Physiological Appetite Regulation and Bariatric Surgery.

Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.

A Single Center Study Investigating Clinical Outcomes of Testing for Multiple Myeloma and Immune Deficiency at Low Globulin Levels.

Background: Both primary (e.g. common variable immune deficiency, CVID) and secondary immune deficiency as well as multiple myeloma (MM) require medical intervention and treatment delay can exacerbate morbidity. This study investigated the potential importance of low levels of calculated globulin to detect immune deficiency and MM associated with immunoparesis (light chain, non-secretory MM). Methods: One hundred and thirty-nine patient serum samples from community physicians and outpatient clinics for liver function tests with low calculated globulin (<16 g/L, RR 18-37 g/L) levels were screened for immunoglobulins and protein electrophoresis. Further, 110 patients with globulin levels ≤16 g/L with screening for immunoglobulin levels and protein electrophoresis, requested through routine clinical care, were included in the analysis. Results: Approximately 47% of patients in this cohort had secondary antibody deficiency as a result of hematological malignancy. Secondary iatrogenic (immunosuppressants, antiepileptic drugs) immune deficiency was detected in 20% of patients and a significant percentage of the patients were found by reflex testing at globulin levels <16 g/L. During the study period the screening detected new light chain and non-secretory MM in 2.2% of patients. Three patients with CVID and six patients with light chain myeloma were previously detected by screening, consequently alerting clinicians and reducing delay in treatment. A further 23% with several co-morbid conditions showed unexpected hypogammaglobulinemia; in this category, the study identified a subgroup that required further investigation. Conclusion: Investigation of low globulin levels detects patients with primary and secondary immune deficiency and MM. Optimizing treatment for decreased immunoglobulins in patients with other clinical co-morbidities may require increased clinician awareness and watchful clinical and laboratory assessment.

Highly sensitive troponin I assay in the diagnosis of coronary artery disease in patients with suspected stable angina.

BACKGROUND: Evaluation of suspected stable angina patients with probable coronary artery disease (CAD) in the community is challenging. In the United Kingdom, patients with suspected stable angina are referred by community physicians to be assessed by specialists within the hospital system in rapid access chest pain clinics (RACPC). The role of a highly sensitive troponin I (uscTnI) assay in the diagnosis of suspected CAD in a RACPC in a "real-life" setting in a non-academic hospital has not been explored. AIM: To examine the diagnostic value of uscTnI (detection limit 0.12 ng/L, upper reference range 8.15 ng/L, and detected uscTnI in 96.8% of the reference population), in the evaluation of stable CAD in a non-selected patient group, with several co-morbidities, who presented to the RACPC. METHODS: One hundred and seventy two RACPC patients were assigned to either functional or anatomical testing according to the hospital protocol. RESULTS: The investigations offered to patients were exercise tolerance test 7.6%, 24 h ECG 1.2%, Echocardiogram 14.5%, stress echocardiogram 8.1%, coronary computed tomography angiography (CCTA) 12.8%, coronary angiogram 13.4%, 17.4% were diagnosed with non-cardiac chest pain, 3.5% treated as stable angina, 8.2% reviewed by cardiologists, electronic medical records were not available in 10.4%. Receiver operating characteristic curves for CAD used uscTnI values measured in patients who underwent functional testing, angiogram or CCTA. Values > 0.52 ng/L showed 100% sensitivity and at > 11.6 ng/L showed 100% specificity. In the range > 0.52-11.6 ng/L, uscTnI may not have the same diagnostic potential. In patients assigned to coronary angiogram higher concentrations of uscTnI was associated with severe CAD. Low levels of uscTnI and low pre-test probability of CAD (QRISK3) may decrease patient numbers assigned to CCTA. CONCLUSION: The uscTnI diagnostic cut-off values in a RACPC will depend on patient population and their presenting co-morbidity. In the presence of clinical comorbidities and previous CAD the uscTnI needs to be used in conjunction with clinical assessment.

Vitamin D Metabolism and Guidelines for Vitamin D Supplementation.

Vitamin D is essential for bone health and is known to be involved in immunomodulation and cell proliferation. Vitamin D status remains a significant health issue worldwide. However, there has been no clear consensus on vitamin D deficiency and its measurement in serum, and clinical practice of vitamin D deficiency treatment remains inconsistent. The major circulating metabolite of vitamin D, 25-hydroxyvitamin D (25(OH)D), is widely used as a biomarker of vitamin D status. Other metabolic pathways are recognised as important to vitamin D function and measurement of other metabolites may become important in the future. The utility of free 25(OH)D rather than total 25(OH)D needs further assessment. Data used to estimate the vitamin D intake required to achieve a serum 25(OH)D concentration were drawn from individual studies which reported dose-response data. The studies differ in their choice of subjects, dose of vitamin D, frequency of dosing regimen and methods used for the measurement of 25(OH)D concentration. Baseline 25(OH)D, body mass index, ethnicity, type of vitamin D (D2 or D3) and genetics affect the response of serum 25(OH)D to vitamin D supplementation. The diversity of opinions that exist on this topic are reflected in the guidelines. Government and scientific societies have published their recommendations for vitamin D intake which vary from 400-1000 IU/d (10-25 µg/d) for an average adult. It was not possible to establish a range of serum 25(OH)D concentrations associated with selected non-musculoskeletal health outcomes. To recommend treatment targets, future studies need to be on infants, children, pregnant and lactating women.

Atypical hereditary spherocytosis phenotype associated with pseudohypokalaemia and a new variant in the band 3 protein.

Red blood cell (RBC) membrane disorders are predominantly caused by mutations resulting in decreased RBC deformability and permeability. We present a family in which, the proband and his daughter presented with pseudohypokalaemia. Studies on the temperature dependence of pseudohypokalaemia suggested a maximum decrease in serum potassium when whole blood is stored at 37°C. Routine haematology suggested mild haemolysis with a hereditary spherocytosis phenotype. These two cases present a novel variant in temperature-dependent changes in potassium transport. A new variant was identified in the SLC4A1 gene which codes for band 3 protein (anion exchanger 1) in RBC membrane which may contribute to the phenotype. This is the first report of familial pseudohypokalaemia associated with changes in RBC membrane morphology. The clinical implications of pseudohypokalaemia are that it can lead to inappropriate investigation or treatment. However, many questions remain to be solved and other RBC membrane protein genes should be studied.

A Single-Center Retrospective Study to Investigate the Follow-Up of Patients with Monoclonal Proteinemia by Community Physicians in the UK.

BACKGROUND: We determined the detection rate of monoclonal gammopathy of undetermined significance (MGUS) and follow-up of MGUS patients in a center that uses reflex testing at globulin levels outside the reference range as part of its routine service to detect monoclonal protein (M-protein). We recorded the natural history and follow-up of these patients. This is one of the first reports on the diagnosis and follow-up of MGUS patients within the UK. PATIENTS AND METHODS: A total of 163 patients diagnosed in 2006 and 393 patients with M-protein on long-term follow-up in 2006 were followed over a period of 10 years (y) by community physicians with laboratory support. RESULTS: In 2006, newly diagnosed patients with an M-protein and total number of patients as a percentage of the Worcestershire population were, respectively, 0.025%, 0.045% (at 45-49y); 0.1%, 0.25% (at 60-64y); and 0.26%, 1.12% (at 75-79y). Patients with M-protein had a survival of 35.5% at 10 y and 43.5% at >10y follow-up. Kaplan-Meier analysis of patients with an M-protein showed that lymphoplasma-cell proliferative disorders (LPD)-free survival was 91% for both 10y and >10y follow-up. LPD-free survival decreased to approximately 73% when competing causes (death due to unrelated causes, transient M-protein, loss to follow-up) were censored. Progression to LPD occurred at initial M-protein values of 3g/L at diagnosis. During follow-up, 38.3% died without evidence of LPD, 12% were diagnosed with transient M-protein, 8.7% developed LPD, 10.9% had stable M-protein, 4.9% showed increasing M-protein, and 25.2% were lost to follow-up. Survival curves showed that M-protein isotype contributed to LPD-free survival in the order IgG=IgM>IgA>biclonal M-protein. CONCLUSION: Geographical variations in the diagnosis and follow-up of MGUS patients in the UK need investigation. From public health viewpoint, it is essential to determine MGUS follow-up to improve clinical care and individualise risk-based follow-up of patients.

Recent advances in physiological lipoprotein metabolism.

Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and post-transcriptional level. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDL-cholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several transcription factors, including the liver X receptor and sterol regulatory element binding protein. This review summarizes recent advances in knowledge of the molecular mechanisms regulating lipoprotein metabolism.

Inherited disorders of calcium homeostasis.

In mammals a complicated homeostatic mechanism has evolved to maintain near consistency of extracellular calcium ion levels. The homeostatic mechanism involves several hormones, which comprise among others, parathyroid hormone and vitamin D. The recent resurge in vitamin D deficiency, as a global health issue, has increased interest in the hormone. In addition to vitamin D deficiency, other causes of rickets are calcium deficiency and inherited disorders of vitamin D and phosphorus metabolism. Vitamin D-resistant syndromes are caused by hereditary defects in metabolic activation of the hormone or by mutations in the vitamin D receptor, which binds the hormone with high affinity and regulates the expression of genes through zinc finger mediated DNA binding and protein-protein interaction. Current interest is to correlate the type/position of mutations that result in disorders of vitamin D metabolism or in vitamin D receptor function with the variable phenotypic features and clinical presentation. The calcium sensing receptor plays a key role in calcium homeostasis. Loss of function mutations in the calcium sensing receptor can cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism when homozygous mutations occur in the calcium sensing receptor. Gain of function mutation can cause the opposite effect causing autosomal dominant hypocalcemia. Mouse models using targeted gene disruption strategies have been valuable tools to study the effect of mutations on the calcium sensing receptor or in the vitamin D activation pathway. Dysfunctional calcium sensing receptors with function altering mutations may be responsive to treatment with allosteric modulators of the calcium sensing receptor. Vitamin D analogs which induce unusual structural conformations on the vitamin D receptor may have a variety of therapeutic indications. This review summarises recent advances in knowledge of the molecular pathology of inherited disorders of calcium homeostasis.

Recent advances in physiological calcium homeostasis.

A constant extracellular Ca2+ concentration is required for numerous physiological functions at tissue and cellular levels. This suggests that minor changes in Ca2+ will be corrected by appropriate homeostatic systems. The system regulating Ca2+ homeostasis involves several organs and hormones. The former are mainly the kidneys, skeleton, intestine and the parathyroid glands. The latter comprise, amongst others, the parathyroid hormone, vitamin D and calcitonin. Progress has recently been made in the identification and characterisation of Ca2+ transport proteins CaT1 and ECaC and this has provided new insights into the molecular mechanisms of Ca2+ transport in cells. The G-protein coupled calcium-sensing receptor, responsible for the exquisite ability of the parathyroid gland to respond to small changes in serum Ca2+ concentration was discovered about a decade ago. Research has focussed on the molecular mechanisms determining the serum levels of 1,25(OH)2D3, and on the transcriptional activity of the vitamin D receptor. The aim of recent work has been to elucidate the mechanisms and the intracellular signalling pathways by which parathyroid hormone, vitamin D and calcitonin affect Ca2+ homeostasis. This article summarises recent advances in the understanding and the molecular basis of physiological Ca2+ homeostasis.

Inherited bleeding disorders: disorders of platelet adhesion and aggregation.

Platelet aggregation at sites of vascular injury is essential for the formation of the primary haemostatic plug. The mechanism of platelet aggregation under conditions of physiological flow is a complex multistep process, which requires the synergistic action of several different platelet receptors. Platelet interaction with collagen at sites of damage to the vascular endothelium involves adhesion, activation, secretion of platelet granular contents and finally aggregation. Other agonists other than collagen, such as fibrinogen, vWF and soluble agonists released from activated platelets (thromboxane A2 (TXA2) and ADP) are involved in platelet aggregation. Platelets express a variety of receptors including GP Ib-IX-V, GP VI, GP Ia-IIa and GP IIb-IIIa. One aspect of this complexity of function is the variety of inherited defects of platelet function. Hereditary disorders of platelet adhesion are Bernard-Soulier syndrome and von Willebrand disease. Glanzmann thrombasthenia is an inherited disorder of platelet aggregation. The application of molecular biology to the study of platelet disorders has identified defects in other collagen receptors, ADP receptors and TXA2 receptors. Defects affecting TXA2 production, the generation of procoagulant activity and secretion from dense bodies and alpha-granules are also encountered. Other rare diseases, Chediak-Higashi, Hermansky-Pudlak and Wiskott-Aldrich syndrome also affect platelet storage granules. In this article, recent advances in the understanding of platelet function and knowledge of inherited disorders that affect platelet adhesion and aggregation is reviewed. As progress advances towards individualisation of therapy the phenotypic bleeding tendency of each patient becomes relevant.

Variant Creutzfeldt-Jakob disease and the potential for its accidental transmission following surgery with contaminated instruments: the risk of transmission in Australia.

We present a simple model for the quantitative risk assessment of vCJD transmission following surgery. Factors that affect the transmission of the disease are prevalence of the disease, concentration of prions in tissues, genetic susceptibility, the number and type of surgical procedures and the effectiveness of decontamination procedures. The main sources of uncertainty are the number of people currently incubating vCJD in Australia and the effectiveness of the decontamination processes for surgical instrumentation. The model serves as a guide for predicting the number of possible vCJD transmissions following individual surgical procedures. It is the uncertainty of the epidemic that poses a challenge to the public health scientist. Greater certainty of the pathogenesis and progression of the disease will only come with increased years of surveillance.