The field of psychotraumatology has its roots in ancient history. During the past decades, the surveillance of the psychobiological background of reactions to and consequences of traumatic stress has made great progress and the complexity of the human stress response system stands out. The hypothalamic-pituitary-adrenocortical axis activity, modulated by various neuroimmunological substances, seems to play a major role in the stress response. However, there are still inconsistencies in explanations of relationships between biological and psychological changes following traumatic stress. Moreover, the matter of predictive factors for the development of posttraumatic morbidity is still in a speculative phase.

The aims of the present thesis were to further develop a commercial serum cortisol radioimmunoassay (RIA) for determination of cortisol in saliva and to test its reliability, specificity and sensitivity as a biochemical assay. The saliva sampling procedures and sample storage stability were also to be tested. Further issues were to investigate determinations of salivary cortisol and serum prolactin in relation to selfratings of posttraumatic psychological distress and general psychological health. Possible predictive and concurrent validity of salivary cortisol as a biochemical marker for posttraumatic psychological distress were to be tested.

Cortisol is present in saliva mainly in non-protein form, representing the free, biologically active fraction of the total plasma cortisol concentration. In a first phase of the present thesis, the commercial serum cortisol RIA was modified for determination of cortisol in saliva. The relation between salivary and serum cortisol concentrations was tested. Reference ranges at 8 AM and 10 PM for the salivary cortisol assay were established from 195 healthy subjects. Salivary cortisol concentrations were tested in relation to serum cortisol in estimating adrenocortical function during endocrine dynamic function tests in 37 patients and 13 healthy controls. In testing salivary cortisol as a marker for stress for fieldwork use, a screening study was performed on 66 male rescue workers. Salivary cortisol at 8 AM and 10 PM and serum prolactin were determined and general psychological health and posttraumatic psychological distress were estimated with the self-rating scales General Health Questionnaire, Impact of Event Scale and Posttraumatic Symptom Scale. These scales were used in the second phase of the thesis. Three applied follow-up studies were performed with sampling of salivary cortisol and self-ratings: (a) a study of 31 UN-soldiers five days, two and nine months after a mine accident; (b) a study of 145 UN-soldiers before, at return, and two and six month after a six month mission. (c) a study of 101 UN-soldiers six and twelve months after a six month mission with severe combat exposure.

The results from the present thesis indicate that the modified method of salivary cortisol determination possesses sufficient precision, accuracy, sample storage stability and procedural advantages for laboratory, clinical and field application. Moreover, it possesses moderate predictive information and moderate to high concurrent validity as a biochemical marker for posttraumatic psychological distress.

Background: The psychobiology of post-traumatic distress is known to some extent, however the pre-trauma psychobiology is not. The aims of the present study were to relate pre- and post-trauma salivary cortisol levels and general health to post-traumatic distress in a Swedish UN-battalion in Bosnia.

Methods: Salivary 8 AM and I 0 PM cortisol levels and "General Health Questionnaire" ratings were collected from 145 subjects before the six months' mission, at return and two and six months after mission. During follow-up, the ratings were extended by the "Impact of Events Scale" (IES) and "Post Traumatic Symptom Scale".

Results: Low pre-trauma morning and evening salivary cortisol levels were statistically significantly related to high scores in all rating scales six months after mission and to increasing IES scores during follow-up. Low morning and high evening post-trauma salivary cortisol levels were related to high ratings of psychological distress six months after mission

Conclusions: Pre-trauma salivary cortisol levels seem to be related to posttrauma psychological distress, however not to the extent that salivary cortisol levels in a simple way could be used for predictive screening.

Background: Because traumatic events are unpredictable, there are few studies of psychobiological states immediately following such events. Our study aimed to determine the relation of salivary cortisol to psychologic distress immediately after a traumatic event and then during follow-up.

Methods: Measurement of morning and evening salivary cortisol and ratings of psychologic distress (using the Impact of Events Scale [IES], the Post Traumatic Symptom Scale, and the General Health Questionnaire) were performed with 31 United Nations soldiers at three time points—5 days and 2 and 9 months—following a mine accident in Lebanon.

Results: Five days after the accident, 15 subjects reported substantial posttraumatic distress according to the IES, as well as significantly lower morning and higher evening cortisol levels compared with the low-impact group. Within 9 months, the posttraumatic distress of the high-impact group was reduced, accompanied by an increase in morning and a decrease in evening cortisol levels. There were significant relationships between evening cortisol and all rating scales at the first and third time points.

Conclusions: Subclinical posttraumatic stress following an adverse event can be measured biologically via salivary cortisol levels soon after the event.

Background: Our group has presented evidence of relationships between salivary cortisol levels and psychological distress before, during and after trauma-related stress. The aim of the present study was to confirm the part of evidence of relationships between salivary cortisol and posttraumatic distress and their change over time.

Methods: Salivary cortisol levels at 8 AM and 10 PM and self-ratings were collected from 106 subjects six and twelve months after a six months UNmission in Bosnia. The rating instruments were the "Impact of Event Scale" (IES), the "Post Traumatic Symptom Scale" and the "General Health Questionnaire".

Results: Significant statistical interactions were found between changes in mean cortisol levels and IES scores over time. Decreasing evening cortisol levels over time were significantly related to decreasing IES scores and vice versa. Morning cortisol levels showed negative, and evening cortisol positive correlations with all rating scores.

Conclusions: The evidence from previous studies on trauma related stress, that salivary cortisol is related to the development of posttraumatic stress reactions, the morning cortisol in reverse (negative) direction to that (positive) of evening cortisol, were confirmed.

Background: Rescue service personnel are often exposed to traumatic events as part of their occupation, and higher prevalence rates of psychiatric illness have been found among this group.

Methods: In 65 rescue workers, salivary cortisol at 8 am and 10 pm and serum prolactin at 8 am were related to the psychiatric self-rating scale General Health Questionnaire (GHQ-28) measuring psychiatric health, and the Impact of Events Scale (IES) and Post Traumatic Symptom Scale (PTSS) measuring posttraumatic symptoms.

Results: Seventeen percent of the study population scored above the GHQ-28 cut-off limit but none scored beyond the cut-off limit in the IES and PTSS questionnaires. Salivary cortisol concentration at 10 pm correlated with statistical significance to anxiety (p < .005) and depressive symptoms (p < .01) measured with GHQ-28, as well as to posttraumatic symptoms, with avoidance behavior measured with IES (p < .01) and PTSS (p < .005). Two of the rescue workers were followed over time with the same sampling procedure after a major rescue commission.

Conclusions: The correlation between evening salivary cortisol and anxiety, depressiveness, and posttraumatic avoidance symptoms indicates that these parameters can be used in screening and follow-up after traumatic stress events.

Background and objective: The efficiency of intraoperative autotransfusion in scoliosis surgery is poorly known but needs to be evaluated, not least because of the large blood losses in these patients. This is a retrospective analysis of transfusion requirements of 43 such patients. Methods: Records from 43 patients were studied. During surgery, the shed blood was salvaged and washed in an autotransfusion device (AT1000 Auto-transfusion Unit«) and a suspension of red cells was reinfused. Results: Fifty-eight per cent of the intraoperative blood loss was salvaged. The total blood loss during the patients' hospital stay was calculated from the haemoglobin balance, 24% of this loss was salvaged by the device. Moreover, 36 of the patients needed allogeneic blood transfusion. Conclusion: The efficiency of the autotransfusion device was relatively low in relation to the total extravasation, mainly because the postoperative blood loss is substantial.

OBJECTIVE: To evaluate the incidence and prognostic importance of micrometastatic disease in regional lymph nodes from Dukes' B colorectal carcinomas.

DESIGN: Retrospective study.

SETTING: University hospital, Sweden.

SUBJECTS: 100 patients operated on for primary colorectal carcinoma, classified as Dukes' B lesions.

INTERVENTIONS: The regional lymph nodes were re-examined immunohistochemically using monoclonal antibodies against cytokeratin.

OUTCOME MEASURES: Incidence and prognostic importance of micrometastases.

RESULTS: Micrometastases were found in 39% (39/100) of the patients. The number of positive cells in the lymph nodes examined varied from 1 to over 100. They appeared as single cells or small clusters of cells located within the capsule or in the peripheral sinus of the lymph node. At least three sections from each of three lymph nodes had to be examined to identify 95% of the patients with lymph node micrometastases. The outcome of the patients with micrometastases was not significantly different from that of patients with no epithelial cells in the lymph nodes.

CONCLUSION: Micrometastases in regional lymph nodes are a interesting phenomenon but clinically seem to be of only weak prognostic value.

This study assessed the role of diagnostic arthroscopy following a wrist injury in patients with normal standard radiographs, an unclear clinical diagnosis and persistent severe pain at 4 to 12 weeks. Forty-three patients were included after conservative management had failed to improve their wrist pain so that a stability test could be performed satisfactorily and underwent arthroscopy within 12 weeks. Arthroscopy revealed recent pathology in 41 wrists, of which 17 had significant ligament lesions that might have benefited from acute repair. We conclude that patients with marked persistent post-traumatic symptoms despite conservative management are likely to have sustained ligament injuries despite normal radiographs. We therefore recommend that under these circumstances an arthroscopy is carried out within 4 weeks if the patient and surgeon wish to acutely repair significant ligament injuries.

Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.

A population consisting of 110 young breast cancer patients, ≤ 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.

Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P = 0.002) and for patients with axillary nodal metastases (P = 0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.

The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.

Objective: Neurocognitive impairment is common after cardiac surgery but few studies have examined the relationship between postoperative neuropsychological test performance and everyday behavior. The influence of postoperative cognitive impairment on car driving has previously not been investigated. The purpose of this study was to evaluate neurocognitive function and driving performance after coronary artery bypass grafting (CABG).

Methods: Twenty-seven patients who underwent coronary artery bypass grafting with standard cardiopulmonary bypass technique and 20 patients scheduled for percutaneous coronary intervention (PCI) under local anesthesia (control group) were enrolled in this prospective study conducted from April 1999 to September 2000. Complete data were obtained in 23 and 19 patients, respectively. The patients underwent neuropsychological examination with a test battery including 12 tests, a standardized on-road driving test and a test in an advanced driving simulator before and 4–6 weeks after intervention.

Results: More patients in the coronary artery bypass grafting group (n=11, 48%) than in the percutaneous coronary intervention group (n=2, 10%) showed a cognitive decline after intervention (P=0.01). In the on-road driving test, patients who underwent coronary artery bypass grafting deteriorated after surgery in the cognitive demanding parts like traffic behavior (P=0.01) and attention (P=0.04). Patients who underwent percutaneous intervention deteriorated in maneuvering of the vehicle (P=0.04). No deterioration was detected in the simulator in any of the groups after intervention. Patients with a cognitive decline after intervention also tended to drop in the on-road driving scores to a larger extent than did patients without a cognitive decline.

Conclusion: This study indicates that cognitive functions important for safe driving may be influenced after cardiac surgery.

Objectives To compare patients with coronary artery disease and healthy controls with respect to cognitive function and driving performance.

Design and setting A controlled study conducted between April 1999 and January 2001.

Subjects Forty-four patients with stable coronary artery disease scheduled for cardiac intervention with coronary artery bypass surgery or percutaneous coronary intervention. Forty volunteers of similar age without symptoms of coronary artery disease served as controls.

Main outcome measures On-road driving scores in five specific test areas with a rating scale from 1 to 5. Neuropsychological test scores, including 12 tests.

Results Compared with controls, patients with coronary artery disease had lower scores in all areas of the on-road driving test (p<0.05) and in the neuropsychological tests assessing psychomotor speed, visual and verbal memory, focused attention and simultaneous capacity (p<0.05). The difference between the groups in the on-road driving test appeared to be more pronounced among those above 65 years-of-age. Both patients and controls rated their performance significantly higher than the traffic inspector (p<0.05).

Conclusions Cognitive function and driving performance may be impaired in patients with coronary artery disease.

Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1.2–11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1–3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.

In order to identify and describe a pattern in bus and coach incident related injuries and fatalities, and to suggest possible future measures for improvement of bus and coach safety, a literature analysis was performed. The results formed a multi-faceted pattern, which briefly can be described as follows, women travelled more frequently by bus as compared to men. Injuries sustained predominantly affected women 60 years of age and older. Of all traffic fatalities in Europe, bus and coach fatalities represented 0.3-0.5%. In the OECD countries, the risk of being killed or seriously injured was found to be seven to nine times lower for bus and coach occupants as compared to those of car occupants. Despite the fact that fatalities were more frequent on rural roads, a vast majority of all bus and coach casualties occurred on urban roads and in dry weather conditions. Boarding and alighting caused about one-third of all injury cases. Collisions were a major injury-contributing factor. Buses and coaches most frequently collided with cars, but unprotected road users were hit in about one-third of all cases of a collision, the point of impact on the bus or the coach being typically frontal or side. Rollovers occurred in almost all cases of severe coach crashes. In this type of crash projection, total ejection, partial ejection, intrusion and smoke inhalation were the main injury mechanisms and among those, ejection being the most dangerous. A 2-point belt may prevent passenger ejection, but in frontal crashes when the upper abdominal parts and the head hit the seatback in front, it could, however, contribute to head and thoracic injuries. Hence, a 3-point belt provides the best restraint in rollovers and frontal crashes. © 2004 Elsevier Ltd. All rights reserved.

The risk for injuries in rollover coach crashes are dependent on whether the occupants are belted or not. However, the influence of the different belt systems for reducing injuries has remained unclear. Since many injuries sustained are caused by impacts with the interior, passenger interactions or ejection through a window, the advantages by proper seat belt systems are evident. In this study, representing the most common serious crash scenario for serious injury, 128 injured in rollover cases were analysed with regard to the injury outcome, mechanisms and the possible injury reduction for occupants when using a safety belt. Furthermore, the different belt systems were compared to explain their contribution to increased safety. Based on medical reports and questioning of the passengers, the injuries sustained are recorded according to the AIS classification. The next step was the identification of the injury mechanisms, using the passenger statements as well as results from numerical occupant simulations. It is important to mention that this study was purely focused on detection of the injury mechanism to avoid the reported injuries. The possibility of additional injuries due to the wearing of a belt were not taken into account. However, the analysis of the 128 injured showed a considerable increase in safety for belted occupants through limiting interior contacts, minimising passenger interaction and reducing the possibility of ejection. © 2005 Elsevier Ltd. All rights reserved.

Caudate nucleus dopamine (DA) D2 receptors were studied in patients with vascular dementia (VaD) and in a control group using [3H]raclopride as a radioligand. There was no significant difference in the number of DA D2 receptors in the VaD group as compared with controls. The binding affinity was significantly lower in the VaD group. When the VaD group was subdivided into subjects with or without neuroleptic treatment, there were no differences in the numbers of receptors as compared with controls, and the significant differences in binding affinity remained for both VaD subgroups. The present results are discussed with reference to the previous finding of a reduced density of caudate nucleus DA uptake sites in the same VaD group and to results from studies on DA D2 receptors in Alzheimer's disease and Parkinson's disease. Copyright ⌐ 2002 S. Karger AG, Basel.

This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n=434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p<0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.

Work has a great influence on most of individuals in society. It influences both identity as well as the structure of the day. Unemployed people are often affected in a negative way through economic and psychological problems. In order to help people with reduced work capacity back to the labour market and decrease unemployment, the Labour Market Board works with vocational rehabilitation. The aim of this study is to investigate experiences of vocational rehabilitation within the Labour Market Board among unemployed people. A qualitative method was used by which interviews were made with 11 unemployed persons who participated in an investigation as a part of vocational rehabilitation within the Labour Market Board. The result shows both positive and negative experiences of the investigation period. The identified experiences were sorted into code groups: Support, Insight, Confidence in the investigation and result, Belief in the future, Motivation, and Participation. Both the actions of the personnel and the presence of the group members influenced the experiences. The support given by the personnel and how it is experienced is of great importance for the future of the unemployed. When the investigation was pursued during a short period of time, there was a lack of confidence in the investigation and result. A suggestions for future studies is to design a questionnaire that can be used in a larger study including a large number of individuals who are participating in vocational rehabilitation within the Labour Market Board.

Clinical and laboratory findings and drug history were studied in 17 patients with suspected hydralazine-associated nephritis, five of whom only had renal disease, while twelve also had extrarenal manifestations. Renal biopsies revealed extracapillary proliferative or focal segmental proliferative glomerulonephritis in 10 patients, and tubulo-interstitial nephritis in five patients. Antinuclear antibody (ANA) was found in 16 patients, but none of the 14 patients tested had antibodies to DNA. Tests for antibodies to myeloperoxidase (anti-MPO) and antibodies to neutrophil cytoplasm antigen (ANCA) were performed by ELISA. Twelve of the 14 patients tested had anti-MPO; five of these 14 patients had ANCA, while one had borderline levels. These findings suggest that hydralazine facilitates the induction of a systemic disease with multiple autoantibody production.

The recording of otoacoustic emissions (OAE) was evaluated as a complementary test method for adults with moderate to profound mental retardation (MR). A portable apparatus, ILO 288 Echoport linked to a Compaq LTE 5100 notebook with software ILO 88 V 4.2, was used. Otoscopy and tympanometry were also performed. Criteria for emissions were S/N 3 dB or more and reproducibility 60% or more for at least three frequency-bands. The criteria for partial emissions were the same, but for only one or two frequencies. Two examiners were needed: one to keep the tested person calm and quiet and the other to handle the keyboard. Thirty-eight people with different degrees of MR in connection with other disabilities were included. They had all exhibited incomplete results in a previous hearing screening of more than 1000 adults with MR. Reproducible transiently evoked OAEs (TEOAE) were recorded from II ears (7 people), partial TEOAEs from 6 ears (4 people) and no emissions from 15 ears (10 people). Registration from 24 ears (13 people) could not be evaluated because of too much external and internal noise. Eight people rejected the examination. Only four people showed emissions in both ears. Accordingly, 34 people (89.5%) had to be re-tested or referred for further investigation, 21 of them (55%) because of noisy recordings or no co-operation. It is concluded that the TEOAE-test in its present form cannot fulfil the demands for a functioning test method for this population. In single cases, however, TEOAE-recording can complement other audiological tests.

Cochlear implants (CI) are one of the most important medical innovations in the last 20 years. A CI can enable hearing and spoken language in children with severe hearing impairment or deafness. However, many children with CIs do not reach the expected level of language. The reasons for this are not yet fully understood and further research is therefore necessary. In the present study 9 children, 6;7-12;4 years old with CIs participated. The purpose of this study was to investigate cognitive and language abilities with focus on working memory and receptive lexicon in children with CI. For this purpose selected parts of the computer based test battery SIPS (Sound Information Processing System) and PPVT (Peabody Picture Vocabulary Test) were used. The test results were analysed on group level and on individual level. In addition the results were compared to results from a control group of children with normal hearing.

The children with CIs achieved lower results than the control group did, measured on a group level. A few individuals though performed at the same level as the children in the control group which implies that it is possible for children with CIs to reach good results on the examined aspects. The results of this study also indicate that late implantation is not necessarily an obstacle for good language development. Correlations between working memory and lexicon were found both in the children with CIs and in the control group. No correlation between the investigated demographic factors and test results was found.

Vid opportunistisk svampinfektion i huden är diagnosen sällan självklar. Ett samarbete mellan dermatolog, patolog och mykolog kan behövas, som i detta fall av kutan alternarios. Denna typ av svampinfektion innefattas i begreppet feohyfomykos.

Glutamate is the principal excitatory neurotransmitter in the central nervous system and it is implicated in neural transmission, learning, memory processes and neuronal plasticity. In the glutamatergic synapse two main components are present; the glutamate receptors and the glutamate transporters. The receptors, the NMDA, AMPA, kainite and the metabotroptic receptors, are responsible for conveying neural transmission, including long term potentiation (LTP), synaptic strengthening and modification. The transporters, located to the neuronal membrane and to the membranes of surrounding astrocytes, regulates the extracellular concentration of glutamate and thereby the duration of the synaptic signal.

Alterations in both receptor and transporter systems have been suggested to be important in the pathogenesis of several acute and chronic nervous system diseases, such as psychosis, mood disorders, epilepsy, Parkinson's disease and Alzheimer's disease. The pathophysiology of these disorders is not yet completely understood and the involvement of glutamate is unclear. In this thesis we have sought to investigate the role of the glutamatergic system in the treatment of mood disorders and dementia. The antidepressant drug amitriptyline exerts its main effects on the serotonergic and noradrenergic systems and the antidementia drug rivastigmine acts mainly on the cholinergic system. However, given the close relationship between different neurotransmitter systems we have investigated the influence of amitriptyline and rivastigmine on the mRNA expression of the neuronal transporter, EAAC1, in rats. The results showed for the first time an involvement of EAAC1 in amitriptyline and rivastigmine treatment. Amitriptyline induced an acute increase in EAAC1 mRNA expression, which 24 hour after administration returned to baseline levels. Chronic treatment, on the other hand, induces a significant decrease in cortical areas, which we suggest results in enhanced neuronal transmission. Rivastigmine treatment, acute as well as chronic, induced increases in the mRNA expression in hippocampus. We hypothesize that this counteracts the excitotoxic glutamate levels seen in Alzheimer's disease.

Further, environmental enrichment has been shown to have beneficial effects on capillary supply, the number of glial cells and dendritic spines, the thickness and weight of cortex, the concentration of cholinesterase, LTP and synaptic strength in animals. It has also been reported that humans that lead an active life have a reduced risk of developing Alzheimer's disease. This suggests that an active and stimulated life may have a protective effect against dementia in man, by creating a cognitive reserve which provides a buffer against brain pathology or age-related changes. We investigated the influence of environmental enrichment on the mRNA expression of NMDA and AMPA receptors and on EAACl and showed for the first time that EAAC1 mRNA is decreased after environmental enrichment. This is probably followed by an increase of glutamate in the synapse, which in turn leads to enhanced neuronal transmission including enhanced memory formation and learning. Furthermore, we confirmed in greater detail previous findings on the upregulation of NMDA mRNA and show that the regulation is regionally and hemisphere specific. We also confirm that AMPA mRNA is not per se changed by environmental enrichment in adult animals.

This work provides further evidence about the involvement of the glutamatergic system in affective and cognitive disorders. Improved knowledge of the glutamatergic system will contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.

Alzheimer’s disease is a neurodegenerative disorder that affects the cholinergic, glutamatergic and monoaminergic systems in the neocortex and hippocampus. Today, the major pharmacological treatment involves the use of acetylcholinesterase inhibitors (AChEIs). In this study, an in situ hybridisation technique (using digoxigenin-labelled cRNA probes) was used to elucidate changes in mRNA expression of the neuronal glutamate transporter, rat excitatory amino carrier 1 (rEAAC1), after treatment with the AChEI rivastigmine. Compared with saline-treated rats, the rats subchronically (3 days) and chronically (21 days), but not acutely, treated with rivastigmine showed a significant increase in rEAAC1 mRNA expression in the hippocampal areas cornu anterior 1 (CA1), CA2, CA3 and dentate gyrus (p < 0.01), but not in the cortical areas. These results provide the first evidence that the glutamatergic system is modulated following acetylcholinesterase inhibition by rivastigmine, a finding, which is likely to be of importance for the clinical effects.

Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment have been shown on neuronal structure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g., in Alzheimer's disease. Glutamatergic pathways are imperative for cognitive functions, such as memory, learning and long-term potentiation, and relies on the AMPA and NMDA glutamate receptors and the hippocampus, with its specific subregions, is an important anatomical substrate in this. The glutamate signalling is also dependent on a fine-tuned transport system, in the hippocampus primarily achieved by the glutamate transporter EAAC1. In this study we show how environmental enrichment modulates these parts of the glutamatergic system using quantitative in situ hybridisation. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly and region specifically decreased in the hippocampus. We also provide evidence for regional and hemisphere-specific upregulation of NMDA mRNA in the hippocampus after environmental enrichment. The current work also shows that AMPA mRNA of the hippocampus is not per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system of specific regions of the hippocampus and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions. © 2007.

Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment has been shown on neuronal strucrure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g. Alzheimer's disease. Glutamatergic corticocortical pathways are imperative for cognitive functions, such as memory and learning, and long term porenriation relies on the AMPA and NMDAglutamate rcceptors. The glutamate signalling is also dependent on a fine-runed transport system, in the hippocampus primarily by theglutamate transporter EAACl. In this study we show how environmental enrichment modulates these parts of the glutamarergic system using in siru hybridization. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly decreased in hippocampal and cortical areas. We also provide further evidence about the upregulation of NMDA mRNA after environmental enrichement, and show it to have a regionally and hemisphere specific regulation. The current work also confirms that AMPA mRNA is nor per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.

Glutamate transporters regulate the glutamate concentration in the synaptic cleft within the CNS, a regulation required for normal brain function. In several neurological conditions, the amount of glutamate is altered. One reason for the changes in glutamate concentration might be impaired glutamate transporter function. In this study, an in situ hybridisation technique has been used to elucidate changes in mRNA expression of the glutamate transporter, excitatory amino acid carrier 1 (EAAC1), after treatment with the tricyclic antidepressant (TCA) amitriptyline. The results lead to the suggestion that treatment with tricyclic antidepressants leads to changes in the EAAC1 mRNA expression in rat brain suggesting involvement of the glutamate system in the tricyclic treatment of depression.

Purpose: To describe new disease-causing RP2 and RPGR-ORF15 mutations and their corresponding clinical phenotypes in Swedish families with X-linked retinitis pigmentosa (XLRP) and to establish genotype-phenotype correlations by studying the clinical spectrum of disease in families with a known molecular defect. Methods: Seventeen unrelated families with RP and an apparent X-linked pattern of disease inheritance were identified from the Swedish RP registry and screened for mutations in the RP2 and RPGR (for the RP3 disease) genes. These families had been previously screened for the RPGR exons 1-19, and disease-causing mutations were identified in four of them. In the remaining 13 families, we sequenced the RP2 gene and the newly discovered RPGR-ORF exon. Detailed clinical evaluations were then obtained from individuals in the three families with identified mutations. Results: Mutations in RP2 and RPGR-ORF15 were identified in three of the 13 families. Clinical evaluations of affected males and carrier females demonstrated varying degrees of retinal dysfunction and visual handicap, with early onset and severe disease in the families with mutations in the ORF15 exon of the RPGR gene. Conclusions: A total of seven mutations in the RP2 and RPGR genes have been discovered so far in Swedish XLRP families. All affected individuals express a severe form of retinal degeneration with visual handicap early in life, although the degree of retinal dysfunction varies both in hemizygous male patients and in heterozygous carrier females. Retinal disease phenotypes in patients with mutations in the RPGR-ORF15 were more severe than in patients with mutations in RP2 or other regions of the RPGR.

Introduction: There is little information available on the effects of problem-based undergraduate curricula on doctors and their performances after graduation. Therefore, we conducted a questionnaire study of all graduates of the new medical programme at the Faculty of Health Sciences, Link÷ping University. Methods: All 446 medical students who had graduated from the new programme were asked to fill in a questionnaire about selected activities during their studies and their careers after graduation. They were also asked to evaluate the quality of their undergraduate education retrospectively. Statistical analysis was performed using descriptive, multivariate and bivariate approaches. Results: A total of 77% of the graduates responded. They showed a high degree of overall contentment with their undergraduate education and felt well prepared for professional life during their preregistration period and specialist education (mean = 4.0 on a 6-point Likert scale ranging from 0 to 5). They felt especially well prepared in terms of skills for communication with patients, collaboration with other health professionals and development of critical thinking/scientific attitudes. The students' age at the beginning of their studies correlated positively with their contentment as graduates, especially in terms of preparation for patient communication and collaboration with other health professionals. No differences between students originally admitted via a local admission procedure and those admitted via a national procedure were detected concerning retrospective evaluation of undergraduate medical education. Conclusion: Graduates of the new curriculum showed a high degree of satisfaction with their undergraduate education and its preparation of them for medical practice. Specifically, they were very content with the particular emphases of the new curriculum.

Aim: To verify the occurrence of cognitive impairment in patients with chronic whiplash-associated disorder (WAD) and to provide a more detailed description of the impairment's character and context. Methods: Thirty (30) patients with chronic WAD and 30 matched healthy controls completed a cognitive test battery. Four computerised tests were used: a) two different types of cognitive tasks (reaction time vs. working memory) and b) two types of information processing (verbal vs. spatial). Before testing and after every randomised subtest, subjects rated their pain level on a visual analogue scale. Results: A worse overall performance among patients with WAD and, specifically, worse results concerning working memory tasks were found. Post-hoc testing revealed a statistically significant difference concerning the single variable "verbal reaction time". Pain intensity among patients increased significantly during testing. Pain intensity after the subtest for verbal mental reaction time (independent of test sequence) was significantly correlated with results in this subtest, the more pain, the more time was needed. Conclusion: Compared to healthy controls, patients performed worse overall. Concerning verbal reaction time, the impairment was correlated with pain intensity. The findings support the hypothesis that pain might be one important factor leading to cognitive impairment in patients with chronic WAD.

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg ╖ kg-1 ╖ day-1), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCl-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.

In the past decade, lysosomal membrane permeabilization (LMP) has emerged as a significant component of cell death signaling. The mechanisms by which lysosomal stability is regulated are not yet fully understood, but changes in the lysosomal membrane lipid composition have been suggested to be involved. Our aim was to investigate the importance of cholesterol in the regulation of lysosomal membrane permeability and its potential impact on apoptosis. Treatment of normal human fibroblasts with U18666A, an amphiphilic drug that inhibits cholesterol transport and causes accumulation of cholesterol in lysosomes, rescued cells from lysosome-dependent cell death induced by the lysosomotropic detergent 0-methyl-serine dodecylamide hydrochloride (MSDH), staurosporine (STS), or cisplatin. LMP was decreased by pretreating cells with U18666A, and there was a linear relationship between the cholesterol content of lysosomes and their resistance to permeabilization induced by MSDH. U18666A did not induce changes in expression or localization of 70-kDa heat shock proteins (Hsp70) or antiapoptotic Bcl-2 proteins known to protect the lysosomal membrane. Induction of autophagy also was excluded as a contributor to the protective mechanism. By using Chinese hamster ovary (CHO) cells with lysosomal cholesterol overload due to a mutation in the cholesterol transporting protein Niemann-Pick type C1 (NPC1), the relationship between lysosomal cholesterol accumulation and protection from lysosome-dependent cell death was confirmed. Cholesterol accumulation in lysosomes attenuates apoptosis by increasing lysosomal membrane stability.

Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

Chronic musculoskeletal pain has biological, psychological and social components. This review deals with the biological factors, with emphasis on the fibromyalgia syndrome (FMS). Studies on central sensitization of pain-transmitting neurons, changes in endogenous pain modulation that give rise to pain disinhibition, referred pain, pain-related decrease in muscle strength and endurance, and pain generators in deep tissues are reviewed. In FMS there is strong scientific support for the statement that the biological part of the syndrome is a longstanding or permanent change in the function of the nociceptive nervous system that can be equated with a disease. Further research is necessary in order to determine which methods are best for diagnosis of the pain hypersensitivity in clinical practice. FMS may be the far end of a continuum that starts with chronic localized/regional musculoskeletal pain and ends with widespread chronic disabling pain. © 2007 Elsevier Ltd. All rights reserved.

This report presents a review of the situation in a number of countries with respect to public health policy for funding of hearing aid services in general and support to bilateral fittings in particular. The data show considerable variations among the countries studied in number of hearing aids fitted per 1000 inhabitants, differing by a factor of 6 between the extremes. Also the percentage of bilateral fittings differs with an average estimated to be of the order of 50%. For hearing-impaired children, bilateral fittings are given full financial support in most countries studied. The data presented indicate the need for a reliable, scientifically valid evidence-base regarding bilateral hearing aid fitting. © 2006 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society.

Objective: This paper intends to discuss issues related to cultural, ethnic, and other nonaudiological variables that may affect the response when trying to determine outcome of audiological rehabilitation in different countries. Design: The ideal measure for the determination of outcome of audiological rehabilitation would be sensitive to changes in disability as well as handicap. Further, it would allow unforeseen effects to be identified and not be limited by language borders or cultural and ethnic differences. A variety of critical factors are discussed that are related to culture, social traditions, ethnic factors, etc. that may affect outcome measures and thus make international equivalence difficult. Conclusions: With careful consideration of the factors discussed, a basic set of questions could be formulated and agreed on, calibrated on suitable populations in different countries, and thereafter used as a bridge across borders to allow comparison of different procedures or meta-analyses of studies performed by different laboratories.