The epidermal PLP concentration was approximately 1.0 microgram/g. When tape-stripping was used to induce ODC activity in the epidermis the concentration of PLP was significantly elevated 4.5 h later at the time of peak ODC activity and when DNA synthesis was reduced. Systemic treatment with the vitamin B-6 antagonist 4'-deoxypyridoxine (4-DOP) significantly reduced the epidermal PLP concentration and DNA synthesis. The ODC activity induced in the epidermis 4.5 after tape-stripping in 4-DOP-treated mice was only 17% of that induced in untreated tape-stripped controls. In in vitro experiments it was shown that while 4-DOP does not inhibit ODC activity, a major metabolite of 4-DOP-phosphate (Ki .06 mM), does. In mixing experiments it was shown that the epidermal extracts from 4-DOP-treated mice did not contain significant amounts of ODC inhibitors. 4-DOP may inhibit ODC induction in the epidermis by depleting the PLP content.