Colony housing promotes structural and functional changes during surgically induced osteoarthritis in rats.

Objective: The aim of the study was to investigate how social housing with high locomotion activity affects experimental osteoarthritis (OA) in rats. Design: Rats were housed either conventionally in type IV cages in pairs or in rat colony cages (RCC) on 4 levels interconnected by jump holes or staircase in groups of 48. OA was induced by anterior cruciate ligament transection and resection of the medial meniscus (ACLT + tMx), medial meniscal tear (MMT) or destabilization of the medial meniscus (DMM). Functional changes were characterized by continues tracking of individual activity and catwalk gait analysis. Cartilage volume and bone structure were investigated at week 20 after surgery by histology and micro-CT. Results: In the RCC, healthy rats changed cage levels 82 ± 15 times daily, reduced by 30% after ACLT + tMx (p < 0.0001). In both housing systems, the order of severity of the investigated models was ACLT + tMx > MMT > DMM in all outcome measures. Compared to Type IV, RCC housed rats developed stronger gait disturbance symptoms (ACLT + tMx; 95%CI = -15-2; p < 0.004), the cartilage volume was reduced (ACLT + tMx: 95%CI = -0.1-0.5; p < 0.0001), serum levels of the cartilage remodeling marker AGNx1 were higher (MMT; 95%CI = -53-(-6); p = 0.001), bone was denser with increased volume (ACLT + tMx; 95%CI = 0.8-7.5; p = 0.004) and joints were less flexible (ACLT + tMx; 95%CI = 3.6-14; p < 0.0001). Conclusion: Housing rats in an environment allowing increased locomotion and socialization promotes structural and functional alterations during joint instability-induced OA. This increases the assay window, improves the relevance for the human disease and enables to discriminate the models in structural and behavioral parameters.

Improvement of medical judgments by numerical training in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: People with multiple sclerosis (MS) have to face important decisions with regard to their medical treatment. The aim of this study was to evaluate whether a targeted cognitive training reduces framing effects and thus improves medical judgments. METHODS: This was a randomized, double-blind, cross-over study enrolling patients with relapsing-remitting MS and healthy controls (HCs). Participants were randomly assigned to training order A (first week, numerical training; second week, control training) or B (reverse order). The primary endpoint was changed in a framing task score (framing effect). In the framing task, participants evaluated the success of fictive medications on a 7-point scale. Medications were described in either positive or negative terms. RESULTS: A total of 37 patients and 73 HCs performed either training order A (n = 56) or B (n = 54). The framing effect decreased after the numerical training regardless of training order. No such decrease was found after the control training. Mean change in framing effect was -0.3 ± 0.8 after the numerical training and 0.03 ± 0.6 after the control training. This specific effect of training type was comparable between groups. CONCLUSION: Judgments of medical information improve in both patients with relapsing-remitting MS and HCs after a targeted numerical training. Thus, a specific cognitive intervention may help patients making informed decisions.

Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block.

BACKGROUND AND PURPOSE: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314. EXPERIMENTAL APPROACH: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed. KEY RESULTS: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314. CONCLUSIONS AND IMPLICATIONS: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.

[Advice for patients diagnosed with ankylosing spondylitis: results of a representative patient survey in Germany]. / Hinweise für Patienten mit der Diagnose Ankylosierende Spondylitis: Ergebnisse einer Repräsentativbefragung der Deutschen Vereinigung Morbus Bechterew e.V.

BACKGROUND: Following the diagnosis of a chronic disease like ankylosing spondylitis (AS), patients need extensive information on what to expect, how to behave and what they need to be aware of in particular in order to contribute to a favourable disease outcome. METHODS: A questionnaire consisting of 82 questions regarding demographics, diagnosis, information received with the diagnosis, disease activity, function, quality of life, treatment, ability to work, smoking etc. was distributed to AS patients by rheumatologists in 51 hospitals and/or private practices. In addition, the questionnaire was sent to 3400 randomly selected members out of the 14,000 patient members of the German Ankylosing Spondylitis Society (Deutsche Vereinigung Morbus Bechterew, DVMB). RESULTS: In all, 1068 DVMB members and 205 non-members responded to the survey. Almost all of these indicated that they had received at least one piece of information regarding what they should be particularly aware of, at the time of diagnosis. A total of 69% were informed about the need for daily exercise, 51% about the value of individual physiotherapy, 38% about the value of group physiotherapy, 37% about the need to maintain an upright posture, and 33% were recommended 3 weeks in a rehabilitation centre. Less than 30% were informed about appropriate sports, appropriate working conditions, suitable chairs, mattress, pillows etc., about the value of radon therapy or about joining a disease-specific patient organisation. To the question regarding what patients meanwhile consider as most important, daily exercise (50%) and sufficient movement at work and leisure (55%) were reported most frequently. Other aspects regarded as important to patients included a flat, firm mattress (53%), avoiding large pillows (42%), keeping an upright posture at work (38%), appropriate sports (36%), and an upright posture also when not at work (34%). Of the DVMB members, 46% had participated in disease-specific standardised patient education, compared with only 31% of non-members (p<0.001).

Cortical motor activation patterns following hand transplantation and replantation.

We studied cortical activation patterns by functional MRI in a patient who received bilateral hand transplantation after amputation 6 years ago. In the early post-operative period, the patient who had had the hand transplantation revealed strong activation of a higher motor area, only weak activation of the primary sensorimotor motor cortex and no activation of the primary somatosensory cortex. At one-year follow-up, a small increase in primary sensorimotor motor cortex activation was observed. Activation of the primary somatosensory cortex was only seen at the 2-year follow-up. Transplantation after long-standing amputation results in cortical reorganisation occurring over a two-year period.

Inhibition of cyclooxygenases by dipyrone.

BACKGROUND AND PURPOSE: Dipyrone is a potent analgesic drug that has been demonstrated to inhibit cyclooxygenase (COX). In contrast to classical COX-inhibitors, such as aspirin-like drugs, dipyrone has no anti-inflammatory effect and a low gastrointestinal toxicity, indicating a different mode of action. Here, we aimed to investigate the effects of dipyrone on COX. EXPERIMENTAL APPROACH: The four major metabolites of dipyrone, including the two pharmacologically active metabolites, 4-methyl-amino-antipyrine (MAA) and amino-antipyrine (AA), were used to characterise their binding to COX and haem as well as their effects on the biochemical properties of COX. Mass spectrometry, UV and visible photometry were used to study binding and prostaglandin production. Levels of anti-oxidant enzymes were assessed by Western blotting. KEY RESULTS: The pharmacologically active metabolites of dipyrone, MAA and AA, did not inhibit COX activity in vitro like classical COX inhibitors, but instead redirected the prostaglandin synthesis, ruling out inhibition of COX through binding to its active site. We found that MAA and AA formed stable complexes with haem and reacted with hydrogen peroxide in presence of haem, ferrous ions (Fe(2+)) or COX. Moreover, MAA reduced Fe(3+) to Fe(2+) and accordingly increased lipid peroxidation and the expression of anti-oxidant enzymes in cultured cells and in vivo. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the pharmacologically active metabolites of dipyrone inhibit COX activity by sequestering radicals which initiate the catalytic activity of this enzyme or through the reduction of the oxidative states of the COX protein.

rFVIIa--for acute rebleeding of a cerebral cavernous malformation.

Recurrent bleeding episodes of cavernomas especially in the brainstem can cause progressive neurological deficits. Therefore brainstem cavernomas are still a therapeutic dilemma and a treatment challenge for the neuro critical care community. We report a 39-year-old woman with spontaneous ataxia diplopia and vomiting, who has been treated for multiple intracerebral cavernomas during the last 10 years. A cerebral computed tomography (cCT) revealed a re-bleeding cavernoma in the left cerebral peduncle with consecutive obstructive hydrocephalus. As a result of the difficult anatomical location, no surgical approach was possible. As an off-label treatment, recombinant activated factor VII (rFVIIa) was administered to prevent possible further bleeding and especially further sequelae. The patient recovered well and no adverse events and especially no further bleeding of the cavernoma were observed. To our knowledge, this is the first report of the safe and successful use of rFVIIa to treat re-bleeding episodes in cavernomas. Further clinical studies are needed to specify the future potential of rFVIIa.

Cortical motor activation patterns following hand transplantation and replantation.

We studied cortical activation patterns by functional MRI in a patient who received bilateral hand transplantation after amputation 6 years ago and in a patient who had received unilateral hand replantation within 2 hours after amputation. In the early postoperative period, the patient who had had the hand transplantation revealed strong activation of a higher motor area, only weak activation of the primary sensorimotor motor cortex and no activation of the primary somatosensory cortex. At 1-year follow-up, a small increase in primary sensorimotor motor cortex activation was observed. Activation of the primary somatosensory cortex was only seen at the 2 year follow-up. By contrast, after hand replantation, the activation pattern was similar to that of the uninjured hand within 6 weeks. This included activation of the primary sensorimotor motor cortex, higher motor areas and primary somatosensory cortex. Transplantation after long-standing amputation results in cortical reorganization occurring over a 2-year period. In contrast, hand replantation within a few hours preserves a normal activation pattern.

Voxel based morphometry reveals a distinct pattern of frontal atrophy in progressive supranuclear palsy.

BACKGROUND: Frontal lobe atrophy is a well known neuropathological feature of progressive supranuclear palsy (PSP), accompanied by characteristic neuropsychological deficits. OBJECTIVE: To determine subregional frontal lobe atrophy patterns in patients with PSP using voxel based morphometry (VBM). METHODS: VBM is an observer unbiased volumetry which allows the investigation of the entire brain. An optimised protocol for normalisation, segmentation, and correction for volume changes in preprocessing was used. Grey matter, white matter, and cerebrospinal fluid (CSF) partitions in 12 patients with probable PSP were compared with 12 healthy controls matched for age and sex. RESULTS: In PSP patients, the following cortical areas were decreased in volume (p(corr)<0.05): the prefrontal cortex, predominantly the medial frontal gyri and a cluster in the left lateral middle frontal gyrus; the insular region including the frontal opercula; both supplementary motor areas; and the left medio-temporal area (V5). White matter comparisons revealed a volume reduction in both frontotemporal regions and the mesencephalon. Analysis of the CSF compartment showed no significant regional changes between the groups. CONCLUSIONS: Frontal atrophy in PSP predominantly involves mesio-frontal targets of striatal projections. This atrophy pattern probably accounts for cardinal PSP associated behavioural deficits.

Learning complex arithmetic--an fMRI study.

Aim of the present functional magnet resonance imaging (fMRI) study was to detect modifications of cerebral activation patterns related to learning arithmetic. Thirteen right-handed subjects were extensively trained on a set of 18 complex multiplication problems. In the following fMRI session, trained and untrained problems (closely matched for difficulty) were presented in blocked order alternating with a number matching task and a fact retrieval task. Importantly, left hemispheric activations were dominant in the two contrasts between untrained and trained condition, suggesting that learning processes in arithmetic are predominantly supported by the left hemisphere. Contrasting untrained versus trained condition, the left intraparietal sulcus showed significant activations, as well as the inferior parietal lobule. A further significant activation was found in the left inferior frontal gyrus. This activation may be accounted for by higher working memory demands in the untrained as compared to the trained condition. Contrasting trained versus untrained condition a significant focus of activation was found in the left angular gyrus. Following the triple-code model [Science 284 (1999) 970], the shift of activation within the parietal lobe from the intraparietal sulcus to the left angular gyrus suggests a modification from quantity-based processing to more automatic retrieval. The present study shows that the left angular gyrus is not only involved in arithmetic tasks requiring simple fact retrieval, but may show significant activations as a result of relatively short training of complex calculation.

Diffusion-weighted imaging discriminates progressive supranuclear palsy from PD, but not from the parkinson variant of multiple system atrophy.

BACKGROUND AND OBJECTIVE: The parkinson variant of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP) present with atypical parkinsonism, which may be misdiagnosed as PD, particularly in early disease stages. It was previously shown that diffusion-weighted MRI (DWI) is a sensitive tool to discriminate MSA-P from PD based on increased apparent diffusion coefficients (ADCs) in the putamen. In this study DWI was evaluated in 10 patients with PSP compared with 13 patients with PD and 12 with MSA-P. METHODS: Disease was diagnosed according to established diagnostic criteria and groups were matched for age, disease duration, and Hoehn and Yahr "off" stage. Regional ADCs (rADCs) were determined in different brain regions including basal ganglia, gray matter, white matter, substantia nigra, and pons. RESULTS: In patients with PSP compared with those with PD, rADCs were significantly increased in putamen, globus pallidus, and caudate nucleus. Stepwise logistic regression analysis followed by receiver operating characteristics analysis identified an optimal cut-off value for putaminal rADC, discriminating PSP and PD with a sensitivity of 90% and a positive predictive value of 100%. DWI failed to discriminate PSP and MSA-P. CONCLUSIONS: These results show that DWI detects basal ganglia abnormalities in PSP patients within few years of disease onset, discriminating patients with PSP from those with PD, but not from those with MSA-P.

Prognostic value of intraventricular blood in perimesencephalic nonaneurysmal subarachnoid hemorrhage.

INTRODUCTION: Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSH) is a distinct type of subarachnoid hemorrhage with a characteristic bleeding pattern, and an excellent clinical outcome. However, the clinical course of patients presenting with a perimesencephalic nonaneurysmal bleeding pattern and intraventricular blood has not yet been investigated. MATERIALS AND METHODS: In this retrospective study we describe the cisternal blood distribution and the clinical course of 34 PNSH patients with (10 patients) and without (24 patients) intraventricular blood. RESULTS/DISCUSSION: Patients without intraventricular blood were in good clinical condition on admission; the in-hospital course was uneventful except for acute hydrocephalus, which was detected in two cases and improved spontaneously in both patients. All patients resumed their previous lifestyles. In contrast, two patients with PNSH and intraventricular blood were drowsy and had focal neurologic deficits on admission. Four patients developed an acute hydrocephalus, and two of these patients needed ventricular shunting. There was evidence for delayed cerebral ischemia in one of these patients. Outcome was excellent in eight cases, and one patient was moderately and one patient was severely disabled at dismissal from the hospital. Rebleeding did not occur in all patients, and repeated four-vessel angiography did not reveal the source of bleeding in any of our patients. CONCLUSION: Our data indicate that the presence of intraventricular blood may be a good indicator for the development of acute hydrocephalus in PNSH. Moreover, our results suggest that PNSH patients with ventricular blood may have a higher complication rate and a poorer outcome compared with PNSH patients without intraventricular blood.

Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study.

Results from a dose-ranging study in a selected group of de novo patients with rotational cervical dystonia (CD) suggest that 500 units of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) is the optimal starting dose. The present study aimed to confirm the efficacy and safety profile of this dose in a population of CD patients more representative of those seen in a typical dystonia clinic. A total of 68 patients with moderate to severe CD (Tsui score > or = 9) were randomly assigned to receive placebo or Dysport 500 units. Treatment was administered according to the clinical pattern of head deviation, using a standardised injection protocol. A total of 21 patients (11 Dysport, 10 placebo) had not previously received botulinum toxin type A (BtxA) injections, and 47 patients (24 Dysport, 23 placebo) had received BtxA more than 12 weeks previously. Assessments were performed at baseline and weeks 4, 8 and 16. Patients defined as non-responders at week 4 were re-treated in an open phase with 500 units of Dysport at week 6, and were followed up at week 10. Significant between-group differences in Tsui scores were present at weeks 4 (p=0.001) and 8 (p=0.002). Similarly, there were significant between-group differences (p < 0.001) in patient and investigator assessments of response in favour of Dysport at weeks 4 and 8. Also, more Dysport (49%) than placebo (33%) patients were pain-free at week 4 (p=0.02). Overall, 30/35 (86 %) Dysport patients and 14/33 (42%) placebo patients were classified as responders at week 4. Adverse events were reported by 15/35 Dysport patients and 9/33 placebo patients. Open phase treatment produced improvements in Tsui (p < 0.001) and pain scores (p=0.011), and 23/24 patients were classified as responders. Although individual dose titration and muscle selection is desirable, this study demonstrated that a dose of 500 units of Dysport injected into clinically identified neck muscles without electromyographic guidance is safe and effective in the treatment of patients with the major clinical types of cervical dystonia.

Frequency of symptom distress and poor prognostic indicators in palliative cancer patients admitted to a tertiary palliative care unit, hospices, and acute care hospitals.

The Edmonton Regional Palliative Care Program was established to increase access to palliative care for terminal cancer patients in the region. Inpatient care is delivered, in decreasing order to distress, at the tertiary palliative care unit, by consult teams in acute care facilities, and in hospices. We reviewed the admission data for all patients discharged from the program between November 1, 1997, and October 31, 1998, in order to determine if demographical and clinical variables suggested appropriate use of the three levels of care. Patients admitted to the tertiary palliative care unit were significantly younger than those admitted to acute care of hospices (61 years versus 68 years and 71 years respectively, p < 0.0001), had a higher frequency of positive screening for alcoholism in the CAGE questionnaire (27% versus 16% and 14% respectively, p < 0.0001), and a higher frequency of poor prognostic pain syndromes as compared to acute care admissions (87% versus 65%, p < 0.0001). Overall, frequency of symptoms and severe symptoms was significantly higher in patients admitted to the palliative care unit than those admitted to the other two settings. Our results suggest that patients with demographic and clinical indications of higher distress are more frequently admitted to the tertiary palliative care unit. The clinical tools are useful predictors of utilization that can be used for monitoring health care delivery.

Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPECT study using 123I-beta-CIT and 123I-IBZM.

Structural imaging suggests that traumatic brain injury (TBI) may be associated with disruption of neuronal networks, including the nigrostriatal dopaminergic pathway. However, to date deficits in pre- and/or postsynaptic dopaminergic neurotransmission have not been demonstrated in TBI using functional imaging. We therefore assessed dopaminergic function in ten TBI patients using [123I]2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane (beta-CIT) and [123I]iodobenzamide (IBZM) single-photon emission tomography (SPET). Average Glasgow Coma Scale score (+/-SD) at the time of head trauma was 5.8+/-4.2. SPET was performed on average 141 days (SD +/-92) after TBI. The SPET images were compared with structural images using cranial computerised tomography (CCT) and magnetic resonance imaging (MRI). SPET was performed with an ADAC Vertex dual-head camera. The activity ratios of striatal to cerebellar uptake were used as a semiquantitative parameter of striatal dopamine transporter (DAT) and D2 receptor (D2R) binding. Compared with age-matched controls, patients with TBI had significantly lower striatal/cerebellar beta-CIT and IBZM binding ratios (P< or =0.01). Overall, the DAT deficit was more marked than the D2R loss. CCT and MRI studies revealed varying cortical and subcortical lesions, with the frontal lobe being most frequently affected whereas the striatum appeared structurally normal in all but one patient. Our findings suggest that nigrostriatal dysfunction may be detected using SPET following TBI despite relative structural preservation of the striatum. Further investigations of possible clinical correlates and efficacy of dopaminergic therapy in patients with TBI seem justified.

Predictors of home death in palliative care cancer patients.

With recent changes in health care there is greater emphasis on providing care at home, including the support of families to enable more home deaths. Since a home death may not be practical or desirable in every family situation, there is a need for an objective way to assess the viability of a home death in each individual family situation. The purpose of this study was to describe the relative role of predictors of home death in a cohort of palliative care patients with advanced cancer. A questionnaire was created as a means of assessing the viability of a home death. Five questions were included. Ninety questionnaires were administered by home care coordinators. A follow-up questionnaire was administered to record the place of death. Of the 73 evaluable patients, 34 (47%) died at home and 39 (53%) died in hospital or hospice. The desire for a home death by both the patient and the caregiver, support of a family physician, and presence of more than one caregiver were all significantly associated with a home death. Logistic regression identified a desire for home death by both the patient and the caregiver as the main predictive factor for a home death. The presence of more than one caregiver was also predictive of home death. The questionnaire is simple and, if our results are confirmed, it can be used for predicting those who will not have a home death.

The impact of a regional palliative care program on the cost of palliative care delivery.

In July 1995 the Edmonton Regional Palliative Care Program (ERPCP) was established in the City of Edmonton to increase the access of patients with terminal cancer to palliative care services, decrease the number of cancer deaths in acute-care facilities, and increase the participation of family physicians in the care of terminally ill patients. The objective of this retrospective study was to determine the cost of implementation of the ERPCP and savings in acute-care facility costs after its implementation. We did this by comparing the cost of care for patients during 1992-93 (prior to the ERPCP) and 1996-97 (with the ERPCP). The main outcome measures were the cost of care and the total hospital stay in days for all patients during their last acute-care hospital admission. The increased funding for the ERPCP was offset by a significant decrease in the overall cost of palliative care in the acute-care facilities. There was a substantial decrease in the palliative care costs in acute facilities from 11,963,846 dollars in 1992/93 to 3,449,055 dollars in 1996/97. This can be explained by the significant decrease in the number of palliative care patient days in acute-care facilities from 22,608 during 1992/93 to 6085 during 1996/97. Physician billings were slightly higher for 1996 as compared to 1992. In 1992, 90% (195,117/427,780) of the billings were made by the specialists (internists, surgeons, and other specialists), while in 1996/97 67% (359,869/537,342) of the payments were made to primary care practitioners (p < 0.0001). Overall, there were estimated saving of 1,650,689 dollars for palliative care costs in 1996/97 as compared to 1992/93. Our results suggest that the establishment of an integrated palliative care program reduced the cost of care. Prospective cost measurement studies are required.