Omega-3 fatty acids inhibit an increase of proinflammatory cytokines in patients with active Crohn's disease compared with omega-6 fatty acids.

BACKGROUND: Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract. Polyunsaturated omega-3 fatty acids given orally may reduce the secretion of proinflammatory cytokines and hereby downregulate the inflammatory process. AIM: To assess the effects of enteral fatty acids, in the form of Impact Powder (Novartis, Switzerland), as adjuvant therapy to corticosteroid treatment on the proinflammatory and anti-inflammatory cytokine profiles in patients with active Crohn's disease. METHODS: The proinflammatory and anti-inflammatory cytokines were measured in plasma from 31 patients with active Crohn's disease. Patients were randomized for oral intake of omega-3 fatty acid (3-Impact Powder) or omega-6 fatty acids (6-Impact Powder). Clinical and biochemical markers of inflammation were studied at baseline and after 5 and 9 weeks. RESULTS: Within the 3-Impact Powder group, no significant changes in concentrations of interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-5 and interleukin-10, whereas a significant differences in concentration of interleukin-1beta and interleukin-4 were observed during therapy. Within the 6-Impact Powder group a significant changes in concentrations of interleukin-1beta, interleukin-6, interferon-gamma, monocyte chemoattractant protein-1, interleukin-2, interleukin-4, interleukin-5 and interleukin-10 were observed. CONCLUSIONS: The 3-Impact Powder showed immunomodulatory properties and might inhibit an increase of proinflammatory cytokines in contrast to the 6-Impact Powder.

In-situ bypass surgery on arteriographically invisible vessels detected by Doppler-ultrasound for limb salvage.

AIM: The aim of this paper was to evaluate our primary experience with bypass surgery on arteries only visible on Doppler-ultrasound in patients suffering from critical lower limb ischemia. METHODS: During a study period of 10 months, Doppler-ultrasound routinely supplemented digital subtraction arteriography (DSA) whenever it failed to reveal patent runoff vessels suitable for in-situ saphenous vein bypass surgery. If an arteriographically invisible runoff artery was detected on Doppler-ultrasound and the patient was eligible for surgery, a bypass procedure was performed. All patients were facing a lower limb amputation due to critical limb ischemia (tissue loss, SVS/ISCV-category 5). Postoperatively the patients were followed according to a standard graft surveillance program, including clinical examination, ankle pressure measurements and a color Doppler-ultrasound at discharge and after 1, 6 and 12 months. RESULTS: Fifty-one in-situ saphenous vein bypasses were performed, 5 (10%) on arteriographically occult runoff vessels detected only on Doppler-ultrasound. After a 12-month follow-up, 3 bypasses were still patent and only one patient had an amputation. One bypass occluded after 6 months but the patient stayed asymptomatic. CONCLUSIONS: Doppler-ultrasound permits in-situ by-pass surgery on arteriographically invisible vessels reducing the proportion of inoperable patients by 10%.

The haemodynamic effect of carotid endarterectomy.

OBJECTIVES: to assess the haemodynamic effect of carotid artery surgery, and to relate postoperative changes to the state of cerebral circulation before revascularisation. MATERIALS AND METHODS: using transcranial Doppler we studied bilateral middle cerebral artery (MCA) flow velocities before and on 1st day, 2nd or 3rd day and 4th or 5th day and 3 months after carotid surgery in 61 patients. In addition, ipsilateral MCA flow velocity was monitored continuously during surgery. Data were related to the internal carotid artery (ICA) perfusion pressure (cerebral perfusion pressure index, CPPI), measured directly before ICA clamping. RESULTS: postoperatively, MCA flow velocities increased significantly overall (p<0.01), mainly due to pronounced and longer lasting flow velocities in the group of 18 patients with CPPI<0.7 (p<0.05). Flow velocities peaked - absolute as well as relative - on the first postoperative day and then gradually levelled off to reach preoperative values after 4-5 days in patients with high CPPI, whereas MCA flow velocities remained increased in the group of patients with low CPPI. At 3 months flow velocities in both groups were normalised. New neurological symptoms occurred in four patients, who all had low CPPI preoperatively (22% (4/18) vs 0%; Fisher's exact test: p=0.006). CONCLUSION: some degree of hyperperfusion was seen in most patients, but the changes were significantly more pronounced in patients with preoperative hypoperfusion, who also suffered significantly more neurological complications.

Can capillary whole blood glucose and venous plasma glucose measurements be used interchangeably in diagnosis of diabetes mellitus?

According to new proposals from the American Diabetes Association (ADA) and WHO, venous peripheral plasma is the preferred system for measuring glucose for diagnosing diabetes mellitus. Owing to the instability of glucose in plasma after blood sampling, strict well-defined and standardized preanalytical conditions are essential to ensure that glucose concentration measured in plasma reflects real blood glucose in the patient. This is in contrast to the capillary whole blood measurements, which are easy to perform and well established. We investigated whether it is possible to perform analysis on capillary whole blood but express the results as plasma glucose values and hence obtain comparable results and the same predictive values for diagnosis in the individual patient? The conclusion of our investigations is that these two systems are not interchangeable and that conversion should not be done for diagnostic purposes where plasma determinations are recommended.

Upper reference limit, analytical quality specifications and clinical use of haemoglobin A1C.

Haemoglobin A1c (HbA1c) is now the key component for monitoring glycaemic control in diabetes mellitus (DM), especially for its close relation to diabetes complications. However, treatment goals in terms of HbA1c concentrations have been difficult to define and compare because of lack of international standardization and lack of common reference values of HbA1c concentrations. The aims of our study were to document our HbA1c analysis and make it traceable to international reference laboratories with the aid of current reference preparations, to establish a reference interval based on a low-risk population, and to evaluate the analytical quality specifications, which could meet clinical needs. The s(analytical) of our method (Tosoh) was < 0.3 HbA1c%, and the mean bias as estimated from Dr Cas Weykamp's reference preparation was below 0.3 HbA1c. This was the same as that for participating Scandinavian and international reference laboratories. The concentrations were made traceable to results from the Diabetes Control and Complication Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). Risk groups for DM were ruled out from a randomly selected population in Vejle County, which isolated a "low-risk" reference population. The 97.5 reference interval in this population (N=430) was from 5.07 HbA1c% (95% CI: 5.02-5.11) to 6.24 HbA1c% (95% CI: 6.19-6.30), and the 99.9 centile was 6.62 HbA1c% (95%) CI 6.55-6.71). Body mass index, age and gender contributed marginally to the level of HbA1c concentrations. A 10% delta risk estimate of DM complications was detectable with a probability of Type I error of 40%, while adoption of a significance level of 95% and consideration to biological variation needed a risk difference of at least 33% to be detected. The critical difference was 11% for changes in either direction at s(analytical) < or = 0.2 HbA1c% and a s(biological) of 0.3 HbA1c%. Based on criteria for sharing common reference intervals and clinical utility, we accepted that the bias and s(analytical) should both be < 0.3 HbA1c% at the level of 7.0 HbA1c%.

Optimization of preanalytical conditions and analysis of plasma glucose. 1. Impact of the new WHO and ADA recommendations on diagnosis of diabetes mellitus.

The new diagnostic criteria for type 2 diabetes from the American Diabetes Association (ADA) and World Health Organization (WHO) recommend measurements on plasma and a lowering of the glucose threshold for diabetes by 0.8 mmol/L. This narrows the distance between the upper end of the reference limit and the discriminatory level to a degree where analytical quality becomes critical. The quality demands for the preanalytical and analytical phase and their consequences on diagnostic performance have to be established in the new technical system, measuring in plasma rather than in capillary whole blood. Because of the instability of glucose in blood samples it is necessary to clarify the influence of different preanalytical and analytical factors on the number of false-positive and false-negative classifications. Thus the aim of the present study was to find optimal conditions for sampling, additives, storage, transport and analysis of plasma glucose combining feasibility with an analytical bias close to zero and a within-imprecision around 1%. We have documented the analytical performance of the method itself and its traceability to an international standard. The preanalytical conditions, such as influence of antiglycolytic agent NaF, conditions for plasma separation, storage temperature and storage time before and after plasma separation were investigated. In conclusion, we recommend that blood should be drawn in tubes containing heparin and NaF and kept on ice water for not more than 1 h until centrifugation at minimum 1000 x g for 10 min. The plasma is then stable for at least 48 h at room temperature.

Plasma glucose reference interval in a low-risk population. 2. Impact of the new WHO and ADA recommendations on the diagnosis of diabetes mellitus.

The aim of the study was to establish a reference interval of fasting venous plasma glucose (FPG) from healthy individuals. A prospective modified cross-sectional population-based study was made with random selection of 2100 persons in age-stratified groups > or = 18 years identified from the local Personal Identification Register. The invitation was accepted by 755 persons, of which 726 aged 18-92 years were eligible. They did not have a diabetes diagnosis, were non-pregnant and capable of fasting for 8 h. All participants filled in a questionnaire on medical risk factors. Blood for the FPG and haemoglobin Alc (HbAlc) measurements was drawn in accordance with a standardized procedure. A total of 302 participants carried diabetes risk indicators and were ruled out. The FPG concentrations in the remaining low-risk population (n=424) was ln Gaussian distributed. The FPG 97.50 centile in this group was 6.4 mmol/L (95% CI: 6.3-6.5 mmol/L), in contrast to the WHO and ADA theoretical limit of 6.1 mmol/L. Their diagnostic decision limit of 7.0 mmol/L FPG corresponded to the 99.86 centile of the FPG reference distribution (95% CI: 6.8-7.1). Subclassification of the reference population showed increasing FPG with increasing BMI and age and was higher in men than in women. The study determined the FPG 95% interfractile reference interval in a healthy population. The interval in glucose concentration between the 97.5 centile of the reference interval and the ADA-WHO diagnostic limit is very narrow. The clinical application of the diagnostic discriminator and the interpretation of the WHO-ADA grey zone from 6.1 to 7.0 mmol/L FPG may consequently be biased because of poorly defined limits and influence from BMI, age and gender.

[Problem-based learning in medical education]. / Problembaseret undervisning på medicinstudiet.

Problem Based Learning (PBL) has not yet been instituted systematically at medical schools in Denmark. We therefore introduced the method in a 10th term course in internal medicine and surgery, eighteen months before graduation, and evaluated the experience after two terms with a total of 93 students and 15 tutors. Compared with traditional education such as bed-side clinics and lectures etc., PBL was the preferred method by 67% of the students, while 28% found the methods equally good and only 2% discredited PBL. The main advantage of PBL was ascribed to motivation and activation, the students finding themselves as being part of the problem-solving situation. The tutors estimated PBL highly when teaching clinical coping strategies, stressing the need for a realistic and appropriate setting. This experience supports the decision to introduce PBL throughout the new medical curriculum in Copenhagen.

Oxygen and 2,3 biphosphoglycerate (2,3-BPG) during haemodialysis.

Eleven patients with chronic renal failure who were being treated with haemodialysis three times a week were monitored for a total of 34 haemodialysis sessions. Erythrocyte 2,3-biphosphoglycerate (2,3-BPG) concentration was analysed immediately before initiation of bicarbonate haemodialysis and 1 h afterwards. The 2,3-BPG concentration was expressed relative to the haemoglobin tetramer (Hb4) concentration as the 2,3-BPG/Hb4 ratio and compared with blood gas analyses and biochemical variables important for characterizing uraemia. During the first hour of haemodialysis the 2,3-BPG/Hb4 ratio decreased (p < 0.002), but the magnitude of the decrease did not significantly correlate with the 2,3-BPG/Hb4 ratio measured before haemodialysis (p=0.104). The decrease is most likely to be caused by the haemodialysis procedure itself. Mechanical stress on the erythrocytes is believed to cause the 2,3-BPG to escape; it is then removed by haemodialysis. Physiologically, an increase in 2,3-BPG would be expected to counteract the hypoxia which is frequently observed during haemodialysis. However, the present results show the opposite, a decrease in 2,3-BPG. No significant correlation was shown between the haemoglobin concentration and the 2,3-BPG/Hb4 ratio before dialysis (p=0.414). The pH showed a significant positive correlation with the 2,3-BPG/Hb4 ratio before dialysis, whereas the arterial pO2 and the 2,3-BPG/Hb4 ratio before dialysis were insignificantly negatively correlated. The concentrations of calcium, phosphate, creatinine, urea and albumin did not correlate significantly with the change in 2,3-BPG/Hb4-ratio after 1 h. The 2,3-BPG/Hb4 ratio (p=0.03) sampled just before dialysis correlated significantly and positively with the total weekly dosage of erythropoietin given to the patients.

Tolerance to head-up tilt and suspension with elevated legs.

OBJECTIVE: Orthostatic hypotension is usually a benign event. However, some patients are disabled by frequent syncopal events, and vertical transportation during helicopter rescue, for example, may even be fatal. Normal orthostatic tolerance is poorly defined, so we evaluated the response to 50 degrees head-up tilt. Also, the effect of leg elevation was examined in order to establish the influence of venous return, and a fatal accident associated with orthostasis is reported. METHODS: There were 79 volunteers who were subjected to 50 degrees head-up tilt, and 9 subjects performed 1 h of suspension by double strops placed around the thorax and knee bends, respectively. The time to presyncope and changes in BP, heart rate, thoracic electrical impedance, central venous pressure and central venous and muscle oxygen saturations were measured. RESULTS: Head-up tilt resulted in hypotension, bradycardia and presyncopal symptoms in 69 subjects within 1 h (87%; half time 27 min), but during suspension with elevated legs in only one subject (11%; p < 0.02). In presyncopal subjects the central blood volume was reduced as reflected by an elevated thoracic electrical impedance and reduced central venous and muscle oxygen saturations. CONCLUSIONS: During 50 degrees head-up tilt, half of 79 subjects near-fainted within 27 min, whereas elevation of the legs secured venous return to the heart and prevented presyncopal symptoms. The high rate of near-fainting in normal subjects should be taken into account during evaluation of patients with syncope, and it emphasizes the use of a position that secures venous return during transportation.

[Thoracic electric impedance and fluid balance during aortic surgery]. / Torakal elektrisk impedans og vaeskebalance ved operationer på aorta.

Indices of fluid balance were evaluated during and after aortic surgery in 16 consecutive patients. Thoracic electrical impedance (TI), heart rate (HR), central venous (CVP), pulmonary artery mean (PAMP), pulmonary wedge (PWP) and mean arterial (MAP) pressures as well as fourteen arterial and venous blood gas variables were followed. Consistent with a reduction of TI during the operation, fluid balance was in excess, and it remained elevated on the first postoperative morning. The HR, MAP and PWP remained stable, while CVP and PAMP decreased. Of the determined variables only TI revealed a meaningful correlation to fluid balance (rho = -0.41; p < 0.01). The results indicate that while central venous and pulmonary artery mean pressures gave the impression of a volume deficit, the positive fluid balance was mirrored by thoracic electrical impedance.

Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres.

The influence of pretreatment serum neuron-specific enolase (S-NSE) in addition to more conventional prognostic factors on survival duration in small-cell lung cancer (SCLC) was investigated in 770 patients from nine centres in six countries. The other variables included stage of disease, performance status (PS), age, sex, serum lactate dehydrogenase (S-LDH), serum alkaline phosphatase (S-AP), and serum carcinoembryonic antigen (S-CEA). Increased values of S-NSE (> 12.5 micrograms-1 l) were observed in 81% of the patients, whereas S-LDH, S-AP and S-CEA were elevated in only half of the patients or less. Multivariable analysis by Cox's proportional hazard model disclosed S-NSE as the most powerful prognostic factor followed by poor PS and extensive stage disease. If PS was ignored, S-LDH came up as a significant prognostic factor. S-AP, S-CEA, age and sex had no significant influence on the prognosis. The three prognostic factors, S-NSE, PS and stage of disease, enabled establishment of a prognostic index (PI) based on a simple algorithm PI = zNSE + z(stage) + 2zPS. This segregated the patients into four groups with clearly different prognosis. The median survival and 95% confidence intervals of the four groups were: 468 days (540-408), 362 days (405-328), 256 days (270-241) and 125 days (179-58). Based on the present results we recommend S-NSE and PS, in addition to stage, for prognostic stratification in treatment trials on SCLC.

Serum neuron specific enolase (S-NSE) reference interval evaluation by time-resolved immunofluorometry compared with a radioimmunoassay.

The serum neuron specific enolase (S-NSE; EC 4.2.1.11) reference interval was evaluated by DELFIA (Wallac) in 161 healthy blood donors and the method compared with the S-NSE RIA assay (Pharmacia). The DELFIA assay total analytical variation coefficient (CV%) was between 3.7% and 6.6%., the RIA CV% 7.6% to 13.1%. Late centrifugation (after hours) increased the variation as a result of contamination with blood cells. Log transformation into a gaussian distribution was selected by Box-Cox analysis and tested by two models: the gauss-distribution and the Refval transformation. The 95% reference intervals and corresponding 90% confidence intervals were: female 2.9-9.6 micrograms/l (2.6-3.2 and 8.5-10.7) micrograms/l and male 3.4-11.7 micrograms/l (3.0-3.8 and 10.2-13.2 micrograms/l). Mean values were significantly different (P < 0.001), female 5.3 (4.9-5.6), male 6.3 (5.8-6.7) micrograms/l. The serum NSE levels were analysed with both methods in a population of 110 patients. The results were significantly correlated (coefficient, 0.9896; r, 0.99; P < 0.0001-two tailed). For high S-NSE values (> 150.0 micrograms/l) differences between the methods exceeded the mean difference + 2S.D., while low concentrations were interconvertible. Maximal diagnostic efficacy was 0.91 for both assays, in DELFIA 17.2-23.9 micrograms/l and for RIA 17.2-21.9 micrograms/l. Identical sensitivity, specificity, discriminative power score, and likelihood ratio were found. The two methods are consequently interconvertible.

Thoracic electrical impedance and fluid balance during aortic surgery.

Indices of fluid balance were evaluated during and after aortic surgery in 16 consecutive patients. Thoracic electrical impedance (TI), heart rate (HR), central venous (CVP), pulmonary artery mean (PAMP), pulmonary wedge (PWP) and mean arterial (MAP) pressure as well as fourteen arterial and venous blood gas variables were followed. Consistent with a reduction of T1 by 4.2 (-5.2 to 9.2) Ohm (median and range) during the operation, fluid balance was in excess of 1.8 (-0.1 to 3.3) 1 when evaporation was not taken into account, and it remained elevated by 1.3 (0.0 to 5.4) 1 on the first postoperative morning. The HR, MAP and PWP remained stable, while CVP and PAMP decreased by 6 (-2 to 13) and 6 (-1 to 22) mmHg, respectively. Of the determined variables only TI revealed a meaningful correlation to fluid balance (rho = -0.41; P < 0.01). Haemoglobin concentrations increased in proportion to the administered packed erythrocytes, while arterial oxygen saturation, pH and base excess decreased in proportion to the excess fluid. The results indicate that while central venous and pulmonary artery mean pressures gave the impression of a volume deficit, the positive fluid balance was mirrored by thoracic electrical impedance, and that even a minor increase of fluid balance may affect pulmonary function in patients subjected to aortic surgery.

Cerebral perfusion during human liver transplantation.

During transplantation of the liver cerebral perfusion was monitored by transcranial Doppler determined middle cerebral artery mean flow velocity (Vmean) and pulsatility index (PI) in six fulminant hepatic failure patients and 11 patients with chronic liver disease. In both groups of patients Vmean, PI and central haemodynamic variables were recorded during (1) the last preanhepatic hour; (2) the anhepatic phase; (3) the first 15 min of reperfusion; and (4) for the following 45 min of reperfusion. No significant differences were detected between the two groups of patients with respect to changes of variables with time. The Vmean (40 +/- 13 cm s-1 [mean +/- SD]), thoracic electrical impedance (TI) (30 +/- 7 Ohm), heart rate (97 +/- 19 beats min-1), mean arterial pressure (84 +/- 9 mmHg) and arterial carbon dioxide tension (PaCO2, 4.5 +/- 0.4 kPa) remained stable in the anhepatic phase, while cardiac output (CO, 7.6 +/- 2.7 to 5.4 +/- 1.41 min-1), stroke volume (SV, 79 +/- 26 to 56 +/- 15 ml) and PI (1.2 +/- 0.3 to 0.9 +/- 0.2) decreased (P < 0.05). During reperfusion, CO (9.9 +/- 4.01 min-1), SV (105 +/- 40 ml), PaCO2 (5.5 +/- 0.6 kPa), Vmean (57 +/- 17 cm s-1) and PI (1.2 +/- 0.2) became elevated. Taken together, during the anhepatic phase of the liver transplantation a maintained central blood volume as indicated by the constant TI served for a stable blood pressure and in turn cerebral perfusion, whereas revascularization of the graft increased cerebral perfusion concomitant with an elevated carbon dioxide tension.

Dynamic exercise enhances regional cerebral artery mean flow velocity.

Dynamic exercise enhances regional cerebral artery mean flow velocity. J. Appl. Physiol. 78(1): 12-16, 1995.--Anterior (ACA) and middle (MCA) cerebral artery mean flow velocities (Vmean) and pulsatility indexes were determined using transcranial Doppler in 14 subjects during dynamic exercise after assessment of the carbon dioxide reactivity for both arteries. Right hand contractions provoked an elevation in left MCA Vmean [19% (12-28); P < 0.01], whereas the pulsatility decreased in all four arteries (P < 0.05). During right foot movement, left ACA Vmean increased by 23% (11-37; P < 0.01) with lesser (approximately 10%; P < 0.05) increases in the other arteries, and pulsatility index decreased (P < 0.05). During cycling, ACA and MCA Vmean increased bilaterally by 23% (10-49) and 18% (5-32), respectively (P < 0.01), and the pulsatility was also elevated (P < 0.05). Cerebral artery pulsatility did not demonstrate a focal response but depended did not demonstrate a focal response but depended on the muscle mass involved during exercise. The data demonstrate a significant increase in Vmean for the artery supplying the cortical projection of the exercising limb. Insignificant and marginally significant increases in Vmean may be related to sympathetically mediated vasoconstriction and/or coactivation of untargeted muscle groups.

Transcranial Doppler ultrasound for cerebral perfusion.

By providing a non-invasive method for continuous display of mean flow velocity (Vmean) in the cerebral arteries, transcranial Doppler (TCD) ultrasound supplements evaluation of cerebral perfusion. Dynamic exercise increases middle cerebral artery (MCA) Vmean from approximately 55 to 65 cm s-1 dependent on work rate, and even more when corrected for changes of the arterial carbon dioxide tension. Evaluation of Vmean corresponds to that of cerebral blood flow as determined with the 133Xenon clearance technique, and reflects regional cortical regulation of the active muscles with important afferent nervous influence. Concomitant increases of mean arterial pressure (MAP) and heart rate is only of minor importance as illustrated during static exercise and post-exercise muscle ischaemia, where Vmean is not significantly elevated. During sustained head-up tilt, the Vmean remained unchanged at a MAP approximately 83 mmHg. Below this level, it decreased in parallel with MAP until MAP reached 50 mmHg. At an even lower MAP, Vmean seemed to approach a lower limit approximately 25 cm s-1, but at a diastolic pressure of 21 mmHg there was no flow in the MCA. Conversely, during post-exercise muscle ischemia, an increase in MAP to 140 mmHg did not influence Vmean. This is in contrast to patients operated for carotid artery stenosis and who develop ipsilateral headache. In these patients the ipsilateral MCA Vmean changed in parallel with MAP, and autoregulation was re-established only after one to two weeks. In patients with severe carotid stenosis and poor collateral circulation, the CO2-reactivity as expressed by Vmean was the lowest, and could be negative on the ipsilateral side. During carotid endarterectomy, a Vmean clamp/Vmean pre-clamp ratio below 0.6 identified patients with a cerebral blood flow below 20 ml 100 g-1 min-1. Furthermore, when the ratio was below 0.4 pathological electroenchephalographic changes developed. Thus, Vmean of the large basal cerebral arteries reflects cerebral perfusion with respect to regional flow distribution, autoregulatory response, and CO2-reactivity in normal man and patients with limited cerebral flow.