| 141. |
- Sparring Björkstén, Karin
(författare)
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Neurobiological aspects on brain function in neuro-psychiatric patients and in healthy subjects
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The levels of insulin-like growth factor-2 (IGF-2) were assessed in lumbar cerebrospinal fluid (CSF) from children with various kinds of brain damage and from Alzheimer (AD) patients and controls. Whole CSF was separated using acid gel chromatography and the presence of insulin-like growth factor binding protein and two different kinds of free IGF-2 m the CSF was established. The levels of CSF-IGF-2 were higher in the new-born infants than in children aged 6 months - 4 years. This difference was ascribed the immature blood-brain barrier in infants. Older children had levels similar to those reported in adults. Children with hydrocephalus had very low levels of IGF-2. The levels ofiGF in unseparated CSF was similar in AD patients and controls.The relationship between CSF spaces and cognitive function was investigated in patients with AD and controls, using a low field magnetic resonance imaging (MRI) technique and psychometric tests. The AD patients had larger relative CSF volumes in all locations investigated. The greatest differences between the two groups were found in the volumes of the temporal horns. The CSF volumes in the basal parts of the brain correlated inversely with episodic memory tests. The relative volumes of the lateral ventricles correlated with the degree of dementia. It was concluded that measurements of the relative CSF volumes of the temporal horns by MRI might be a reliable diagnostic sign of AD as well as providing an estimation of the severity of the disease.Demented subjects with either a severely disorganised sleep-wake schedule or regular sleep habits underwent serial blood saropling. The subjects with disorganised sleep-wake schedules had disturbed circadian rhythms of plasma melatonin (MT) and cortisol, whereas those with regular sleep habits had normal plasma MT and cortisol profiles. An 82-year old lady with vascular dementia and a disturbed sleep-wake pattern improved her sleep and normalised plasma MT and cortisol patterns after the removal of a beta-adrenergic blocker, substitution of cobalamin deficiency and cataract surgery. A man with frontal lobe dementia who was assessed repeatedly showed inability to suppress MT as assessed by a light test. A disorganised sleep-wake cycle in demented patients may in some cases be reflected by irregularities in the secretion of MT and cortisol.Eleven healthy elderly with normal levels of plasma cobalamin were hospitalised for a serial blood sampling procedure drawing blood every two hours over a 24 hourperiod. It was concluded that there was no circadian variation of plasma cobalamin, unsaturated binding capacity of transcobalamin and haptocorrin, or transcobalamin bound cobalamin other than what can be explained by posture. The proposed role for cobalamin in the regulation of the circadian rhythm could not be confirmed by this study.Different methods of assessing the circadian rhytm were reviewed. Awristworn, computerised instrument recording activity and light expsoure was introduced. The light exposure in 14 healthy elderly in Linköping, Sweden, under normal living conditions was analysed using the new instrument. The subjects were exposed to very little light, mostly indoor illumination. The median subject spent 60 % of the time in illumination <:1 Lux, 10 % in <: 100 Lux, and 2 % in <:1000 Lux. Only four subjects were exposed to <: 1000 Lux for 60 minutes or more, which is regarded as a minimum requirement for maximal MT suppression.In addition, simultaneous light recording and blood saropling was done over a 24 hour period. All subjects showed low day-time levels and distinct nocturnal rises of MT. Cosinor analysis was applied on the MT and light data. The time interval from the acrophase of light to the acrophase of MT was delayed with the progress of the autunm and diminishing light.
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| 142. |
- Stankovics, Nenad
(författare)
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Cutaneous effects of nerve injury : An experimental study in the rat
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the most difficult tasks of the hand surgeon is to reach a satisfactory restoration of the nerve functions of the injuried hand. In spite of the use of meticulous microsurgery, the results of nerve repair are disappointing, particularly with respect to mixed nerve trunks. In order to understand better the factors influencing axon regeneration and to improve further the outcome of surgical nerve repair, experimental studies are imperative. Studies in the rat show that the number of axons crossing a sharp sciatic nerve lesion may be high at nerve trunk level, whereas the sensibility of the foot skin is very deficient. This mismatch led us to study, with immunohistochemistry, the restoration of nerve endings in rat foot skin after various nerve injuries. In addition, some effects of nerve injury on the non-nervous epidermal components are elucidated through histology, autoradiography and immunohistochemistry. The results show that the occurrence of epidermal protein gene product 9.5 (PGP 9.5) immunoreactive axon profiles in the skin of the foot is statistically normal3 months after a crush lesion, but deficient 3 months after sciatic neurotomy and suture. The epidermal axon profiles return late after neurotomy and suture. The occurrence of {putative sensory) calcitonin gene-related peptide- and/or substance P-immunoreactive profiles, and {putative sympathetic) tyrosine hydroxylase-immunoreactive axon profiles in rat foot skin is partly abnormal after sciatic nerve crush and very abnormal after sciatic neurotomy and suture, when the contralateral side is also affected. In rats subjected to sciatic neurotomy and suture or neurectomy, the plantar epidermis becomes abnormally thin, but this is not seen after nerve crush. The epidermal thinning concurs with a decreased occurrence of mitotic cells. Both sutured and neurectornized rats, but not crushed cases, showed a markedly abnormal gait. However, rats subjected to selective division of sciatic foot branches exhibited a normal postural and locomotor behavior. In these rats, the occurrence of mitotic epidermal cells was similar on the operated and contralateral sides. This indicates that the effect of sciatic nerve division on the epidennal thickness of rat plantar skin is indirect, probably being caused by an ab~onnal load situation. The presence of PGP 9.5-immunoreactive epidermal dendritic cells in rat plantar skin is statistically normal3 months after sciatic crush injury, but significantly increased 1 week-3 months after neurotomy and suture. Finally, we show that the epidermal PGP 9.5- imrnunoreactive dendritic cells present in rat plantar skin represent la-immunoreactive Langerhans cells and that the plantar skin of albino rats is devoid ofepidermal NKJ-immunoreactive melanocytes.
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| 143. |
- Stenmark-Askmalm, Askmalm Marie, 1966-
(författare)
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p53 Alterations in Breast Cancer Related to Prognosis and Results of Therapy
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignant tumour disease and also the main cause of cancer-related deaths among women. The lifetime risk in western countries is 10%. The basic treatment for a patient with a localised tumour is surgery. In addition, different pathobiological variables are considered and an estimation of the risk of recurrence is made before deciding whether adjuvant therapy should be recommended. This therapy can be chemotherapy, which mainly prevents distant recurrence, or radiotherapy, which is effective against local recurrence. The treatment can be combined with anti-oestrogen, which prevents distant recurrence among patients exhibiting an oestrogen-receptor-positive tumour. However, breast cancer remains the chief cause of cancerrelated deaths and there is a need· for further pathobiologica! variables that, at an early stage, both can be prognostic and predict the outcome of adjuvant therapy.The p53 gene and its product p53 have been shown to play a central role in tumour suppression by regulating the cell cycle or initiating apoptosis. Certain mutations are associated with a stabilisation of the protein, leading to an accumulation that is detectable by immunohistochemistry.The main purposes of this study were to analyse p53 protein accumulation and gene mutation in exons 5-8 and to investigate the prognostic and predictive role of p53.p53 protein accumulation was investigated with immunohistochemistry in frozen tumour samples from 776 patients; 164 patients with stage U, 205 patients with stage I and 407 patients with either lymph node metastases and/or a tumour diameter exceeding 30mm. Of the latter, 139 were premenopausal and 268 were postmenopausal. These 407 patients had been randomiscd to adjuvant CMF chemotherapy or postoperative radiotherapy. Gene analyses with PCR-SSCP followed by direct sequencing were performed in the 268 postmenopausal patients. The predictive value of p53 was only analysed in the randomised patient material.The results showed that nuclear p53 accumulation ranged between 9% and 25%. p53 accumulation was significantly associated with several pathobiological variables, "indicating an aggressive tumour, which was more likely to be oestrogen receptor negative, DNA aneuploid, and have a high S-phase fraction. p53 accumulation was also significantly correlated with an increased rate of distant recurrence, whereas mutations that were found in 16% of the 268 cases investigated were not significantly correlated with an increased risk of distant recurrence. However, the investigation of both protein accumulation and gene mutation in exons 5-8 contributed further information than was achieved with one of the methods alone. The protein accumulation reflected to a certain extent mutations of the gene, mainly missense mutations. A majority of the severe mutations that included alteration of the reading frame did not lead to any protein accumulation. Sixty-one per cent of the tumours exhibiting protein accumulation did not show any mutation in exons 5-8. Subgroups of different p53 alteration patterns seemed to be related to different prognoses.The patients with p53 altered tumours, either showing protein accumulation, gene mutation or both, benefited significantly from CMF chemotherapy compared with the radiotherapy group. This benefit could not be seen among the patients without p53 alterations. The test for interaction between p53 status and relative rate was significant. This response was most pronounced among premenopausal patients. Postmenopausal patients seemed to benefit although not significantly.In conclusion, the present study suggests that p53 accumulation is a prognostic factor associated with an increased risk of distant recurrence. p53 alteration defined as protein accumulation, gene mutation in exons 5-8, or both, was a predictor of good response to CMF chemotherapy as compared to postoperative radiotherapy. This benefit could not be seen among patients without p53-altered tumours.
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| 144. |
- Stenninger, Erik, 1956-
(författare)
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Aspects of hypoglycaemia in newborns of diabetic mothers and in children with Type 1 diabetes
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The occurrence and possible causal factors of macrosomia and postnatal hypoglycaemia were investigated in infants of diabetic mothers. Acute neurophysiological effects, the long-term nemodevelopmental outcome, and the use of glucagon in prevention and treatment of hypoglycaemia, were also studied in children with insulin-dependent diabetes mellitus (IDDM) and infants of diabetic mothers.Infants born 1986-1993 of diabetic mothers, and children 7-12 years of age with !DD M, were investigated at Orebro Medical Centre Hospital. Macrosomia (birth weight>+ 2SD, adjusted for gender and gestational age) occurred in 27% of infants of mothers with gestational diabetes mellitus (GDM) and in 30% of those of mothers with !DD M. Postnatal hypoglycaemia (B-glucose < 1.5 rnmol/l) was observed in 38% of the infants. A highly positive con-elation was found between cord plasma insulin growth factor-! (IGF-l) and relative birth weight ratios in infants of diabetic mothers (r ~ 0.64, p < 0.0007), suggesting a role for IGF-I in the development of macrosomia in diabetic pregnancy. Early postnatal hypoglycaemia was related to cord serum C-peptide levels, supporting the theory of foetal hyperinsulinaemia as the most important pathogenetic factor. Maternal glucose concentration at labour was also related to cord C-peptide concentration, indicating that maternal glucose regulation close to delivery is important for postnatal glucose regulation in the infants. At follow-up at the age of 8 years, children with neonatal hypoglycaemia of diabetic mothers had a lower total developmental score than control children. More difficulties at an :MBD screening test and more behavioural problems were also noted in this group. At quantitative EEG analysis, children with neonatal hypoglycaemia of diabetic mothers more often showed a pattern similar to that in children with attention deficit hyperactivity disorders/attention deficit disorders compared with those who were "normoglycaemic" in the neonatal period.To treat neonatal hypoglycaemia, an injection of subcutaneous glucagon, 20 Jlg/kg, was given 3 hours postnatally in addition to early oral feeding. This caused a significant rise in blood glucose concentration lasting for up to 60 min (p < 0.01), compared to oral feeding alone, without major side-effects. However, the duration of the hyperglycaemic effect was too brief to eliminate the need for additional intravenous glucose infusion.IDDM children, with a short duration of disease and good metabolic control, showed no progressive neurophysiological effects, as measured by brainstem auditory evoked potentials (BAEP), during short-term induced hypoglycaemia (1.7 mmolll). This suggests that children with IDDM better adapt to low blood glucose levels than adult diabetic patients. Nor did the IDDM children show permanent BAEP changes during normoglycaemia, compared with a control group of healthy children of the same age.In treatment of hypoglycaemia in IDDM children intranasal administration of glucagon (1 mg) and subcutaneous glucagon injection (0.5 mg) had similar hyperglycaemic effects as observed for up to 30 minutes. Fewer side-effects, including nausea and vomiting, and only minor nasal irritation were reported after intranasal glucagon administration.
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| 145. |
- Ståhlbom, Bengt, 1956-
(författare)
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Dimethylethylamine and dimethylbenzylamine in foundries and the epoxy industry : Analysis, metabolism, biological monitoring, toxicological effects and occupational exposure
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dimethylethylamine (DMEA) and dimethylbenzylamine (DMBA) are tertiary aliphatic amines, used as catalysts e.g., in mould core manufacturing and heat cured epoxy systems. Health effects such as visual disturbances and respiratory irritation occur among workers handling DMEA and airway symptoms are recorded by many workers exposed to DMBA. In this thesis, gas chromatographic methods for the determination of DMEA and DMBA in air and DMEA, dimethylethylamine- N-oxide (DMEAO), DMBA and dimethylbenzylaminc-N-oxide (DMBAO) in urine have been developed in order to monitor the air concentration of the amines, to investigate the metabolism and to establish methods useful for biological monitoring. Studies have been performed on volunteers in experimental exposures and on workers in the industrial setting. Dose-effect and dose-response relations were investigated for both DMEA and DMBA. An exposurechamber was developed, using a permeation technique, for the generation of low air levels of DMBA.DMEA and DMBA were rapidly absorbed through the respiratory tract and quickly distributed in the body. DMEA was to a large extent (90 %) metabolised into DMEAO and DMEA and DMEAO (SumDMEA) were excreted into the urine following a biphasic pattern. DMBA was metabolised to nearly 100 % and eliminated into the urine with a half-life of 4.3 h. More than 50 % was eliminated within 2 hours after the exposure. There was a significant correlation between the time-weighted average exposure level (TWA) of the two amines and the concentration of the amines and their metabolites (SumDMEA, SumDMBA) in the post-shift urine, in both the experimental and industrial study. Thus, both U-SumDMEA and U-SumDMBA may become important biomarkers in order to monitor industrial exposures of the corresponding amine.DMEA exposure to a constant air level of 40-50 mg/m3 during eight hours caused epithelial corneal oedema with visual disturbances and respiratory irritalion. A 15 min exposure at 80 mg/m 3 caused eye irritation but no visual disturbances and 8 h exposure at 20 mg/m3 did not cause visual disturbances or eye irritation.Low air concentrations (20-120 )Jg/m3 ) of DMBA increased the number of metachromatic cells and eosinophils in a dose-response related manner in the nasal mucosa in healthy vountecrs, without causing significant clinical symptoms.Industrial exposure levels of DMEA in mould core manufacturing workers were determined. The mean TWA of DMEA was 3.7 mg/m3 (range 0.5-14). The determination of DMBA in epoxy workers showed a mean TW A air concentration of 18 pg/m3 (range 3-48), with a 2 h peak exposure of 91 µ/m3.This thesis will facilitate the evaluation and assessment of risk and threshold limit values of DMEA, DMBA, and other related compounds.
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| 146. |
- Svensson, Erik
(författare)
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Pharmacodynamic effects of antibiotics on growing and nongrowing bacteria
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main objective of this thesis was to study antibiotic effects on nongrowing baCteria and to study the development of resistance in Staphylococcus epidermidis, a bacterium which is often found in biofilm infections. The antibiotic effect on biofilm infections is generally weak, which probably is due to decreased growth rate of the bacteria. The effects of antibiotics on growing and nongrowing bacteria were studied with pharmacodynamic parameters. One of these parameters is postantibiotic effect (PAE). The conventional PAE measurement is performed with viable count. Viable counting is very laborious, which is why other methods have been used. However, the results may differ from those obtained with the viable count method for determining PAE. In this study effective regrowth time (ERT) and control-related effective regrowth time (CERT) were shown to be independent of the method used for bacterial quantification. With CERT and PAE it possible to study antibiotic effects on nongrowing and growing bacteria.CERT and PAE of amikacin, ciprofloxacin, and imipenem were investigated on growing and nongrowing Escherichia coli and Pseudonumas aeruginosa. All drugs had long CERT and PAE on growing bacteria. Arnikacin and ciprofloxacin, but not imipenem had long CERT and PAE on nongrowing bacteria.Amikacin, imipenem, ofloxacin, rifampicin, and vancomycin induced CERT and PAE on growing S. epidermidis, and imipenem combination with amikacin or vancomycin had a synergistic CERT and PAE in these cultures. Only rifampicin or antibiotic combinations containing rifampicin were effective against nongrowing S. epidermidis. There was no synergistic CERT or PAE on nongrowing bacteria.Selection and regrowth of highly rifampicin resistant S. epidermidis, which was present at a frequency of 10·7 in the initial inoculum, were seen when the bacteria were in~ubated with rifampicin at a high inoculum. Rifampicin combined with high concentrations of amikacin or ofloxacin prevents selection and regrowth of rifampicin resistant bacteria.
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| 147. |
- Sydsjö, Adam, 1940-
(författare)
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Sickness absence during pregnancy
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study represents a series of surveys concerning the variation in rate and average duration of sickness absence during pregnancy from 1978 to 1997 in two Swedish communities, Linköping and Värnamo. The variation observed was related to the obstetrical course and outcome of the pregnancies, the reproductive histories of the women investigated, the occcupations held, the degree of employment, the prevalence of "back-pain during pregnancy" as a cause of sick-listing and the use before delivery of the special social benefits associated with childbearing, i.e. the Parental benefit and the Pregnancy benefit. The attitudes towards the subjective consequences of the state of pregnancy and the concept of being off-work for different reasons while pregnant, were examined by means of a questionnaire. A direct comparison was made between all pregnant women delivered during 1986 in the Värnamo community and the Hamar community in Norway, with special regard to the amounts of sickness absence registered during pregnancy in the two communities. Finally, with the help of two independent data bases, one computerized and based on routine reports and one manually extracted, we estimated the proportion of pregnant women among all sicklisted women, aged 16-44 years, during 1986 in Linköping, and their contribution to the total amount of sickness absence registered within these age strata. In total, 6 628 Swedish and 645 Norwegian pregnant women were included in the surveys.As a main result we found that the mean number of days of sickness absence per pregnant woman, aged 16-44 years, rose by more than 100 per cent, from 1978 to 1986. The corresponding increase for all women aged 16-44, was 20 per cent. Concurrently, there was no evidence of an "obstetric" explanation for these findings. "Back-pain during pregnancy" was the most frequent "complaint "to legitimate the sick-leave spells, increasing to about 30 per cent among employed pregnant women 1986. In 1997 it had decreased to 17 per cent. It was most often found in the younger pregnant women (< 25 years).No relation was observed between the occupation held by the pregnant women and the variation in sickness rate or the average duration of the sickness absence observed between 1978 and 1997. Nor was there any simple relation observed between the degree of unemployment among pregnant women and the amount of sickness absence registered.The variations in the social benefits offered to pregnant women was not found, either, to be related in a simple way to the rate and duration of sickness absence during pregnancy. Thus, when the social benefits, i.e. the Parental and the Pregnancy benefits, were substantially ameliorated in Sweden between 1978 and 1986, the sickness absence among pregnant women rose dramatically. In 1992 and 1997, when a modest reduction in the pregnancy associated social benefits had taken place, a decline in the amount of sickness absence was registered, i.e. down to 0.60 and 0.53. In 1986, 48 per cent of the employed pregnant women in Hamar were sicklisted during pregnancy as compared with 75 per cent in Vlimamo. This was in spite of the fact that the social benefits available to pregnant and employed women were much more favourable in Sweden than in Norway.In the questionnaire study about personal attitudes in 1995 we found, that 74 per cent of the women who had been sick-listed during pregnancy stated that they had enjoyed a "good" or "excellent" health during the whole of their pregnancy. Only 4.2 per cent of the women stated that they had suffered from a clearly pregnancy-related disorder. The present findings may indicate that a change in attitude towards pregnancy and its subjective consequences, together with a sensible adaptation to the prevailing conditions within the social security insurance system, may well be the most plausible explanation to the observed variations in sick-listing during the study period. When data from the two independent data bases were compared, it was found that 5.4 per cent of all sicklisted women aged 16-44, were pregnant. These women contributed as much as 22 per cent of all sickness absence registered. Only 46 per cent of the actually pregnant women could be identified in the computerized data base with the help of "pregnancy-related" diagnoses noted in the sick-leave certificates. To preclude misinterpretations, based on public health statistics, one must be properly informed on the reproductive state of thewomen sick-listed.
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| 148. |
- Söderhamn, Olle
(författare)
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Potential for self-care : Assessing and describing self-care ability among elderly people
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to explore the nature of elderly people's potential for selfcare from a nursing perspective. The research was performed within an empirical frame of reference as well as within a phenomenological frame at a descriptive and hermeneutical level.In order to implement a relation-searching study, one instrument was translated and a new instrument constructed. Both tools were tested for reliability and validity. A relation-searching study and a phenomenological study were then performed. The participating elderly were 65+ years of age and Jiving in a health district in western Sweden. The study groups consisted of 1) a convenience sample comprising inpatients (n=52) and their caregivers (n=53) in three nursing homes and one geriatric rehabilitation department, 2) a consecutive sample of in-patients (n=57) in a geriatric rehabilitation department, 3) an age stratified random sample, from which 125 persons agreed to participate in the study, and 4) for the phenomenological study, nine persons from the original age stratified random sample participated together with two conveniently chosen persons lrom a pilot study.The in-patients were interviewed, and the home dwelling persons completed a mailed questionnaire and wrote self-reports, respectively. Bivariate and multivariate statistical methods were used in the quantitative studies. The Empirical Phenomenalogical Psychological (EPP) method and a phenomenological-hermeneutical method were used in the analyses of the self-reported narratives.The results showed that the constructed instrument, the Self-care Ability Scale for the Elderly (SASE), is a reliable and valid tool for the appraisal of elderly people's perceived ability for self-care. The Swedish version of the Appraisal of Self-care Agency (ASA) scale is a reliable and valid tool for the appraisal of elderly people's perceived activation of self-care ability. The proposed theoretical relationship between self-care ability and self-care activity was empirically supported. Self-care ability and self-care agency declined for the studied home dwelling elderly 75+ years of age. One hypothesis was generated, saying that self-care ability among elderly people may be reinforced by physical activity and by the development of self-awareness.In the phcnomenological study, the structure of self-care ability among the home dwelling elderly persons was found to be twofold; it entailed, I) being present to the opportunity to act on certain perceived influences on the body and 2) alone or with support from somebody else, to be able to bring about a change in attitude towards ones personal lifestyle or life situation. The meaning of actualising the self-care ability into self-care activity was interpreted as self-realisation and self-transcendence.
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| 149. |
- Sörensen, John
(författare)
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Pain analysis : A study in patients with chronic low back pain or fibromyalgia
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic low back pain (CLBP} and fibromyalgia (FM} are two common chronic pain conditions in which the pain processing mechanisms are not well understood. To identify the types of pain, we used different intravenous {t.v.} and epidural pharmacological test procedures as well as questionnaires with pain intensity ratings, pain drawings, self-assessment of functional status, disability and depression. 93 patients with CLBP and 49 women with FM were included in 7 studies. CLBP patients were classified, by response to t.v. morphine, t.v. lidocaine and epidurally administered fentanyl and local anaesthetic, into the different pain types; nociceptive, neuropathic, and idiopathic {non-responding) pain. In about 85% of CLBP patients it was possible to classify the pain of which about 300;6, admitted for assessment of suitability for surgery, had non-responding {idiopathic) pain. CLBP patients chosen for lumbar fusion surgery were prospectively evaluated as to whether preoperative pha:nnacological pain classification associated with the outcome of surgical treatment. A significantly poorer (P<0.05) outcome in the non-responding group suggests that pharmacological pain analysis might be useful as a predictor of surgical outcome. Patients with persistent pain after low back surgery were examined by standard clinical and radiological methods and different questionnaires. The pharmacological test battery was used to classify the patients into different pain groups. With the phannacologtcal classification taken as astandard, the clinical judgement seemed to have difficulty mainly in the differentiation between neuropathic pain and idiopathic pain. The pharmacological pain classification can support the surgeon in deciding when further surgery should be avoided and also be helpful in avoiding an inappropriate diagnostic label. The patients with "failed back surgery syndrome" were also assessed with t.v. phentolamine to identify those with sympathetically maintained pain (SMP). It was concluded that SMP is either an uncommon cause of persistent pain in this type of failed back surgery patients or, the phentolamine test as we performed it was unable to identify SMP. Patients with FM diagnosed according to tlle American College of Rheumatology (ACR) criteria were classified pharmacologtcally into responders and non-responders by response to t.v. morphine, i.v. lidocaine, i.v. ketamine and t.v. saline (placebo). The effects on muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and non-tender point areas were also assessed. Ketamine, an NMDA-receptor antagonist. significantly reduced pain intensity, and increased pressure pain threshold and pain tolerance at tender points and non-tender point areas. The ACR classification in FM seems to allow inclusion of patients with different pain processing mechanisms. An experimental study examined 1) whetller non-painful sites in FM patients showed evidence of lowered pressure pain thresholds and 2) lowered pain thresholds as a response to either single or repeated electrical stimulation of the skin and into a non-painful muscle, and 3) the responses to injection of an algesic substance, hypertonic saline, into the underlying, non-painful muscle. Compared to age-matched controls FM patients had lower pressure-pain thresholds, but unaltered electrical skin responstvity and greater pain duration and wider spatial distribution of pain following the injection of hypertonic saline. The results suggests an upregulation in the central nociceptive system in FM patients.
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| 150. |
- Terman, Alexei, 1957-
(författare)
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Mechanisms of lipofuscin/ceroid accumulation and its impact on the function of the lysosomal system
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The accumulation of lipofuscin - an electron-dense, autofluorescent, polymeric, intralysosomal substance - is a recognized hallmark of aging postmitotic cells. Ceroid- a substance very close, or perhaps even identical, to lipofuscin - is a characteristic of various pathological processes, such as lysosomal storage diseases, malnutrition, atherosclerosis, oxidative stress, ionizing radiation, etc. Although the mechanisms of lipofuscin formation are now rather well understood (Brunk et al., 1992), what causes it to accumulate within aging postmitotic cells (namely, the role of its possibly impaired degradation/exocytosis) is still disputed. Moreover, little is known about whether lipofuscin accumulation interferes with normal cellular functions, perhaps it even promotes cell death and age-associated pathologies. The role, if any, of ceroid accumulation in the pathogenesis of many diseases also is not clear.To gain a better insight into the mechanisms of lipofuscin/ceroid accumulation, and to test whether this accumulation has any negative impact on cellular functions, especially on the autophagocytotic process, we decided to study: (l) the role of oxidative stress (normobaric hyperoxia) and/or lysosomal protease inhibition (leupeptin treatment) in lipofuscin/ceroid accumulation in cultured AG-1518 human fibroblasts and neonatal rat cardiac myocytes; (2) the fate of formed lipofuscin/ceroid after the cessation of oxidative stress and/or protease inhibition; (3) the possible reversal of lipofuscin/ceroid accumulation in vitro with an anti-aging drug centrophenoxine; (4) the survival of lipofuscin/ceroid-loaded fibroblasts under amino acid starvation; (5) the effect of lipofuscin/ceroid accumulation on autophagocytosis and intralysosomal degradation; and (6) the sensitivity of lipofuscin/ceroid-loaded fibroblasts to oxidative stress.We have shown that: (1) both oxidative stress and lysosomal protease inhibition accelerated lipofuscin/ceroid formation, however the effects of these two factors increased dramatically when they acted concurrently; (2) protease-inhibition by itself does not lead to lipofuscin/ceroid formation, but rather allows the prolonged time needed for oxidative modification of autophagocytosed material; (3) lipofuscin/ceroid inclusions formed due to oxidative stress and protease inhibition do not disappear either after returning the cultured cells to normal conditions, during amino acid starvation, or under the influence of centrophenoxine; (4) lipofuscin/ceroid-loaded cells exposed to amino acid starvation show decreased survival time and diminished autophagocytosis; (5) exposure of fibroblasts with various amounts of lipofuscin/ceroid to naphthazarin (a redox cycling quinone producing 0 2 ·-and H20 2) results in selective survival of cells with lower quantities of the pigment; and (6) lipofuscin/ceroid-rich cells have an expanded lysosomal compartment with increased amounts of cathepsin D.The results suggest that: (i) lipofuscin/ceroid forms within secondary lysosomes due to oxidative damage of autophagocytosed material resulting in cross-linking of protein residues by aldehydes formed from decomposed peroxidized unsaturated lipids; (ii) lipofuscin/ceroid is not substantially eliminated from non-dividing cells by degradation or exocytosis, which explains the progressive accumulation of lipofuscin in postmitotic cells with age; and (iii) a heavy lipofuscin/ceroid loading of cells interferes with normal lysosomal functions by making them less able to autophagocytose and more sensitive to oxidative stress, conceivably due to increased amounts of lysosomal enzymes (potential mediators of oxidative damage) and/or due to a possible catalyzing role of lipofuscin/ceroid-associated iron.
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