School meals in the UK: ultra-processed, unequal, and inadequate

Recent research paints an alarming picture of the school food system in the UK. This commentary discusses the issues that undermine healthy school meals and considers the actions required to ensure the school food system can meet the challenges ahead

Kinetic characterization of selective peroxisome-proliferator-activated receptor gamma modulators in vitro

Background: The ligand-activated transcription factor, peroxisome-proliferator-activated receptor gamma (PPARγ), has been shown to play an essential role in immunosuppression during sepsis. PPARγ is upregulated in T cells of septic patients, sensitizing these cells to PPARγ-dependent apoptosis and thus contributing to T-cell depletion. In the polymicrobial cecum ligation and puncture (CLP) sepsis model in mice, both T-cell-specific gene knockout (Lck-Cre PPARγfl/fl) and systemic pharmacological PPARγ antagonism by GW9662 improved survival. Because GW9662 was only effective when applied 3 hours after CLP, we were interested to extend this time frame. For this reason we characterized the kinetics of SPPARγMs when administered before or in combination with the agonist thiazolidinedione, rosiglitazone. Methods: A PPARγ-dependent transactivation assay was used in HEK293T cells. It is based on the vector pFA-PPARγ-LBD-GAL4-DBD encoding the hybrid protein PPARγ-LBD-GAL4-DBD and the reporter vector pFR-Luc, carrying a GAL4-responsive element in front of the Firefly luciferase gene. These two vectors were co-transfected, in combination with a control vector encoding Renilla luciferase (pRL-CMV) to normalize Firefly luciferase activity for transfection efficiency. Following transfection, cells were incubated with the SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 for different times (2 to 48 hours) and at increasing doses (0.01 to 10 μM), with or without rosiglitazone (0.01 to 10 μM). Transactivation was analyzed using a 96-well plate format. Results: Rosiglitazone transactivated PPARγ in a time-dependent and dose-dependent manner, the response gradually increasing to a maximum at 48 hours with 10 μM. Low concentrations (0.01 to 0.1 μM) of SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 all exerted dose-independent antagonistic effects at an early incubation time point (2 hours). From 10 hours onwards, MCC-555 and GW9662, given alone, both exerted PPARγ agonistic effects, MCC-555 in parallel to responses to rosiglitazone, but GW9662 with characteristics of partial antagonism. F-MOC showed no dose-dependent effect at any concentration at later time points. Only GW9662 (1 to 10 μM) was able to inhibit rosiglitazone (0.1 to 1 μM)-induced PPARγ transactivation after 10 hours. Conclusion: Our kinetic analysis reveals clear differences in the modulatory characteristics of PPARγ inhibitors, with previously unreported early inhibitory effects and late agonistic or partial agonistic activity. New SPPARγMs with extended inhibitory activity may prove useful in the therapy of sepsis

Immunomodulatory approaches to the treatment of infections

Imunološki sustav nudi široki izbor potencijalnih ciljnih mjesta za modulaciju kod liječenja infektivnih bolesti. Raspoložive mogućnosti dozvoljavaju i profilaktičku i terapijsku imunomodulaciju za suportivno i direkto liječenje infekcija. Odgovarajuća prehrana koja sadrži biljne polifenole, osobito one iz voća, te mikronutrijente kao što su selen i cink, uz redovitu umjerenu fizičku aktivnost pomaže u održavanju učinkovite obrane domaćina od blagih do umjereno teških infekcija. Ovakva nadopuna prehrani obično je prijeko potrebna kod životno ugroženih bolesnika, tako neki biljni pripravci mogu smanjiti težinu i/ili duljinu trajanja infekcija gornjih dišnih putova. Primjena probiotika također potpomaže imunološkoj obrani gastrointestinalnog trakta. Nekoliko antibiotika, prvenstveno makrolidi i tetraciklini, osim antibakterijskog djelovanja imaju i imunomodulatorna i/ili protuupalna svojstva koja potpomažu uništavanju bakterija i/ili štite tkivo od "bystander" ozljeda. Također, mogu biti korisni i u prevenciji tzv. "citokinske oluje" izazvane virusima. Imunoglobulini, nekoliko rekombinantnih humanih citokina te različiti agonisti receptora sličnih Tollu zbog svog visoko specifičnog djelovanja na određene imunološke procese, posredovanog receptorima učinkoviti su kod mnogih infekcija. Vrlo je vjerojatno da bi razvoj novih imunomodulatora koji ciljaju specifične receptore mogao zamijeniti primjenu nespecifičnih modulatora prirođene imunosti kao pomoći pri obrani domaćina od infekcije.The immune system offers a wide variety of potential targets for modulation in the treatment of infectious diseases. Available possibilities permit both prophylactic and therapeutic immunomodulation for supportive and direct treatment of infections. In addition to regular moderate exercise, an adequate diet containing plant polyphenols, particularly from fruit, and micronutrients such as selenium and zinc helps maintain effective host defence against mild to moderate infections. Supplementation with these dietary constituents is usually necessary in critically ill patients and like some standardized phytopharmaceuticals, may also reduce the severity and/or duration of upper airways infections. Administration of probiotics also promotes gastrointestinal immune defence. Several antibiotics, especially the macrolides and tetracyclines, possess in addition to their antibacterial actions, immunomodulatory and/or anti-inflammatory properties which facilitate bacterial killing and/or protect tissue from bystander injury. They may also be useful in prevention of the virally-induced cytokine storm. Immunoglobulins, several recombinant human cytokines and selective agonists of Toll-like receptors are effective against many infections in their own right because of highly specific receptor-mediated actions on defined immune processes. The development of novel receptor-targeted immunomodulators is likely to replace the use of non-specific modulators of innate immunity in promoting host defence during infection

Editorial

Terapeutici, infekcija i imunomodulacijaTherapeutics, infection and immunomodulatio

From Cancer to Immune-Mediated Diseases and Tolerance Induction: Lessons Learned From Immune Oncology and Classical Anti-cancer Treatment

Success in cancer treatment over the last four decades has ranged from improvements in classical drug therapy to immune oncology. Anti-cancer drugs have also often proven beneficial for the treatment of inflammatory and autoimmune diseases. In this review, we report on challenging examples that bridge between treatment of cancer and immune-mediated diseases, addressing mechanisms and experimental models as well as clinical investigations. Patient-derived tumor xenograft (PDX) (humanized) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. However, new developments using human ex vivo approaches modeling cancer, for example in microfluidic human organs-on-chips, promise to identify key molecular, cellular and immunological features of human cancer progression in a fully human setting. Classical drugs which bridge the gap, for instance, include cytotoxic drugs, proteasome inhibitors, PI3K/mTOR inhibitors and metabolic inhibitors. Biologicals developed for cancer therapy have also shown efficacy in the treatment of autoimmune diseases. In immune oncology, redirected chimeric antigen receptor (CAR) T cells have achieved spectacular remissions in refractory B cell leukemia and lymphoma and are currently under development for tolerance induction using cell-based therapies such as CAR Tregs or NK cells. Finally, a brief outline will be given of the lessons learned from bridging cancer and autoimmune diseases as well as tolerance induction

Is the Healthy Start scheme associated with increased food expenditure in low-income families with young children in the United Kingdom?

Introduction: Healthy Start is a food assistance programme in the United Kingdom (UK) which aims to provide a nutritional safety-net and enable low-income families on welfare benefits to access a healthier diet through the provision of food vouchers. Healthy Start was launched in 2006 but remains under-evaluated. This study aims to determine whether participation in the Healthy Start scheme is associated with differences in food expenditure in a nationally representative sample of households in the UK. Methods: Cross-sectional analyses of the Living Costs and Food Survey dataset (2010-2017). All households with a child (0-3 years) or pregnant woman were included in the analysis (n=4,869). Multivariable quantile regression compared the expenditure and quantity of fruit and vegetables (FV), infant formula and total food purchases. Four exposure groups were defined based on eligibility, participation and income (Healthy Start Participating, Eligible Non-participating, Nearly Eligible low-income and Ineligible high-income households). Results: Of 876 eligible households, 54% participated in Healthy Start. No significant differences were found in FV or total food purchases between participating and eligible non-participating households, but infant formula purchases were lower in Healthy Start participating households. Ineligible higher-income households had higher purchases of FV. Conclusion: This study did not find evidence of an association between Healthy Start participation and FV expenditure. Moreover, inequalities in FV purchasing persist in the UK. Higher participation and increased voucher value may be needed to improve programme performance and counteract the harmful effects of poverty on diet

Management of non-visualization following dynamic sentinel lymph node biopsy for squamous cell carcinoma of the penis

Objectives: To review the management and clinical outcomes of uni- or bilateral non-visualization of inguinal lymph nodes during dynamic sentinel lymph node biopsy (DSNB) in patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), and to develop an algorithm for the management of patients in which non-visualization occurs. Patients and Methods: This is a retrospective observational study over a period of 4 years, comprising 166 patients with penile squamous cell carcinoma undergoing DSNB and followed up for a minimum of 6 months. All cases diagnosed with uni- or bilateral non-visualization of sentinel nodes in this cohort were identified from a penile cancer database. The management of the inguinal lymph nodes after non-visualization and the oncological outcomes including local and regional recurrence rates were documented. Results: Out of 166 consecutive patients undergoing DSNB, 20 patients (12%) had unilateral non-visualization after injection of intradermal 99mTc. Of these 20 patients, seven underwent repeat DSNB at a later date, with six having successful visualization. One patient had persistent non-visualization and proceeded to a superficial modified inguinal lymphadenectomy (SML). None of these patients experienced recurrence at follow-up. A further seven patients underwent modified SML with on-table frozen-section analysis of the lymph node packet; none of these patients were found to have micrometastatic disease in the inguinal lymph nodes, although one patient developed metastatic inguinal node disease at a later date. Six patients elected to undergo clinical surveillance and have remained disease-free. Conclusion: Patients with impalpable inguinal lymph nodes undergoing DSNB with ≥G2 T1 disease should ideally have bilateral visualization of the sentinel lymph nodes, reflecting the drainage pattern from the primary tumour. In the present series, 12% of patients were found to have unilateral non-visualization after DSNB. Among patients offered a repeat DSNB at a later date, localizing the sentinel node was successful in 86% of cases. Patients with favourable histological characteristics can be placed on clinical surveillance. Those with high-risk disease can be offered a repeat DSNB procedure on the proviso that SML may be carried out if there is repeated non-visualization. Larger cohorts are required to validate this proposed algorithm

Hydro-ionothermal synthesis of lanthanide-organic frameworks with 1,4-phenylenebis(methylene)diphosphonate

A synthetic approach combining hydrothermal and ionothermal (eutectic mixture of choline chloride and malonic acid) procedures is proposed that allowed the isolation of the first lanthanide-organic frameworks with residues of 1,4-phenylenebis(methylene)- diphosphonic acid (H4pmd), [Ln(Hpmd)(H2O)] (where Ln3+ ) Ce3+ and Pr3+), exhibiting an unprecedented trinodal topology with 3- and 8-connected nodes. The structural details were unveiled from single-crystal X-ray diffraction and the materials were characterized using standard techniques.FCT - POCI-PPCDT/QUI/58377/2004FEDER - POCIGrant - SFRH/BPD/9309/200