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  • 101.
    Gedeborg, Rolf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Swedish medical products agency, Uppsala, Sweden.
    Cline, Charles
    Zethelius, Björn
    Salmonson, Tomas
    Pragmatic clinical trials in the context of regulation of medicines2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, p. 1-5Article in journal (Refereed)
    Abstract [en]

    The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non-interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as 'pragmatic'.

  • 102.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Multidisciplinary treatment of patients with rectal cancer: Development during the past decades and plans for the future2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 225-236Article in journal (Refereed)
    Abstract [en]

    In rectal cancer treatment, both the local primary and the regional and systemic tumour cell deposits must be taken care of in order to improve survival. The three main treatments, surgery, radiotherapy, and chemotherapy, each with their own advantages and limitations, must then be combined to improve results. Several large randomized trials have shown that combinations of the modalities have markedly reduced the loco-regional recurrences, but have not yet had any major influence on overall survival. The best integration of the weakest modality, to date the drugs (conventional cytotoxics and biologicals), is not known. A new generation of trials exploring the best sequence of treatments is required. Furthermore, treatment of rectal cancer is administered to populations of individuals, based upon clinical factors and imaging, and can presently not be further individualized. There is an urgent need to develop response predictors.

  • 103.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    On a prolonged interval between rectal cancer (chemo) radiotherapy and surgery2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 1-10Article, review/survey (Refereed)
    Abstract [en]

    Preoperative radiotherapy (RT) or chemoradiotherapy (CRT) is often required before rectal cancer surgery to obtain low local recurrence rates or, in locally advanced tumours, to radically remove the tumour. RT/CRT in tumours responding completely can allow an organ-preserving strategy. The time from the end of the RT/CRT to surgery or to the decision not to operate has been prolonged during recent years. After a brief review of the literature, the relevance of the time interval to surgery is discussed depending upon the indication for RT/CRT. In intermediate rectal cancers, where the aim is to decrease local recurrence rates without any need for down-sizing/-staging, short-course RT with immediate surgery is appropriate. In elderly patients at risk for surgical complications, surgery could be delayed 5-8 weeks. If CRT is used, surgery should be performed when the acute radiation reaction has subsided or after 5-6 weeks. In locally advanced tumours, where CRT is indicated, the optimal delay is 6-8 weeks. In patients not tolerating CRT, short-course RT with a 6-8-week delay is an alternative. If organ preservation is a goal, a first evaluation should preferably be carried out after about 6 weeks, with planned surgery for week 8 if the response is inadequate. In case the response is good, a new evaluation should be carried out after about 12 weeks, with a decision to start a 'watch-and-wait' programme or operate. Chemotherapy in the waiting period is an interesting option, and has been the subject of recent trials with promising results.

  • 104.
    Gordh, Torsten E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mair, William G. P.
    Uppsala University.
    Sourander, Patrick
    Swedenborg, Linnaeus and brain research and the roles of Gustaf Retzius and Alfred Stroh in the rediscovery of Swedenborg's manuscripts2007In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 112, no 2, p. 143-164Article in journal (Refereed)
    Abstract [en]

    Emanuel Swedenborg (1688 - 1772) at the end of his long life became famous as a visionary mystic and founder of a new religion. However, at younger age, he was recognized as a prominent mining engineer and natural philosopher, particularly interested in geology, mineralogy, cosmology, paleontology and last but not least physiology of the brain. In his Oeconomica regni animalis (1740) and in several posthumously published extensive manuscripts, he described and analyzed e. g. the structural and functional organization of the cerebral cortex, the hierarchical construction of the nervous system, the localization of the cerebrospinal fluid and the secretory functions of the pituitary gland. In these fields, he presented remarkable insights and far reaching conclusions which in some cases have been experimentally verified in modern times. In spite of family relations Swedenborg rarely met the 19 years younger Linnaeus. Linnaeus was not only the founder of the systemic botany but as physician a keen and to some extent original observer of neurological symptoms; one of the first who adequately described motor aphasia. To regard these two men, among the few Swedish authors of the 18(th) century whose names are still internationally well known, as early precursors of neurological research, seems justified. The young Canadian, Alfred H. Stroh (1878 - 1922), had a crucial importance for the research on the works of Swedenborg, and the rediscovery of his manuscripts. His work was supported and financed to a large extent by professor Gustaf Retzius, at that time the most prominent Swedish researcher in anatomy and histology. There are many reasons to be thankful for the important contributions made by Alfred Stroh and Gustaf Retzius to stimulate the interest for Emanuel Swedenborg in Sweden and internationally.

  • 105.
    Gottvall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Grandahl, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Höglund, Anna T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stenhammar, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Andrae, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Tydén, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Trust versus concerns: how parents reason when they accept HPV vaccination for their young daughter2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Background. From spring of 2012, human papillomavirus (HPV) vaccine against cervical cancer is offered free of charge to all girls aged 10-12 years through a school-based vaccination programme in Sweden. The aim of this study was to explore how parents reason when they accept HPV vaccination for their young daughter and also their views on HPV-related information. Methods. Individual interviews with parents (n = 27) of 11-12-year-old girls. The interviews were recorded, transcribed verbatim, and analysed using thematic content analysis. Results. Three themes emerged through the analysis: Trust versus concern, Responsibility to protect against severe disease, and Information about HPV and HPV vaccination is important. The parents expressed trust in recommendations from authorities and thought it was convenient with school-based vaccination. They believed that cervical cancer was a severe disease and felt a responsibility to protect their daughter from it. Some had certain concerns regarding side effects and vaccine safety, and wished for a dialogue with the school nurse to bridge the information gaps. Conclusions. Trust in the recommendations from authorities and a wish to protect their daughter from a severe disease outweighed concerns about side effects. A school-based vaccination programme is convenient for parents, and the school nurse has an important role in bridging information gaps. The findings from this qualitative study cannot be generalized; however, it can provide a better understanding of how parents might reason when they accept the HPV vaccination for their daughter.

  • 106.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Methods in neuroendocrine histopathology: a methodological overview2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 3, p. 243-260Article, review/survey (Refereed)
    Abstract [en]

    Light microscopy is still the main tool in diagnostic histopathology, though it does not always lead to a definitive diagnosis. It has therefore been a constant ambition to develop methods which can add further information to the diagnosis. In endocrine pathology, a major problem has been to distinguish between neuroendocrine and non-neuroendocrine tumours. The silver stains, such as the Bodian, Grimelius and Sevier-Munger methods, were the first useful "general neuroendocrine" markers. Electron microscopy can also be useful for identifying neuroendocrine tumours. A further step forward was the introduction of histochemical fluorescence methods, as these could identify biogenic amines. With the introduction of immunohistochemical techniques, tumours could be characterized in a more specific way regarding peptide hormones and biogenic amines content, proliferation factors, hormone receptors, etc. Another method, DNA cytometry, has been used mainly in predicting the prognosis. In situ hybridization can be a useful complement to the histopathological diagnosis when other methods have failed to demonstrate the neuroendocrine nature of the tumour. Some endocrine tumours, especially the well-differentiated ones, still cause diagnostic problems in predicting tumour behaviour, why further complementary methods would be of great value.

  • 107.
    Grimelius, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Johansson, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Segerström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Pancreatic Islet Cells in Experimental Hypo- and Hyperparathyroidism in Rats1972In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 77, no 3, p. 140-142Article in journal (Refereed)
    Abstract [en]

    The hypocalcaemic effect of glucagon is well documentedin the literature. In this investigation the pancreatic isletcells were studied in hypocalcaemic (parathyroidectomized)and hypercalcaemic (parathyroid hormone treated) rats.Observations were made after 1 and 8 weeks of hypocalcaemiaand after 3 days of hypercalcaemia. No qualitativeor quantitative changes in the islet cells were observed. Theresults are discussed.

  • 108.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose control of glucagon secretion: 'There's a brand-new gimmick every year'2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 120-132Article, review/survey (Refereed)
    Abstract [en]

    Glucagon from the pancreatic alpha-cells is a major blood glucose-regulating hormone whose most important role is to prevent hypoglycaemia that can be life-threatening due to the brain's strong dependence on glucose as energy source. Lack of blood glucose-lowering insulin after malfunction or autoimmune destruction of the pancreatic beta-cells is the recognized cause of diabetes, but recent evidence indicates that diabetic hyperglycaemia would not develop unless lack of insulin was accompanied by hypersecretion of glucagon. Glucagon release has therefore become an increasingly important target in diabetes management. Despite decades of research, an understanding of how glucagon secretion is regulated remains elusive, and fundamentally different mechanisms continue to be proposed. The autonomous nervous system is an important determinant of glucagon release, but it is clear that secretion is also directly regulated within the pancreatic islets. The present review focuses on pancreatic islet mechanisms involved in glucose regulation of glucagon release. It will be argued that alpha-cell-intrinsic processes are most important for regulation of glucagon release during recovery from hypoglycaemia and that paracrine inhibition by somatostatin from the delta-cells shapes pulsatile glucagon release in hyperglycaemia. The electrically coupled beta-cells ultimately determine islet hormone pulsatility by releasing synchronizing factors that affect the alpha- and delta-cells.

  • 109.
    Halford, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anderzén, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Arnetz, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Self-rated health, life-style, and psychoendocrine measures of stress in healthy adult women2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 4, p. 266-274Article in journal (Refereed)
    Abstract [en]

    Background. Self-rated health (SRH) is a robust predictor of subsequent health outcome, independent of objective health measures and life-style-related health risk factors. However, the determinants of SRH are as yet largely unknown. In accordance with the prevailing stress theory, we hypothesized that SRH is associated with personal coping resources, psychological strain, life-style variables, and endocrine variables.

    Methods. A total of 106 healthy women, 22-59 years of age, were followed for up to 3 years with annual blood sampling (cortisol, prolactin, testosterone) and written questionnaires in which information on SRH, psychological strain, coping resources, socio-economic and life-style variables was sought.

    Results. In bivariate, screening logistic regression analyses, intended to find candidate variables for a final analysis model, all coping resource variables (sense of coherence, mastery, and self-esteem) were significantly related to SRH, and so were two psychological strain variables (vital exhaustion, and sleep disturbances), one life-style variable (fitness), but none of the endocrine variables. In the final multivariate analysis model, including all candidate variables, only vital exhaustion (P < 0.0001), fitness (P = 0.0002), and sense of coherence (P = 0.0006) were independently associated with SRH, together explaining 74% of the SRH variance.

    Conclusion. Some elements of the hypothesis, i.e. the effects of coping resources, psychological strain, and life-style variables on SRH, were supported by the results, while others, i.e. effects of endocrine measures on SRH, were not, indicating a possible gender difference.

  • 110.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cystatin C vs creatinine as markers of renal function in patients on digoxin treatment2004In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 109, no 3, p. 247-253Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: The kidney function is a major determinant of the serum concentration of digoxin as this drug is mainly eliminated unchanged through the kidneys. Since digoxin is widely prescribed among the elderly, and the glomerular filtration rate (GFR) declines with age, it is important that the clinician takes the patient's GFR into account when prescribing digoxin. Serum cystatin C has been suggested to be superior to creatinine for estimation of GFR, which may have relevance for the optimization of treatment with digoxin. METHODS: To evaluate which of the two GFR markers serum creatinine and serum cystatin C that best correlates with serum digoxin, we compared the serum levels of digoxin with the serum levels of creatinine and cystatin C in 149 patients on therapeutic drug monitoring of digoxin at our hospital. RESULTS: Overall, there was a stronger correlation between serum digoxin concentrations and cystatin C (p=0.00001) as compared to creatinine (p= 0.00003). Interestingly, of the patients with a serum digoxin concentration > or = 1.5 nmol/L, 29% had a serum creatinine level within normal limits, as compared to 20% with normal cystatin C levels. CONCLUSIONS: In this study, serum cystatin C correlated better to serum digoxin than did serum creatinine. With improved GFR monitoring, digoxin concentrations should be better controlled.

  • 111.
    Halldorsdottir, Sandra
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Dahlstrand, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Gynecologists are afraid of prescribing hormone replacement to endometrial/ovarian cancer survivors despite national guidelines-a survey in Sweden2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 4, p. 225-229Article in journal (Refereed)
    Abstract [en]

    Background: Prolonged survival in ovarian and endometrial cancer patients increases the importance of paying attention to quality of life. Hormone replacement therapy (HRT) after gynecologic cancer has been controversial. With this survey, we sought to describe Swedish gynecologists’ and gynecologic oncologists’ attitudes towards prescribing HRT to these cancer survivors and see if prescribing practice is consistent with the available evidence and national guidelines.

    Material and methods: A web-based survey containing three hypothetical cases with a total of 15 questions was distributed to gynecologists and gynecologic oncologists in Sweden. Respondents were asked about their HRT prescription practices in endometrial/ovarian cancer patients with moderate to severe menopausal symptoms.

    Results: In total 262 gynecologists and 24 gynecologic oncologists answered the survey. In the low-risk endometrial cancer case a majority of the gynecologists (55%) and gynecologic oncologists (66.7%) would prescribe local estrogen. A total of 30% of the gynecologists would prescribe estrogen replacement therapy (ERT) in the high-risk endometrial cancer case compared to 58.3% of the gynecologic oncologists. The gynecologic oncologists felt more comfortable treating patients with endometrial cancer than did gynecologists, and the gynecologists were more likely to read the national guidelines. In the ovarian cancer case, 63.7% of the gynecologists would prescribe HRT compared to 92% of the gynecologic oncologists.

    Conclusion: Swedish gynecologic oncologists have a more favorable attitude towards HRT for endometrial/ovarian cancer patients and feel more comfortable treating their patients than do gynecologists. This study illustrates a need for education in these matters in order not to withhold HRT from women due to doctors’ sometimes unjustified anxiety.

  • 112. Haller, Olle
    et al.
    Karlsson, Lars
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Can low-dose abdominal CT replace abdominal plain film in evaluation of acute abdominal pain?2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 113-120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Non-contrast computed tomography (NCT) has become an important diagnostic tool in acute abdominal pain, but the drawback is the increased radiation dose compared to abdominal plain film (APF). PURPOSE: To evaluate whether NCT, including low-dose computed tomography (LDCT, using 50 mAs), provides more diagnostic information than APF in patients presenting with acute non-traumatic abdominal pain and if the use of CT can reduce the total number of additional radiograms. A second aim was to compare the diagnostic outcome between standard-dose computed tomography (SDCT) and LDCT. MATERIAL AND METHODS: During 2000, 2002, and 2004 a total of 222 patients were retrospectively reviewed, and 86 patients had APF, 60 had SDCT, and 76 had LDCT. The radiological report of each patient was compared with the final diagnosis obtained from the medical record within 30 days. Additional radiograms were registered, and a total radiation dose excluding or including APF or NCT was calculated. RESULTS: NCT gave a correct diagnosis in 50%, compared to 20% with APF (P < 0.001). The total number of additional radiograms was substantially lower in the computed tomography (CT) group compared to the APF group (P < 0.001), and the average sum of radiation dose was similar for APF and LDCT. CONCLUSION: NCT was found to be significantly better at providing diagnostic information than APF in patients presenting with acute abdominal pain. It reduced the number of additional radiograms, but the total patient dose remained somewhat higher in the CT group even when using LDCT with 50 mAs.

  • 113.
    Halvorsen, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Neural injury after use of vasopressin and adrenaline during porcine cardiopulmonary resuscitation2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, p. 11-19Article in journal (Refereed)
    Abstract [en]

    Background. Our aim was to investigate cerebral and cardiac tissue injury subsequent to use of vasopressin and adrenaline in combination compared with vasopressin alone during cardiopulmonary resuscitation (CPR). Methods. In a randomized, prospective, laboratory animal study 28 anesthetized piglets were subject to a 12-min untreated cardiac arrest and subsequent CPR. After 1 min of CPR, 10 of the piglets received 0.4 U/kg of arg(8)-vasopressin (V group), and 10 piglets received 0.4 U/kg of arg(8)-vasopressin, 1 min later followed by 20 mu g/kg body weight of adrenaline, and another 1 min later continuous administration (10 mu g/kg/min) of adrenaline (VA group). After 8 min of CPR, the piglets were defibrillated and monitored for another 3 h. Then they were killed and the brain immediately removed pending histological analysis. Results. During CPR, the VA group had higher mean blood pressure and cerebral cortical blood flow (CCBF) but similar coronary perfusion pressure. After restoration of spontaneous circulation there was no difference in the pressure variables, but CCBF tended to be (36% +/- 16%) higher in the V group. Neuronal injury and signs of a disrupted blood-brain barrier (BBB) were greater, 20% +/- 4% and 21% +/- 4%, respectively, in the VA group. In a background study of repeated single doses of adrenaline every third minute after 5 min arrest but otherwise the same protocol, histological measurements showed even worse neural injury and disruption of the BBB. Conclusion. Combined use of vasopressin and adrenaline caused greater signs of cerebral and cardiac injury than use of vasopressin alone during experimental cardiopulmonary resuscitation.

  • 114.
    Hedborg, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Anderberg, Ulla Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Muhr, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stress in migraine: personality-dependent vulnerability, life events, and gender are of significance2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 3, p. 187-199Article in journal (Refereed)
    Abstract [en]

    Background and aim. The individual's experiences of stress as well as constitutional factors, including high neuroticism and female gender, are known determinants for migraine. The present aim was to further elucidate factors of personality and stress, including life events, in relation to gender in migraine. Methods. A cross-sectional study was performed on 150 persons, 106 women and 44 men, suffering from at least two migraine attacks a month. All obtained a doctor-defined migraine diagnosis based on a structured face-to-face interview concerning their health situation and current and prior stress. All of them also answered validated questionnaires regarding personality traits (SSP), life events, and perceived ongoing stress. Results. The personality trait inventory showed high mean scores for stress susceptibility and low mean scores for aggressiveness and adventure seeking, both for women and for men, as well as high mean scores for psychic and somatic anxiety in women. Stress susceptibility, the overall most deviant trait, correlated strikingly with current level of stress in both sexes. In women, stress susceptibility also correlated strongly with experiences of negative life events. Tension-type headache, anxiety, and depression were approximately twice as prevalent in women compared to men. Conclusions. The present study confirms previous research, showing that stress is an important factor in migraine. Stress susceptibility, life events, and concomitant psychosomatic illnesses should be considered important when evaluating individuals with migraine, and gender aspects need to be taken into account.

  • 115.
    Hedborg, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Muhr, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multimodal behavioral treatment of migraine: An Internet-administered, randomized, controlled trial2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 3, p. 169-186Article in journal (Refereed)
    Abstract [en]

    Introduction. Multimodal approaches in behavioral treatment have gained recent interest, with proven efficacy for migraine. The utility of the Internet has been demonstrated for behavioral treatment of headache disorders, but not specifically for migraine. The aim of the study was to develop and evaluate an Internet-based multimodal behavior treatment (MBT) program for migraine and to test hand massage treatment as an adjunct. Methods. Eighty-three adults, 58 women and 25 men, with at least two migraine attacks a month were recruited via advertisements. An MBT program aiming at improvements in life-style and stress coping was developed for this study and, together with a diary, adapted for use over the Internet. Participants were randomized to MBT with and without hand massage and to a control group, and were followed for 11 months. Questionnaires addressing issues of quality of life (PQ23) and depressive symptoms (MADRS-S) were used. Results. A 50%, or greater, reduction in migraine frequency was found in 40% and 42% of participants of the two groups receiving MBT (with and without hand massage, respectively), who statistically were significantly more improved than participants in the control group. No effect of hand massage was detected, and gender did not show any independent contribution to the effect in a multivariate analysis. Conclusions. MBT administered over the Internet appears feasible and effective in the treatment of migraine, but no effect of hand massage was found. For increased knowledge on long-term effects and the modes of action of the present MBT program, further studies are needed.

  • 116.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    When do we need clinical endpoint adjudication in clinical trials?2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 1, p. 42-45Article in journal (Refereed)
    Abstract [en]

    Clinical endpoint adjudication (CEA) is a standardized process for assessment of safety and efficacy of pharmacologic or device therapies in clinical trials. CEA plays a key role in many large clinical trials with the aim of achieving consistency and accuracy of the study results, by applying independent and blinded evaluation of suspected clinical events reported by investigators. However, due to high costs there are different opinions regarding the use of central adjudication versus more simplified strategies or site-based assessments and whether the final results differ significantly. There is a lack of scientific evaluation of different adjudication strategies, and more knowledge is needed on the optimal adjudication process and how to achieve the best cost-effectiveness. New methodologies using national registry data and artificial intelligence may challenge the traditional adjudication strategy and could potentially reduce cost considerably with a similar result. Further research and evidence in this field of clinical trials methodology are essential.

  • 117.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Autocrine PDGF stimulation in malignancies2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 83-91Article, review/survey (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) isoforms are important mitogens for different types of mesenchymal cells, which have important functions during the embryonal development and in the adult during wound healing and tissue homeostasis. In tumors, PDGF isoforms are often over-expressed and contribute to the growth of both normal and malignant cells. This review focuses on tumors expressing PDGF isoforms together with their tyrosine kinase receptors, thus resulting in autocrine stimulation of growth and survival. Patients with such tumors could benefit from treatment with inhibitors of either PDGF or PDGF receptors.

  • 118.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Development and possible clinical use of antagonists for PDGF and TGF-beta2004In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 109, no 3, p. 165-178Article, review/survey (Other academic)
    Abstract [en]

    Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are examples of signaling molecules which control the growth, survival motility and differentiation of cells. PDGF stimulates the growth mainly of connective tissue cells, whereas TGF-beta inhibits the growth of most cell types. PDGF and TGF-beta exert their cellular effects by binding to receptors equipped with tyrosine and serine/threonine kinase activities, respectively. Both factors have important roles e.g. during the embryonal development and in wound healing. Overactivity of PDGF or PDGF receptors contributes to the development of certain diseases characterized by excessive cell growth including fibrotic disorders, atherosclerosis and malignancies. Overactivity of TGF-beta also contributes to fibrotic conditions, since TGF-beta promotes accumulation of extracellular matrix molecules. In cancer, TGF-beta is initially a tumor suppressor due to its ability to inhibit cell growth, however, at later stages of tumor progression TGF-beta has tumor promoting activity by enhancing the invasive properties of tumor cells and by suppressing the immune system and promoting angiogenesis. The involvement of PDGF in TGF-beta in serious diseases makes clinically useful antagonists highly desirable. A low molecular weight receptor kinase inhibitor of the PDGF receptor kinase is now tested clinically, and TGF-beta antagonists are under development. The present review discusses the development and possible clinical use of antagonsts for PDGF and TGF-beta.

  • 119.
    Hellman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pulsatility of insulin release: a clinically important phenomenon2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 4, p. 193-205Article, review/survey (Refereed)
    Abstract [en]

    The mechanisms and clinical importance of pulsatile insulin release are presented against the background of more than half a century of companionship with the islets of Langerhans. The insulin-secreting beta-cells are oscillators with intrinsic variations of cytoplasmic ATP and Ca2+. Within the islets the beta-cells are mutually entrained into a common rhythm by gap junctions and diffusible factors (ATP). Synchronization of the different islets in the pancreas is supposed to be due to adjustment of the oscillations to the same phase by neural output of acetylcholine and ATP. Studies of hormone secretion from the perfused pancreas of rats and mice revealed that glucose induces pulses of glucagon anti-synchronous with pulses of insulin and somatostatin. The anti-synchrony may result from a paracrine action of somatostatin on the glucagon-producing alpha-cells. Purinoceptors have a key function for pulsatile release of islet hormones. It was possible to remove the glucagon and somatostatin pulses with maintenance of those of insulin with an inhibitor of the P2Y(1) receptors. Knock-out of the adenosine A, receptor prolonged the pulses of glucagon and somatostatin without affecting the duration of the insulin pulses. Studies of isolated human islets indicate similar relations between pulses of insulin, glucagon, and somatostatin as found during perfusion of the rodent pancreas. The observation of reversed cycles of insulin and glucagon adds to the understanding how the islets regulate hepatic glucose production. Current protocols for pulsatile intravenous infusion therapy (PIVIT) should be modified to mimic the anti-synchrony between insulin and glucagon normally seen in the portal blood.

  • 120.
    Hellström, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nilsson, Kent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Åslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Effects of adolescent online gaming time and motives on depressive, musculoskeletal, and psychosomatic symptoms2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 4, p. 263-275Article in journal (Refereed)
    Abstract [en]

    Aim. To investigate whether adolescent online gaming time and the additive effect of gaming motives were associated with depressive, musculoskeletal, and psychosomatic symptoms. The hypothesis was that adolescents who engage in online gaming with escape motives and increased online gaming time have higher probability for depressive, musculoskeletal, and psychosomatic symptoms compared to adolescents with other online gaming motives and/or less online gaming time.

    Method. An anonymous and voluntary questionnaire was completed during class hours by 7,757 Swedish adolescents aged 13-18 years. The questionnaire included demographic background, gaming habits, and depressive, musculoskeletal, and psychosomatic symptoms.Results. It was found that increased online gaming time during weekdays increased the probability of having depressive, musculoskeletal, and psychosomatic symptoms. However, these relations with time spent gaming were further explained by online gaming motives. Weekday online gaming for more than five hours a day, in combination with escape motives, was associated with an increased probability of depressive symptoms (odds ratio (OR) 4.614, 95% CI 3.230-6.590), musculoskeletal symptoms (OR 2.494, 95% CI 1.598-3.892), and psychosomatic symptoms (OR 4.437, 95% CI 2.966-6.637). The probability of ill health decreased when gaming was for fun or had social motives.

    Conclusion. Excessive gaming time and escape motives were found to be associated with increased probability of ill health among adolescents. Gaming motives may identify gamers in need of support to reduce unhealthy gaming behaviour as well as identify individuals at risk for ill health.

  • 121.
    Hellström, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. School of Health, Care and Social Welfare, Mälardalen University.
    Wagner, Philippe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nillson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Aslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Gambling frequency and symptoms of attention-deficit hyperactivity disorder in relation to problem gambling among Swedish adolescents: A population-based study2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 22, no 2, p. 119-126Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate the associations between gambling frequency, attention-deficit hyperactivity disorder (ADHD) symptoms, and problem gambling among adolescent boys and girls. One hypothesis was that adolescents with increased ADHD symptoms have a higher frequency of gambling compared to adolescents with fewer ADHD symptoms.

    Method: A population-based sample of adolescents (aged 15–18 years) completed a questionnaire on demographics, gambling habits, ADHD symptoms, and problematic gambling; 1412 adolescents (from 4440 sampled) with gambling experience were included in the final sample.

    Results: A zero-inflated negative binomial regression analysis revealed that increased ADHD symptoms, higher gambling frequency, and higher age were associated with lower odds for being non-susceptible to gambling problems. Moreover, gambling frequency interacted with ADHD symptoms in predicting probability of being non-susceptible to gambling problems. However, when analysing those already susceptible to problem gambling, ADHD symptoms did not modify the effect of gambling frequency on the expected magnitude of gambling problems. In susceptible individuals, problem gambling increased with both increased ADHD symptoms and increased gambling frequency, but the level of problems due to gambling frequency did not change depending on the ADHD symptom level. There was an interaction effect between sex and gambling frequency in relation to gambling problems.

    Conclusions: Adolescents with ADHD symptoms seem to be more sensitive to gambling, in terms of being susceptible to developing gambling problems. However, once susceptible, adolescents with ADHD symptoms are affected by gambling frequency similarly to other susceptible participants.

  • 122.
    Hellström, Hans-Olov
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lindh, Ulf
    Mjöberg, Bengt
    Measurement accuracy of aluminium content in bone2000In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 105, no 1, p. 67-71Article in journal (Refereed)
    Abstract [en]

    The aluminium content in bone has been related in several ways: to the weight of wet bone, to the weight of dry bone, to the weight of bone-ash and to the calcium content of bone. We determined the accuracy and precision of measurement (using an inductively coupled mass-spectrometer) in 30 bone samples taken from one patient. The coefficient of variation of the aluminium/weight-quotient was 12.4 per cent for wet bone, 4.7 for dry bone and 5.0 for bone ash; and the coefficient of variation of the aluminium/calcium-weight-quotient was 7.5 per cent. Thus, the aluminium content in bone seems to be best related to the weight of dry bone.

  • 123. Henriques, Thomas
    et al.
    Cunningham, Bryan W.
    Mcafee, Paul C.
    Olerud, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    In vitro biomechanical evaluation of four fixation techniques for distractive-flexion injury stage 3 of the cervical spine2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 198-206Article in journal (Refereed)
    Abstract [en]

    Purpose. Anterior plate fixation has been reported to provide satisfactory results in cervical spine distractive flexion (DF) injuries stages 1 and 2, but will result in a substantial failure rate in more unstable stage 3 and above. The aim of this investigation was to determine the biomechanical properties of different fixation techniques in a DF-3 injury model where all structures responsible for the posterior tension band mechanism are torn. Methods. The multidirectional three-dimensional stiffness of the subaxial cervical spine was measured in eight cadaveric specimens with a simulated DF-3 injury at C5-C6, stabilized with four different fixation techniques: anterior plate alone, anterior plate combined with posterior wire, transarticular facet screws, and a pedicle screw-rod construct, respectively. Results. The anterior plate alone did not improve stability compared to the intact spine condition, thus allowing considerable range of motion around all three cardinal axes (p > 0.05). The anterior plate combined with posterior wire technique improved flexion-extension stiffness (p = 0.023), but not in axial rotation and lateral bending. When the anterior plate was combined with transarticular facet screws or with a pedicle screws-rod instrumentation, the stability improved in flexion-extension, lateral bending, and in axial rotation (p < 0.05). Conclusions. These findings imply that the use of anterior fixation alone is insufficient for fixation of the highly unstable DF-3 injury. In these situations, the use of anterior fixation combined with a competent posterior tension band reconstruction (e.g. transarticular screws or a posterior pedicle screws-rod device) improves segmental stability.

  • 124.
    Heyman, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bejarano, Maria-Teresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Access, excess, and ethics—towards a sustainable distribution model for antibiotics2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 134-141Article, review/survey (Refereed)
    Abstract [en]

    The increasing antibiotic resistance is a global threat to health care as we know it. Yet there is no model of distribution ready for a new antibiotic that balances access against excessive or inappropriate use in rural settings in low-and middle-income countries (LMICs) where the burden of communicable diseases is high and access to quality health care is low. Departing from a hypothetical scenario of rising antibiotic resistance among pneumococci, 11 stakeholders in the health systems of various LMICs were interviewed one-on-one to give their view on how a new effective antibiotic should be distributed to balance access against the risk of inappropriate use. Transcripts were subjected to qualitative 'framework' analysis. The analysis resulted in four main themes: Barriers to rational access to antibiotics; balancing access and excess; learning from other communicable diseases; and a system-wide intervention. The tension between access to antibiotics and rational use stems from shortcomings found in the health systems of LMICs. Constructing a sustainable yet accessible model of antibiotic distribution for LMICs is a task of health system-wide proportions, which is why we strongly suggest using systems thinking in future research on this issue.

  • 125.
    Holzgraefe, Bernhard
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.;Arvika Community Hosp, Cty Council Varmland, Dept Anaesthesia Surg Serv & Intens Care Med, Arvika, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    von Kobyletzki, Laura
    Lund Univ, Skane Univ Hosp, Dept Dermatol, Malmo, Sweden.;Karlstad Univ, Dept Publ Hlth Sci, Karlstad, Sweden..
    Do we have scientific evidence about the effect of hypoxaemia on cognitive outcome in adult patients with severe acute respiratory failure?2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 68-70Article in journal (Refereed)
  • 126. Hron, Gregor
    et al.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thiele, Thomas
    Althaus, Karina
    Busemann, Christoph
    Friesecke, Sigrun
    Greinacher, Andreas
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Alternative diagnosis to heparin-induced thrombocytopenia in two critically ill patients despite a positive PF4/heparin-antibody test2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Thrombocytopenia can cause diagnostic challenges in patients who have received heparin. Heparin-induced thrombocytopenia (HIT) is often considered in the differential diagnosis, and a positive screening can be mistaken as confirmation of the disorder. We present two patients who both received low-molecular-weight heparin for several days. In the first patient, clinical judgment rejected the suspicion of HIT despite a positive screening assay, and treatment for the alternative diagnosis of post-transfusion purpura was correctly initiated. In the second patient, the inaccurate diagnosis HIT was pursued due to a positive screening assay, while the alternative diagnosis of drug-dependent thrombocytopenia caused by piperacillin/tazobactam was rejected. This resulted in re-exposure to piperacillin/tazobactam which caused a second episode of severe thrombocytopenia. A positive screening assay for platelet factor 4/heparin-antibody should be verified by a functional assay, especially in patients with low pretest probability for HIT.

  • 127.
    Hughes, Diarmaid
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Discovery and preclinical development of new antibiotics2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 162-169Article, review/survey (Refereed)
    Abstract [en]

    Antibiotics are the medical wonder of our age, but an increasing frequency of resistance among key pathogens is rendering them less effective. If this trend continues the consequences for cancer patients, organ transplant patients, and indeed the general community could be disastrous. The problem is complex, involving abuse and overuse of antibiotics (selecting for an increasing frequency of resistant bacteria), together with a lack of investment in discovery and development (resulting in an almost dry drug development pipeline). Remedial approaches to the problem should include taking measures to reduce the selective pressures for resistance development, and taking measures to incentivize renewed investment in antibiotic discovery and development. Bringing new antibiotics to the clinic is critical because this is currently the only realistic therapy that can ensure the level of infection control required for many medical procedures. Here we outline the complex process involved in taking a potential novel antibiotic from the initial discovery of a hit molecule, through lead and candidate drug development, up to its entry into phase I clinical trials. The stringent criteria that a successful drug must meet, balancing high efficacy in vivo against a broad spectrum of pathogens, with minimal liabilities against human targets, explain why even with sufficient investment this process is prone to a high failure rate. This emphasizes the need to create a well-funded antibiotic discovery and development pipeline that can sustain the continuous delivery of novel candidate drugs into clinical trials, to ensure the maintenance of the advanced medical procedures we currently take for granted.

  • 128.
    Hårdstedt, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Lindblom, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    A novel model for studies of blood-mediated long-term responses to cellular transplants2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, p. 28-39Article in journal (Refereed)
    Abstract [en]

    Aims

    Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h.

    Methods

    Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability.

    Results

    Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen.

    Conclusion

    A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

  • 129.
    Högberg, Dominika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery. NU Hosp Org, Dept Surg, Trollhattan, Sweden..
    Dellagrammaticas, Demosthenes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Kragsterman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Simplified ultrasound protocol for the exclusion of clinically significant carotid artery stenosis2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 3, p. 165-169Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate a simplified ultrasound protocol for the exclusion of clinically significant carotid artery stenosis for screening purposes. Material and methods: A total of 9,493 carotid arteries in 4,748 persons underwent carotid ultrasound examination. Most subjects were 65-year-old men attending screening for abdominal aortic aneurysm. The presence of a stenosis on B-mode and/or a mosaic pattern in post-stenotic areas on colour Doppler and maximum peak systolic velocity (PSV) in the internal carotid artery (ICA) were recorded. A carotid stenosis was defined as The North American Symptomatic Carotid Endarterectomy Trial (NASCET) >20% and a significant stenosis as NASCET >50%. The kappa (kappa) statistic was used to assess agreement between methods. Sensitivity, specificity, positive predictive (PPV), and negative predictive (NPV) values were calculated for the greyscale/mosaic method compared to conventional assessment by means of PSV measurement. Results: An ICA stenosis was found in 121 (1.3%) arteries; 82 (0.9%) were graded 20%-49%, 16 (0.2%) were 50%-69%, and 23 (0.2%) were 70%-99%. Eighteen (0.2%) arteries were occluded. Overall, the greyscale/mosaic protocol showed a moderate agreement with ICA PSV measurements for the detection of carotid artery stenosis, x=0.455. The sensitivity, specificity, PPV, and NPV for detection of >20% ICA stenosis were 91% (95% CI 0.84-0.95), 97% (0.97-0.98), 31% (0.26-0.36), and 97% (0.97-0.97), respectively. The corresponding figures for >50% stenosis were 90% (0.83-0.95), 97% (0.97-0.98), 11% (0.08-0.15), and 100% (0.99-1.00). Conclusion: Compared with PSV measurements, the simplified greyscale/mosaic protocol had a high negative predictive value for detection of >50% carotid stenosis, suggesting that it may be suitable as a screening method to exclude significant disease.

  • 130.
    Högman, Marieann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Meriläinen, Pekka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Guidance for a personal target value of F(E)NO in allergic asthma: case report and theoretical example2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 1, p. 59-61Article in journal (Refereed)
    Abstract [en]

    In clinically stable asthma the exhaled NO values (FENO) are generally higher than in control subjects. Therefore, reference values are of limited importance in clinical practice. This is demonstrated in this case report, but it is also shown that NO parameters from non-linear modelling do have a clinical value. A subject with asthma was treated with inhaled corticosteroids for 1 week. The non-linear NO model was used to measure the response to treatment. The NO parameters from subjects with atopic rhinitis and asthma were fed into a computer program to generate theoretical FENO50 values, i.e. target values. There was a dramatic decrease in FENO50 due to treatment, from 82 to 34 ppb, but it remained higher than in healthy controls. This is due to the elevated diffusion rate of NO, unchanged by treatment. When the NO parameters are known, a personal best value of FENO50 (fractional concentration of exhaled NO in the gas phase, 50 mL/s) can be calculated, which can be the target value when only FENO50 can be monitored. In conclusion, reference values for NO parameters are shown to be clinically useful. It is essential that every patient receives his/her target value of FENO50, when only a single NO measurement is available. In our opinion, this is the reason why there are few successful studies of trying to target the NO value with inhaled corticosteroids. 

  • 131.
    Högman, Marieann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Meriläinen, Pekka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Guidance for a personal target value of FeNO in allergic asthma: Case report and theoretical example2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 1, p. 59-61Article in journal (Refereed)
    Abstract [en]

    In clinically stable asthma the exhaled NO values (FENO) are generally higher than in control subjects. Therefore, reference values are of limited importance in clinical practice. This is demonstrated in this case report, but it is also shown that NO parameters from non-linear modelling do have a clinical value. A subject with asthma was treated with inhaled corticosteroids for 1 week. The non-linear NO model was used to measure the response to treatment. The NO parameters from subjects with atopic rhinitis and asthma were fed into a computer program to generate theoretical FENO0.05 values, i.e. target values. There was a dramatic decrease in FENO0.05 due to treatment, from 82 to 34 ppb, but it remained higher than in healthy controls. This is due to the elevated diffusion rate of NO, unchanged by treatment. When the NO parameters are known, a personal best value of FENO0.05 (fractional concentration of exhaled NO in the gas phase, 0.05 L/s) can be calculated, which can be the target value when only FENO0.05 can be monitored. In conclusion, reference values for NO parameters are shown to be clinically useful. It is essential that every patient receives his/her target value of FENO0.05, when only a single NO measurement is available. In our opinion, this is the reason why there are few successful studies of trying to target the NO value with inhaled corticosteroids.

  • 132.
    Jabbar, Rowa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Saldeen, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    A new predictor of risk for sudden cardiac death2006In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 111, no 2, p. 169-177Article in journal (Refereed)
    Abstract [en]

    Background. Long-chain fatty acids, particularly omega-3 fatty acids found primarily in fish oil, are beneficial in different physiological conditions in the human body. High intake of omega-3 fatty acids has been found to have a strong inverse relationship to sudden cardiac death. An index showing the relationship between different fatty acids in the blood could be an important risk indicator for sudden cardiac death. Methods. Whole-blood samples from the fingertip were collected and fatty acids were measured by a new simple method using direct transmethylation. Two groups were compared: subjects who had been taking fish oil daily during the last 6 years, and subjects who had not been taking fish oil. Results. Six different fatty acid indices were calculated. Five of them take both DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) into consideration, and the sixth includes only EPA and not DHA in the calculation. This latter index, the ratio between EPA and arachidonic acid, gave the best result, with the largest difference between the two groups. This index varied between 5 and 118 among the different individuals; 70% of the fish oil consumers having an index >= 50. Based on the present knowledge about the relationship between blood levels of omega-3 fatty acids and sudden cardiac death obtained from studies of 14,000 individuals, a subject with an index below 50 should be advised to increase his/her intake of omega-3 fatty acids. Conclusion. The EPA/arachidonic acid index may be an important new predictor of risk for sudden cardiac death, and reflects the individual requirement for consumption of omega-3 fatty acids.

  • 133.
    Jabbari, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Reiser, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hakelius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Correlations between initial cleft size and dental anomalies in unilateral cleft lip and palate patients after alveolar bone grafting2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, p. 33-37Article in journal (Refereed)
    Abstract [en]

    Objective To determine in individuals with unilateral cleft lip and palate the correlation between initial cleft size and dental anomalies, and the outcome of alveolar bone grafting. Methods A total of 67 consecutive patients with non-syndromic unilateral complete cleft lip and palate (UCLP) were included from the cleft lip and palate-craniofacial center, Uppsala University Hospital, Sweden. All patients were operated by the same surgeon and treated according to the Uppsala protocol entailing: lip plasty at 3 months, soft palate closure at 6 months, closure of the residual cleft in the hard palate at 2 years of age, and secondary alveolar bone grafting (SABG) prior to the eruption of the permanent canine. Cleft size was measured on dental casts obtained at the time of primary lip plasty. Dental anomalies were registered on radiographs and dental casts obtained before bone grafting. Alveolar bone height was evaluated with the Modified Bergland Index (mBI) at 1 and 10-year follow-up. Results Anterior cleft width correlated positively with enamel hypoplasia and rotation of the central incisor adjacent to the cleft. There was, however, no correlation between initial cleft width and alveolar bone height at either 1 or 10 years follow-up. Conclusions Wider clefts did not seem to have an impact on the success of secondary alveolar bone grafting but appeared to be associated with a higher degree of some dental anomalies. This finding may have implications for patient counseling and treatment planning.

  • 134.
    Jabbari, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Reiser, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Thor, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
    Hakelius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Corrlations between initial cleft size and dental anomalies in unilateral cleft lip and palate patients after alveolar bone graftingIn: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967Article in journal (Refereed)
  • 135.
    Jansson, Emil
    et al.
    Avesta Hosp, Dept Internal Med, Avesta, Sweden.
    Nevéus, Tryggve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Rectal diameter assessment in enuretic children-exploring the association between constipation and bladder function2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 3, p. 179-182Article in journal (Refereed)
    Abstract [en]

    Objectives: Detrusor overactivity and constipation often co-exist in children with enuresis. Constipation is known to be linked to detrusor overactivity. The voiding chart is the best non-invasive way to investigate bladder function, whereas the ultrasonographical detection of rectal dilatation is the best way to objectify constipation. We wanted to investigate a possible relationship between the rectal diameter and voiding chart data in enuretic children.

    Methods: Children with therapy-resistant enuresis were retrospectively evaluated. All had completed a voiding chart for at least 48 h. The rectal diameter was assessed ultrasonographically. The cutoff for rectal dilatation was set at 30 mm.

    Results: We evaluated 74 patients (12 girls) aged 10.2 +/- 2.8years, 35 of whom had rectal dilatation. No significant differences in voiding chart parameters were found between children with normal versus dilated rectum. Neither did urgency or a history of daytime incontinence differ between the groups. Boys were more likely to have rectal dilatation than girls (p = 0.02).

    Conclusions: The absence of differences regarding voiding chart data may be explained as two mechanisms neutralizing each other: behavioral factors may make the constipated children void seldom and with large volumes, whereas detrusor overactivity caused by rectal compression of the bladder may have the opposite effect. Another option may be that the voiding chart is too blunt an instrument to detect detrusor overactivity. Constipation, and thus presumably bladder dysfunction, seems to be more important in enuretic boys than girls.

  • 136.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Drott, Carl Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gao, Xiang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kallskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lau, Joey Börjesson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Liljebäck, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Quach, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Strömberg, Victoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ullsten, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Pancreatic islet blood flow and its measurement2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 81-95Article, review/survey (Refereed)
    Abstract [en]

    Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

  • 137.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Orjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Glucose-induced time-dependent potentiation of insulin release, but not islet blood perfusion, in anesthetized rats2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 1, p. 47-56Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Repeated administration of glucose in vivo leads to a time-dependent potentiation of insulin release. Glucose is also known to stimulate pancreatic islet blood flow, but whether this is associated with a time-dependent potentiation is unknown. We therefore repeatedly administered glucose to anesthetized rats and evaluated effects on insulin release and islet blood flow. METHODS: Male Wistar-Furth rats, anesthetized with thiobutabarbital, were injected intravenously with 1 ml of saline or glucose at times 0, 30 and 60 min. The combinations used were saline + saline + saline (SSS), glucose + saline + saline (GSS), saline + saline + glucose (SSG) and glucose + glucose + glucose (GGG). Regional organ blood flow values were measured 3 min after the final injection with a microsphere technique, and at this time also serum insulin concentrations were determined with ELISA. RESULTS: Serum insulin concentrations as well as total pancreatic, pancreatic islet and duodenal blood flow were higher in SSG and GGG-treated rats when compared to those given SSS and GSS. However, only insulin concentrations, not blood flow values, were higher in GGG rats when compared to SSG animals. CONCLUSIONS: Glucose-induced time-dependent potentiation of insulin release occurs in vivo in thiobutabarbital-anesthetized rats, but is not associated with a further increase in islet blood flow.

  • 138.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Arginase increases total pancreatic and islet blood flow in anaesthetized mice2007In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 112, no 2, p. 165-173Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have demonstrated that the high basal pancreatic islet blood perfusion is crucially dependent on nitric oxide formation. Arginase can interfere with the formation of nitric oxide by limiting substrate availability. The aim of the present study was to evaluate the influence of arginase on islet blood perfusion in anaesthetized mice. METHODS: The blood perfusion of the pancreatic islets was measured with a microsphere technique in anaesthetized NMRI mice after administration of arginase. RESULTS: Arginase administration increased both total pancreatic and islet blood flow to the same degree. Also adrenal blood flow was increased, whereas other organ blood flow values were unaffected. CONCLUSION: Arginase induces a paradoxical increase in pancreatic and islet blood flow, the reasons for which are still unknown.

  • 139.
    Jansson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Functional stimulation of graft nerves has minor effects on insulin release from transplanted rat pancreatic islets2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 209-216Article in journal (Refereed)
    Abstract [en]

    Introduction. Morphological evidence for reinnervation of pancreatic islet grafts is plentiful. However, to what extent intra-graft nerves influence the endocrine functions of the islet transplant is largely unknown. We therefore aimed to directly stimulate nerves leading to islet grafts with electrodes and measure insulin secretion in response to this.

    Methods. We implanted syngeneic islets under the renal capsule of rats, and examined them 1 or 7-9 months later. In anesthetized rats blood samples were collected from the renal vein and femoral artery, respectively, during electrode stimulation of the nerves leading to the islet grafts. Results. As expected, nerve stimulation decreased renal blood flow. However, serum insulin concentrations in samples derived from the renal vein or femoral artery changed in concert with one another, both during normoglycemia and acute hyperglycemia.

    Conclusion. Reinnervation which occurs after islet transplantation under the renal capsule has minor effects on graft endocrine function.

  • 140.
    Jasovsky, Dusan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Littmann, Jasper
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Antimicrobial resistance-a threat to the world's sustainable development2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 3, p. 159-164Article, review/survey (Refereed)
    Abstract [en]

    This commentary examines how specific sustainable development goals (SDGs) are affected by antimicrobial resistance and suggests how the issue can be better integrated into international policy processes. Moving beyond the importance of effective antibiotics for the treatment of acute infections and health care generally, we discuss how antimicrobial resistance also impacts on environmental, social, and economic targets in the SDG framework. The paper stresses the need for greater international collaboration and accountability distribution, and suggests steps towards a broader engagement of countries and United Nations agencies to foster global intersectoral action on antimicrobial resistance.

  • 141.
    Jernberg-Wiklund, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Targeting the IGF-1R signaling and mechanisms for epigenetic gene silencing in human multiple myeloma2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 166-177Article, review/survey (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell-cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM.

  • 142.
    Jiang, Yiwen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    On the origin of glioma2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 113-121Article in journal (Refereed)
    Abstract [en]

    Glioma is the most frequent primary brain tumor of adults that has a presumably glial origin. Although our knowledge regarding molecular mechanisms and signaling pathways involved in gliomagenesis has increased immensely during the past decade, high-grade glioma remains a lethal disease with dismal prognosis. The failure of current therapies has to a large extent been ascribed the functional heterogeneity of glioma cells. One reason for this heterogeneity is most certainly the large number of variations in genetic alterations that can be found in high-grade gliomas. Another factor that may influence glioma heterogeneity could be the cell type from which the glioma is initiated. The cell of origin for glioma is still undefined, and additional knowledge about this issue may prove critical for a more complete understanding of glioma biology. Based on information from patients, developmental biology, and experimental glioma models, the most putative target cells include astrocytes, neural stem cells, and oligodendrocyte precursor cells, which are all discussed in more detail in this article. Animal modeling of glioma suggests that these three cell types have the capability to be the origin of glioma, and we have reason to believe that, depending on the initiating cell type, prognosis and response to therapy may be significantly different. Thus, it is essential to explore further the role of cellular origin in glioma.

  • 143.
    Johansson, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The Swedish system for compensation of patient injuries2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 88-90Article in journal (Refereed)
    Abstract [en]

    Since 1975 Sweden has had a patient insurance system to compensate patients for health-related injuries. The system was initially based on a voluntary patient insurance solution, but in 1997 it was replaced by the Patient Insurance Act. The current Act covers both physical and mental injuries. Although about 9,000-10,000 cases are processed in Sweden annually, compensation is paid in barely half of these cases. In the Swedish patient injury claim processing system, the Patient Claims Panel is the authority that plays an important role in ensuring fair and consistent application of the Act.

  • 144.
    Johansson, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The Uppsala anatomist Ivar Sandstrom and the parathyroid gland2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2, p. 72-77Article in journal (Refereed)
  • 145.
    Johansson, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Uppsala University Hospital 300 yearsa survey of the surgical development2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 1, p. 2-11Article in journal (Refereed)
    Abstract [en]

    Professor Lars Roberg, the initiator of the Nosocomium Academicum (1708), our first university hospital in Sweden, claimed that 'no-one who does not understand surgery is a completely trained doctor'. However, it was not until the end of 19th century that modern surgery was born. The Academic Hospital was opened in 1867, and at the turn of that century Uppsala had a flourishing period under the influence of Karl Gustav Lennander, professor of surgery. In 1889 he performed the first appendectomy in Scandinavia. At the end of the 19th century the surgical tree began to branch out. In Uppsala gynaecology and obstetrics was the first to be an independent speciality (1891). It was followed by ophthalmology (1894) with Allvar Gullstrand as professor and head of the department. Gullstrand received the Nobel Prize in medicine in 1911. A separate department for diseases of the ear, nose, and throat was founded in 1916 with the Nobel laureate Robert Barany as head. Thoracic surgery began in Uppsala in the 1940s with lung surgery and was separated from general surgery in 1958 with Viking Olov Bjork as head of the department. Bjork introduced open heart surgery in Uppsala. In 1951 reconstructive plastic surgery was organized by Tord Skoog, who devoted special interest to operations for cleft lip and palate surgery. Neurosurgery was established in 1962, and Uppsala has held a prominent position in the development of modern neurointensive care. During the 1970s general surgery became subspecialized into gastrointestinal, endocrine, and vascular surgery. At the same time fracture surgery was transferred to the orthopaedists, and urological surgery became an independent speciality. Transplantation surgery was introduced in Uppsala in 1967, when Professor Lars Thoren performed the first kidney transplantation. Today Uppsala has a leading position in transplantation of pancreatic islets cells.

  • 146.
    Johansson, Henry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Segerström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function1972In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 77, no 3, p. 183-188Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal propulsive motility was studied afterinhgastric deposition of a non-absorbable isotope inrats after subcutaneous glucagon injections. Glucagonadministration was followed by retardation of gastricemptying. The results indicated that the retarding effectof glucagon on gastrointestinal propulsion was independentof the presence of both thyroid and parathyroid tissue.The hypocalcemic effect of glucagon was exerted independentlyof the presence of thyroid tissue, Le. thyrocalcitonin.

  • 147.
    Johansson, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Aarts, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Darj, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    First-time parents' experiences of home-based postnatal care in Sweden2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 131-137Article in journal (Refereed)
    Abstract [en]

    Aim. To gain a deeper understanding of first-time parents’ experiences of early discharge from hospital after delivery andhome-based postnatal care.Material and methods. The study was comprised of focus group interviews, interviews with couples and with fathers. Twentyoneparents participated. Inclusion criteria: healthy women who have given birth to their first child after a normal pregnancyand delivery, the women’s partners, healthy and full term babies, Swedish-speaking, discharge from the delivery ward within24 hours, resident in the Uppsala community, the parents cohabited at the time of the delivery. The material was analysed byqualitative content analysis.Results. Three themes emerged: The family’s strategy, which describes the family’s expectations of postnatal care and theirexperiences of the real situation. Some are flexible concerning going home early, and others have decided in advance. Selfrelianceand strength, which explores the parents’ feelings of security and uncertainty, freedom and independence, and sharedresponsibility. Breast-feeding is described as the ‘main thing’, an interactive learning process. Professional support in the homesummarizes the parents’ experience of the midwife’s support at home. While conflicting feelings may be revealed during thefirst days, the midwife confirms their new roles as parents. The midwife is seen as a support and adviser to the parents.Conclusion. This study shows that parents welcome home-based postnatal care with professional support from midwives. Weconclude that this care suits healthy families. We think it will be more important in the future to discriminate between healthyfamilies and those in need of hospital care, than to focus on the moment when they leave the hospital, early or late.

  • 148. Kallings, L V
    et al.
    Emtner, M
    Bäcklund, L
    Exercise-induced bronchoconstriction in adults with asthma--comparison between running and cycling and between cycling at different air conditions.1999In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 104, no 3, p. 191-8Article in journal (Refereed)
    Abstract [en]

    The bronchial response to cycling and running was compared in six adult asthmatic persons. The effects of different air conditions during cycling regarding the induction of bronchoconstriction was studied. The exercise consisted of 6 minutes' work at an intensity of 80-85% of maximal heart rate. Heart rate, oxygen consumption and ventilation were measured to check that the exercise level was the same in all tests. Peak expiratory flow (PEF) was used to test for bronchoconstriction. Bicycling and treadmill running were performed under indoor conditions and bicycling while breathing cold, dry air (-18 degrees C) and room-tempered humid air (60% RH), respectively. No difference in bronchoconstriction was found between cycling and running under indoor conditions. However, bicycling exercise with inhalation of cold dry air provoked more bronchoconstriction than when inhalating humid air (PEF reductions of 19.4+/-6% and 6.1+/-2%, respectively). No differences were found between the exercise modes in heart rate, oxygen consumption, ventilation per minute, respiratory rate, carbon dioxide elimination or subjective ratings of perceived exertion and breathlessness. It is concluded that it is not the type of exercise, but the ventilation demand and humidity of the inspired air that are the main determinants of the occurrence and degree of bronchoconstriction.

  • 149.
    Kamble, Prasad G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cook, Naomi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 234-242Article in journal (Refereed)
    Abstract [en]

    AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

    METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

    RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

    CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

  • 150.
    Kanaykina, Nadya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Abelson, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comparative Medicine.
    King, Dale
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Liakhovitskaia, Anna
    Schreiner, Silke
    Wegner, Michael
    Kozlova, Elena N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    In vitro and in vivo effects on neural crest stem celldifferentiation by conditional activation of Runx1 short isoform and its effecton neuropathic pain behavior2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, p. 56-64Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Runx1, a Runt domain transcription factor, controls thedifferentiation of nociceptors that express the neurotrophin receptor Ret,regulates the expression of many ion channels and receptors, and controls thelamina-specific innervation pattern of nociceptive afferents in the spinal cord. Moreover, mice lacking Runx1 exhibit specific defects in thermal and neuropathic pain. We investigated whether conditional activation of Runx1 short isoform(Runx1a), which lacks a transcription activation domain, influencesdifferentiation of neural crest stem cells (NCSCs) in vitro and in vivo duringdevelopment and whether postnatal Runx1a activation affects the sensitivity toneuropathic pain. METHODS: We activated ectopic expression of Runx1a in cultured NCSCs using the Tet-ON gene regulatory system during the formation ofneurospheres and analyzed the proportion of neurons and glial cells originatingfrom NCSCs. In in vivo experiments we applied doxycycline (DOX) to pregnant mice (days 8-11), i.e. when NCSCs actively migrate, and examined the phenotype ofoffsprings. We also examined whether DOX-induced activation of Runx1a in adultmice affects their sensitivity to mechanical stimulation following a constrictioninjury of the sciatic nerve. RESULTS: Ectopic Runx1a expression in cultured NCSCsresulted in predominantly glial differentiation. Offsprings in which Runx1a hadbeen activated showed retarded growth and displayed megacolon, pigment defects,and dystrophic dorsal root ganglia. In the neuropathic pain model, the threshold for mechanical sensitivity was markedly increased following activation of Runx1a.CONCLUSION: These data suggest that Runx1a has a specific role in NCSCdevelopment and that modulation of Runx1a activity may reduce mechanicalhypersensitivity associated with neuropathic pain.

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