Microstructural white matter brain abnormalities in patients with idiopathic fecal incontinence.

BACKGROUND: Abnormal central nervous system processing of visceral sensation may be a part of the pathogenesis behind idiopathic fecal incontinence (IFI). Our aim was to characterize brain differences in patients with IFI and healthy controls by means of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: In 21 female patients with IFI and 15 female healthy controls, whole-brain structural differences in gray matter volume (GMV), cortical thickness, and white matter tracts fractional anisotropy (FA) were quantified. For this purpose, we used voxel-based morphometry, surface based morphometry and tract-based spatial statistic, respectively. Furthermore, associations between structural brain characteristics and latencies of rectal sensory evoked electroencephalography potentials were determined. KEY RESULTS: Compared to healthy controls, IFI patients had significantly reduced FA values, reflecting reduced white matter tract integrity, in the left hemisphere superior longitudinal fasciculus (SLF), posterior thalamic radiation, and middle frontal gyrus (MFG), all P<.05. No differences were observed in GMV or in cortical thickness. The reduced FA values in the SLF and MFG were correlated with prolonged latencies of cortical potentials evoked by rectal stimuli (all P<.05). CONCLUSIONS & INFERENCES: This explorative study suggests that IFI patients have no macrostructural brain changes, but exhibit microstructural changes in white matter tracts relevant for sensory processing. The clinical relevance of this finding is supported by its correlations with prolonged latencies of cortical potentials evoked by rectal stimulation. This supports the theories of central nervous system changes as part of the pathogenesis in IFI patients.

Extracorporeal cardiopulmonary resuscitation after out-of-hospital cardiac arrest in a Danish health region.

BACKGROUND: Extracorporeal Cardiopulmonary Resuscitation (ECPR) has emerged as a feasible rescue therapy for refractory, normothermic out-of-hospital cardiac arrest (OHCA). Reported survival rates vary and comparison between studies is hampered by heterogeneous study populations, differences in bystander intervention and in pre-hospital emergency service organisation. We aimed to describe the first experiences, treatment details, complications and outcome with ECPR for OHCA in a Danish health region. METHODS: Retrospective study of adult patients admitted at Aarhus University Hospital, Denmark between 1 January 2011 and 1 July 2015 with witnessed, refractory, normothermic OHCA treated with ECPR. OHCA was managed with pre-hospital advanced airway management and mechanical chest compression during transport. Relevant pre-hospital and in-hospital data were collected with special focus on low-flow time and ECPR duration. Survival to hospital discharge with Cerebral Performance Category (CPC) of 1 and 2 at hospital discharge was the primary endpoint. RESULTS: Twenty-one patients were included. Median pre-hospital low-flow time was 54 min [range 5-100] and median total low-flow time was 121 min [range 55-192]. Seven patients survived (33%). Survivors had a CPC score of 1 or 2 at hospital discharge. Five survivors had a shockable initial rhythm. In all survivors coronary occlusion was the presumed cause of cardiac arrest. CONCLUSION: Extracorporeal cardiopulmonary resuscitation is feasible as a rescue therapy in normothermic refractory OHCA in highly selected patients. Low-flow time was longer than previously reported. Survival with favourable neurological outcome is possible despite prolonged low-flow duration.

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex.

BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P>0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1-4Hz) band (P=0.03) and increased the activity in the alpha (8-12Hz) band (P=0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P=0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P>0.05). CONCLUSIONS: Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated.

Fusobacterium necrophorum tonsillitis: an important cause of tonsillitis in adolescents and young adults.

The role of Fusobacterium necrophorum in tonsillitis in adolescents and young adults was retrospectively investigated by culture examination. We compared the prevalence of F. necrophorum in 212 subjects with confirmed clinical tonsillitis and in 176 subjects with confirmed no clinical tonsillitis. The prevalence of F. necrophorum was significantly higher (p < 0.001) in subjects with clinical tonsillitis (27%) compared to subjects with no clinical tonsillitis (6%). These results clearly demonstrate the role of F. necrophorum in tonsillitis. By diagnosing and treating F. necrophorum tonsillitis with, for example, penicillin, metronidazole, or both, we might prevent some cases of Lemierre syndrome.

Functional reorganization of brain networks in patients with painful chronic pancreatitis.

BACKGROUND: The underlying pain mechanisms of chronic pancreatitis (CP) are incompletely understood, but recent research points to involvement of pathological central nervous system processing involving pain-relevant brain areas. We investigated the organization and connectivity of brain networks involved in nociceptive processing in patients with painful CP. METHODS: Contact heat-evoked potentials (CHEPs) were recorded in 15 patients with CP and in 15 healthy volunteers. The upper abdominal area (sharing spinal innervation with the pancreatic gland) was used as a proxy of 'pancreatic stimulation', while stimulation of a heterologous region remote to the pancreas (right forearm) was used as a control. Subjective pain scores were assessed by visual analogue scale. The brain source organization and connectivity of CHEPs components were analysed. RESULTS: After pancreatic area stimulation, brain source analysis revealed abnormalities in the cingulate/operculo-insular network. A posterior shift of the operculo-insular source (p = 0.004) and an anterior shift of the cingulate source (p < 0.001) were seen in CP patients, along with a decreased strength of the cingulate source (p = 0.01). The operculo-insular shift was positively correlated with the severity of patient clinical pain score (r = 0.61; p = 0.03). No differences in CHEPs characteristics or source localizations were seen following stimulation of the right forearm. CONCLUSIONS: CP patients showed abnormal cerebral processing after stimulation of the upper abdominal area. These changes correlated to the severity of pain the patient was experiencing. Since the upper abdominal area shares spinal innervation with the pancreatic gland, these findings likely reflect maladaptive neuroplastic changes, which are characteristic of CP.

Central response to painful electrical esophageal stimulation in well-defined patients suffering from functional chest pain.

BACKGROUND: Functional chest pain (FCP) of presumed esophageal origin is considered a common cause for chest pain in which central nervous system hyperexcitability is thought to play an important role. We aimed to compare cerebral responses with painful esophageal stimuli between FCP patients and healthy subjects (HS). METHODS: Thirteen patients with FCP (seven females, mean age 50.4 ± 7.5 years) and 15 HS (eight females, mean age 49.1 ± 12.9 years) were enrolled. Inclusion criteria consisted of typical chest pain, normal coronary angiogram, and normal upper gastrointestinal evaluation. Electrical stimulations evoking the pain threshold were applied in the distal esophagus, while cortical evoked potentials were recorded from the scalp. Pain scores, resting electroencephalogram (EEG), evoked potential characteristics and brain electrical sources to pain stimulation were compared between groups. KEY RESULTS: No differences were seen between patients and HS regarding (i) pain thresholds (patients: 20.1 ± 7.4 mA vs HS: 22.4 ± 8.3 mA, all P > 0.05), (ii) resting-EEG (P > 0.05), (iii) evoked brain potential latencies (N2: patients 181.7 ± 25.7 mS vs HS 182.2 ± 25.8 mS, all P > 0.05) and amplitudes (N2P2: patients 8.2 ± 7.2 µV vs HS: 10.1 ± 3.4 µV, all P > 0.05), (iv) topography (P > 0.05), and (v) brain source location (P > 0.05). CONCLUSIONS & INFERENCES: No differences in activation of brain areas to painful esophageal stimulation were seen in this group of well characterized patients with FCP compared with sex- and age-matched HS. The mechanism of pain in FCP and whether it originates in the esophagus remains unsolved.

Remote ischemic perconditioning in thrombolysed stroke patients: randomized study of activating endogenous neuroprotection - design and MRI measurements.

BACKGROUND: Intravenous administration of alteplase is the only approved treatment for acute ischemic stroke. Despite the effectiveness of this treatment, 50% of patients suffer chronic neurological disability, which may in part be caused by ischemia-reperfusion injury. Remote ischemic perconditioning, performed as a transient ischemic stimulus by blood-pressure cuff inflation to an extremity, has proven effective in attenuating ischemia-reperfusion injury in animal models of stroke. Remote ischemic perconditioning increases myocardial salvage in patients undergoing acute revascularization for acute myocardial infarction. To clarify whether a similar benefit can be obtained in patients undergoing thrombolysis for acute stroke, we included patients from June 2009 to January 2011. AIM AND DESIGN: The aims of the study are: to estimate the effect of remote ischemic perconditioning as adjunctive therapy to intravenous alteplase of acute ischemic stroke within the 4-h time window and to investigate the feasibility of remote ischemic perconditioning performed during transport to hospital in patients displaying symptoms of acute stroke. Patients are randomized to remote ischemic perconditioning in a single-blinded fashion during transportation to hospital. Only patients with magnetic resonance imaging-proven ischemic stroke, who subsequently are treated with intravenous alteplase, and in selected cases additional endovascular treatment, are finally included in the study. STUDY OUTCOMES: Primary end-point is penumbral salvage. Penumbra is defined as hypoperfused yet viable tissue identified as the mismatch between perfusion-weighted imaging and diffusion-weighted imaging lesion on magnetic resonance imaging scans. Primary outcome is a mismatch volume not progressing to infarction on one-month follow-up T2 fluid attenuated inversion recovery. Secondary end-points include: infarct growth (expansion of the diffusion-weighted imaging lesion) from baseline to the 24-h and one-month follow-up examination. Infarct growth inside and outside the acute perfusion-weighted imaging-diffusion-weighted imaging mismatch zone is quantified by use of coregistration. Clinical outcome after three-months. The influence of physical activity (Physical Activity Scale for the Elderly score) on effect of remote ischemic perconditioning. Feasibility of remote ischemic perconditioning in acute stroke patients. SUMMARY: This phase 3 trial is the first study in patients with acute ischemic stroke to evaluate the effect size of remote ischemic perconditioning as a pretreatment to intravenous alteplase, measured as penumbral salvage on multimodal magnetic resonance imaging and clinical outcome after three-months follow-up.

Cerebral excitability is abnormal in patients with painful chronic pancreatitis.

BACKGROUND: We investigated whether patients with painful chronic pancreatitis (CP) present abnormalities in the cerebral response to experimental pain stimuli. METHODS: Contact heat-evoked potentials (CHEPS) were recorded in 15 patients with CP and in 15 healthy volunteers during repetitive stimulation of the upper abdominal region (pancreatic 'viscerotome') and the right forearm (heterologous area). Three sequences of painful stimuli were applied at each site. Subjective pain scores were assessed by a visual analogue scale. Habituation was calculated as the relative change in CHEPS amplitudes between the first and the third stimulation sequence. RESULTS: As expected pain scores decreased in healthy volunteers during successive stimulations at both sites (i.e., habituation), while in the CP group, they remained unchanged. The cerebral response consisted of an early-latency, low-amplitude response (N1, contralateral temporal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). During successive stimulation of the pancreatic area, N2/P2 amplitude increased 25% in CP patients, while they decreased 20% in healthy volunteers (p = 0.006). After stimulation of the forearm, N2/P2 amplitudes increased 3% in CP patients compared to a decrease of 20% in healthy volunteers (p = 0.06). CONCLUSIONS: Taken together, CP patients had an abnormal cerebral response to repetitive thermal stimuli. This was most prominent after stimulation of the upper abdominal area. As this area share spinal innervation with the pancreatic gland, these findings likely mirror distinctive abnormalities in cerebral pain processing.

Fast and direct measurements of the electrical properties of graphene using micro four-point probes.

We present measurements of the electronic properties of graphene using a repositionable micro four-point probe system, which we show here to have unique advantages over measurements made on lithographically defined devices; namely speed, simplicity and lack of a need to pattern graphene. Measurements are performed in ambient, vacuum and controlled environmental conditions using an environmental scanning electron microscope (SEM). The results are comparable to previous results for microcleaved graphene on silicon dioxide (SiO(2)). We observe a pronounced hysteresis of the charge neutrality point, dependent on the sweep rate of the gate voltage; and environmental measurements provide insight into the sensor application prospects of graphene. The method offers a fast, local and non-destructive technique for electronic measurements on graphene, which can be positioned freely on a graphene flake.

P73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis.

The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription-deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcription-independent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.

Itch inhibition regulates chemosensitivity in vitro.

Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy.

Disentangling surface, bulk, and space-charge-layer conductivity in Si(111)-(7 x 7).

A novel approach for extracting genuine surface conductivities is presented and illustrated using the unresolved example of Si(111)-(7 x 7). Its temperature-dependent conductivity was measured with a microscopic four point probe between room temperature and 100 K. At room temperature the measured conductance corresponds to that expected from the bulk doping level. However, as the temperatures is lowered below approximately 200 K, the conductance decreases by several orders of magnitude in a small temperature range and it saturates at a low temperature value of approximately 4 x 10(-8) Omega(-1), irrespective of bulk doping. This abrupt transition is interpreted as the switching from bulk to surface conduction, an interpretation which is supported by a numerical model for the measured four point probe conductance. The value of the surface conductance is considerably lower than that of a good metal.

Smac/DIABLO is not released from mitochondria during apoptotic signalling in cells deficient in cytochrome c.

We have characterised the apoptotic defects in cells null for cytochrome c (cyt c-/-). Such cells treated with staurosporine (STS) exhibited translocation to the mitochondria and activation of the proapoptotic signalling molecule Bax but failed to release Smac/DIABLO from these organelles, judged by both confocal microscopy and Western blotting. While reference cells expressing cytochrome c released both it and Smac/DIABLO under a variety of conditions of apoptotic induction, we have never observed release of Smac/DIABLO from cyt c-/- cells. We eliminate the possibility that proteasomal degradation of cytosolically localised Smac/DIABLO is responsible for our failure to visualise the protein outside the mitochondria. Our findings indicate an unanticipated nexus between release of cytochrome c and Smac/DIABLO from mitochondria, previously thought to be a more or less synchronised event early in apoptosis. We suggest that the failure of cyt c-/- cells to release Smac/DIABLO after recruitment of Bax to mitochondria represents an extreme manifestation of some inherent difference in the regulation of release of these two proteins from mitochondria.

Comparison of dual X-ray absorptiometry (DXA), digital X-ray radiogrammetry (DXR), and conventional radiographs in the evaluation of osteoporosis and bone erosions in patients with rheumatoid arthritis.

OBJECTIVE: To compare the relationship between bone mineral density (BMD) in the metacarpal bones and forearm measured by dual X-ray absorptiometry (DXA) and digital X-ray radiogrammetry (DXR) and radiological alterations in patients with early and established rheumatoid arthritis (RA). PATIENTS AND METHODS: In each of the three disease duration groups, 11 female RA patients were included. The patients were further divided into two groups according to bone erosions. BMD in the metacarpals was evaluated by DXA and DXR. RESULTS: A significant relationship between DXA-BMD and DXR-BMD was observed. DXR-BMD and the individually combined cortical thickness (CT) of the metacarpo-phalangeal (MCP) joints were related to disease duration and erosions. Patients with erosive disease had lower values of age- and sex-adjusted BMD measured with DXA, but most significantly with DXR. CONCLUSION: DXR appears to be a more sensitive method than DXA in detecting early bone loss in patients with RA. The relationship of DXR-BMD to disease duration and bone damage indicates that the DXR method may be useful in the evaluation of disease activity and progression.

Bone loss in unclassified polyarthritis and early rheumatoid arthritis is better detected by digital x ray radiogrammetry than dual x ray absorptiometry: relationship with disease activity and radiographic outcome.

OBJECTIVE: To compare changes in regional bone mineral density (BMD) of the metacarpal joints measured by dual x ray absorptiometry (DXA) and digital x ray radiogrammetry (DXR) in relation to disease activity and radiographic outcome in a two year follow up study of patients with early RA and unclassified polyarthritis. PATIENTS AND METHODS: 72 patients with symmetrically swollen and tender second and third metacarpophalangeal or proximal interphalangeal joints for at least four weeks and less than two years were included. 51 patients fulfilled the ACR criteria for RA. 21 patients had unclassified polyarthritis. The patients with RA were divided into groups according to mean disease activity, average glucocorticoid dose, and MRI and x ray detected bone erosions in the hands. Clinical and biochemical measurements were made every month and an x ray examination of the hands and BMD of the metacarpal joints every six months. RESULTS: DXR BMD decreased significantly only in patients with RA from month 6 and was associated with the mean disease activity. Patients with RA and erosive as well as non-erosive disease showed a significant decrease in the rate of bone loss, greatest in those with erosive disease. No changes in BMD measured by DXA were seen in any patient group. CONCLUSION: DXR is a useful measure of the destructive disease activity in patients with RA and unclassified polyarthritis, providing valuable information about bone changes associated with disease activity and erosive disease in early RA. DXR is better than DXA for detecting and monitoring periarticular osteoporosis of the metacarpal bone.

Adaptation into Danish of the Stanford Health Assessment Questionnaire (HAQ) and the Rheumatoid Arthritis Quality of Life Scale (RAQoL).

OBJECTIVES: The study was designed to adapt the Stanford Health Assessment Questionnaire (HAQ) and the Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) for use in Denmark. METHOD: The instruments were translated into Danish and then field-tested with 10 RA patients for relevance, and face and content validity. Reliability and validity were assessed by administering the new measures and a comparator instrument (the Danish Nottingham Health Profile) to 80 RA patients on two occasions. RESULTS: Patients found both measures acceptable and easy to complete. They had good test-retest reliability (>0.90) and internal consistency and were both able to discriminate between groups with different levels of functional status and self-perceived severity. When compared with the NHP sections, both measures showed expected convergence and divergence. CONCLUSION: Given the excellent psychometric properties of the Danish versions of the RAQoL and HAQ, both are recommended for inclusion in clinical trials and studies.

[Pregnancy associated pelvic pain. I: Prevalence and risk factors]. / Graviditetsrelaterede baekkensmerter. I: Praevalens og risikofaktorer.

With this study, we wanted to determine the incidence of symptom-giving pelvic girdle relaxation during pregnancy and the prevalence post partum, identify predisposing factors, and determine the frequency of sick leave. A total of 1600 pregnant women entered the study. The incidence during pregnancy was 14%, the prevalence two, six, and twelve months post partum was 5%, 4%, and 2%, respectively. Multivariate analysis indicated that the most important predisposing factor was pelvic pain in a previous pregnancy. Other factors were uncomfortable working conditions, lack of exercise, and previous low back and low abdominal pain. At least 37% of the women with symptom-giving pelvic girdle relaxation were on sick leave during pregnancy, on average for twelve weeks. Symptom-giving pelvic girdle relaxation is a considerable problem both in pregnancy and post partum. The occupational risk can possibly be prevented. The syndrome has a great social impact because of the high frequency of sick live.

[Pregnancy associated pelvic pain. II: Symptoms and clinical findings]. / Graviditetsrelaterede baekkensmerter. II: Symptomer og kliniske fund.

Pelvic pain in pregnancy appears to be a problem on the increase. This study was undertaken to describe and analyse the relationship between subjective symptoms, daily disability, and clinical findings in women with symptom-giving pelvic girdle relaxation in pregnancy. Out of 1600 pregnant women, 238 had pelvic pain. After a clinical examination 11 women were excluded due to low back pain. The rest, 227 women, was considered to have symptom-giving pelvic girdle relaxation during pregnancy. Symptom-giving pelvic girdle relaxation in pregnancy seriously interferes with many activities of daily living such as housekeeping, walking, working, and sexual life. The women's statements of pelvic pain are well correlated to the number of positive clinical tests. Symptom-giving pelvic girdle relaxation in pregnancy causes considerable disabilities concerning daily activities.