GP strategies to avoid imaging overuse. A qualitative study in Norwegian general practice

ObjectivesThe aim of the study was to identify general practitioners’ (GPs) strategies to avoid unnecessary diagnostic imaging when encountering patients with such expectations and to explore how patients experience these strategies.Design, setting and subjectsWe conducted a qualitative study that combined observations of consultations and interviews with GPs and patients. A total of 24 patients visiting nine different GPs in two Norwegian urban areas were included in the study. Of these, 12 consultations were considered suitable for studying GP strategies and were therefore selected for a more thorough analysis.Main outcome measuresGPs’ communication strategies to avoid unnecessary medical imaging and patients’ experiences with such strategies.ResultsFive categories of strategies were identified: (1) wait and see – or suggest an alternative; (2) the art of rejection; (3) seek support from a professional authority; (4) partnership and shared decision-making and (5) reassurance, normalisation and recognition. The GPs often used multiple strategies. Factors related to a long-term doctor–patient relationship seemed to influence both communication and how both parties experienced the decision. Three important factors were evident: the patient trusted the doctor, the doctor knew the patient’s medical history and the doctor knew the patient as a person. The patients seemed to be generally satisfied with the outcomes of the consultations.ConclusionGPs largely combine different strategies when meeting patients’ expectations of diagnostic imaging that are not strictly medically indicated. Continuity of the doctor–patient relationship with good personal knowledge and trust between doctor and patient appeared crucial for patients to accept the doctors'' decisions.

Key points

• GPs usually combine a broad range of strategies to avoid unnecessary medical imaging
• The patients appeared generally satisfied regardless of the strategy the strategy used by the GPs and even where their referral request were rejected
• Factors related to a long-term doctor–patient relationship appeared decisive

     

Breaking the speed of the sound of loneliness: Sexual partner change and the fear of intimacy

Following a thematic analysis of responses, a qualitative study of sexuality and alcohol use was undertaken in three bars/clubs in Oslo. Interviews with two persons (one male, one female) with high rates of sexual partner change were selected for detailed interpretative and contextual analysis, the aim being to examine the underlying motives for this mode of action. The principal motivations underpinning the man's behaviour linked to sex drive, impulsivity, and opportunity. He expressed cynicism, distance, loneliness and an element of narcissism. The woman's sexual activity on the other hand was motivated by intoxication, chance, the desire to offer care, arousal, and love. The data suggest that much more than sexual pleasure is being sought in the kinds of encounters described. A basic motive underpinning this behaviour appears to be a fear of intimacy mixed with the search for a sense of self-worth.     

Important risk factors and attributable risk of vertebral fractures in the population-based Tromsø study

ABSTRACT: BACKGROUND: Vertebral fractures, the most common type of osteoporotic fractures, are associated with increased risk of subsequent fracture, morbidity, and mortality. The aim of this study was to examine the contribution of important risk factors to the variability in vertebral fracture risk. METHODS: Vertebral fracture was ascertained by VFA method (DXA, GE Lunar Prodigy) in 2887 men and women, aged between 38 and 87 years, in the population-based Tromso Study 2007/2008. Bone mineral density (BMD; g/cm2) at the hip was measured by DXA. Lifestyle information was collected by questionnaires. Multivariable logistic regression model, with anthropometric and lifestyle factors included, was used to assess the association between each or combined risk factors and vertebral fracture risk. Population attributable risk was estimated for combined risk factors in the final multivariable model. RESULTS: In both sexes, age (odds ratio [OR] per 5 year increase: 1.32; 95% CI 1.19-1.45 in women and 1.21; 95% CI 1.10-1.33 in men) and BMD (OR per SD decrease: 1.60; 95% CI 1.34-1.90 in women and1.40; 95% CI 1.18-1.67 in men) were independent risk factors for vertebral fracture. At BMD levels higher than 0.85 g/cm2, men had a greater risk of fracture than women (OR 1.52; 95% CI 1.14-2.04), after adjusting for age. In women and men, respectively, approximately 46% and 33% of vertebral fracture risk was attributable to advancing age (more than 70 years) and low BMD (less than 0.85 g/cm2), with the latter having a greater effect than the former. CONCLUSIONS: These data confirm that age and BMD are major risk factors for vertebral fracture risk. However, in both sexes the two factors accounted for less than half of fracture risk. The identification of individuals with vertebral fracture is still a challenge.     

Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.Studies in human and rodent models have revealed deleterious effects of excess lipid availability on peripheral insulin sensitivity (1,2). Intracellular increases in fatty acid metabolites, such as diacylglycerol (DAG) and ceramide, may play critical roles in mediating lipid-induced insulin resistance by inducing serine phosphorylation of insulin-receptor substrate 1 (IRS-1) (3–6) and consequently inhibiting downstream signaling to GLUT4 translocation. However, recent reports challenge such causality. These studies revealed unaltered signal transduction at the level of IRS-1, IRS-1–associated phosphatidylinositol-3-kinase (PI3K) activity, Akt, and TBC1 domain family member 4 (TBC1D4) phosphorylation (phospho-Akt-substrate [PAS] an unspecific antibody recognizing phosphorylated Akt substrate motifs), after 2–7 h of lipid infusion (7–11). When DAG and/or ceramide levels were reported, no changes in skeletal muscle DAG or ceramide levels were found after lipid infusion (7,11).We recently showed that lactate release in human skeletal muscle is augmented along with reduced respiratory exchange ratio (RER) values during lipid infusion (11). This could indicate suppressed activity of the pyruvate dehydrogenase (PDH) complex, which in turn could lead to a reduction in glucose uptake according to the Randle cycle (12). Here, we wished to investigate whether this increase in leg lactate release and reduced RER values were accompanied by altered regulation of PDH, measured by site-specific phosphorylation.Exercise increases peripheral insulin sensitivity (13–15). After an acute bout of exercise, the ability for insulin to stimulate glucose uptake in skeletal muscle is increased several hours into recovery (14,16). This effect can be ascribed to adaptations in the exercised muscle rather than changes in systemic factors (13,17,18) and is observed in both healthy and insulin-resistant states (e.g., obesity) (19) and type 2 diabetes (20). A recent study has shown that a single bout of exercise can prevent subsequent lipid-induced impairments in whole-body glucose tolerance assessed by an intravenous glucose tolerance test (IVGTT) (2). It was hypothesized that repartitioning fatty acids toward intramuscular triacylglycerol (IMTG) synthesis and storage rather than DAG or ceramide might be a primary mediator of the beneficial effects of exercise on lipid-induced impairments in glucose tolerance (2). Enhanced insulin sensitivity after a bout of exercise is associated with increased GLUT4 recruitment to the plasma membrane (21) and not with altered protein synthesis (e.g., GLUT4 protein) (22), but has not been associated with altered signal transduction through the insulin receptor, IRS-1, PI3K, or Akt (13,22,23). Recently, the hypothesis was put forward (24) that the guanosine triphosphatase (GTPase) activating proteins TBC1 domain family member 1 (TBC1D1) and 4 (TBC1D4) might serve as points of convergence for insulin dependent and independent signaling pathways to GLUT4 translocation. In agreement with this hypothesis, PAS phosphorylation of TBC1D4 is elevated along with insulin-stimulated glucose uptake for up to 27 h after exercise in skeletal muscle of rats (25), and we recently showed that phosphorylation of TBC1D4 on specific residues was elevated 4 h after a single bout of exercise in human skeletal muscle (26).TBC1D4/D1 are multikinase substrates proposed to be involved in contraction- and insulin-stimulated glucose uptake in mice (27,28), and exercise and insulin both substantially increase TBC1D4/D1 phosphorylation in human skeletal muscle (29,30). TBC1D4/D1 contain several phosphorylation sites distinctly phosphorylated by various kinases, including Akt and 5′AMP-activated protein kinase (AMPK) (28,31–33). Phosphorylation of TBC1D4/D1 and subsequent 14-3-3 binding is proposed to lead to inactivation of the GTPase-activating proteins, decreasing their inhibitory function on the GLUT4 translocation process and thus, potentially, increasing the GLUT4 capacity of the surface membrane.In the current study we tested the hypothesis that prior exercise prevents subsequent lipid-induced insulin resistance in human skeletal muscle through regulation of the signaling molecules TBC1D4/TBC1D1.     

Experimental and Numerical Investigation of an Axial Rotary Blood Pump

Left ventricular assist devices (LVADs) have become a standard therapy for patients with severe heart failure. As low blood trauma in LVADs is important for a good clinical outcome, the assessment of the fluid loads inside the pump is critical. More specifically, the flow features on the surfaces where the interaction between blood and artificial material happens is of great importance. Therefore, experimental data for the near‐wall flows in an axial rotary blood pump were collected and directly compared to computational fluid dynamic results. For this, the flow fields based on unsteady Reynolds‐averaged Navier–Stokes simulations‐computational fluid dynamics (URANS‐CFD) of an axial rotary blood pump were calculated and compared with experimental flow data at one typical state of operation in an enlarged model of the pump. The focus was set on the assessment of wall shear stresses (WSS) at the housing wall and rotor gap region by means of the wall‐particle image velocimetry technique, and the visualization of near‐wall flow structures on the inner pump surfaces by a paint erosion method. Additionally, maximum WSS and tip leakage volume flows were measured for 13 different states of operation. Good agreement between CFD and experimental data was found, which includes the location, magnitude, and direction of the maximum and minimum WSS and the presence of recirculation zones on the pump stators. The maximum WSS increased linearly with pressure head. They occurred at the upstream third of the impeller blades and exceeded the critical values with respect to hemolysis. Regions of very high shear stresses and recirculation zones could be identified and were in good agreement with simulations. URANS‐CFD, which is often used for pump performance and blood damage prediction, seems to be, therefore, a valid tool for the assessment of flow fields in axial rotary blood pumps. The magnitude of maximum WSS could be confirmed and were in the order of several hundred Pascal.     

Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC γ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.Nephrotic syndrome is characterized by proteinuria, sodium retention, and edema. Increased renal sodium reabsorption occurs in the cortical collecting duct (CCD),^1,2 where a rate-limiting step in transepithelial sodium transport is the epithelial sodium channel (ENaC), which is composed of the three homologous subunits: α, β, γ.³ENaC activity is regulated by hormones, such as aldosterone and vasopressin (AVP)^4,5; however, adrenalectomized rats and AVP-deficient Brattleboro rats are capable of developing nephrotic syndrome,^1,6 and nephrotic patients do not consistently display elevated levels of sodium-retaining hormones,^7,8 suggesting that renal sodium hyper-reabsorption is independent of systemic factors. Consistent with this, sodium retention is confined to the proteinuric kidney in the unilateral puromycin aminonucleoside (PAN) nephrotic model.^2,9,10There is evidence that proteases contribute to ENaC activation by cleaving the extracellular loops of the α- and γ-subunits.^11–13 Proteolytic activation of ENaC by extracellular proteases critically involves the cleavage of the γ subunit,^14–16 which probably leads to the release of a 43-residue inhibitory peptide from the ectodomain.¹⁷ Both cleaved and noncleaved channels are present in the plasma membrane,^18,19 allowing proteases such as channel activating protease 1 (CAP1/prostasin),²⁰ trypsin,²⁰ chymotrypsin,²¹ and neutrophil elastase²² to activate noncleaved channels from the extracellular side.^23,24 We hypothesized that the defective glomerular filtration barrier in nephrotic syndrome allows the filtration of ENaC-activating proteins into the tubular fluid, leading to stimulation of ENaC. The hypothesis was tested in the PAN nephrotic model in rats and with urine from patients with nephrotic syndrome.     

Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.     

Reduction in Fracture Rate and Back Pain and Increased Quality of Life in Postmenopausal Women Treated with Teriparatide: 18-Month Data from the European Forsteo Observational Study (EFOS)

The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study.     

Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise

We investigated the effects of caffeine ingestion on skeletal muscle glucose uptake, glycogen synthase (GS) activity, and insulin signaling intermediates during a 100-min euglycemic-hyperinsulinemic (100 microU/ml) clamp. On two occasions, seven men performed 1-h one-legged knee extensor exercise at 3 h before the clamp. Caffeine (5 mg/kg) or placebo was administered in a randomized, double-blind fashion 1 h before the clamp. During the clamp, whole-body glucose disposal was reduced (P < 0.05) in caffeine (37.5 +/- 3.1 micromol x min(-1) x kg(-1)) vs. placebo (54.1 +/- 2.9 micromol x min(-1) x kg(-1)). In accordance, the total area under the curve over 100 min (AUC(0--100 min)) for insulin-stimulated glucose uptake in caffeine was reduced (P < 0.05) by approximately 50% in rested and exercised muscle. Caffeine also reduced (P < 0.05) GS activity before and during insulin infusion in both legs. Exercise increased insulin sensitivity of leg glucose uptake in both caffeine and placebo. Insulin increased insulin receptor tyrosine kinase (IRTK), insulin receptor substrate 1-associated phosphatidylinositol (PI) 3-kinase activities, and Ser(473) phosphorylation of protein kinase B (PKB)/Akt significantly but similarly in rested and exercised legs. Furthermore, insulin significantly decreased glycogen synthase kinase-3alpha (GSK-3alpha) activity equally in both legs. Caffeine did not alter insulin signaling in either leg. Plasma epinephrine and muscle cAMP concentrations were increased in caffeine. We conclude that 1) caffeine impairs insulin-stimulated glucose uptake and GS activity in rested and exercised human skeletal muscle; 2) caffeine-induced impairment of insulin-stimulated muscle glucose uptake and downregulation of GS activity are not accompanied by alterations in IRTK, PI 3-kinase, PKB/Akt, or GSK-3alpha but may be associated with increases in epinephrine and intramuscular cAMP concentrations; and 3) exercise reduces the detrimental effects of caffeine on insulin action in muscle.