A retrospective case-control cohort analysis of comorbidity and health expenditure in hospitalized adults diagnosed with obesity utilizing ICD-10 diagnostic coding.

The cost and comorbidity of obesity in hospitalized inpatients, is less known. A retrospective study of patients presenting to a large district hospital in Western Sydney (April 2016-February 2017) using clinical, pathological as well as diagnostic coding data for obesity as per ICD-10. Of 43 212 consecutive hospital presentations, 390 had an obesity-coded diagnosis (Ob, 0.90%), of which 244 were gender and age-matched to a non-obesity coded cohort (NOb). Weight and BMI were higher in the Ob vs NOb group (126 ± 37 vs 82 ± 25 kg; BMI 46 ± 12 vs 29 ± 8 kg/m2 , P < .001) with a medical record documentation rate of 62% for obesity among Ob. The Ob cohort had 2-5× higher rates of cardiopulmonary and metabolic complications (P < .001), greater pharmacologic burden, length of stay (LOS, 225 vs 89 hours, P < .001) and stay in intensive care but no differences in the prevalence of mental disorders. Compared with BMI <35 kg/m2 , inpatients with BMI >35 kg/m2 were 5× more likely to require intensive care (OR 5.08 [1.43-27.3, 95% CI], P = .0047). The initiation of obesity-specific interventions by clinical teams was very low. People with obesity who are admitted to hospital carry significant cost and complications, yet obesity is seldom recognized as a clinical entity or contributor.

A novel assay to measure B cell responses to keyhole limpet haemocyanin vaccination in healthy volunteers and subjects with systemic lupus erythematosus.

The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics.

Inflammatory posterior interosseous nerve palsy in a patient with psoriatic arthropathy.

Psoriasis is a chronic, relapsing, inflammatory skin disorder with a strong genetic basis. Five patterns of psoriatic arthritis have been identified: asymmetrical oligoarticular arthritis, symmetrical polyarthritis, distal interphalangeal arthropathy, arthritis mutilans and spondylitis with or without sacroiliitis. Extra-articular disease is uncommon. We report a rare case of an inflammatory posterior interosseus nerve palsy in a patient with known psoriatic arthropathy, where investigation warranted medical treatment over a surgical approach. The commonest cause of posterior interosseus nerve palsy is entrapment at the proximal forearm. Other possible aetiologies include extension of elbow synovitis as described in rheumatoid arthritis, trauma eg. Monteggia fractures, tumours and iatrogenic injuries. We discuss the diagnostic dilemma and the management issues for upper limb surgeons.

Henoch-Schonlein Purpura with thrombocythaemia: an abnormality in Smad4 expression?

We discuss a patient with Henoch-Schonlein Purpura (HSP) and a thrombocythaemia which was diagnosed as a coincidental Essential Thrombocythaemia. We suggest that deficiencies in Smad4 expression may allow for escape thrombocythaemia under the influence of the high levels of TGF-beta found in HSP. With normal Smad4 expression TGF-beta provides inhibition of thrombocyte proliferation. While this needs further elucidation, it could lead to a new approach to classification and management of HSP.

BCG (Bacille Calmette-Guérin) HspCs (heat-shock protein-peptide complexes) induce T-helper 1 responses and protect against live challenge in a murine aerosol challenge model of pulmonary tuberculosis.

The need for an effective TB (tuberculosis) vaccine remains acute, with tuberculosis still one of the major killers worldwide and 3 million new infections annually. We report here on the immune responses elicited by HspCs (heat-shock protein-peptide complexes) isolated from BCG (Bacille Calmette-Guérin) vaccine. These HspCs elicit both the appropriate cellular and protective immune responses required to merit their further development as TB vaccine candidates.

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be 'blind' to tumours, thereby challenging the theory of immune surveillance.

Tau glycation is involved in aggregation of the protein but not in the formation of filaments.

A tau peptide, peptide 2R, with capacity for self assembly into filaments was used as a model to test the role of glycation on tau assembly or aggregation. Our results indicate that glycation of that peptide facilitates dimer formation but not assembly into filaments. However, glycation of tau results in the bundling of the tau filaments formed by glycosaminoglycan-induced polymerisation. These results suggest a role of glycation in the formation of covalent links among pre-formed filaments but not in the assembly of those filaments.

Sulphated glycosaminoglycans prevent the neurotoxicity of a human prion protein fragment.

Although a number of features distinguish the disease isoform of the prion protein (PrPSc) from its normal cellular counterpart (PrPC) in the transmissible spongiform encephalopathies (TSEs), the neuropathogenesis of these diseases remains an enigma. The amyloid fibrils formed by fragments of human PrP have, however, been shown to be directly neurotoxic in vitro. We show here that sulphated polysaccharides (heparin, keratan and chondroitin) inhibit the neurotoxicity of these amyloid fibrils and this appears to be mediated via inhibition of the polymerization of the PrP peptide into fibrils. This provides a rationale for the therapeutic effects of sulphated polysaccharides and suggests a rapid in vitro functional screen for TSE therapeutics.

Towards a unified theory of immunity: dendritic cells, stress proteins and antigen capture.

In less than a decade, the archetypal view that the immune system exists primarily to distinguish "self" from "non-self" has been replaced by the paradigm that the immune system functions primarily to distinguish dangerous from non-dangerous antigens. This change is in part due to the recent reassertion of the importance of so-called innate immunity, which consists of non-specific components of the immune system such as macrophages that are active prior to exposure to antigens (In contrast, so-called acquired immunity depends upon the generation of B and T lymphocytes that are produced after exposure to the antigens and are specific for the antigens). The paradigm shift is also due to the recent proposal of the "danger model" of the immune system, which provides a conceptual mechanism by which the immune system might distinguish dangerous from non-dangerous antigens. The role of dendritic cells (DCs) in activating T lymphocytes is key to both innate immunity and the danger model. The purpose of this commentary is to add an additional piece to the emerging picture of immune-system function by suggesting that heat-shock, or stress, proteins play a central role in the activation of T lymphocytes by DCs. The uptake of stress proteins--whose expression is induced by monokines in the earliest phases of the innate immune response--by DCs might constitute a "danger" signal. However, through such a mechanism, DCs may capture antigens bound to stress proteins and improve their ability to present the antigens to other components of the immune system, such as cytotoxic T-cells. Invoking stress proteins to amplify the immune response in this manner can explain how animals can mount an effective primary immune response to an antigen despite having few T lymphocytes specific for that antigen. Finally, the "affinity-maturation" of antibody following a primary immune response would enable the much more efficient, specific antigen-capture by high affinity antibodies in a secondary immune response, resulting in a rapid and specific response or "memory" on re-exposure to the pathogen.

Primary Sjögren's syndrome, ulcerative colitis and selective IgA deficiency.

A 24-year-old man with primary Sjögren's syndrome presented with xerophthalmia, xerostomia, and marked parotid swelling. He had a previous history of selective IgA deficiency and ulcerative colitis treated with sulphasalazine. Immunosuppression and withdrawal of sulphasalazine resulted in rapid resolution of the parotitis and disappearance of autoantibodies. A possible role for sulphasalazine in the induction of autoimmunity in this case is discussed.

The role of the Maillard reaction in other pathologies: Alzheimer's disease.

Many approaches have and are being undertaken to treat Alzheimer's disease but, as yet, no therapy is available with any established efficacy. Given the heterogeneity of the aetiological factors involved in Alzheimer's disease and the difficulties encountered in the clinical diagnosis, the lack of pharmacological success is not surprising. Furthermore, the lack of an adequate animal model of Alzheimer's disease has delayed the development of novel therapeutic strategies. At present, and with the exception of the rarer forms of familial Alzheimer's disease, the need remains to treat the symptoms rather than the causes of the disease, primarily because the pathogenesis of Alzheimer's disease is still unknown. The evidence for the role of glycation and advanced glycation end-products (AGEs) in the formation of neurofibrillary tangles and neuritic plaques, the characteristic histopathological lesions of Alzheimer's disease, is briefly reviewed. While the role of glycation in the pathogenesis of Alzheimer's disease is not yet unequivocally proven, it is the only single protein modification that would explain the formation of both the characteristic histopathological lesions first described by Alois Alzheimer in 1907. With our improved understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the aetiological causes will afford more suitable targets for therapeutic intervention. In this respect it is interesting to note that the anti-inflammatory compounds indomethacin and acetylsalicylic acid, both inhibitors of the Maillard reaction, have been reported to have therapeutic potential and the nootropic agent tenilsetam inhibits protein cross-linking by AGEs.