An extended high-frequency ultrasound protocol for detection of vessel wall inflammation.

OBJECTIVE: The aim of this study was to evaluate an extended protocol of the large vessels using high-frequency duplex ultrasound (DUS) for detection of vessel wall inflammation. METHODS: Fifty-eight patients performed a DUS examination where arteritis could not be excluded. All DUS examinations were performed using ACUSON S2000 TM ultrasound system (Siemens Medical Solutions USA, Inc.). High-frequency linear transducers were used (18L6 MHz, 9L4MHz) or curve linear for the aortic arch (6C2 MHz). Carotid, vertebral, central neck arteries (subclavian, axillary, innominate) arteries, aortic arch and femoral arteries were studied. Circumferential, homogenous wall thickening, with or without a hyperechogenic stripe lining the innermost layer, were regarded as typical signs of arteritis. Intima-media thickness (IMT) was measured in the patients and a normal control group. The latest clinical updated diagnosis was assessed at least 6 months after DUS. RESULTS: The DUS findings showed normal vessels (n = 14), arteritis and atherosclerosis (n = 13), atherosclerosis (n = 15) and arteritis (n = 16). The latter group had a significant increased IMT in the common femoral artery and the common carotid artery (mean 1·0 ±  SD 0·3 mm versus 0·6 ± 0·2 mm in the normal group (n = 37), P<0·00001, 1·2 ± 0·5 mm versus 0·8 ± 0·2 mm in the normal group (n = 40), P<0·00001). In the groups with sonographic signs implying arteritis (n = 29), 20 patients had a clinical diagnosis of arteritis, whereas eight patients had another main diagnosis such as malignancy/other inflammatory or infectious disease complicated by inflammation of the vessel wall. One patient had multiple diagnoses and was not possible to classify. CONCLUSION: An extended ultrasound protocol for central neck and leg arteries could be of value for diagnosis of arteritis. In case of atypical vessel wall inflammation, other main diagnoses should be considered.

Prediction of Post-interventional Outcome in Great Saphenous Vein Incompetence: The Role of Venous Plethysmography with Selective Superficial Vein Occlusion.

OBJECTIVE/BACKGROUND: To evaluate whether the outcome of radiofrequency ablation (RFA) treatment of great saphenous vein (GSV) incompetence may be predicted using strain-gauge plethysmography (SGP) with selective occlusion of the superficial venous system. METHODS: Seventeen patients (20 limbs) underwent endovenous RFA treatment for GSV incompetence (Clinical Etiology Anatomy Pathophysiology classification C2-C5; "C-group"). Duplex ultrasound (DUS) and SGP were performed with selective occlusion of superficial veins before and after RFA. Selective superficial occlusion was validated, in a control group (C-group) of 12 patients (14 legs), by ascending phlebography. In the RFA group, the time taken to reach 50% and 90% (T50, T90) of maximum venous volume was measured, as well as relative maximal reflux rates (%EV/min). The methodological error and coefficient of variation (CV) were assessed. RESULTS: Nineteen of 20 legs had complete post-operative GSV obliteration using DUS, and refilling times were improved after RFA (T50 11 ± 3 vs. 19 ± 3 s; p < .001; T90 27 ± 5 vs. 47 ± 6 s; p < .001). With SGP, the methodological error and CV for T50 were 4 s and 16%, respectively. Equivalence between pre-operative superficial occlusion and post-operative baseline measurements was achieved in 15 of 17 legs for T50, and 12 of 17 for T90 (three of the 20 legs were excluded due to treatment failure [n = 1], and untreated perforating veins [n = 2]). Mean differences (95% confidence interval) were within the equivalence ranges (T50 1 [-1 to 3] seconds; T90 -3 [-11 to 4] seconds). In the C-group superficial vein occlusion was possible in 12 of 14 legs. The remaining patient (two legs) showed incomplete superficial vein occlusion at ankle level (lipodermatosclerosis) and complete superficial vein occlusion at calf level. CONCLUSION: SGP with standardized superficial venous occlusion seems to be a reliable method for identifying venous reflux and may be useful in predicting the results of successful RFA treatment.

Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease.

OBJECTIVE: Regulatory T cells (Tregs) are considered atheroprotective, and low levels have been associated with the acute coronary syndrome (ACS), particularly non-ST elevation (NSTE)-ACS. However, the functional properties as well as homeostasis of Tregs are mainly unknown in coronary artery disease (CAD). Here, we investigated the composition and functional properties of naïve (n) and memory (m)Tregs in patients with NSTE-ACS and in patients 6-12 months post-ACS. METHODS: Based on the expression of CD25, FOXP3, CD127, CD45RA, CD39 and CTLA-4, Treg subsets were defined by flow cytometry in whole blood or isolated CD4(+) T cells. The functional properties of nTregs and mTregs were examined in terms of proliferative capacity and modulation of cytokine secretion. To understand the potential consequences of Treg defects, we also investigated correlations with lipopolysaccharide (LPS)-induced cytokine secretion and ultrasound-defined carotid atherosclerosis. RESULTS: Both NSTE-ACS and post-ACS patients exhibited reduced levels of nTregs (P < 0.001) compared with healthy control subjects, but without compensatory increases in mTregs. Both nTregs and mTregs from patients showed significantly lower replicative rates and impaired capacity to modulate T-cell proliferation and secretion of interferon-gamma and IL-10. The Treg defect was also associated with LPS-induced cytokine secretion and increased burden of carotid atherosclerosis. CONCLUSION: Our results demonstrate a functional and homeostatic Treg defect in patients with NSTE-ACS and also in stabilized patients 6-12 months after ACS. Moreover, this defect was associated with a subclinical proinflammatory and atherogenic state. We believe that the failure to preserve Treg function and homeostasis reflects a need for immune-restoring strategies in CAD.

Fe(III) distribution varies substantially within and between atherosclerotic plaques.

PURPOSE: Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. METHODS: Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. RESULTS: Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01). CONCLUSION: Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

Diameter and compliance of the greater saphenous vein - effect of age and nitroglycerine.

OBJECTIVES: The greater saphenous vein (GSV) is commonly used in autologous vein graft surgery. GSV diameter has proven to influence graft patency, and furthermore venous compliance might be of importance. The purpose of the study was to evaluate the effect of age on GSV diameter and compliance, and to evaluate the effect of nitroglycerine (NTG). METHODS: The diameter and compliance of the GSV, with and without NTG, were examined with B-mode ultrasound in 12 elderly (70·3 ± 1·2 year) and 15 young (25·1 ± 0·6 year) men. The GSV diameter at the thigh and calf level was measured at rest, after 6 min of venous stasis (60 mmHg) and after NTG administration. Pressure-area curves during a linear venous pressure decrease were produced. Venous compliance was calculated using the quadratic regression equation (area) = ß(0) + ß(1) (cuff pressure) + ß(2) (cuff pressure)(2) . RESULTS: GVS diameter between the groups showed significant lower diameter in elderly compared to young men (P<0·05). Venous occlusion increased GSV diameter in elderly men (P<0·01) as well as young men (P<0·001). NTG increased GSV diameter in elderly men (P<0·01) with an equal trend in young men. During venous occlusion, after administration of NTG, GSV diameter increased further in both elderly (P<0·01) and young men (P<0·001). GSV compliance was decreased in elderly (ß(1) , 0·037 ± 0019, ß(2,) -0·000064 ± 00017) versus young men (ß(1) , 0·128 ± 0·013, ß(2) , -0·00010 ± 000018) [P<0·001 (ß(1) ), P<0·02 (ß(2) )]. CONCLUSIONS: Baseline GSV diameter as well as GSV compliance is decreased in elderly men compared to the young subjects. As reduced GSV diameter as well as reduced compliance is related to decreased graft patency, these findings might be of importance for the uses of GSV as graft material in cardiovascular bypass surgery. The clinical value has to be clarified in future studies.

What you use decides what you get: comparing classificatory procedures for the Adult Attachment Interview in eating disorder research.

Studies of attachment and eating disorders use different types of measures, including different coding procedures for the Adult Attachment Interview (AAI). Generalizability of findings across studies is therefore uncertain. We compare the Main & Goldwyn procedure with the Dynamic Maturational Method, the two most common procedures for classifying AAI in eating disorder research. The sample consists of 20 female patients with a diagnosis of anorexia nervosa (mean age 22.9 (3.5) years). Attachment insecurity is by far most common, regardless of procedure. Within the insecure categories, there is little overlap between procedures in comparable categories. Both procedures discriminate between Anorexia subgroups (restricting vs bingeing), but do so differently. Findings suggest that comparing findings across methods, beyond the secure/insecure dichotomy, should be avoided.

Soft tissue discrimination ex vivo by dual energy computed tomography.

PURPOSE: Dual Energy Computed Tomography (DECT) may provide additional information about the chemical composition of tissues compared to examination with a single X-ray energy. The aim of this in vitro study was to test whether combining two energies may significantly improve the detection of soft tissue components commonly present in arterial plaques. METHODS: Tissue samples of myocardial and psoas muscle, venous and arterial thrombus as well as fat from different locations were scanned using a SOMATOM Definition Dual Source CT system (Siemens AG, Medical Solutions, Forchheim, Germany) with simultaneous tube voltages of 140 and 80 kV. The attenuation (Hounsfield units, HU) at 80 and 140 kV was measured in representative regions of interest, and the association between measured HU values and tissue types was tested with logistic regression. RESULTS: The combination of two energy levels (80 and 140 kV) significantly improved (p<0.001) the ability to correctly classify venous thrombus vs arterial thrombus, myocardium or psoas; arterial thrombus vs myocardium or psoas; myocardium vs psoas; as well as the differentiation between fat tissue from various locations. Single energy alone was sufficient for distinguishing fat from other tissues. CONCLUSION: DECT offers significantly improved in vitro differentiation between soft tissues occurring in plaques. If this corresponds to better tissue discrimination in vivo needs to be clarified in future studies.

Attachment in anorexia nervosa: an exploration of associations with eating disorder psychopathology and psychiatric symptoms.

Previous research on attachment and eating disorder has to a great extent presupposed direct links between states of mind with respect to attachment and eating disorder diagnoses. The authors provide a brief review stating that no such association can be found in current literature. The authors suggest that the association might exist on the level of eating disorder pathology and psychiatric symptoms, rather than diagnostic level. Based on 20 Adult Attachment Interviews coded with the Dynamic-Maturational method from patients diagnosed with anorexia, the authors explore the associations between attachment and diagnostic subgroups, eating disorder psychopathology (Eating Disorder Inventory--2nd edition), and psychiatric symptoms. All patients were coded within the range of insecure attachment. State of mind with respect to attachment did not differentiate between diagnostic subgroup and eating disorder pathology. Individuals classified as dismissing reported higher levels of anxiety-related distress than those classified as preoccupied or mixed dismissing/preoccupied. A high frequency of unresolved traumas and losses was found. The findings support previous reports of high frequencies of insecure attachment and unresolved traumas in anorexic patients. The high level of anxiety-related stress in the dismissing group lead the author to suggest that attachment plays a role in the patient's handling of distress following the eating disorder, rather than in the disorder itself.

Changes in middle cerebral artery blood flow after carotid endarterectomy as monitored by transcranial Doppler.

OBJECTIVE: By using transcranial Doppler (TCD) it is possible to measure blood flow velocities within the circle of Willis. In this study, TCD was performed before and after carotid endarterectomy (CEA) with the aim to describe cerebral hemodynamics after normalization of the carotid artery blood flow. METHODS: Thirty CEA patients were consecutively entered into the TCD study, whereas 15 patients were referred for postoperative TCD for various clinical reasons. All 45 patients were investigated by using TCD: first preoperatively, then during the first few days after CEA before discharge from the hospital, and finally 3 to 12 months later. In addition, all patients underwent duplex investigation of the internal carotid artery the day before surgery and 3 months postoperatively. For the analysis, the patients were divided into two groups, one with (S-group), suspected postoperative neurologic complications/symptoms and another one without (C-group). Six patients were assigned to the S-group and 37 to the C-group, the latter including two patients who underwent bilateral CEAs. RESULTS: In the whole study group,a significant postoperative increase in systolic flow velocity was recorded bilaterally in the middle cerebral artery (MCA) as measured some days after surgery. The patients in the S-group showed high blood flow velocities mainly in the MCA on the ipsilateral side. A contralateral flow velocity increase did not occur in patients with very severe contralateral stenosis or occlusion (n = 9) if the late follow-up investigation was chosen as a reference value. Twenty patients in the C-group formed a subgroup with high blood pressure and/or headache postoperatively (CB-group) The other 19 patients were referred to as the CA-group. The CB- and S-groups showed more pronounced vessel disease in internal carotid artery on the contralateral side combined with lower collateral capacity in the circle of Willis compared to the CA-group. In the S-group the mean +/- standard deviation peak systolic velocity in ipsilateral MCA increased from a preoperative value of 0.71 +/- 0.22 m/sec to 2.23 +/- 0.72 m/sec (P <.005). In the CB-group, we observed a bilateral MCA blood flow velocity increase from 0.72 +/- 0.18 to 1.35 +/- 0.56 m/sec (P <.0001) on the ipsilateral side and from 0.82 +/- 0.37 to 1.28 +/- 0.66 m/sec (P < 0.001) on the contralateral side. In the CA-group, we observed minor bilateral blood flow velocity increases in the MCA, from 0.79 +/- 0.25 m/sec to 1.03 +/- 0.33 m/sec on the ipsilateral (P <.001) and from 0.70 +/- 0.17 m/sec to 0.93 +/- 0.26 m/sec on the contralateral side (P <.005). At the follow-up 3 to 12 months after surgery, the MCA flow velocities had returned to normal. CONCLUSIONS: Soon after surgery, blood flow velocity increases often bilaterally in the MCA. However a contralateral flow velocity increase did not occur in patients with very severe contralateral stenosis or occlusion if the late follow-up investigation was chosen as a reference value. The clinical significance of bilateral flow velocity increases is uncertain, but very high blood flow velocities might be a signal for cerebrovascular hyperperfusion. In those patients, increased postoperative surveillance is recommended.

Influence of poststenotic collateral pressure on blood flow velocities within high-grade carotid artery stenosis: differences between morphologic and functional measurements.

PURPOSE: The driving force for blood flow through a high-grade stenosis in the internal carotid artery can be expressed as the pressure gradient over the stenosis itself, which, however, might be reduced by the back pressure exerted by distal collateral vessels. Theoretically the maximum blood flow velocity as a measure of the functional grade of obstruction may therefore be lower than what is expected from morphologic gradations of the stenosis. This study was designed to test prospectively the influence of intracranial collateral vessels on blood flow velocities within high-grade internal carotid artery stenoses. PATIENTS AND METHODS: Forty-five consecutive patients (age 66 +/- 11) with high-grade internal carotid artery stenoses were investigated before and during carotid endarterectomy. The preoperative investigations included duplex ultrasound scanning of the neck vessels, transcranial Doppler scanning for assessment of collateral flow to the middle cerebral artery and angiography. Carotid endarterectomy was performed with patients under deep general anesthesia without a shunt. Systolic and diastolic internal carotid artery blood pressures were measured before and during intraoperative cross-clamping (ie, stump pressure) of the carotid arteries. RESULTS: Within high-grade internal carotid artery stenoses, maximum systolic and end-diastolic blood flow velocities showed a significant inverse correlation to the corresponding systolic and diastolic stump blood internal carotid artery blood pressures. All patients with spontaneous collateral flow to the ipsilateral anterior part of the circle of Willis were divided into a group with relatively high and another one with low end-diastolic blood flow velocities. The stump pressure was significantly lower in patients with high end-diastolic blood flow velocities in spite of the fact that the mean angiographic grade of stenosis did not differ significantly between the groups. CONCLUSIONS: Flow velocities within a high-grade internal carotid artery stenosis are inversely dependent on the stump pressure, that is the poststenotic collateral perfusion pressure. This should be taken into consideration in case of discrepancies between angiography and ultrasound outcome.

Evaluation of posterior cerebral artery blood flow with transcranial Doppler sonography: value and risk of common carotid artery compression.

PURPOSE: Investigations of the posterior cerebral arteries (PCA) by transcranial Doppler sonography (TCD) may be less reliable than investigations of the anterior part of the circle of Willis. Nevertheless, a true PCA may be identified by manual compression of the proximal common carotid artery (CCA) during TCD. Therefore, we used CCA compression in clinically indicated TCD studies and assessed retrospectively its risks and prospectively its benefits for PCA evaluations. METHODS: Using the transtemporal approach, we prospectively assessed flow velocities in posteriorly located blood vessels in 180 consecutive patients before and during CCA compression. The complications of CCA compression were retrospectively reviewed in all 3,383 clinical TCD investigations performed over an 8-year period. RESULTS: Decreased flow velocities during ipsilateral CCA compression occurred in 17% of patients. A PCA-like vessel with perfusion from the carotid artery or PCA supply from the carotid circulation was unmasked. Mixed distal PCA support by the posterior communicating artery and proximal PCA could not be shown by TCD. Transient cerebral symptoms occurred in less than 0.4% of the 3,383 retrospectively reviewed TCD investigations; no other adverse effects were seen. CONCLUSIONS: TCD without CCA compression may lead to false identification of the PCA. Since transient cerebral symptoms during CCA compression are rare, CCA compression can be used when a clinical TCD investigation of intracranial collateral blood flow compensation is indicated or when the identification of a cerebral artery is uncertain.

High diastolic flow velocities in severe internal carotid artery stenosis: a sign of increased surgical risk?

PURPOSE: We reviewed the history and preoperative investigations of patients with early postoperative neurologic events after carotid thromboendarterectomy in an attempt to identify risk factors for neurologic complications. METHODS: Patients with neurologic events/complications (S group, n = 14 patients) were compared with an age- and disease-matched control group (C group, n = 42 patients) selected from the whole carotid thromboendarterectomy material between 1987 and 1996. In this retrospective study, we re-evaluated the maximum systolic and end diastolic flow velocities within the internal carotid artery (ICA) using video recordings of preoperative Duplex ultrasound scan investigations. The flow velocity variables were compared with preoperative carotid angiography and intraoperative ICA stump pressure measurement. RESULTS: S-group did not differ from C-group concerning either cardiovascular risk factors or diseases, ipsilateral and contralateral angiographic grade of ICA stenosis, or history of cerebral infarctions. Nevertheless, in contrast to control subjects, patients with early postoperative major stroke had higher end diastolic flow velocities and lower ICA stump pressures. Patients with postoperative minor stroke, transient ischemic attack, or amaurosis fugax did not differ significantly from the control subjects. Among patients with ICA stenosis of 75% or more, end diastolic flow velocities were correlated to the diastolic stump pressures. CONCLUSION: Diastolic flow velocities within severe internal carotid artery stenosis are dependent on the level of the collateral perfusion pressure distally to the stenosis (ie, high values indicate a low internal carotid artery stump pressure), which seems to be a risk factor for early postoperative strokes.

Middle cerebral artery circulation during carotid surgery. A transcranial Doppler study.

OBJECTIVE: Perioperative carotid cross-clamping might induce low stump pressures as well as hypoperfusion of the middle cerebral artery. In this study blood flow velocities in the middle cerebral artery were compared with intraoperative measurements of the poststenotic carotid blood pressure. DESIGN: Forty-one patients with internal carotid artery stenosis were operated on without shunting, under general anesthesia. Poststenotic carotid pressures and middle cerebral artery flow velocities were measured before and during cross-clamping. The hemodynamic responses to preoperative carotid compressions and intraoperative cross-clamping were evaluated. RESULTS: In seven patients the poststenotic carotid blood pressure decreased on clamping despite unchanged or even increased middle cerebral artery blood flow velocities. In all other patients, pressure changes were significantly correlated to the decrease in middle cerebral artery blood flow velocities. Autoregulatory blood flow velocity responses after preoperative common carotid artery compression were not reproducible by cross-clamping. CONCLUSIONS: Stump blood pressure measurements may not reflect middle cerebral artery perfusion in about 20% of thrombendarterectomies performed under general anesthesia. A possible explanation might be dimished cerebral autoregulation and changes in collateral flow distributions.

The role of the growth hormone/insulin-like growth factor I axis in stimulation of protein synthesis in skeletal muscles following oral refeeding.

The mechanisms behind stimulation of protein synthesis in skeletal muscles following oral feeding are not well understood. Previous research has not confirmed that insulin is a major factor behind this stimulation. In the present study we have used genetically altered mice, with either a lack of GH secretion due to a mutational gene inactivation [GH (-/-) dwarf, DW/JOrlBom-dw] or mice with a homozygous site-specific insertion mutation in the insulin-like growth factor-1 gene [IGF-I (m/m)], leading to a deficient IGF-I production. These gene knock-outs were used in comparison to their normal wild types for evaluation of the role that the GH/IGF-I axis may have in activation of nutritionally induced stimulation of protein synthesis in skeletal muscles during oral refeeding. Weight stable adult C57B16 mice served as an additional normal control group. Protein synthesis was measured by a modified flooding dose technique with radioactive L-[14C-U]phenylalanine incorporation into acid precipitated muscle proteins. Fractional protein synthesis in skeletal muscles after an overnight fast was comparable among C57B16 (0.076 +/- 0.009%/h), wild-type IGF-I(+/+) (0.061 +/- 0.008) and IGF-I(m/m) deficient mice (0.068 +/- 0.006%/h), whereas GH(-/-) incompetent mice had a lower fractional synthesis rate compared with GH(+/+) competent mice (0.045 +/- 0.006 vs. 0.068 +/- 0.007, P < 0.05). Refeeding with standard chow diet stimulated protein synthesis in muscles by more than 60% in all animal groups. This response was independent of circulating GH, total IGF-I concentrations in blood, as well as up-regulation of locally produced IGF-I messenger RNA (mRNA) in skeletal muscles.

Selectivity of superficial vein occlusion at the ankle and calf level: a methodological study in healthy volunteers.

Judgement of deep venous function may be necessary before surgery for superficial vein incompetence is performed. Assessment of deep venous function needs selective entrapment of superficial venous compartments between the ankle and knee, which may not be guaranteed if conventional tourniquets are used. This study was, therefore, aimed at modifying the technique of selective compression of superficial vein compartments. Twenty apparently normal legs of 10 volunteers were investigated on two study days. The subjects were in a supine position with the feet resting 30 cm above heart level. Ankle cuffs (3 cm wide) were placed just above the malleoli and stepwise inflated with air. The steady-state venous volume of the forefoot as a function of the pressure within the ankle cuff was measured with a mercury-in-rubber strain gauge. The maximum venous outflow velocity from the foot was also measured at each cuff pressure step after the addition of conventional thigh vein occlusion. The same protocol was used on the second study day: calf cuffs (3 cm wide) were then used instead of the ankle cuffs. In the forefoot, venous volume increased and the maximum venous outflow velocity decreased significantly either at ankle cuff pressures > 30 mmHg or at calf cuff pressures of > 60 mmHg. By using small cuffs, selective superficial vein occlusion seems to occur at cuff pressures ranging between 10 and 30 mmHg (ankle) and between 30 and 60 mmHg (calf), provided the feet are 30 cm above heart level. Higher cuff pressures seem to interact with deep venous function.

Role of insulin and IGF-I in activation of muscle protein synthesis after oral feeding.

The aim was to evaluate the role of insulin and insulin-like growth factor I (IGF-I) in activation of muscle protein synthesis after oral feeding. Synthesis rate of globular and myofibrillar proteins in muscle tissue was quantified by a flooding dose of radioactive phenylalanine. Muscle tissue expression of IGF-I mRNA was measured. Normal (C57 Bl) and diabetic mice (type I and type II) were subjected to an overnight fast (18 h) with subsequent refeeding procedures for 3 h with either oral chow intake or provision of insulin, IGF-I, glucose, and amino acids. Anti-insulin and anti-IGF-I were provided intraperitoneally before oral refeeding in some experiments. An overnight fast reduced synthesis of both globular (38 +/- 3%) and myofibrillar proteins (54 +/- 3%) in skeletal muscles, which was reversed by oral refeeding. Muscle protein synthesis, after starvation/ refeeding, was proportional and similar to changes in skeletal muscle IGF-I mRNA expression. Diabetic mice responded quantitatively similarly to starvation/refeeding in muscle protein synthesis compared with normal mice (C57 Bl). Both anti-insulin and anti-IGF-I attenuated significantly the stimulation of muscle protein synthesis in response to oral feeding, whereas exogenous provision of either insulin or IGF-I to overnight-starved and freely fed mice did not clearly stimulate protein synthesis in skeletal muscles. Our results support the suggestion that insulin and IGF-I either induce or facilitate the protein synthesis machinery in skeletal muscles rather than exerting a true stimulation of the biosynthetic process during feeding.

The effect of recombinant human IGF-I on protein metabolism in post-operative patients without nutrition compared to effects in experimental animals.

This study has evaluated the effects of recombinant human insulin-like growth factor I (rhIGF-I) to moderately stressed post-operative patients provided with dextrose as the only exogeneous substrate. Thirty patients who underwent elective colorectal surgery were randomized to receive either rhIGF-I (80 micrograms kg-1 bw) subcutaneously twice daily or placebo injections in a double-blind parallel group design. Nitrogen balance, urinary 3-methyl-histidine excretion plasma growth hormone (GH), serum cortisol, IGF-I binding proteins (IGFBP-1,3), glomerular filtration rate, plasma amino acid concentrations and whole-body energy expenditures were measured as effector variables during days 1-5 post-operatively. Animal and isolated tissue experiments were performed as additional control experiments to confirm cellular effectiveness of the recombinant material. rhIGF-I increased significantly the glomerular filtration rate and prevented the adaptive decrease in whole-body energy expenditure in response to partial starvation in the postoperative period. Serum and plasma concentrations of IGFBP-1,3 cortisol, blood glucose and amino acids were not significantly influenced by rhIGF-I administration, while plasma GH levels decreased significantly as expected. rhIGF-I had no effect on either nitrogen balance or protein breakdown (3-methylhistidine excretion) in post-operative patients on dextrose supplementation only, although plasma concentrations of IGF-I increased from 130-140 ng mL-1 to a range of 300-450 ng mL-1. In contrast, IGF-I stimulated the synthesis of both globular and myofibrillar proteins (+50%, P < 0.01), when given as a single dose (100 micrograms kg-1) 2 h before measurements of protein synthesis in skeletal muscles of overnight fasted adult mice. This stimulatory effect by IGF-I (1 microgram mL-1) was also confirmed by measurements of skeletal muscle protein synthesis in vitro (+40%, P < 0.05). Orally re-fed mice had a normal transcription of IGF-I mRNA in skeletal muscle cells, while overnight fasted mice showed a trend to down-regulated transcription. Our results demonstrate that rhIGF-I has several significant physiological effects, without major side-effects, when supplied to partially starved patients in the post-operative phase. The lack of a whole-body nitrogen sparing effect by rhIGF-I alone to post-operative patients is not clear, but was most likely explained by subnormal plasma concentrations of amino acids.

Insulin selectively attenuates breakdown of nonmyofibrillar proteins in peripheral tissues of normal men.

The role of insulin to control protein synthesis and degradation in the human leg and forearm was investigated in eight healthy individuals. The glucose clamp technique with simultaneous infusion of crystalline amino acids were used to create hyperinsulinemia (100-120 mU/l) in combination with euglycemia and elevated plasma concentrations of amino acids (> 4 mmol/l). A primed constant infusion with L-[U-14C]tyrosine and L-[phenyl-2H5]phenylalanine was used for simultaneous measurements of the disposal (protein synthesis) and the release (protein degradation) of tyrosine and phenylalanine, respectively, across the leg and forearm before and during hyperinsulinemia. The balance of 3-methylhistidine was also determined as a measure of muscle breakdown. Insulin stimulated tissue glucose and net amino acid uptake across the arm and leg tissues, whereas the disposal of both tyrosine and phenylalanine (protein synthesis) was not stimulated across the arm and the leg during hyperinsulinemia. The release of tyrosine and phenylalanine was significantly decreased from both leg and arm tissues (protein degradation) in response to insulin. However, the release of 3-methylhistidine from skeletal muscles was totally unaffected by hyperinsulinemia. We conclude that it is unlikely that insulin contributes to the normal stimulation of protein synthesis during feeding in humans and that insulin has no effect on breakdown of the large myofibrillar protein pool in skeletal muscles in unstressed individuals.

Whole body energy expenditure protein breakdown and polyamine excretion during high dose treatment with interleukin-2 and interferon-alpha.

OBJECTIVE: To correlate changes in whole body resting energy expenditure and protein breakdown with the production of stress hormones, excretion of polyamines, and circulating concentrations of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), in patients undergoing treatment with high doses of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). DESIGN: Prospective open study. SETTING: University Department of Surgery. SUBJECTS: 11 Patients with malignant melanoma (n = 8) or renal cell carcinoma (n = 3) all of whom had a Karnofsky score of 80 or more. INTERVENTIONS: Daily intravenous infusion of IL-2 (18 x 10(6) IU/m2/day) and subcutaneous injection of IFN-alpha (3 x 10(6) IU/m2/day) for days 1-5 and 8-12 in two courses with a three week interval. MAIN OUTCOME MEASURES: Energy expenditure measured by indirect calorimetry, body temperature, heart rate, urinary excretion of amino acids and nitrogen, and plasma cytokine concentrations. RESULTS: Three patients had a partial response. IL-1 was not detectable in plasma; and concentrations of IL-2 increased rapidly during the infusion before falling rapidly when it stopped, of IL-6 increased significantly (mean (SEM) 3.44 (1.6) to 11 (2) U/ml, p < 0.05), and of TNF-alpha increased by 295% (p < 0.05). Resting energy expenditure increased from 92 (4) to 113 (4) kJ/kg/day (p < 0.001) during the infusion and this was accompanied by a rise in temperature and an increase in the urinary excretion of cortisol (which also correlated with increased breakdown of whole body protein). CONCLUSION: The increased energy expenditure and protein breakdown were probably a result of stimulation of production of catecholamines and cortisol, as after injury, but the direct effects on temperature regulating neurons may be important.

Insufficient effect of total parenteral nutrition to improve protein balance in peripheral tissues of surgical patients.

Previous studies have indicated that unstressed and malnourished patients do not necessarily obtain amino acid balance across peripheral tissues during total parenteral nutrition (TPN) treatment, indicating treatment inefficiency. Therefore, the aim of this study was to evaluate to what extent (prevalence) insufficient therapeutic amino acid balance occurs in surgical patients receiving TPN for standard medical reasons. Thirty-two patients treated in an ordinary surgical ward (n = 17) or in the intensive care unit (ICU) (n = 15) were examined. The arteriovenous balance across the leg of amino acids, glucose, glycerol, lactate, and oxygen was measured in relationship to plasma levels of insulin. All patients had been receiving TPN for at least 7 days before the investigation. All measurements were performed when amino acids had been infused for at least 4 hours and thus expected to support the resynthesis of lean body mass. Patients treated in the ICU and the surgical ward were in positive whole-body energy balance (+1127 +/- 121 and +917 +/- 123 kcal, respectively). Glucose uptake and oxygen consumption across the leg were similar in both patient groups. Glycerol release was not different from zero balance, indicating that inhibition of lipolysis across the leg during feeding and lactate was normally released in both groups. However, approximately 50% of the patients treated in the ordinary ward and 80% to 100% of the patients in the ICU remained in negative amino acid balance across the leg as judged from significant release of either methionine, tyrosine, or phenylalanine despite concomitant infusion of amino acids (approximately 0.3 g of N per kilogram per day) and nonprotein calories.(ABSTRACT TRUNCATED AT 250 WORDS)