Danish Medical Journal 

About: Danish Medical Journal is an academic journal published by Danish Medical Association. The journal publishes majorly in the area(s): Population & Medicine. It has an ISSN identifier of 2245-1919. Over the lifetime, 1266 publications have been published receiving 13953 citations. The journal is also known as: Danish medical bulletin & DMJ.

Danish national guidelines for treatment of diverticular disease.

Abstract: In order to elaborate evidence-based, national Danish guidelines for the treatment of diverticular disease the literature was reviewed concerning the epidemiology, staging, diagnosis and treatment of diverticular disease in all its aspects. The presence of colonic diverticula, which is considered to be a mucosal herniation through the intestinal muscle wall, is inversely correlated to the intake of dietary fibre. Other factors in the genesis of diverticular disease may be physical inactivity, obesity, and use of NSAIDs or acetaminophen. Diverticulosis is most common in Western countries with a prevalence of 5% in the population aged 30-39 years and 60% in the part of the population > 80 years. The incidence of hospitalization for acute diverticulitis is 71/100,000 and the incidence of complicated diverticulitis is 3.5-4/100,000. Acute diverticulitis is conveniently divided into uncomplicated and complicated diverticulitis. Complicated diverticulitis is staged by the Hinchey classification 1-4 (1: mesocolic/pericolic abscess, 2: pelvic abscess, 3: purulent peritonitis, 4: faecal peritonitis). Diverticulitis is suspected in case of lower left quadrant abdominal pain and tenderness associated with fever and raised WBC and/or CRP; but the clinical diagnosis is not sufficiently precise. Abdominal CT confirms the diagnosis and enables the classification of the disease according to Hinchey. The distinction between Hinchey 3 and 4 is done by laparoscopy or, when not possible, by laparotomy. Uncomplicated diverticulitis is treated by conservative means. There is no evidence of any beneficial effect of antibiotics in uncomplicated diverticulitis, but antibiotics may be used in selected cases depending on the overall condition of the patients and the severity of the infection. Abscess formation is best treated by US- or CT-guided drainage in combination with antibiotics. When the abscess is < 3 cm in diameter, drainage may be unnecessary, and only antibiotics should be instituted. The surgical treatment of acute perforated diverticulitis has interchanged between resection and non-resection strategies: The three-stage procedure dominating in the beginning of the 20th century was later replaced by the Hartmann procedure or, alternatively, resection of the sigmoid with primary anastomosis. Lately a non-resection strategy consisting of laparoscopy with peritoneal lavage and drainage has been introduced in the treatment of Hinchey stage 3 disease. Evidence so far for the lavage regime is promising, comparing favourably with resection strategies, but lacking in solid proof by randomized, controlled investigations. In recent years, morbidity has declined in complicated diverticulitis due to improved diagnostics and new treatment modalities. Recurrent diverticulitis is relatively rare and furthermore often uncomplicated than previously assumed. Elective surgery in diverticular disease should probably be limited to symptomatic cases not amenable to conservative measures, since prophylactic resection of the sigmoid, evaluated from present evidence, confers unnecessary risks in terms of morbidity and mortality to the individual as well as unnecessary costs to society. Any recommendation for routine resection following multiple cases of diverticulitis should await results of randomized studies. Laparoscopic resection is preferred in case of need for elective surgery. When malignancy is ruled out preoperatively, a sigmoid resection with preservation of the inferior mesenteric artery, oral division of colon in soft compliant tissue and anastomosis to upper rectum is recommended. Fistulae to bladder or vagina, or stenosis of the colon may be dealt with according to symptoms and comorbidity. Resection of the diseased segment of colon is preferred when possible and safe; alternatively, a diverting stoma can be the best solution.

The validity of the schizophrenia diagnosis in the Danish Psychiatric Central Research Register is good.

Abstract: Introduction The Danish Psychiatric Central Research Register (DPCRR) has been used extensively for research purposes during the past decades. The aim of this study was to investigate the validity of the International Classification of Diseases (ICD)-10 schizophrenia diagnosis in the DPCRR. Material and methods A random sample of 300 patients with a first-time diagnosis of schizophrenia (ICD-10 codes F20.0-F20.3 and F20.9) in 2009 was drawn from the register to assess its validity. The case records were reviewed by a Schedules for Clinical Assessment in Neuropsychiatry-certified psychiatric resident using the ICD-10 diagnostic criteria as reference. Results The sample of 300 patients with schizophrenia represented 23.3% of all incident cases (n = 1,288) registered in 2009. We obtained 291 (97.0%) of the case records (nine were lost or inaccessible). Two case records (0.7%) were excluded because of foreign citizenship as these patients had prior episodes in other countries. Thirteen cases (4.3%) were erroneously registered as schizophrenia in the DPCRR. Of the remaining 276 patients, 269 (97.5%) fulfilled the ICD-10 diagnostic criteria for schizophrenia. In a worst case model including all 300 case records, the validity of the schizophrenia diagnosis was 89.7%. Conclusion According to this assessment of patient case records, the diagnosis of schizophrenia in the DPCRR has a high validity and is well-suited for research. Funding Aalborg Psychiatric Hospital funded the study, but the institution had no influence on the planning of the study or the preparation of the manuscript. Trial registration not relevant.

Possible better long-term survival in left versus right-sided colon cancer - a systematic review.

Abstract: Introduction Colon cancer is one of the most frequent types of cancer in Denmark and the western world. Recent studies indicate that there are differences between right- and left-sided colon cancer with regard to epidemiology, clinical manifestation, pathology and prognosis. The present systematic literature review focuses on this subject. Method PubMed, the Ovid Database and the Cochrane Library of Systematic Reviews were searched for relevant literature in October 2011. Only 17 studies fulfilled the inclusion criteria, which were 1) literature published after 1998, 2) written in Danish or English, and 3) peer-reviewed publication. Results We found that patients with right-sided colon cancer were older, more often females, possibly had more co-morbidities, had more advanced tumour stages, increased tumour sizes, more poorly differentiated tumours, different molecular biological tumour patterns and a poorer prognosis than patients with left-sided colon cancer. Multivariate analyses showed that age, gender, mode of presentation (emergency/elective), co-morbidity and stage had significant influence on survival, but it was uncertain whether tumour location itself had such an effect, though the different molecular biological patterns indicate this. Conclusion The findings potentially have consequences for the planning of screening and treatment of colon cancer, but further research in the area is needed.

Candida and candidaemia. Susceptibility and epidemiology.

Abstract: In our part of the world invasive fungal infections include invasive yeast infections with Candida as the absolutely dominating pathogen and invasive mould infections with Aspergillus as the main organism. Yeasts are part of our normal micro-flora and invasive infections arise only when barrier leakage or impaired immune function occurs. On the contrary, moulds are ubiquitous in the nature and environment and their conidia inhaled at a daily basis. Hence invasive mould infections typically arise from the airways whereas invasive yeast infections typically enter the bloodstream causing fungaemia. Candida is by far the most common fungal blood stream pathogen; hence this genus has been the main focus of this thesis. As neither the Danish epidemiology nor the susceptibility of fungal pathogens was well described when we initiated our studies we initially wanted to be able to include animal models in our work. Therefore, a comprehensive animal study was undertaken comparing the virulence in a haematogenous mouse model of eight different Candida species including the five most common ones in human infections (C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and in addition three rarer species C. guilliermondii, C. lusitaniae and C. kefyr). We found remarkable differences in the virulence among these species and were able to group the species according to decreasing virulence in three groups I: C. albicans and C. tropicalis, II: C. glabrata, C. lusitaniae and C. kefyr, and III: C. krusei, C. parapsilosis and C. guilliermondii. Apart from being necessary for our subsequent animal experiments exploring in vivo antifungal susceptibility, these findings also helped us understand at least part of the reason for the differences in the epidemiology and the pitfalls associated with the establishment of genus rather than species specific breakpoints. In example, it was less surprising that C. albicans has been the dominant pathogen and associated with a significantly higher mortality than C. parapsilosis and that C. glabrata and C. krusei mainly emerged in the post fluconazole era and in settings with azole selection pressure. Moreover, it was less surprising that infections due to mutant C. albicans isolates with echinocandin MICs of 1-2 mg/l were not good targets for the echinocandins despite the fact that the outcome for infections involving wild type C. parapsilosis for which similar echinocandin MICs were similar was not inferior. This last observation highlights the importance of providing optimal, reproducible and sensitive reference susceptibility testing methods and notably accompanied by appropriate breakpoints that allow a separation and detection of susceptible and resistant isolates against which the commercial tests can be validated. Correct detection of resistant isolates is for obvious reasons crucial in order to avoid inappropriate treatment. And if the test method cannot correctly identify resistant isolates it makes little sense performing susceptibility testing at all. On the other hand misclassification of susceptible isolates as resistant is also an issue as the patient is thereby deprived an appropriate treatment option among the few available. These comments may seem very basic; nevertheless, it has taken a lot of effort and patience to optimise the susceptibility tests, understand the variability issue for caspofungin testing, to provide appropriate breakpoints that reduced misclassifications to a minimum and not the least to facilitate a harmonisation of breakpoints across the Atlantic sea. We initially realised that the CLSI method and echinocandin breakpoint misclassified resistant isolates. This was due to the endorsement of a single susceptibility breakpoint across all Candida species and the three echinocandins and therefore set as high as 2 mg/l in order to include and not bisect the C. parapsilosis population. Through our comprehensive comparisons of echinocandin susceptibility testing using EUCAST, CLSI, Etest, disk diffusion and agardilution with different media with and without the supplementation of bovine serum albumin we provided data that supported the current reference methodologies, provided that drug and species specific breakpoints were selected. Moreover, the issues of caspofungin variability and of overlap between micafungin MICs for wild type and mutant C. glabrata populations were handled and understood. Anidulafungin EUCAST breakpoints are now published and publically available at the www.eucast.org website and anidulafungin testing recommended as a marker for the echinocandin class. Our antifungal EUCAST breakpoint setting approach has been adopted by the CLSI leading to revision and harmonisation of breakpoints for the three echinocandins, fluconazole and voriconazole. Our epidemiological studies developed gradually over the years following our observation of a notably high incidence rate of fungaemia compared to our Nordic neighbours. Initially, we anticipated that our high incidence was at least in part related to the fact that the capture area for our initial studies was skewed with dominance of university hospitals and inclusion of all centres performing solid organ or bone marrow transplantation. However, when the surveillance was extended to the entire country, the high incidence remained a consistent finding and we even demonstrated that the incidence rate is still increasing. Additionally we demonstrated a changing epidemiology as a high and increasing proportion of the cases involved fluconazole resistant isolates and that this proportion also was significantly higher than in the other Nordic countries. This appears to be related to a significantly higher and increasing fluconazole use in Denmark than in the other Nordic countries. Exploring the incidence rate for the individual hospitals and age groups we demonstrated not unexpectedly that the incidence rate was highest at the university centres, but also that whereas the age specific incidence rate was comparable in children and the younger adults with that in the other Nordic countries it was notably higher in the elderly population. This in combination with the fact that it is increasing specifically in the elderly men and that the incidence rates in the Nordic countries were comparable two decades back suggest that host specific factors including antifungal consumption rather than genetic differences in susceptibility to fungaemia account for the differences, and hence that it is possibly modifiable by implementing relevant measures. Hence, it was important to investigate the underlying clinical conditions and diagnostic factors and the outcome in Danish patients with fungaemia. In this study we demonstrated that two thirds of the patients had received abdominal surgery or intensive care treatment prior to the development of the fungaemia, a proportion that is higher than in most other studies. We also demonstrated that unless surveillance cultures are handled with careful attention the detection of non-C. albicans may go unnoticed which imply a risk of inappropriate treatment in cases involving intrinsically resistant species. Finally, we demonstrated the necessity of using a fungal blood culture flask in addition to the conventional aerobic and anaerobic ones if all C. glabrata infections (BACTEC) and all polymicrobial infections (BacT/ALERT) are to be diagnosed. Hence close monitoring with the use of improved diagnostic options (such as frequent BC including a mycosis bottle, surveillance cultures and mannan antigen and antibody screening) of particularly ICU and abdominal surgery patients may help better identify patients with fungaemia and allow early treatment. With respect to treatment and outcome we found that the fluconazole resistant species C. glabrata, C. krusei and S. cerevisiae were significantly more common in patients exposed to at least 7 days of antifungal prophylaxis (mainly fluconazole). We also demonstrated that a significant proportion of the patients initially received inappropriate antifungal treatment and that the outcome was significantly improved when patients with C. glabrata received caspofungin as their first line agent. This has today been incorporated in the Danish and international treatment guidelines. The prevalence of acquired antifungal resistance remained very low throughout the study period, however, we may only have detected the tip of the resistance iceberg due to the study design, where for epidemiological purposes only the initial isolate was included with the lowest antifungal exposure, and as the susceptibility tests and breakpoints were not optimal for the detection of resistance at all centres. Most Danish laboratories either do not susceptibility test or use commercial tests such as the Etest and later the VITEK system. These are FDA approved with the CLSI breakpoints which, as we have shown, have been far too high to reliably detect resistance and which despite having now been revised and harmonised are not yet in formal CLSI print and hence not incorporated in the product inserts for the commercial tests on the market. Finally, even for laboratories aware of these issues challenges are still ahead as the official breakpoints not always lead to a correct classification for MIC endpoints obtained using the commercial systems or as the commercial tests do not include a relevant concentration range for all drug bug combinations. I thus believe, the studies included in this thesis have contributed significantly to the understanding of the interplay between the Candida virulence, epidemiology and susceptibility and the importance of appropriate diagnostics and treatment choice. It is my hope that we thereby have contributed to the improved options and outcome for patients with candidaemia.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

Abstract: Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal muscle in vivo by activation of the insulin signaling cascade to glucose transport through the enzymes IRS1, PI3K, Akt2, AS160/TBC1D4 and RAC1, and to glycogen synthesis through Akt2, inhibition of GSK3 and activation of glycogen synthase (GS) via dephosphorylation of serine residues in both the NH2-terminal (site 2+2a) and the COOH-terminal end (site 3a+3b). In type 2 diabetes, obesity and PCOS, there is, although with some variation from study to study, defects in insulin signaling through IRS1, PI3K, Akt2 and AS160/TBC1D4, which can explain reduced insulin action on glucose transport. In type 2 diabetes an altered intracellular distribution of SNAP23 and impaired activation of RAC1 also seem to play a role for reduced insulin action on glucose transport. In all common metabolic disorders, we observed an impaired insulin activation of GS, which seems to be caused by attenuated dephosphorylation of GS at site 2+2a, whereas as the inhibition of GSK3 and the dephosphorylation of GS at its target sites, site 3a+3a, appeared to be completely normal. In individuals with inherited insulin resistance, we observed largely the same defects in insulin action on IRS1, PI3K, Akt2 and GS, as well as a normal inhibition of GSK3 and dephosphorylation of GS at site 3a+3b. In these individuals, however, a markedly reduced insulin clearance seems to partially rescue insulin signaling to glucose transport and GS. Adiponectin is thought to improve insulin sensitivity primarily by increasing lipid oxidation through activation of the enzyme AMPK, and possibly via cross-talking of adiponectin with insulin signaling, and hence glucose transport and glycogen synthesis. We demonstrated a strong correlation between plasma adiponectin and insulin action on glucose disposal and glycogen synthesis in obesity, type 2 diabetes and PCOS. In individuals with inherited insulin resistance, plasma adiponectin was normal, but the correlation of adiponectin with insulin-stimulated glucose uptake and glycogen synthesis was at least equally strong. Moreover, we found a correlation between plasma adiponectin and insulin activation of GS. This result is supported by a number of recent studies of animal models and muscle cell lines, which have shown that adiponectin augments insulin action on enzymes in the insulin signaling cascade. In contrast, we observed no differences in the abundance or activity of AMPK in obesity, type 2 diabetes, PCOS or inherited insulin resistance. This indicates that reduced insulin sensitivity in these conditions is not mediated via abnormal AMPK activity. The results from these studies demonstrate that the well-established abnormalities in insulin action on glucose uptake and glycogen synthesis are reflected by defects in insulin signaling to these cellular processes in type 2 diabetes, obesity, and PCOS, and as expected also in inherited insulin resistance caused by a mutation in INSR. In common metabolic disorders, low plasma adiponectin may contribute to insulin resistance and defects in insulin signaling, whereas in inherited insulin resistance a normal plasma adiponectin and reduced insulin clearance could contribute to maintain a sufficient activation of the insulin signaling cascade. The insight gained from these studies have improved our understanding of the molecular mechanisms underlying insulin resistance in skeletal muscle of humans, and can form the basis for further studies, which can lead to the development of treatment that more directly targets insulin resistance, and hence reduce the risk of type 2 diabetes and cardiovascular disease.