bluuebunny/crossref_metadata_2025 huggingface dataset:
The educated patient: new challenges for the medical profession
Authors: Neuberger J.
Published: March 2003

Abstract. Neuberger J (King’s Fund, London, UK). The educated patient: new challenges for the medical profession (Review). J Intern Med 2000; 247: 6–10.

The medical profession is facing significant changes in the way the rest of society relates to it. Mass education, mass media and mass consumerism have boomed in the 20th century, putting an increasing amount of pressure on professionals to meet rising public expectations. If doctors are to continue to provide a service that meets the demands of citizens and taxpayers, they need to develop a new relationship with patients, acting not as instructors but as guides, to help people make decisions about their own health. They will have to be more accountable for the quality of care they provide and work with a wider range of health and non‐health professionals to meet patients’ needs. Doctors need not only to accept the consumer society but also, I will argue, to encourage it. They can work to ensure that the benefits of the information revolution are felt by people excluded from consumerism because of poverty and social isolation, working to create an empowered, informed public whose members are given the best opportunity to look after their own health.
Association of coronary heart disease with age‐adjusted aortocoronary calcification in patients with familial hypercholesterolaemia
Authors: Jensen J. M. , Gerdes L. U. , Jensen H. K. , Christiansen T. M. , Brorholt‐Petersen J. U. , Faergeman O.
Published: March 2003

Abstract. Jensen JM, Gerdes LU, Jensen HK, Christiansen TM, Brorholt‐Petersen JU, Faergeman O (Aarhus Amtssygehus University Hospital, Aarhus, Denmark). Association of coronary heart disease with age‐adjusted aortocoronary calcification in patients with familial hypercholesterolaemia. J Intern Med 2000; 247: 479–484.

Objectives. Existing algorithms of risk of coronary heart disease (CHD) do not pertain to patients with familial hypercholesterolaemia (FH), whose arteries have been exposed to hypercholesterolaemia since birth. We studied a cohort of FH patients to compare four diagnostic models of CHD: traditional risk factors of CHD (age, sex, cholesterol, hypertension, smoking and body mass index), cholesterol year score, and aortic as well as coronary calcium measured by spiral computed tomography (CT).

Subjects. We invited 88 individuals with molecularly defined FH of whom 80 (91%) decided to participate.

Results. Analysis of receiver operating characteristic curves showed that the age‐adjusted coronary calcium score was more strongly associated with clinical manifestations of CHD than were traditional risk factors (P < 0.002), cholesterol year score (P << 0.0001), and the age‐adjusted aortic calcium score (P < 0.0004).

Conclusions. Age‐adjusted coronary calcium score shows promise as an indicator of CHD in FH patients.
Heterogeneity of autoantibodies against cardiolipin and oxidatively modified LDLs revealed by human monoclonal antibodies
Authors: Lefvert A. K.
Published: March 2003

Abstract. Lefvert AK (Center for Molecular Medicine and Department of Medicine, Karolinska Institutet, Stockholm, Sweden). Heterogeneity of autoantibodies against cardiolipin and oxidatively modified LDLs revealed by human monoclonal antibodies (Minisymposium). J Intern Med 2000; 247: 385–390.

Human monoclonal antibodies against cardiolipin, native and oxidatively modified LDL and against apoB100 were obtained by Epstein–Barr virus transformation of peripheral blood mononuclear cells followed by cloning. The antibodies were used to analyse the cross‐reactivity between monoclonals with different specificities and to study the repertoire of antibodies present in sera from patients. Monoclonal antibodies selected for binding to cardiolipin were the least cross‐reactive, whereas antibodies against different modifications of LDL frequently also reacted with other modifications.

Inhibition studies showed that serum antibodies against cardiolipin and against oxidatively modified LDL were to a different extent inhibited by the different monoclonal antibodies and thus markedly heterogeneous.
Progress in haematopoietic stem cell transplantation for multiple myeloma
Authors: Gahrton G. , Björkstrand B.
Published: March 2003

Abstract. Gahrton G. & Björkstrand B. (Departments of Medicine and Hematology, Karolinska Institutet and Huddinge University Hospital, Huddinge, Sweden). Progress in haematopoietic stem cell transplantation for multiple myeloma (Review). J Intern Med 2000; 248: 185–201.

High‐dose myeloablative treatment followed by autologous haematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with multiple myeloma as compared with conventional chemotherapy. However, all patients seem to relapse and molecular remissions are rare.

Results of allogeneic transplantation, still hampered by high transplant‐related mortality, have improved dramatically over the last 5–6 years and this is an option for patients younger than 50–55 years old. The relapse rate is lower than with autologous transplantation and molecular remissions are frequent. Some patients are still in complete haematological remission more the 10 years following transplantation.

Autologous transplantation followed by nonmyeloablative allogeneic transplantation is on trial and may be a way to eventually cure a fraction of younger patients with multiple myeloma.
Direct medical costs for patients with type 2 diabetes in Sweden
Authors: Henriksson F. , Agardh C.‐D. , Berne C. , Bolinder J. , Lönnqvist F. , Stenström P. , Östenson C.‐G. , Jönsson B.
Published: March 2003

Abstract. Henriksson F, Agardh C‐D, Berne C, Bolinder J, Lönnqvist F, Stenström P. Östenson C‐G, Jönsson B (Centre for Health Economics, Stockholm; Department of Endocrinology, University Hospital MAS, Malmö; Department of Internal Medicine, Uppsala University Hospital; Centre for Metabolism and Endocrinology and SmithKline Beecham Pharmaceuticals AB, Karolinska Institute; Diabetes Prevention Unit, Karolinska Hospital, Stockholm, Sweden). Direct medical costs for patients with type 2 diabetes in Sweden. J Intern Med 2000; 248: 387–396.

Objectives. To estimate the total direct medical costs to society for patients with type 2 diabetes in Sweden and to investigate how different factors, for example diabetic late complications, affect costs.

Design. Cross‐sectional data regarding health care utilization, clinical characteristics and quality of life, were collected at a single time‐point. Data on resource use cover the 6‐month period prior to this time point.

Setting. Patient recruitment and data collection were performed in nine primary care centres in three main regions in Sweden.

Subjects. Only patients with an age at diabetes diagnosis ≥ 30 years (type 2 diabetes) were included (n = 777).

Results. The total annual direct medical costs for the Swedish diabetes type 2 population were estimated at about 7 billion SEK (Swedish Kronor) in 1998 prices, which is about 6% of the total health care expenditures and more than four times higher than the former Swedish estimate obtained when using diabetes as main diagnosis for calculating costs. The annual per patient cost was about 25 000 SEK. The largest share of this cost was hospital inpatient care. Costs increased with diabetes duration and were higher for patients treated with insulin compared to those treated with oral hypoglycaemic drugs or with life style modification only. Patients with both macro‐ and microvascular complications had more than three times higher costs compared with patients without such complications.

Conclusions. Type 2 diabetes is a serious and expensive disease and the key to reducing costs seems to be intensive management and control in order to prevent and delay the associated late complications.
Amplification of IS6110 sequence for detection of Mycobacterium tuberculosis complex in HIV‐negative patients with fever of unknown origin (FUO) and evidence of extrapulmonary disease
Authors: Ritis K. , Tzoanopoulos D. , Speletas M. , Papadopoulos E. , Arvanitidis K. , Kartali S. , Sideras P.
Published: March 2003

Abstract. Ritis K, Tzoanopoulos D, Speletas M, Papadopoulos E, Arvanitidis K, Kartali S, Sideras P (Democritus University of Thrace, Regional Hospital of Alexandroupolis, Alexandroupolis, Greece, and University of Umeå, Umeå, Sweden). Amplification of IS6110 sequence for detection of M. tuberculosis complex in HIV‐negative patients with fever of unknown origin (FUO) and evidence of extrapulmonary disease. J Intern Med 2000; 248: 415–424.

Objectives. Extrapulmonary tuberculosis (TB) constitutes the main cause of classic fever of unknown origin (FUO) in many populations. The aim of this study was to improve the diagnostic field of the disease using a nested polymerase chain reaction (PCR) assay, specific for the IS6110 insertion element of Mycobacterium tuberculosis complex, in order to achieve a more timely diagnosis and treatment.

Setting. Twenty‐four, HIV‐negative classic FUO patients who were admitted to the Regional Hospital of Alexandroupolis between April 1997 and July 1999.

Subjects and design. The above patients were considered as putative extrapulmonary TB after 3 weeks of in‐patient investigation and underwent exhaustive examination for diagnosis of the disease. For this purpose, specimens were obtained from peripheral blood and bone marrow from these patients, as well as from damaged tissues, and analysed by both PCR and conventional methods. Anti‐tuberculous treatment was initiated in 16 out of 24 patients and the response to this regimen was considered as the final criterion for diagnosis of tuberculosis.

Results. Extrapulmonary TB was established in 11 patients. The PCR‐based methodology, when applied to samples derived from bone marrow aspirations and suspected damaged tissues, was able to diagnose 10 of them, whereas the conventional methods were able to detect only two.

Conclusions. Our results confirm the diagnostic value of molecular detection of M. tuberculosis in cases of FUO, thus supporting the application of PCR in tissue samples suspected of bacillus infection. Furthermore, our studies demonstrate that bone marrow aspiration specimens constitute an alternative, easy, safe and reliable source for such PCR analysis.
Ehlers–Danlos syndrome type IV with a unique point mutation in COL3A1 and familial phenotype of myocardial infarction without organic coronary stenosis
Authors: Nishiyama Y. , Nejima J. , Watanabe A. , Kotani E. , Sakai N. , Hatamochi A. , Shinkai H. , Kiuchi K. , Tamura K. , Shimada T. , Takano T. , Katayama Y.
Published: March 2003

Abstract. Nishiyama Y, Nejima J, Watanabe A, Kotani E, Sakai N, Hatamochi A, Shinkai H, Kiuchi K, Tamura K, Shimada T, Takano T, Katayama Y (Nippon Medical School, Tokyo, and Chiba University School of Medicine, Chiba, Japan). Ehlers–Danlos syndrome type IV with a unique point mutation in COL3 A1 and familial phenotype of myocardial infarction without organic coronary stenosis (Case Report). J Intern Med 2001; 249: 103–108.

We report on a 43‐year‐old male patient with Ehlers–Danlos syndrome (EDS) type IV with acute myocardial infarction (MI) without organic coronary stenosis. The disease was complicated with pneumothorax, subcutaneous and mediastinal emphysema, and splenic artery rupture. Three of the patient’s family members suffered sudden cardiac death or MI. A diagnosis of EDS type IV was confirmed by decreased production of type III collagen by 86%. Mutation analysis revealed a point mutation in the COL3A1 gene that substituted glycine for aspartate at amino acid position 877. This mutation had not been reported as pathogenic for EDS type IV. These findings suggest close linkage between the mutation and the phenotype with familial MI.
Aphasia in acute stroke and relation to outcome
Authors: Laska A. C. , Hellblom A. , Murray V. , Kahan T. , Von Arbin M.
Published: March 2003

Abstract. Laska AC, Hellblom A, Murray V, Kahan T, von Arbin M (Danderyd Hospital, Danderyd, Sweden). Aphasia in acute stroke and relation to outcome. J Intern Med 2001; 249: 413–422.

Objectives. The natural course of aphasia in unselected, consecutive stroke patients is not well established. We investigated morbidity, mortality and recovery for different types of aphasia in consecutive unselected aphasic patients with acute stroke.

Setting and subjects. In 119 aphasic patients, the type and degree of aphasia were assessed acutely and at 3, 6 and 18 months after stroke onset, using Reinvang’s ‘Grunntest for afasi’ and Amsterdam‐Nijmegen‐Everyday‐Language‐Test.

Results. About one‐third of patients with acute stroke had presented with aphasia. Mortality among the aphasic patients during the 18‐month follow‐up was twice that in non‐aphasics (36 vs. 16%). Presence of atrial fibrillation was associated with poorer prognosis. At 18 months, 24% of the 119 aphasic patients had recovered completely, 43% still had significant aphasia, and 21% had died. The proportion with global aphasia decreased from almost 25% acutely to a few per cent after 18 months, that with Wernicke’s aphasia from 25% to less than 10%, whereas conduction aphasia increased from 13 to 23% during follow‐up. Among those with initial mild aphasia, 70% recovered completely. Great improvement was observed in patients with initial low degree of speech function. Younger patients recovered to a greater extent than older patients.

Conclusion. The high long‐term mortality among aphasics may be seen as an indirect sign of advanced cardiovascular disease. A combination of different and adjusted aphasia tests provided the possibility to assess almost all acute aphasic patients. Irrespective of type and degree of aphasia, great improvements were seen in almost all aphasic patients. Even patients with severe speech impairment have a considerable potential for recovery, particularly in the first 3 months after stroke.
Cell adhesion molecules and secretory type II phospholipase A2 in relation to carotid atherosclerosis in patients with hypercholesterolaemia
Authors: Wiklund O. , Hulthe J. , Bondjers G. , Hurt‐Camejo E.
Published: March 2003

Abstract. Wiklund O, Hulthe J, Bondjers G, Hurt‐Camejo E (Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden). Cell adhesion molecules and secretory type II phospholipase A2 in relation to carotid atherosclerosis in patients with hypercholesterolaemia. J Intern Med 2001; 249: 441–449.

Objective. There has been no previous study investigating the relationship between subclinical atherosclerosis, as measured by ultrasound, and circulating levels of cell‐adhesion molecules and snpPLA2 in patients with hypercholesterolaemia. The main aims of the present study were therefore to investigate the relationship between subclinical atherosclerosis, cell‐adhesion molecules and snpPLA2 in a group of subjects with hypercholesterolaemia and also in a healthy control group; and to investigate the relationship between conventional riskfactors, cell‐adhesion molecules and snpPLA2 in these groups.

Methods. Study subjects were recruited from the general population (50 subjects with hypercholesterolaemia and all 105 controls) and from the lipid clinic of Sahlgrens Hospital, Gothenburg (55 subjects with hypercholesterolaemia). Cell‐adhesion molecules and snpPLA2 were analyzed by ELISA.

Results. The levels of sICAM turned out to be positively and significantly associated with plaque occurrence and plaque size in the carotid artery in the patient group, but not in the control group. There were no significant relationships between sVCAM, sE‐selectin or snpPLA2 and atherosclerosis, as measured by ultrasound. However, sICAM was significantly associated with sVCAM, sE‐selectin and snpPLA2 both in the patient and in the control groups. In the patient group sICAM was positively and significantly associated with triglyceride levels and also negatively associated with high density lipoprotein (HDL) levels.

Conclusions. The present study showed that sICAM‐1 was significantly associated with atherosclerosis, as measured by ultrasound, in the carotid artery in patients with hypercholesterolaemia. Furthermore, sICAM‐1 levels were associated with plasma levels of snpPLA2 (r=0.44, P < 0.001), which recently have been shown to predict coronary events. Finally, high sICAM‐1 levels were associated with an atherogenic lipid profile including high triglyceride levels and low HDL levels.
Betablocker treatment in diabetes mellitus
Authors: Sawicki P. T. , Siebenhofer A.
Published: March 2003

Sawicki PT, Siebenhofer A (St Franziskus Hospital in Cologne, Germany; Karl‐Franzens University in Graz, Austria). Betablocker treatment in diabetes mellitus (Review). J Intern Med 2001; 250: 11–17.

Objectives. Betablockers have been convincingly shown to reduce total and cardiovascular morbidity and mortality of hypertensive diabetic patients. In diabetic patients, after myocardial infarction, these agents confer a twice as high protective effect when compared to non‐diabetic patients. However, most paradoxically, betablocking agents are used less frequently in diabetes. Control of hypertension is insufficient in most of the diabetic patients, probably because a combination of antihypertensive agents including betablockers is frequently needed to sufficiently control blood pressure but is not used in these patients. The fear of betablocker‐associated side effects in diabetes may be partly responsible for the frequent antihypertensive mono‐therapy and the resulting poor quality of blood pressure control among diabetic patients.

Design. We have performed an analysis of the literature to assess whether possible adverse metabolic effects, a higher risk of hypoglycaemia or less nephroprotective effects of ß1‐selective betablocking agents could justify the reticence in prescribing these antihypertensive agents to diabetic patients.

Results. A thorough review of the literature does not indicate that ß1‐selective betablocking agents have important adverse effects on glucose metabolism, prolong hypoglycaemia or mask hypoglycaemic symptoms. In diabetic nephropathy, betablockers are as nephroprotective as angiotensin converting enzyme inhibitors.

Conclusions. The unnecessary less frequent prescription of ß1‐selective betablockers in diabetes mellitus may contribute to the higher cardiovascular mortality among these patients.
Effects of intramyocardial injection of phVEGF‐A165 as sole therapy in patients with refractory coronary artery disease – 12‐month follow‐up: Angiogenic gene therapy
Authors: Sarkar N. , Rück A. , Källner G. , Y‐Hassan S. , Blomberg P. , Islam K. B. , Van Der Linden J. , Lindblom D. , Nygren A. T. , Lind B. , Brodin L.‐Å. , Drvota V. , Sylvén C.
Published: March 2003

Abstract. Sarkar N, Rück A, Källner G, Y‐Hassan S, Blomberg P, Islam KB, van der Linden J, Lindblom D, Nygren AT, Lind B, Brodin L‐Å, Drvota V, Sylvén C (Karolinska Institute, Huddinge University Hospital, Novum, Stockholm, Sweden). Effects of intramyocardial injection of phVEGF‐A165 as sole therapy in patients with refractory coronary artery disease: 12‐month follow‐up. Angiogenic gene therapy. J Intern Med 2001; 250: 373–381.

Objective. To test the safety and bioactivity of phVEGF‐A165 after intramyocardial injection during 12‐month follow‐up.

Design. Open‐labelled study.

Subjects. Inclusion criteria were angina pectoris, Canadian Cardiovascular Society (CCS) class III–IV, unamenable to further revascularization, ejection fraction (EF) >30%, perfusion defects extending over >10% of the anterolateral left ventricle wall detectable with adenosine single photon emission computerized tomography (SPECT) and at least one patent vessel visible by coronary angiography. Seven of 39 patients referred for gene therapy were included.

Intervention. Via a mini‐thoracotomy under general anaesthesia, phVEGF‐A165 was injected directly into the myocardium at four sites in the anterolateral region of the left ventricle.

Results. Operative procedures were uneventful. Perioperative release of myocardial markers and electrocardiogram (ECG) changes were detected in two patients. There were no perioperative deaths but one patient died 7 months postoperatively because of myocardial infarction. Plasma vascular endothelial growth factor (VEGF)‐A levels increased two to threefold peaking 6 days postoperatively (P < 0.004) and returning to baseline by day 30. A significant reduction in angina pectoris was reported. The CCS class improved from 3.3 ± 0.2 to 1.9 ± 0.3 (P < 0.01) and nitroglycerine intake decreased from 39 ± 15 to 12 ± 5 tablets week–1 (P < 0.001) 2 months after gene transfer. Improvements remained after 12 months when nitroglycerine consumption approached zero. Improved myocardial function in the phVEGF‐A165 injection region was documented in all patients (P < 0.016) by tissue velocity imaging (TVI). Reduced reversible ischaemia was detected by adenosine SPECT in four patients. Improved collateralization was detected in four patients with coronary angiography.

Conclusion. Intramyocardial injection of phVEGF‐A165 is safe and may lead to improved myocardial perfusion and function with longstanding symptomatic relief in end‐stage angina pectoris. Based on these results this therapeutic potential is being tested in a double‐blind placebo controlled multicentre trial, EUROINJECT ONE.
Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette–Guérin immunotherapy
Authors: Schattner Ami , Gilad Avi , Cohen Joel
Published: March 2003

Abstract. Schattner A, Gilad A, Cohen J (Kaplan Medical Center, Rehovot; and Hebrew University‐Hadassah Medical School, Jerusalem, Israel). Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette–Guérin immunotherapy (Case report). J Intern Med 2002; 251: 272–277.
Cholesterol and triglyceride concentration as risk factors for myocardial infarction and death in women, with special reference to influence of age
Authors: Lindquist P. , Bengtsson C. , Lissner L. , Björkelund C.
Published: March 2003

Abstract. Lindqvist P, Bengtsson C, Lissner L, Björkelund C (Department of Primary Health Care, Göteborg University, Gothenburg, Sweden). Cholesterol and triglyceride concentration as risk factors for myocardial infarction and death in women, with special reference to influence of age.J Intern Med2002;251: 484–489.

Objective. To evaluate the importance of serum cholesterol and triglyceride concentrations as predictors of myocardial infarction and death in women of different ages.

Design. Prospective observational study, initiated in 1968–69.

Setting. Gothenburg, Sweden, with about 430 000 inhabitants.

Subjects. A population‐based sample of 1462 women aged 38, 46, 50, 54 and 60 years at start of the study, followed up for 24 years.

Main outcome measures. Within each age group, myocardial infarction and death were predicted by serum cholesterol and triglyceride concentrations and smoking in a multivariate model.

Results. In the total population only serum triglyceride concentration was a strong independent risk factor for both end‐points studied. Serum triglyceride concentration measured in 38‐ and 46‐year‐old women had no predictive value with respect to 24‐year incidence of myocardial infarction or death. In 50‐, 54‐ and 60‐year‐old women, high serum triglyceride concentration consistently predicted myocardial infarction and total mortality. Serum cholesterol concentration, on the other hand, showed evidence of direct association for 24‐year all‐cause mortality in the younger premenopausal group. Serum cholesterol had no predictive value for myocardial infarction or mortality in the peri‐ and postmenopausal ages.

Conclusions. There appears to be age‐specificity in association between serum lipids and these end‐points in women, serum cholesterol concentration being more important for younger women and serum triglyceride concentration more important for postmenopausal women as risk factors, observations which need further attention.
Validity of D‐dimer tests in the diagnosis of deep vein thrombosis: a prospective comparative study of three quantitative assays
Authors: LARSEN T. B. , STOFFERSEN E. , CHRISTENSEN C. S. , LAURSEN B.
Published: March 2003

Abstract. Larsen TB, Stoffersen E, Christensen CS, Laursen B (Aalborg Hospital, Aalborg, Denmark). Validity of D‐dimer tests in the diagnosis of deep vein thrombosis: a prospective comparative study of three quantitative assays. J Intern Med 2002; 252: 36–40.

Objectives. To assess the diagnostic reliability of a new quantitative D‐dimer assay (VIDAS New®) and an established quick test (Nycocard® D‐dimer assay) in the diagnosis of deep vein thrombosis (DVT) compared with ultrasonography. A third assay (Auto Dimer®) became available during sample collection and has been included in the final assessment. The diagnostic performance of the Auto Dimer® assay was evaluated on three different coagulation analysers.

Design. A clinical prospective study of patients admitted to hospital for evaluation of DVT.

Setting. The admission ward at Aalborg Hospital.

Subjects. A total of 113 outpatients with suspected DVT.

Main outcome measures. Compression ultrasonography was used as the reference method for a diagnosis of DVT and compared with different D‐dimer assays. The results were expressed as sensitivity, specificity, positive predictive value and negative predictive value (NPV).

Results. Deep vein thrombosis was established in 49 patients (43%). Two D‐dimer assays (VIDAS New® and Auto Dimer®) showed sensitivities of 90 and 88%, specificities of 42 and 44%, and NPV's of 85 and 83%, respectively. The Nycocard® D‐dimer assay showed a sensitivity of 63%, specificity of 67% and NPV of 71%.

Conclusions. The diagnostic performance of VIDAS New® and the Auto Dimer® D‐dimer assays is almost identical, but this study suggests that neither of the D‐dimer assays is suitable as the only screening method for DVT, in a situation with a high pretest probability of DVT. This call for a differential strategy that distinguishes between cases of low and high clinical probability using either a D‐dimer test or ultrasonography.

Abbreviations DVT, deep venous thrombosis, NPV, negative predictive value, PPV, positive predictive value
Homocysteine, malondialdehyde and endothelial markers in dialysis patients during low‐dose folinic acid therapy
Authors: Apeland T. , Mansoor M. A. , Seljeflot I. , Brønstad I. , Gøransson L. , Strandjord R. E.
Published: March 2003

Abstract. Apeland T, Mansoor MA, Seljeflot I, Brønstad I, Gøransson L, Strandjord RE (Rogaland Central Hospital, Stavanger; and Ullevål University Hospital, Oslo; Norway). Homocysteine, malondialdehyde and endothelial markers in dialysis patients during low‐dose folinic acid therapy. J Intern Med 2002; 252: 456–464.

Objectives. Haemodialysis patients have elevated levels of the atherogenic amino acid homocysteine. We wanted to assess the effects of small doses of intravenous folinic acid (the active form of folic acid) on some biochemical risk factors of cardiovascular disease.

Design. Longitudinal and open intervention study.

Setting. Two dialysis units in the County of Rogaland.

Subjects. All patients on maintenance haemodialysis were invited, and 32 of 35 patients gave their informed consent.

Interventions. After each dialysis session, the patients were given 1.0 mg of folinic acid intravenously thrice a week for a period of 3 months. Prior to and during the study, all patients were on maintenance supplementation with small doses of vitamins B1, B2, B3, B5, B6 and B12.

Main outcome measures. Changes in the levels of (i) plasma total homocysteine (p‐tHcy) and folate, (ii) circulating endothelium related proteins – markers of endothelial activation and (iii) serum malondialdehyde (S‐MDA) – a marker of oxidative stress and lipid peroxidation.

Results. The p‐tHcy levels were reduced by 37% (P < 0.0001), whilst the serum and erythrocyte folate levels increased by 95 and 104%, respectively (P < 0.0001 for both). The circulating levels of endothelium related cellular adhesion molecules and haemostatic factors remained high and unchanged, except the thrombomodulin (TM) levels increased (P = 0.0004). The high levels of S‐MDA were reduced by 26% (P = 0.003).

Conclusions. Low doses of folinic acid given intravenously to dialysis patients reduced their levels of p‐tHcy and S‐MDA and thus improved their cardiovascular risk profile. The concurrent increment in TM levels was unexpected and of unknown clinical significance.
Impact of smokeless tobacco use on smoking in northern Sweden
Authors: Rodu B. , Stegmayr B. , Nasic S. , Asplund K.
Published: March 2003

Abstract. Rodu B, Stegmayr B, Nasic S, Asplund K (University of Alabama at Birmingham, AL, USA and University Hospital, Umeå, Sweden). Impact of smokeless tobacco use on smoking in northern Sweden. J Intern Med 2002; 252: 398–404.

Background and objectives. For many years Swedish men have had the world's lowest rates of smoking and smoking‐related mortality. Despite these facts, a thorough analysis of tobacco use patterns in Sweden has not been performed. The purpose of this study was to examine the prevalence and interaction of cigarette smoking and use of Swedish moist snuff (snus) in the population of northern Sweden.

Design. The study cohort of 2998 men and 3092 women aged 25–64 was derived from the northern Sweden MONICA study, consisting of population‐based surveys in 1986, 1990, 1994 and 1999. Detailed information on tobacco use was used to develop prevalence data, and the prevalence ratio was used to compare rates amongst various subgroups.

Results. Amongst men ever‐tobacco use was stable in all survey years at about 65%, but the prevalence of smoking declined from 23% in 1986 to 14% in 1999, whilst snus use increased from 22% to 30%. In women the prevalence of smoking was more stable in the first three surveys (∼27%) but was 22% in 1999, when snus use was 6%. In all years men showed higher prevalence of ex‐smoking than women. A dominant factor was a history of snus (PR = 6.18, CI = 4.96–7.70), which was more prevalent at younger ages.

Conclusions. The recent transition from smoking to snus use amongst men, and incipiently amongst women, in northern Sweden is remarkable and relevant to the global discussion on strategies to reduce smoking.
Difficult treatment issues in sarcoidosis
Authors: Baughman R. P. , Lynch J. P.
Published: March 2003

Baughman RP, Lynch JP (University of Cincinnati, Cincinnati, OH, USA; University of Michigan, AnnArbor, MI, USA). Difficult treatment issues in sarcoidosis (Minisymposium).J Intern Med2003;253:41–45.

The management of sarcoidosis includes several crucial decisions. Not all patients with sarcoidosis need treatment. At least a third of patients will never be treated. It is unclear whether asymptomatic patients ever need therapy, even if they have extensive lung disease. One reason that clinicians are reluctant to start therapy is that many patients who are started on corticosteroids have a difficult time getting off therapy, even after 2 years. In the chronic patient, alternatives to corticosteroids have been developed. These include drugs such as methotrexate, azathioprine and hydroxychloroquine. These agents have been the standard second line of therapy for patients with chronic disease. However, these drugs do not always work. In addition, they are associated with their own toxicities. Another group of sarcoidosis patients have also emerged. These are the refractory patients, who have progressive disease whilst on therapy. For these patients, new agents such as thalidomide and the monoclonal antibodies to tumour necrosis factor have been occasionally helpful. This paper reviews several important issues in the management of sarcoidosis.
Fever of unknown origin in adults: 40 years on
Authors: Knockaert D. C. , Vanderschueren S. , Blockmans D.
Published: March 2003

Abstract.  Knockaert DC, Vanderschueren S, Blockmans D. (Gasthuisberg University Hospital, Leuven, Belgium). Fever of unknown origin in adults: 40 years on (Review). J Intern Med 2003; 253: 263–275.

A revision of the criteria of fever of unknown origin (FUO), established in 1961, is desirable because of important evolutions in medical practice and the emergence of new patient populations. The development of rapid laboratory tests and powerful diagnostic tools, such as ultrasonography, computed tomography and magnetic resonance imaging often makes hospitalization unnecessary and new categories of patients such as those with HIV infection, neutropenia, immunosuppression and nosocomial illness require an approach different from classical FUO. The more then 200 reported causes of FUO can be classified into four diagnostic categories; infections, tumours, noninfectious inflammatory diseases (NIID) and miscellaneous. A uniform classification system is highly wanted to allow comparison between different series. The reports of the 1990s show slight changes in the distribution of causes, namely less infections, less tumours, more NIID and more undiagnosed cases. A uniform diagnostic strategy cannot be determined. The initial investigation should be directed by potentially diagnostic clues revealed by extensive history, meticulous physical examination and a standard set of laboratory tests. 18Fluoro‐deoxy‐glucose‐positron‐emitted‐tomgraphy is a new valuable total body scintigraphy in the search for the site of origin of the fever. In view of the rather good long‐term prognosis, a wait‐and‐see strategy may be more appropriate than a systematic staged approach. Elderly patients and patients with episodic fever represent two specific groups of classical FUO that require a distinct approach. HIV‐associated, nosocomial and neutropenic FUO should be considered as separate clinical entities.
A simple method of using an internal standard for X‐ray microanalysis of microdroplets
Authors: XU  , Marshall
Published: March 2003

The use of an introduced internal standard for the X‐ray microanalysis of microdroplets of very small volumes of fluid has hitherto depended on the measurement of equal volumes of sample and standard fluids taken up in a tapered micropipette. It is shown that this difficult procedure can be circumvented by taking up variable volumes of fluids in a constant diameter micropipette. Only the lengths which the fluids occupy in the micropipette need be measured. These parameters are entered into the equation for the thin film model to calculate elemental concentrations. This considerably simplifies the preparation and analysis of microdroplets of biological fluids. Relative elemental sensitivities (k factors) can be reliably obtained either from thin crystals of binary standards or from calibration curves. It is also shown that rapid air‐drying of microdroplets incorporating PVP results in crystals of acceptable dimensions for analysis.
Imaging surface and submembranous structures with the atomic force microscope: a study on living cancer cells, fibroblasts and macrophages
Authors: Braet  , Seynaeve  , De Zanger  , Wisse
Published: March 2003

Atomic force microscopy (AFM) has been used to image a wide variety of cells. Fixed and dried‐coated, wet‐fixed or living cells were investigated. The major advantage of AFM over SEM is the avoidance of vacuum and electrons, whereas imaging can be done at environmental pressure and in aqueous conditions. Evidence of the successful application of AFM in biological imaging is provided by comparing results of AFM with SEM and/or TEM. In this study, we investigated surface and submembranous structures of living and glutaraldehyde‐fixed colon carcinoma cells, skin fibroblasts and liver macrophages by AFM. Special attention was paid to the correct conditions for the acquisition of images of the surface of these cells, because quality SEM examinations have already been abundantly presented.

AFM imaging of living cells revealed specific structures, such as the cytoskeleton, which were not observed by SEM. Membrane structures, such as ruffles, lamellipodia, microspikes and microvilli, could only clearly be observed after fixing the cells with 0.1% glutaraldehyde. AFM images of living cells were comparable to SEM images of fixed, dried and coated cells, but contained a number of artefacts due to tip–sample interaction. In addition, AFM imaging allowed the visualization of cytoplasmic submembranous structures without the necessity for further preparative steps, allowing us: (i) to follow cytoskeletal changes in fibroblasts under the influence of the microfilament disrupting agent latrunculin A; (ii) to study particle phagocytosis in macrophages. Therefore, in spite of the slow image acquisition of the AFM, the instrument can be used for high‐resolution real‐time studies of dynamic changes in submembranous structures.
Theory of confocal fluorescence imaging in the programmable array microscope (PAM)
Authors: Verveer  , Hanley  , Verbeek  , Van Vliet  , Jovin
Published: March 2003

The programmable array microscope (PAM) uses a spatial light modulator (SLM) to generate an arbitrary pattern of conjugate illumination and detection elements. The SLM dissects the fluorescent light imaged by the objective into a focal conjugate image, Ic, formed by the ‘in‐focus’ light, and a nonconjugate image, Inc, formed by the ‘out‐of‐focus’ light. We discuss two different schemes for confocal imaging using the PAM. In the first, a grid of points is shifted to scan the complete image. The second, faster approach, uses a short tiled pseudorandom sequence of two‐dimensional patterns. In the first case, Ic is analogous to a confocal image and Inc to a conventional image minus Ic. In the second case Ic and Inc are the sum and the difference, respectively, of a conventional and a confocal image. The pseudorandom sequence approach requires post‐processing to retrieve the confocal part, but generates significantly higher signal levels for an equivalent integration time.
Reduction of charging in protein electron cryomicroscopy
Authors: Brink  , Gross  , Tittmann  , Sherman  , Chiu
Published: March 2003

Charging causes a loss of resolution in electron cryomicroscopy with biological specimens prepared without a continuous carbon support film. Thin conductive films were deposited onto catalase crystals prepared across holes using ion‐beam sputtering and thermal evaporation and evaluated for the effectiveness of charge reduction. Deposits applied by ion‐beam sputtering reduced charging but concurrently resulted in structural damage. Coatings applied by thermal evaporation also reduced charging, and preserved the specimen structure beyond 5 Å resolution as judged from electron diffraction patterns and images of glucose‐embedded catalase crystals tilted to 45° in the microscope. This study demonstrates for the first time the feasibility of obtaining high‐resolution data from unstained, unsupported protein crystals with a conductive surface coating.
Saving the photons: mapping X‐rays by position‐tagged spectrometry
Authors: MOTT R. B. , FRIEL J. J.
Published: March 2003

Since the early years of X‐ray spectrometry in electron microscopes, mapping the locations of chemical elements has been important. The X‐rays needed in large numbers for this are rare, owing to poor production efficiency compared with electron signals, and at risk of loss by many mechanisms such as missing the limited solid angle of the detector, absorption before reaching the detector and pulse pile‐up conventional digital mapping hardware reduces the information contained in the X‐ray spectrum at each pixel to the itegrated counts from a few regions of interest.

The acquisition technique of position‐tagged spectrometry eliminates the conflict between the desire to see full frame X‐ray images quickly versus the analytical advantages of having complete spectra for each pixel. As the beam is scanned rapidly relative to traditional X‐ray mapping, photons are counted in a virtual 3‐D multichannel analyser on disk, preserving both spatial and spectral information. Along with the sophisticated post‐processing allowed by storing an entire spectrum per pixel, a unique degree of dynamic interaction with the developing data is made possible by integrating many short scans instead of using a single long dwell time at each pixel.
Energy‐filtered transmission electron microscopy of multilayers in semiconductors
Authors: LIU  , BOOTHROYD  , HUMPHREYS
Published: March 2003

Quantitative analysis of novel semiconductors with wide or ultrathin multilayers of atomic dimensions is very important in order to control electronic and optical properties, but rather difficult due to the limited resolution in most techniques. In this paper we attempt to assess how effectively the total As dopant concentration in ultrathin As doped layers in InP and the Ti atomic fraction in a TixAl1−xN multilayer can be analysed quantitatively using energy‐filtered imaging. These two materials have characteristic edges located at widely different energy losses, with the L edge of As being above 1000 eV, while that of Ti is around 450 eV. We have quantified the As concentration using the three‐window technique and theoretical cross‐sections and we find that the resolution limit is dominated by the signal‐to‐noise ratio in this delta‐doped specimen. However, the accuracy of the Ti atomic fraction in TixAl1−xN can be as good as 10 at% for specimens of uniform thickness made by focused ion beam milling. We will compare our results with measurements of the composition made using Fresnel contrast, high resolution imaging and high angle annular dark field techniques.
A simple channelling model for HREM contrast transfer under dynamical conditions
Authors: SINKLER  , MARKS
Published: March 2003

The application of electron channelling theory to dynamical exit wave calculations is briefly reviewed, and a comparison of channelling results with full dynamical calculations is presented. The channelling expression to the exit wave is combined with conventional imaging theory, and it is shown that a simple expression can be obtained for a dynamical contrast transfer function (D‐CTF), which incorporates imaging aberrations and thickness‐dependent dynamical scattering effects. The D‐CTF can provide detailed insight into HREM images of a mixed cation oxide at thicknesses up to 200 Å, whereby an approximate correction for non‐linear effects is utilized in the larger thickness regime.
The influence of atomic vibrations on the imaging properties of atomic focusers
Authors: ANSTIS
Published: March 2003

The resolving power of atomic focusers consisting of from one to several gold atoms in a column is examined through consideration of the optical transfer function of the system. It is found that resolutions better than 0.1 nm are possible for ten‐atom focusers, but for greater numbers of atoms the effects of atomic vibrations degrade the resolving power. For accurate characterization of the transfer function it is necessary to take into account electrons which have transferred vibrational energy to the focuser.
High‐speed scanning by dual feedback control in SNOM/AFM
Authors: Egawa A. , Chiba N. , Homma K. , Chinone K. , Muramatsu H.
Published: March 2003

We have developed a high‐speed scanning near‐field optical microscope (SNOM)/atomic force microscope (AFM) system including dual feedback controllers. The system includes an additional piezoelectric actuator with fast response in the z direction and a correction circuit to eliminate unnecessary components from the feedback signal. From the measurement of a patterned chromium layer of 2 × 2 μm2 checks on a quartz glass plate, we confirmed that our system had more effective feedback control and faster scanning than current SNOM/AFM systems that use only a piezo‐tube. The scanning speed of the present system was estimated to be about five times faster than that of current SNOM/AFM systems.
Applicability of deconvolution and nonlinear optimization for reconstructing optical images from near‐field optical microscope images
Authors: Hatano H. , Kawata S.
Published: March 2003

We have made a computer reconstruction of a nanometric optical image of a sample from an observed near‐field optical image. The near‐field microscope image used for investigation was obtained numerically in three dimensions with the finite‐difference time‐domain (FDTD) method. The sample is dielectric substrate containing nanometric two strips made of dielectric or metal. Deconvolution with non‐negativity constraint is used to reconstruct the nanometric structure of dielectric strips, while nonlinear optimization is used to reconstruct the metallic strips. The difference in choice of reconstruction method between two samples comes from the difference in degree of interaction or multiple scattering of the sample structure and the probe. It is shown in the results, the resolution limit attainable in deconvolution is as fine as the size of aperture of probe.
A comparison of grain imaging and measurement using horizontal orientation and colour orientation contrast imaging, electron backscatter pattern and optical methods
Authors: DAY A. P. , QUESTED T. E.
Published: March 2003

The problems associated with the definition of a grain, grain size measurement, and the issues associated with making one‐ and two‐dimensional measurements on a three‐dimensional structure are discussed. The relatively new scanning electron microscope (SEM)‐based techniques of colour orientation contrast imaging (COCI) and automated electron backscatter pattern (EBSP) are explained and examples given. Comparisons with conventional (horizontal) orientation contrast imaging (HOCI) in the SEM are made. A direct comparison is made between conventional metallographic methods and these new techniques on precisely the same region of an interstitial free iron specimen. Both optical imaging and HOCI were found to miss a large number of grain boundaries (7 and 12%, respectively), and to create boundaries (≈ 2%). COCI was found to be reliable, with only 3% of boundaries missed. EBSP was taken to be the standard against which the others were compared, as it unambiguously measured changes in crystallographic orientation. Errors in the number of grain boundaries that are detected have a considerable effect on grain size measurements, e.g. mean linear intercept, and a follow‐on effect on the modelling of mechanical properties. New methods for increasing the acquisition speed of orientation maps are discussed, along with examples. The combination of COCI (for grain location) and EBSP (for orientation measurement) is promising, but requires improvements in either imaging or image analysis to be totally reliable.
Soft X‐ray microscopy with a cryo scanning transmission X‐ray microscope: I. Instrumentation, imaging and spectroscopy
Authors: Maser  , Osanna  , Wang  , Jacobsen  , Kirz  , Spector  , Winn  , Tennant
Published: March 2003

We have developed a cryo scanning transmission X‐ray microscope which uses soft X‐rays from the National Synchrotron Light Source. The system is capable of imaging frozen hydrated specimens with a thickness of up to 10 μm at temperatures of around 100 K. We show images and spectra from frozen hydrated eukaryotic cells, and a demonstration that biological specimens do not suffer mass loss or morphological changes at radiation doses up to about 1010 Gray. This makes possible studies where multiple images of the same specimen area are needed, such as tomography (
Wang et al. (2000
) Soft X‐ray microscopy with a cryo scanning transmission X‐ray microscope: II. Tomography. J. Microsc. 197, 80–93) or spectroscopic analysis.