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  • 1.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Eriksson, Robert
    Clinical Neurophysiology, Umeå University Hospital, Umeå, Sweden.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis2023In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 55, no 2, article id 2239269Article in journal (Refereed)
    Abstract [en]

    Introduction: In hereditary transthyretin amyloidosis (ATTRv), two different fibrillar forms causing the amyloid deposition, have been identified, displaying substantially cardiac or neuropathic symptoms. Neuropathic symptoms are more frequent in early-onset patients, whereas late-onset patients, besides cardiac symptoms, seem to develop carpal tunnel syndrome, more often. With ultrasonography (US) of peripheral nerves, it is possible to distinguish structural changes, and enlarged cross-sectional area (CSA). The main purpose of this study was, for the first time, to elucidate US of peripheral nerves in Swedish ATTRv patients at an early stage of the disease, and to evaluate possible early enlarged CSA.

    Material and methods: This prospective study included first visit data of 13 patients, aged 30–88 years, of which 11 with late-onset age. All had a positive V30M mutation. Eight men and six women (aged 28–74 years) served as controls.

    Results: Significantly enlarged CSA was seen in ATTRv patients for the tibial nerve at the ankle (p =.001), the sural nerve (p <.001), the peroneal nerve at the popliteal fossa (p =.003), and the ulnar nerve at the middle upper arm (p =.007).

    Conclusion: US of peripheral nerves could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression.

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  • 2.
    Carlsson, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Sundsvall Hosp, Dept Occupat & Environm Med, SE-85186 Sundsvall, Sweden.
    Burström, Lage
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Heldestad Lilliesköld, Victoria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Tohr
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Sundsvall Hosp, Dept Occupat & Environm Med, SE-85186 Sundsvall, Sweden.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wahlström, Jens
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Neurosensory sequelae assessed by thermal and vibrotactile perception thresholds after local cold injury2014In: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 73, article id 23540Article in journal (Refereed)
    Abstract [en]

    Background. Local freezing cold injuries are common in the north and sequelae to cold injury can persist many years. Quantitative sensory testing (QST) can be used to assess neurosensory symptoms but has previously not been used on cold injury patients.

    Objective. To evaluate neurosensory sequelae after local freezing cold injury by thermal and vibrotactile perception thresholds and by symptom descriptions.

    Design. Fifteen patients with a local freezing cold injury in the hands or feet, acquired during military training, were studied with QST by assessment of vibrotactile (VPT), warmth (WPT) and cold (CPT) perception thresholds 4 months post-injury. In addition, a follow-up questionnaire, focusing on neurovascular symptoms, was completed 4 months and 4 years post-injury.

    Results. QST demonstrated abnormal findings in one or both affected hands for VPT in 6 patients, for WPT in 4 patients and for CPT in 1 patient. In the feet, QST was abnormal for VPT in one or both affected feet in 8 patients, for WPT in 6 patients and for CPT in 4 patients. Freezing cold injury related symptoms, e. g. pain/discomfort when exposed to cold, cold sensation and white fingers were common at 4 months and persisted 4 years after the initial injury.

    Conclusions. Neurosensory sequelae after local freezing cold injury, in terms of abnormal thermal and/or vibration perception thresholds, may last at least 4 months after the initial injury. Symptoms such as pain/discomfort at cold exposure, cold sensations and white fingers may persist at least 4 years after the initial injury.

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  • 3.
    Heldestad Lilliesköld, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Method-of-limits: Cold and warm perception thresholds at proximal and distal body regions2018In: Clinical Neurophysiology Practice, E-ISSN 2467-981X, Vol. 3, p. 134-140Article in journal (Refereed)
    Abstract [en]

    Objective: Thermal quantitative sensory testing with the 'Method-of-Limits' is an established rationale for detection of small nerve fiber dysfunction, but adequate reference values are crucial for such evaluations, regardless of the underlying cause. This study assessed reference data for cold- (CPT) and warm- (WPT) perception thresholds at both proximal and distal sites in eight body regions of the lower and upper extremities, all determined within the same test session for each subject.

    Methods: Seventy-five healthy subjects (aged 16-72 years) were tested according to the method-of-limit for CPT and WPT at the dorsum of the foot, the medial and lateral lower leg, the ventral thigh, the thenar eminence, the radial and ulnar part of the lower arm, and the anterior deltoid part of the upper arm.

    Results: Overall, thermal perception thresholds (TPT) varied with test location, but were higher in the lower than in the upper part of the body, also WPT were generally higher than CPT. TPT at the dorsum foot highly correlated with age, while inconsistent correlations were noted between TPT and age or height at other tested locations.

    Conclusion: This study describes for the first time reference values at eight defined body regions, at both proximal and distal sites.

    Significance: The report enables refined evaluations of general small nerve fiber function, as assessed by quantitative thermal sensory testing with the Method-of-Limits.

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  • 4.
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Methodological aspects and usefulness of Quantitative Sensory Testing in early small fiber polyneuropathy: a clinical study in Swedish hereditary transthyretin amyloidosis patients2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Generalised polyneuropathy (PNP) is a common cause to neurological impairment, and may be an early symptom of a severe systemic disease. One such illness is hereditary transthyretin (TTR) amyloidosis (ATTR), a progressive fatal disorder caused by a mutation on the TTR gene. More than 100 such mutations have been found worldwide, of which Val30Met is the most common neuropathic variant with initial clinical manifestations indicating small fiber impairment. Differences in onset age, penetrance and phenotypes are present between endemic areas. Liver transplantation generally slows the progress of the symptom development, especially in patients with short disease duration. Ongoing research has also shown promising results with drug interventions. In any event, early diagnosis of PNP onset in ATTR patients is crucial to ensure early therapeutic interventions. Nerve conduction studies (NCS) and electromyography (EMG) provide the basis for evaluation of the functional state of the thick myelinated nerve fibres in patients with symptoms of PNP, but no such quantitative methods are available for the thin myelinated or unmyelinated fibers. Instead, a psychophysical method with thermal quantitative sensory testing (QST) can provide indirect information about the overall function in the afferent small fiber systems. The purpose of thesis was to evaluate the applicability of QST by the Method-of-limits (MLI) for early detection of PNP in Swedish ATTR patients with the Val30Met mutation.

    In healthy subjects the repeatability of the MLI was assessed, and reference values for thermal perception thresholds (TPT) in several body regions were determined. No significant differences in TPT or pain thresholds were found at repeated testing with MLI, indicating that the MLI is a reliable method. However, the results show that the arrangement of the testing order is of importance, as cold (CT) and warm (WT) perception thresholds were significantly elevated when tested after thermal pain assessments, instead of before. I general, the TPT was more elevated at lower parts of the body compared to the upper part, and with higher WT than CT, fully in accordance with the underlying anatomical and physiological prerequisites for QST. In biopsy verified ATTR patients lacking EMG and NCS abnormalities, significantly elevated TPT were found compared to controls. Furthermore, significantly more increased TPT were observed in patients with an early onset of the disease, compared those with a late onset. Finally, a combined detailed evaluation of QST and heart rate variability (HRV) analyses demonstrated correlations between QST and HRV abnormalities in patients with late onset, but not in those with early onset.

    The present thesis emphasizes the importance of incorporating QST early in the clinical evaluation of ATTR patients with a Val30Met mutation and with symptoms of thin fiber PNP. This is particularly indicated when patients report symptoms, or show signs, of neuropathic small fiber affection, but simultaneously exhibit normal EMG and NCS findings. The results furthermore underline the importance of performing both QST and HRV for a complete evaluation of both the thin somatic and autonomic nerve fibers, as both types of nerves may be affected early in the ATTR disease.

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  • 5.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Sellersjö, Lisa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Reproducibility and influence of test modality order on thermal perception and thermal pain thresholds in quantitative sensory testing2010In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 121, no 11, p. 1878-1885Article in journal (Refereed)
    Abstract [en]

    The findings show that QST with the MLI is a reliable tool for indirect evaluation of human small nerve fiber function.

  • 6.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy2007In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 35, no 2, p. 189-195Article in journal (Refereed)
  • 7.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Thermal perception thresholds: reference data and response characteristicsManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: To establish reference data for separate cold and warm perception thresholds at quantitative sensory testing with the method-of-limits at eight different body regions, and to evaluate the psychophysical response characteristics to consecutive cold and warm stimuli.

    Methods: 75 healthy subjects were tested at the dorsum of the foot, the medial and lateral lower leg, the ventral thigh, the thenar eminence, the radial and ulnar part of the lower arm, and the anterior deltoid part of the upper arm. Thermal perception thresholds were assessed with the method of limits, and estimated from the average responses during ten consecutive cold and warm stimuli.

    Results: At all tested sites, the TPT were significantly higher in the lower part of the body compared to the upper, and also the warm thresholds were significantly higher than the cold thresholds. Inconsistent correlations were noted between thermal perception thresholds and age or height, but thresholds at the dorsal foot were highly correlated with age.

    Conclusions: Reference data from separate body regions in the lower and upper extremities are essential for adequate evaluation of thermal detection and perception capacity. At testing of thermal thresholds in individual subjects the thermal perception generally decreases distally in elderly and particularly in the lower extremities.

  • 8.
    Heldestad, Victoria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Obayashi, Konen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR2011In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 18, no 4, p. 183-190Article in journal (Refereed)
    Abstract [en]

    Patients with transthyretin amyloidosis (ATTR) polyneuropathy, a hereditary fatal disease, often report defects in both thermal perception and autonomic nervous system function as their first clinical symptoms. While elevated thermal perception thresholds (TPT) for cold and warmth only recently have been shown as an early marker of small nerve fiber dysfunction in these patients, heart rate variability (HRV) has frequently been used to quantify autonomic neuropathy. The main purpose with this report was to elucidate a possible relationship between estimates of HRV and TPT in a selected group of early and late-onset Swedish Val30Met ATTR patients. The results show significantly more pronounced elevation of TPT in early compared to late-onset patients. Significant correlations between HRV and TPT were found among late-onset cases, indicating a possible relationship between loss of thin nerve fibers in somatic and autonomic nerves, while generally no such relationships were found among early-onset cases. This observation emphasizes the importance of testing both HRV and TPT to ensure optimal early detection of neuropathic changes in an as wide as possible range of small nerve fibers in suspected ATTR patients. This is of particular importance as the phenotype of the ATTR disease varies between groups with different age of onset.

  • 9. Quttineh, M.
    et al.
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. IBL (The Swedish Institute of Biomedical Laboratory Science), Stockholm, Sweden.
    Wijkmark, T.
    Rehnberg, M.
    Larsson Larsson, G.
    Great interest in a Swedish nationally regulated specialist education among biomedical laboratory scientists and biomedical laboratory scientist students2021In: International Journal of Biomedical Laboratory Science, E-ISSN 2308-7706, Vol. 10, no 1, p. 28-35Article in journal (Refereed)
    Abstract [en]

    Biomedical laboratory scientists (BLS) work in many different disciplines but one common denominator for all the fields within the profession is the rapid development in biomedicine and the corresponding increase of advanced technology. A nationally regulated specialist training for BLS is a way for the profession to gain advanced skills and to create career opportunities. From a larger study set, the aims of this sub-study were to investigate BLS student’s and professional’s view on education, choice of workplace, career development, advanced studies and a potential nationally regulated specialist training program. Two surveys were designed using webbenkater.com. The surveys were sent to BLS student members (n=483) and professional members (n=2083) of The Swedish Institute of Biomedical Laboratory Science (IBL), the professional organization of BLS´s in Sweden. Response rate was 57% (276/483) for the student sub-survey and 44% (n=923/2083) for the professional sub-survey. Students from all semesters (1-6, n=272) were represented, with a majority from semester 2, 4 and 6. Top reasons for choosing the BLS education were; easy to get a job (65%), stimulating work tasks (59%) and a good education for further studies (39%). A majority of the students planned for further advanced academic studies (64%) and 54% percent were interested in a potential nationally regulated specialist training. Among professionals, 21% stated there were explicit career paths at their workplace. The individual interest for a potential nationally regulated specialist training was 53% and most responders (93%) stated a need for such an education in Sweden. Among IBL members, there is great interest in a nationally regulated specialized training among both future and present professionals in Sweden. In relation to a future shortage, we also show that in order to attract students to BLS training, we need to be able to offer advanced training as well.

  • 10. Rocksén, David
    et al.
    Elfsmark, Daniel
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Wallgren, Karin
    Cassel, Gudrun
    Göransson Nyberg, Ann
    An animal model to study health effects during continuous low-dose exposure to the nerve agent VX2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 250, no 1, p. 32-38Article in journal (Refereed)
    Abstract [en]

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  • 11.
    Suhr, Ole B.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Gustavsson, Sandra
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    New Insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: A single center’s experience2012In: Degenerative Neurological and Neuromuscular Disease, ISSN 1179-9900, Vol. 2012:2, p. 93-106Article in journal (Refereed)
    Abstract [en]

    Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.

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