High Prevalence of Stunting and Anaemia Is Associated with Multiple Micronutrient Deficiencies in School Children of Small-Scale Farmers from Chamwino and Kilosa Districts,Tanzania

Inadequate macro- and micronutrient nutrition and its consequences, such as anaemia, iron and vitamin deficiency, and growth retardation, could particularly affect children of small-scale farmers. In the present cross-sectional study, 666 school children aged 5–10 years from villages of Chamwino and Kilosa districts were studied for associations between nutritional and micronutrient status and dietary intake. The overall prevalence of stunting, underweight, and overweight was 28.1, 14.4, and 5%, while that of anaemia and deficiency of iron (ID), vitamin A (VAD), and zinc (ZnD) was 42.9, 29.3, 24.9, and 26.4%, respectively. Dietary recalls (24h) revealed that, except of iron (74%), only small proportions of children reached the recommended daily micronutrient intakes: 4% for zinc, 19% for vitamin A, and 14–46% for B vitamins. Stunting was highly associated with wasting in both districts and with VAD in Chamwino. Anaemia was predicted by ID, VAD, and ZnD in Chamwino and by elevated infection markers, C-reactive protein (CRP) and α-1 glycoprotein (AGP), in Kilosa. Overall, elevated CRP and/or AGP increased the risk while higher serum carotenoids indicating a diet of more fruit and vegetables reduced the risk of VAD. The significantly lower prevalence of anaemia and ID in Chamwino was related to higher iron and vitamin A intake and the consumption of mainly bulrush millet with dark green leafy vegetables compared to maize or rice with legumes in Kilosa. Nutrition and hygiene education integrated with home and school garden programmes could reduce the multiple burdens of anaemia; micronutrient deficiencies and infections; and, in the long term, the prevalence of stunting.     

Pimecrolimus for the treatment of inflammatory skin disease

Pimecrolimus (SDZ ASM 981, Elidel ) is an ascomycin macrolactam derivative and a cell-selective inhibitor of inflammatory cytokines specifically developed to treat inflammatory skin diseases. Pimecrolimus combines high anti-inflammatory activity in the skin with a low potential to impair systemic immune reactions. Multi-centre studies have proved the efficacy and safety of pimecrolimus cream in patients with atopic dermatitis (AD) and confirmed that it is suitable for short-term treatment and long-term management of AD in adults, children and infants as young as 3 months. Topical application in humans is not associated with the atrophogenic side effects observed with corticosteroids. Pimecrolimus blood levels remained consistently low after repeated topical application and no clinically relevant drug-related systemic adverse events have been reported among the 8000 patients treated in clinical trials so far. Short-term, Phase I/II and Phase II trials of pimecrolimus administered orally in psoriasis and AD have shown that this drug is highly effective in a dose-dependent manner in patients with these diseases and has high safety profile. This finding is confirmed by pharmacogenomic blood analysis. Available data thus indicates that pimecrolimus, in both the cream and oral formulations, may represent a new option for the treatment of inflammatory skin diseases.     

Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor

Basal cell carcinoma (BCC) is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the primary cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs in NBCCS. LDE225, a distinct, selective antagonist of SMO, showed potent inhibition of basaloid tumor nest formation and mediated regression of preformed basaloid tumors in organ cultures of skin derived from Ptch1 heterozygous knockout mice. In a double-blind, randomized, vehicle-controlled, intraindividual study, a total of 8 NBCCS patients presenting 27 BCCs were treated twice daily with 0.75% LDE225 cream or vehicle for 4 weeks. Application of 0.75% LDE225 cream was well tolerated and showed no skin irritation. Of 13 LDE225-treated BCCs, 3 showed a complete, 9 a partial, and only 1 no clinical response. Except for one partial response, the vehicle produced no clinical response in any of the 14 treated BCCs. Treatment with 0.75% LDE225 cream in NBCCS patients was very well tolerated and caused BCC regression, thus potentially offering an attractive therapeutic alternative to currently available therapies for this indication.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.     

Pimecrolimus identifies a common genomic anti-inflammatory profile,is clinically highly effective in psoriasis and is well tolerated

The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.     

SPINK5 knockdown in organotypic human skin culture as a model system for Netherton syndrome: effect of genetic inhibition of serine proteases kallikrein 5 and kallikrein 7

Netherton syndrome (NS; OMIM 256500) is a genetic skin disease resulting from defects in the serine protease inhibitor Kazal‐type 5 (SPINK5) gene, which encodes the protease inhibitor lympho‐epithelial Kazal type inhibitor (LEKTI). We established a SPINK5 knockdown skin model by transfecting SPINK5 small interfering RNA (siRNA) into normal human epidermal keratinocytes, which were used together with fibroblast‐populated collagen gels to generate organotypic skin cultures. This model recapitulates some of the NS skin morphology: thicker, parakeratotic stratum corneum frequently detached from the underlying epidermis and loss of corneodesmosomes. As enhanced serine protease activity has been implicated in the disease pathogenesis, we investigated the impact of the kallikreins KLK5 [stratum corneum trypsin‐like enzyme (SCTE)] and KLK7 [stratum corneum chymotrypsin‐like enzyme (SCCE)] on the SPINK5 knockdown phenotype by generating double knockdowns in the organotypic model. Knockdown of KLK5 or KLK7 partially ameliorated the epidermal architecture: increased epidermal thickness and expression of desmocollin 1 (DSC1), desmoglein 1 (DSG1) and (pro)filaggrin. Thus, inhibition of serine proteases KLK5 and KLK7 could be therapeutically beneficial in NS.     

Structural features that influence the ability of lipid A and its analogs to abolish expression of suppressor T cell activity.

Lipid A preparations derived from the lipopolysaccharides of several gram-negative bacteria, as well as chemically defined synthetic lipid A's and their analogs (both glucosamine mono- and disaccharides), were used to establish the chemical structures required for (i) abolishing the expression of suppressor T cell (Ts) function and (ii) inducing polyclonal activation of B cells. Salmonella minnesota R595 lipid A (diphosphoryl lipid A) possesses both of these activities. Decreasing the number of phosphate groups in lipid A from two to one (monophosphoryl lipid A) as well as decreasing the fatty acyl content, primarily by removing the residue at the 3 position, resulted in a progressive reduction in toxicity; however, these structural modifications did not influence its ability to abolish the expression of Ts function. Reducing the fatty acyl content from five to four (lipid A precursor IVA or Ia) eliminated the capacity to influence Ts function but not to induce polyclonal activation of B cells. None of the monosaccharide analogs of lipid A examined influenced the expression of Ts activity, although some were able to activate B cells polyclonally. Thus, in order to be able to abolish the expression of Ts function, lipid A (i) must be a glucosamine disaccharide, (ii) may have either one or two phosphate groups, and (iii) must have at least five fatty acyl groups. Also, the chain length of the nonhydroxylated fatty acid, as well as the location of acyloxyacyl groups (2' versus 3' position), may play an important role. These findings indicate that the chemical structures responsible for the toxicity of lipid A differ from those that influence its capacity to abolish the expression of Ts function and to induce polyclonal activation of B cells.     

Antiendotoxin Activity of Lipid A Analogues: Requirements of the Chemical Structure

Lipid X, a monosaccharide precursor of lipid A, has been found to prevent death in animals given a lethal dose of endotoxin, but the mechanism of this protective effect is unknown. We previously reported that lipid X blocks endotoxin-induced priming of human neutrophils in a manner consistent with competitive inhibition. To determine the molecular requirements for this antiendotoxin activity, we studied several derivatives of lipid X using the neutrophil priming assay. Neutrophil priming was quantitated by measuring stimulated superoxide (O₂ ^–) release. The removal of either acyl group from lipid X or even the simple change of the amide to an ester linkage at C2 of the glucosamide ring resulted in a marked loss of antagonism. Monosaccharide analogues, structurally related to native lipid A by the presence of acyloxyacyl side chains, demonstrated marked inhibition of endotoxin-induced priming at low concentrations but an endotoxin-like, priming effect at high concentrations. The addition of a phosphate group at position 4 of the sugar moiety was the only modification studied so far that produced a pure antagonist with increased antiendotoxin activity. Demonstration of these structural requirements for the antiendotoxin activity of lipid A analogues supports the hypothesis that this effect may be mediated via specific cellular binding sites. Lipid X derivatives may be useful for studying the interaction of endotoxin with cells and their antiendotoxin activity may prove beneficial in the treatment of septicemia.     

Impact of Food Rations and Supplements on Micronutrient Status by Trimester of Pregnancy: Cross-Sectional Studies in the Maela Refugee Camp in Thailand

Micronutrient fortified flour (MFF), supplementary food rations and micronutrient (MN) supplements may prevent deficiencies among pregnant women. Objectives of cross-sectional surveys in 2004 (n = 533) and 2006 (n = 515) were to assess the impact of new food rations (flour, oil) and supplements on MN status by trimester of pregnancy in the Maela refugee camp. Hemoglobin, iron status, zinc, retinol, β-carotene and tryptophan decreased, while α-/γ-tocopherol and 5-methyltetrahydrofolate (5-MTHF) increased from first to third trimester. In 2006, mean zinc and α-tocopherol for each trimester was significantly higher than in 2004. The weeks of supplemented thiamine and folic acid were positively correlated with thiamine diphosphate (TDP) and 5-MTHF, but not for ferrous sulfate as iron deficiency was observed in 38.5% of third-trimester women. Frequent consumption of fish paste and owning a garden or animal were associated with significantly higher iron status, retinol, β-carotene, and 5-MTHF. In conclusion, MFF and supplementary oil were most likely to explain improved zinc and α-tocopherol status, while thiamine and folate supplements ensured high TDP and 5-MTHF in late pregnancy. MN supplements, MN-rich staple food, small gardens, and programs to improve iron compliance are promising strategies to prevent MN deficiencies during pregnancy in vulnerable populations.