Childhood obesity: A review of current and future management options.

Obesity is becoming increasingly prevalent in paediatric populations worldwide. In addition to increasing prevalence, the severity of obesity is also continuing to rise. Taken together, these findings demonstrate a worrying trend and highlight one of the most significant challenges to public health. Childhood obesity affects multiple organs in the body and is associated with both significant morbidity and ultimately premature mortality. The prevalence of complications associated with obesity, including dyslipidaemia, hypertension, fatty liver disease and psychosocial complications are becoming increasingly prevalent within the paediatric populations. Treatment guidelines currently focus on intervention with lifestyle and behavioural modifications, with pharmacotherapy and surgery reserved for patients who are refractory to such treatment. Research into adult obesity has established pharmacological novel therapies, which have been approved and established in clinical practice; however, the research and implementation of such therapies in paediatric populations have been lagging behind. Despite the relative lack of widespread research in comparison to the adult population, newer therapies are being trialled, which should allow a greater availability of treatment options for childhood obesity in the future. This review summarizes the current evidence for the management of obesity in terms of medical and surgical options. Both future therapeutic agents and those which cause weight loss but have an alternative indication are also included and discussed as part of the review. The review summarizes the most recent research for each intervention and demonstrates the potential efficacy and limitations of each treatment option.

Growth failure and hormone therapy.

One of the causes of growth failure is growth hormone deficiency. The outcome of growth hormone therapy to treat this depends on a number of multifaceted issues, including the child, the family and the choice of medication device. Providing support and promoting adherence--key nurse roles--are essential for success

Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents.

OBJECTIVES: Childhood obesity is a public health concern worldwide, with rates continuing to rise, despite preventive measures. Lifestyle modification remains the mainstay in the treatment of patients with excessive weight, but unfortunately, this is not always successful. Options for medical management of obesity in the paediatric population are limited. METHODS: Seven adolescents (all girls, mean age 14.9 years) with a body mass index (BMI) above 98th percentile and serious complications secondary to obesity were offered an intense weight management programme. The participants were reviewed by a multidisciplinary team every two weeks for advice and support, and treated with daily subcutaneous injections of liraglutide (dose range 1.2-3.0 mg). Scores for anxiety and depression were evaluated using the Revised Child Anxiety and Depression Scale. RESULTS: The results showed a significant weight loss over the three months with an average reduction of 5.4 kg (4.2%; 95% CI 1.93-8.78; p=0.0087). The mean drop in BMI was 2.1 kg/m2, which is statistically significant (95% CI 0.973-3.199; p=0.0037). Resolution of complications (raised intracranial pressure and steatohepatitis) was noted following weight loss. Anxiety and depressive symptoms improved over the three-month intervention course, especially features of separation anxiety disorder. Liraglutide was well tolerated by all patients. CONCLUSIONS: Liraglutide medication, alongside a dedicated multidisciplinary team guided lifestyle therapy, is effective and safe in the treatment for excessive weight in adolescents, leading to the reversal of the complications related to obesity and improvement in the psychological symptoms.

Adapting Rapid Diagnostic Tests to Detect Historical Dengue Virus Infections.

The only licensed dengue vaccine, Dengvaxia®, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer's instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.

Polysialylated insulin: synthesis, characterization and biological activity in vivo.

Polysialic acids (PSA) (colominic acid; CA) of 22 and 39 kDa average molecular weight were oxidized with sodium periodate at carbon 7 of the nonreducing end to form an aldehyde group. The oxidized CAs (96-99% oxidation) were then reacted with the amino groups of recombinant human insulin at various CA/insulin molar ratios (25:1 to 150:1 range) for up to 48 h in the presence of sodium cyanoborohydride (reductive amination). Polysialylated insulin conjugates were precipitated (together with intact nonreacted insulin, if any) at time intervals from the reaction mixtures with ammonium sulfate, further purified by size exclusion chromatography and/or ion exchange chromatography (IEC), and the final conjugates assayed for PSA and protein. Results showed an initial rapid conjugation rate peaking at about 12 h, to form a plateau over a period of 12-48 h. Moreover, the extent of polysialylation (CA/insulin molar ratios in the conjugate) was dependent on the PSA used, the initial CA/insulin molar ratios in the reaction mixture and the time of the coupling reaction. Thus at 48 h of incubation, CA/insulin molar ratios in the conjugates were 1.60-1.74 for the 22-kDa CA and 2.37-2.45 for the 39-kDa CA. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of intact insulin and insulin reacted with non-oxidized CA for 48 h revealed well-resolved single bands which migrated similar distances in the gel. On the other hand, polysialylated (22-kDa CA) insulin yielded multiple diffused bands suggesting heterogenicity as a result of differential polysialylation. The pharmacological activity of polysialylated insulin was compared with that of intact insulin in normal female outbred T/O mice. After subcutaneous injection of intact insulin (0.3 units per mouse), blood glucose levels were reduced to nadir values at 1 h to return to normal at 3 h. In contrast, blood glucose levels in animals injected with polysialylated insulin (0.3 units or protein equivalence for polysialylated insulin), having attained nadir values also at 1 h, returned to normal levels after 6 h (39 kDa) and 9 h (22 kDa CA-insulin). It is concluded that polysialylation offers a promising strategy for the enhancement of the therapeutic value of insulin and other pharmacologically active peptides.

Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids.

Peptide and protein drugs are a growing class of therapeutics. However, their effective application in the clinic is compromised by problems, for instance proteolysis in the circulating blood, premature clearance through the kidneys, and immunogenicity. A number of approaches have been used to circumvent such shortcomings including changes in the primary peptide structure, entrapment into nanoparticles (e.g. liposomes) and conjugation to polymers. Polysialylation, namely, conjugation of peptides and proteins to the naturally occurring, biodegradable alpha-(2-->8) linked polysialic acid is a recent development, which promises to be at least as effective as PEGylation but without its potential toxicity. Polysialylation of a range of peptide and protein therapeutics has led to markedly reduced proteolysis, retention of their activity in vivo, prolongation of their half-life in the circulation and reduction in immunogenicity and antigenicity. It is anticipated that polysialylation will lead to a new generation of peptide and protein constructs with significantly improved pharmacological profiles.

Liposomal co-entrapment of CD40mAb induces enhanced IgG responses against bacterial polysaccharide and protein.

BACKGROUND: Antibody against CD40 is effective in enhancing immune responses to vaccines when chemically conjugated to the vaccine antigen. Unfortunately the requirement for chemical conjugation presents some difficulties in vaccine production and quality control which are compounded when multivalent vaccines are required. We explore here an alternative to chemical conjugation, involving the co-encapsulation of CD40 antibody and antigens in liposomal vehicles. METHODOLOGY/PRINCIPAL FINDINGS: Anti-mouse CD40 mAb or isotype control mAb were co-entrapped individually in cationic liposomal vehicles with pneumococcal polysaccharides or diphtheria and tetanus toxoids. Retention of CD40 binding activity upon liposomal entrapment was assessed by ELISA and flow cytometry. After subcutaneous immunization of BALB/c female mice, anti-polysaccharide and DT/TT responses were measured by ELISA. Simple co-encapsulation of CD40 antibody allowed for the retention of CD40 binding on the liposome surface, and also produced vaccines with enhanced imunogenicity. Antibody responses against both co-entrapped protein in the form of tetanus toxoid, and Streptococcus pneumoniae capsular polysaccharide, were enhanced by co-encapsulation with CD40 antibody. Surprisingly, liposomal encapsulation also appeared to decrease the toxicity of high doses of CD40 antibody as assessed by the degree of splenomegaly induced. CONCLUSIONS/SIGNIFICANCE: Liposomal co-encapsulation with CD40 antibody may represent a practical means of producing more immunogenic multivalent vaccines and inducing IgG responses against polysaccharides without the need for conjugation.

The 'co-delivery' approach to liposomal vaccines: application to the development of influenza-A and hepatitis-B vaccine candidates.

DNA vaccination with mammalian-expressible plasmid DNA encoding protein antigens is known to be an effective means to elicit cell-mediated immunity, sometimes in the absence of a significant antibody response. This may be contrasted with protein vaccination, which gives rise to antibody responses with little evidence of cell-mediated immunity. This has led to considerable interest in DNA vaccination as a means to elicit cell-mediated immune responses against conserved viral antigens or intracellular cancer antigens, for the purpose of therapeutic vaccination. However, almost all current vaccines are used prophylactically and work by producing antibodies rather than cell mediated immune responses. In the present study we have therefore explored the combination of DNA and protein forms of an antigen using two exemplary prophylactic vaccine antigens, namely inactivated influenza virion and hepatitis-B surface antigen. We studied the effects of various combinations of DNA and protein on the antibody response. Co-administration of soluble forms of DNA and protein representations of the same antigen gave rise to the same level of antibody response as if protein were administered alone. In contrast, we found that when these antigens are entrapped in the same liposomal compartment, that there was a strong synergistic effect on the immune response, which was much greater than when either antigen was administered alone, or in various other modes of combination (e.g. co-administration as free entities, also pooled liposomal formulations where the two materials were contained in separate liposomal vehicles in the same suspension). The synergistic effect of liposomally co-entrapped DNA and protein exceeded, markedly, the well known adjuvant effects of plasmid DNA and liposomes. We have termed this new approach to vaccination 'co-delivery' and suggest that it may derive from the simultaneous presentation of antigen via MHC class-I (DNA) and MHC class-II (protein) pathways to CD8+ and CD4+ cells at the same antigen presenting cell--a mode of presentation that would commonly occur with live viral pathogens. We conclude that co-delivery is a very effective means to generate protective antibody responses against viral pathogens.