GIP(Lys16PAL) and GIP(Lys37PAL): novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential.

Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(LyS(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

Low-power radio telemetry: the potential for remote patient monitoring

Radio-based signalling devices will play an important role in future generations of remote patient monitoring equipment, both at home and in hospital. Ultimately, it will be possible to sample vital signs frompatients, whatever their location and without them necessarily being aware that a measurement is being taken. This paper reviews currentmethods for the transmission by radio of physiological parameters over ranges of 0.3, 3 and 30 m, and describes the radiofrequency hardware required and the carrier frequencies commonly used. Future developments, including full duplex systems and the use of more advanced modulation schemes, are described. The paper concludeswith a case studyof a humantemperature telemeter built to indicateovulation. Clinical results clearly show the advantage to be had in adopting radio biotelemetry in this instance.

FMRFamide-like peptides in root knot nematodes and their potential role in nematode physiology

FMRFamide-like peptides (FLPs) are a diverse group of neuropeptides that are expressed abundantly in nematodes. They exert potent physiological effects on locomotory, feeding and reproductive musculature and also act as neuromodulators. However, little is known about the specific expression patterns and functions of individual peptides. The current study employed rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR) to characterize flp genes from infective juveniles of the root knot nematodes, Meloidogyne incognita and Meloidogyne minor. The peptides identified from these transcripts are sequelogs of FLPs from the free-living nematode, Caenorhabditis elegans; the genes have therefore been designated as Mi-flp-1, Mi-flp-7, Mi-flp-12, Mm-flp-12 and Mi-flp-14. Mi-flp-1 encodes five FLPs with the common C-terminal moiety, NFLRFamide. Mi-flp-7 encodes two copies of APLDRSALVRFamide and APLDRAAMVRFamide and one copy of APFDRSSMVRFamide. Mi-flp-12 and Mm-flp-12 encode the novel peptide KNNKFEFIRFamide (a longer version of RNKFEFIRFamide found in C. elegans). Mi-flp-14 encodes a single copy of KHEYLRFamide (commonly known as AF2 and regarded as the most abundant nematode FLP), and a single copy of the novel peptide KHEFVRFamide. These FLPs share a high degree of conservation between Meloidogyne species and nematodes from other clades, including those of humans and animals, perhaps suggesting a common neurophysiological role which may be exploited by novel drugs. FLP immunoreactivity was observed for the first time in Meloidogyne, in the circumpharyngeal nerve ring, pharyngeal nerves and ventral nerve cord. Additionally, in situ hybridization revealed Mi-flp-12 expression in an RIR-like neuron and Mi-flp-14 expression in SMB-like neurons, respectively. These localizations imply physiological roles for FLP-12 and FLP-14 peptides, including locomotion and sensory perception.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomised placebo controlled trial

OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy.

BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI.

METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio.

RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P = 0.1).

CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes.

Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics.

The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage.

We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Digital Dermatitis in Dairy Cows: A Review of Risk Factors and Potential Sources of Between-Animal Variation in Susceptibility

Digital dermatitis (DD) is a bacterial disease that primarily affects the skin on the heels of cattle. It is a major cause of lameness in dairy cows and a significant problem for the dairy industry in many countries, causing reduced animal welfare and economic loss. A wide range of infection levels has been found on infected farms, prompting investigations into both farm level and animal level risk factors for DD occurrence. There also appears to be individual variation between animals in susceptibility to the disease. The identification of factors affecting individual variation in susceptibility to DD might allow changes in breeding policies or herd management which could be used to reduce DD prevalence. Factors mentioned in the literature as possibly influencing individual variation in susceptibility to DD include physical factors such as hoof conformation and properties of the skin, physiological factors such as the efficacy of the immune response, and behavioural factors such as standing half in cubicles. Further work is required to determine the influence of these factors, identify the genetic basis of variation, clarify the level of heritability of DD susceptibility and to determine how this is correlated with production and health traits currently used in breeding programmes.

Mechanisms of plant resistance to metal and metalloid ions and potential biotechnological applications

Metal and metalloid resistances in plant species and genotypes/accessions are becoming increasingly better understood at the molecular and physiological level. Much of the recent focus into metal resistances has been on hyperaccumulators as these are excellent systems to study resistances due to their very abnormal metal(loid) physiology and because of their biotechnological potential. Advances into the mechanistic basis of metal(loid) resistances have been made through the investigation of metal(loid) transporters, the construction of mutants with altered metal(loid) transport and metabolism, a better understanding of the genetic basis of resistance and hyperaccumulation and investigations into the role of metal(loid) ion chelators. This review highlights these recent advances. © Springer 2005.