Herbert Sandström

Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23

Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

Intravascular haemolysis and increased prevalence of myeloma and monoclonal gammopathy in congenital dyserythropoietic anaemia, type III

Abstract:  A family with congenital dyserythropoietic anaemia type III was studied. Twenty patients and 10 of their healthy siblings were clinically examined and questioned about their medical history. Blood sampling and bone marrow aspirations were also performed. Forty‐five percent of the patients reported symptoms of anaemia and 35% regularly felt weakness, fatigue, or headache. However, the majority of the patients regarded themselves as healthy. The bone marrow showed a uniform picture of erythroid hyperplasia with multinuclear erythroblasts and gigantoblasts with up to 12 nuclei. There was laboratory evidence of intravascular haemolysis and mild anaemia. We also observed a high prevalence of monoclonal gammopathy of undetermined significance (3 cases) and myeloma (1 case) among the patients.

Patterns of tobacco use: A 10-year follow-up study of smoking and snus habits in a middle-aged Swedish population

Aims: To study longitudinal patterns of tobacco use over a 10-year period among middle-aged men and women in Vaösterbotten County, Northern Sweden. Methods: The study is based on data from the 16,486 (8800 women and 7686 men) in the Vaösterbotten Intervention Programme (VIP) where people were invited to a health screening and counselling programme at 30, 40, 50 and 60 years of age. Results: Smoking decreased from 22.3% to 15.6% among women and from 18.5% to 12.7% among men. Use of snus (Swedish moist snuff) increased from 3.1% to 6.0% among women and from 24.6% to 26.3% among men. The number of people who used both snus and cigarettes was stable: 0.5% to 0.8% from baseline to follow-up for women, and 4.1% to 3.3% for men. The number of tobacco-free adults increased from 75.2% to 79.2% for women and from 61.1% to 64.3% for men. Of those who became smoke-free during the 10-year follow-up period, 80% of the women and 66% of the men quit smoking without transitioning to snus use. Conclusions: The majority of middle-aged Swedish men and women in this cohort that quit smoking did so without becoming snus dependent. In spite of an increasing use of snus, overall there was a decline in the number of people using tobacco products.

Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III)

Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22.

Observations on two members of the Swedish family with congenital dyserythropoietic anaemia, type III

Abstract: Two affected individuals of the Swedish family with CDA, type III, in which the disease is transmitted as an autosomal dominant character, were studied. Both cases displayed features hitherto undescribed in this family but described in patients with CDA, type III, in whom the inheritance may have been as an autosomal recessive character. Such features were: (a) haemosiderinuria, (b) grossly disorganised erythroblast nuclei, (c) differences in the ultrastructural appearances of individual nuclei within the same multinucleate erythroblast and (d) intraerythroblastic inclusions resembling precipitated globin chains. In both cases the giant mononucleate erythroblasts and the multinucleate erythroblasts had total DNA contents up to 28c (1c = haploid DNA content) and 48c respectively, and some DNA synthesising bi‐ and multinucleate erythroblasts contained one or more nuclei which were unlabelled with 3H‐thymidine. These findings are similar to those in patients with the autosomal recessive type of disease. Thus no major phenotypic differences are yet apparent between cases of CDA, type III, with different patterns of inheritance. Analysis of the surface erythrocyte proteins of the 2 Swedish CDA, type III, patients with monoclonal antibodies recognising Band 3, glycophorins A, B, C and D, Rh, CD44, CD47, CD55, CD58, CD59, Lutheran, Kell, LW and acetylcholinesterase did not reveal any gross abnormality of expression of these proteins. A slightly altered expression of blood group antigens A and H was revealed by the lectins Dolichos biflorus and Ulex europaeus and the Mr of Band 3 as judged by SDS polyacrylamide gel electrophoresis was also slightly reduced, suggesting that there may be minor alterations in the degree of N‐glycosylation of some red cell membrane constituents.

Vitamin D Status during Pregnancy: a Longitudinal Study in Swedish Women from Early Pregnancy to Seven Months Postpartum

Low vitamin D levels during pregnancy may have negative consequences for the health of both the mother and child. Cross-sectional studies in childbearing women suggest that vitamin D levels are low during pregnancy, but few studies have followed the same women during pregnancy and postpartum. The aims of this study were to longitudinally assess vitamin D status during pregnancy and postpartum and identify the factors associated with vitamin D status in pregnant women in northern Sweden. Between September 2006 and March 2009, 184 women were consecutively recruited at five antenatal primary care clinics. Blood was sampled, and dietary intake was estimated using a food frequency questionnaire with 66 food items/food aggregates and questions on the intake of vitamin supplements at gestational weeks 12, 21, and 35, as well as at 12 and 29 weeks after birth. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry. At least one-third of the women had 25(OH) vitamin D levels <50 nmol/L on at least one sampling occasion. Plasma levels increased slightly over the gestation period and peaked in late pregnancy. The levels reverted to the baseline levels after birth. Multivariate analysis showed that gestational and postpartum week, season, dietary intake of vitamin D, and vitamin supplementation were significantly related to plasma levels. There was also an influence of season on the longitudinal concentration patterns. In conclusion, more than one-third of the women studied had low 25(OH) vitamin D levels, and gestational and postpartum week was related to 25(OH) vitamin D levels after adjustment for season and vitamin D intake.

Intermittent short ECG recording is more effective than 24-hour Holter ECG in detection of arrhythmias.

BackgroundMany patients report symptoms of palpitations or dizziness/presyncope. These patients are often referred for 24-hour Holter ECG, although the sensitivity for detecting relevant arrhythmias is comparatively low. Intermittent short ECG recording over a longer time period might be a convenient and more sensitive alternative. The objective of this study is to compare the efficacy of 24-hour Holter ECG with intermittent short ECG recording over four weeks to detect relevant arrhythmias in patients with palpitations or dizziness/presyncope.MethodsDesign: prospective, observational, cross-sectional study. Setting: Clinical Physiology, University Hospital. Patients: 108 consecutive patients referred for ambiguous palpitations or dizziness/presyncope. Interventions: All individuals underwent a 24-hour Holter ECG and additionally registered 30-second handheld ECG (Zenicor EKG® thumb) recordings at home, twice daily and when having cardiac symptoms, during 28 days. Main outcome measures: Significant arrhythmias: atrial fibrillation (AF), paroxysmal supraventricular tachycardia (PSVT), atrioventricular (AV) block II–III, sinus arrest (SA), wide complex tachycardia (WCT).Results95 patients, 42 men and 53 women with a mean age of 54.1 years, completed registrations. Analysis of Holter registrations showed atrial fibrillation (AF) in two patients and atrioventricular (AV) block II in one patient (= 3.2% relevant arrhythmias [95% CI 1.1–8.9]). Intermittent handheld ECG detected nine patients with AF, three with paroxysmal supraventricular tachycardia (PSVT) and one with AV-block-II (= 13.7% relevant arrhythmias [95% CI 8.2–22.0]). There was a significant difference between the two methods in favour of intermittent ECG with regard to the ability to detect relevant arrhythmias (P = 0.0094). With Holter ECG, no symptoms were registered during any of the detected arrhythmias. With intermittent ECG, symptoms were registered during half of the arrhythmia episodes.ConclusionsIntermittent short ECG recording during four weeks is more effective in detecting AF and PSVT in patients with ambiguous symptoms arousing suspicions of arrhythmia than 24-hour Holter ECG.

Medical intelligence in Sweden. Vitamin B12: oral compared with parenteral?

Background: Sweden is the only country in which oral high dose vitamin B12 has gained widespread use in the treatment of deficiency states. Objective: The aim of the study was to describe prescribing patterns and sales statistics of vitamin B12 tablets and injections in Sweden 1990–2000. Design, setting, and sources: Official statistics of cobalamin prescriptions and sales were used. Results: The use of vitamin B12 increased in Sweden 1990–2000, mainly because of an increase in the use of oral high dose vitamin B12 therapy. The experience, in statistical terms a “total investigation”, comprised 1 000 000 patient years for tablets and 750 000 patient years for injections. During 2000, 13% of residents aged 70 and over were treated with vitamin B12, two of three with the tablet preparation. Most patients in Sweden requiring vitamin B12 therapy have transferred from parenteral to oral high dose vitamin B12 since 1964, when the oral preparation was introduced. Conclusion: The findings suggest that many patients in other post-industrial societies may also be suitable for oral vitamin B12 treatment.

Reported dietary intake in early pregnant compared to non-pregnant women – a cross-sectional study

BackgroundA woman’s nutritional status before conception and during pregnancy is important for maternal health and the health of the foetus. The aim of the study was to compare diet intake in early pregnant women with non-pregnant women.MethodsBetween September 2006 and March 2009, 226 women in early pregnancy were consecutively recruited at five antenatal clinics in Northern Sweden. Referent women (n = 211) were randomly selected from a current health screening project running in the same region (the Västerbotten Intervention Program; VIP). We collected diet data with a self-reported validated food frequency questionnaire with 66 food items/food aggregates, and information on portion size, alcohol consumption, and supplement intake. Data were analysed using descriptive, comparative statistics and multivariate partial least square modelling.ResultsIntake of folate and vitamin D from foods was generally low for both groups. Intake of folate and vitamin D supplements was generally high in the pregnant group and led to significantly higher total estimated intake of vitamin D and folate in the pregnant group. Iron intake from foods tended to be lower in pregnant women although iron supplement intake evened out the difference with respect to iron intake from foods only. Energy intake was slightly lower in pregnant women but not significant, a reflection of that they reported consuming significantly less of potatoes/rice/pasta, meat/fish, and vegetables (grams/day) than the women in the referent group.ConclusionsIn the present study, women in early pregnancy reported less intake of vegetables, potatoes, meat, and alcohol than non-pregnant women. As they also had a low intake (below the Nordic Nutritional Recommendations) of folate, vitamin D, and iron from foods, some of these women and their unborn children are possibly at risk for adverse effects on the pregnancy and birth outcome.

Development and validation of a new grading scale for otitis media.

Background: Grading of acute otitis media (AOM) is important in clinical situations as well as in research. Current grading scales for AOM have used a 6 to 9 point scoring system primarily based on variation of redness and bulging of the tympanic membrane (TM). This study aimed to develop and validate a new scale for grading AOM. Method: The scale was developed in 3 stages based on 32 patients with images taken of the TM when a child attended healthcare centre with othalgia and at follow-up visits. Content validity was used as the method for the first 2 stages. An expert panel reviewed the scale and repeated the process on a revised scale. Reliability was tested with a different expert panel that used the final scale on a sample of TM images in a test–retest and inter-rater and intra-rater agreements were calculated. Results: The scale was developed in 3 steps using expert committees. During the process the description of vascularization was judged to be of insufficient importance for our scale. Inter-rater agreement was moderate (&kgr; = 0.52) and intra-rater agreement was good (&kgr; = 0.66 to 0.89) in the test–retest of the final scale. Conclusions: The developed AOM image-based grading scale demonstrates substantial inter- and intra-rater reliability with potential use in clinical research and telemedicine applications. Furthermore, the parameter “redness of TM” is of less importance in our scale as compared with other available grading systems.