Role of plerixafor in autologous stem cell mobilization with vinorelbine chemotherapy and granulocyte-colony stimulating factor in patients with myeloma: a phase II study (PAV-trial)

Current practice in Switzerland for the mobilization of autologous stem cells in patients with myeloma is combining vinorelbine chemotherapy and granulocyte-colony stimulating factor (G-CSF) cytokine stimulation. We prospectively investigated adding intravenous plerixafor to the vinorelbine/G-CSF combination (VGP), and compared it with vinorelbine/plerixafor (VP) and G-CSF/plerixafor (GP) combinations. In a final cohort (VP-late), plerixafor was given on the first day of CD34 + cells increasing to > 15 000/mL peripheral blood. Four consecutive cohorts of 10 patients with myeloma were studied. We observed that intravenously administered plerixafor can be safely combined with vinorelbine/G-CSF. VGP was superior in mobilizing peripheral stem and progenitor cells compared to the three double combinations (VP, GP and VP-late), and GP mobilized better than VP. Our data indicate that the triple combination of VGP is an efficient strategy to collect autologous CD34 + cells, with G-CSF contributing predominantly in this concept. Plerixafor can be safely added to G-CSF and/or vinorelbine chemotherapy.

Modeling of electroosmotic and electrophoretic mobilization in capillary and microchip isoelectric focusing

Our dynamic capillary electrophoresis model which uses material specific input data for estimation of electroosmosis was applied to investigate fundamental aspects of isoelectric focusing (IEF) in capillaries or microchannels made from bare fused-silica (FS), FS coated with a sulfonated polymer, polymethylmethacrylate (PMMA) and poly(dimethylsiloxane) (PDMS). Input data were generated via determination of the electroosmotic flow (EOF) using buffers with varying pH and ionic strength. Two models are distinguished, one that neglects changes of ionic strength and one that includes the dependence between electroosmotic mobility and ionic strength. For each configuration, the models provide insight into the magnitude and dynamics of electroosmosis. The contribution of each electrophoretic zone to the net EOF is thereby visualized and the amount of EOF required for the detection of the zone structures at a particular location along the capillary, including at its end for MS detection, is predicted. For bare FS, PDMS and PMMA, simulations reveal that EOF is decreasing with time and that the entire IEF process is characterized by the asymptotic formation of a stationary steady-state zone configuration in which electrophoretic transport and electroosmotic zone displacement are opposite and of equal magnitude. The location of immobilization of the boundary between anolyte and most acidic carrier ampholyte is dependent on EOF, i.e. capillary material and anolyte. Overall time intervals for reaching this state in microchannels produced by PDMS and PMMA are predicted to be similar and about twice as long compared to uncoated FS. Additional mobilization for the detection of the entire pH gradient at the capillary end is required. Using concomitant electrophoretic mobilization with an acid as coanion in the catholyte is shown to provide sufficient additional cathodic transport for that purpose. FS capillaries dynamically double coated with polybrene and poly(vinylsulfonate) are predicted to provide sufficient electroosmotic pumping for detection of the entire IEF gradient at the cathodic column end.

Rhyming the National Spirit: Taras Shevchenko and Ilia Chavchavadze

The paper is a comparative inquiry into the roles of Ilia Chavchavadze (1837-1907) and Taras Shevchenko (1818-1861) as national poets and anti-colonial (anti-Tsarist) intellectuals within the context of their respective national traditions (Georgia and Ukraine). During the period of their activity (19th and the beginning of 20th century) both Ukraine and Georgia were under Tsarist imperial rule, albeit the two poets lived in different periods of Russian empire history. Through their major works, each called on their communities to ‘awaken’ and ‘revolt’ against oppression, rejected social apathy caused by Tsarist subjugation and raised awareness about the historical past of their nations. The non-acceptance of present and belief in an independent future was one of the dominant themes in the poetry and prose of both. Their contemporary importance is illustrated in political discourse both after Orange Revolution in Ukraine (2004), and Rose Revolution in Georgia (2003) where both poets are referred “as founding fathers of national ideology”, the history textbooks alluding to them as “symbols of anti-colonial resistance”. To this day, however, there has been surprisingly little academic writing in the West endeavoring to compare the works and activities of the two poets and their impact on national mobilization in Tsarist Ukraine and Georgia, even though their countries are often mentioned in a same breath by commentators on contemporary culture and politics. The paper attempts to fill this gap and tries to understand the relationship between literature and social mobilization in 19th century Russian Empire. By reflecting on Taras Shevchenko’s and Ilia Chavchavadze’s poetry, prose and social activism, I will try to explain how in different periods of Russian imperial history, the two poets helped to develop a modern form of political belonging among their compatriots and stimulated an anti-colonial mobilization with different political outcomes. To theorize on the role of poets and novelists in anti-colonial national movement, I will reflect on the writings of Benedict Anderson (1991), John Hutchinson (1994; 1999), Rory Finnin (2005; 2011) and problematize Miroslav Hroch’s (1996) three phase model of the development of national movements. Overall, the paper would aim to show the importance of, what John Hutchinson called, ‘cultural nationalists’ in understanding contemporary nationalist discourse in Georgian and Ukrainian societies.

Impact of coil position and electrophysiological monitoring on determination of motor thresholds to transcranial magnetic stimulation

OBJECTIVE: We compared motor and movement thresholds to transcranial magnetic stimulation (TMS) in healthy subjects and investigated the effect of different coil positions on thresholds and MEP (motor-evoked potential) amplitudes. METHODS: The abductor pollicis brevis (APB) 'hot spot' and a standard scalp position were stimulated. APB resting motor threshold (APB MEP-MT) defined by the '5/10' electrophysiological method was compared with movement threshold (MOV-MT), defined by visualization of movements. Additionally, APB MEP-MTs were evaluated with the '3/6 method,' and MEPs were recorded at a stimulation intensity of 120% APB MEP-MT at each position. RESULTS: APB MEP-MTs were significantly lower by stimulation of the 'hot spot' than of the standard position, and significantly lower than MOV-MTs (n=15). There were no significant differences between the '3/6' and the '5/10' methods, or between APB MEP amplitudes by stimulating each position at 120% APB MEP-MT. CONCLUSIONS: Coil position and electrophysiological monitoring influenced motor threshold determinations. Performing 6 instead of 10 trials did not produce different threshold measurements. Adjustment of intensity according to APB MEP-MT at the stimulated position did not influence APB MEP amplitudes. SIGNIFICANCE: Standardization of stimulation positions, nomenclature and criteria for threshold measurements should be considered in design and comparison of TMS protocols.

Quality of pain treatment after caesarean section: Results of a multicentre cohort study.

BACKGROUND A large cohort study recently reported high pain scores after caesarean section (CS). The aim of this study was to analyse how pain after CS interferes with patients' activities and to identify possible causes of insufficient pain treatment. METHODS We analysed pain scores, pain-related interferences (with movement, deep breathing, mood and sleep), analgesic techniques, analgesic consumption, adverse effects and the wish to have received more analgesics during the first 24 h after surgery. To better evaluate the severity of impairment by pain, the results of CS patients were compared with those of patients undergoing hysterectomy. RESULTS CS patients (n = 811) were compared with patients undergoing abdominal, laparoscopic-assisted vaginal or vaginal hysterectomy (n = 2406, from 54 hospitals). Pain intensity, wish for more analgesics and most interference outcomes were significantly worse after CS compared with hysterectomies. CS patients with spinal or general anaesthesia and without patient-controlled analgesia (PCA) received significantly less opioids on the ward (62% without any opioid) compared with patients with PCA (p < 0.001). Patients with PCA reported pain-related interference with movement and deep breathing between 49% and 52% compared with patients without PCA (between 68% and 73%; p-values between 0.004 and 0.013; not statistically significant after correction for multiple testing). CONCLUSION In daily clinical practice, pain after CS is much higher than previously thought. Pain management was insufficient compared with patients undergoing hysterectomy. Unfavourable outcome was mainly associated with low opioid administration after CS. Contradictory pain treatment guidelines for patients undergoing CS and for breastfeeding mothers might contribute to reluctance of opioid administration in CS patients.

Effects of subthalamic nucleus stimulation on cognition and mood in Parkinson’s disease (PD)

Objective: To assess the neuropsychological outcome as a safety measure and quality control in patients with subthalamic nucleus (STN) stimulation for PD. Background: Deep brain stimulation (DBS) is considered a relatively safe treatment used in patients with movement disorders. However, neuropsychological alterations have been reported in patients with STN DBS for PD. Cognition and mood are important determinants of quality of life in PD patients and must be assessed for safety control. Methods: Seventeen consecutive patients (8 women) who underwent STN DBS for PD have been assessed before and 4 months after surgery. Besides motor symptoms (UPDRS-III), mood (Beck Depression Inventory, Hamilton Depression Rating Scale) and neuropsychological aspects, mainly executive functions, have been assessed (mini mental state examination, semantic and phonematic verbal fluency, go-no go test, stroop test, trail making test, tests of alertness and attention, digit span, wordlist learning, praxia, Boston naming test, figure drawing, visual perception). Paired t-tests were used for comparisons before and after surgery. Results: Patients were 61.6±7.8 years old at baseline assessment. All surgeries were performed without major adverse events. Motor symptoms ‘‘on’’ medication remained stable whereas they improved in the ‘‘off’’ condition (p<0.001). Mood was not depressed before surgery and remained unchanged at follow-up. All neuropsychological assessment outcome measures remained stable at follow-up with the exception of semantic verbal fluency and wordlist learning. Semantic verbal fluency decreased by 21±16% (p<0.001) and there was a trend to worse phonematic verbal fluency after surgery (p=0.06). Recall of a list of 10 words was worse after surgery only for the third attempt of recall (13%, p<0.005). Conclusions: Verbal fluency decreased in our patients after STN DBS, as previously reported. The procedure was otherwise safe and did not lead to deterioration of mood.

Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization: a prospective multicenter phase II trial (protocol SAKK 34/02)

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (> or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients.

Video-based quantification of body movement during social interaction indicates the severity of negative symptoms in patients with schizophrenia

In schizophrenia, nonverbal behavior, including body movement, is of theoretical and clinical importance. Although reduced nonverbal expressiveness is a major component of the negative symptoms encountered in schizophrenia, few studies have objectively assessed body movement during social interaction. In the present study, 378 brief, videotaped role-play scenes involving 27 stabilized outpatients diagnosed with paranoid-type schizophrenia were analyzed using Motion Energy Analysis (MEA). This method enables the objective measuring of body movement in conjunction with ordinary video recordings. Correlations between movement parameters (percentage of time in movement, movement speed) and symptom ratings from independent PANSS interviews were calculated. Movement parameters proved to be highly reliable. In keeping with predictions, reduced movement and movement speed correlated with negative symptoms. Accordingly, in patients who exhibited noticeable movement for less than 20% of the observation time, prominent negative symptoms were highly probable. As a control measure, the percentage of movement exhibited by the patients during role-play scenes was compared to that of their normal interactants. Patients with negative symptoms differed from normal interactants by showing significantly reduced head and body movement. Two specific positive symptoms were possibly related to movement parameters: suspiciousness tended to correlate with reduced head movement, and the expression of unusual thought content tended to relate to increased movement. Overall, a close and theoretically meaningful association between the objective movement parameters and the symptom profiles was found. MEA appears to be an objective, reliable and valid method for quantifying nonverbal behavior, an aspect which may furnish new insights into the processes related to reduced expressiveness in schizophrenia.

Characteristics of aleveolar bone associated with physiological movement of molar in mice: a histological and histochemical study

Mouse molars undergo distal movement, during which new bone is formed at the mesial side of the tooth root whereas the preexisting bone is resorbed at the distal side of the root. However, there is little detailed information available regarding which of the bones that surround the tooth root are involved in physiological tooth movement. In the present study, we therefore aimed to investigate the precise morphological differences of the alveolar bone between the bone formation side of the tooth root, using routine histological procedures including silver impregnation, as well as by immunohistochemical analysis of alkaline phosphatase and tartrate-resistant acid phosphatase activity, and immunohistochemical analysis of the expression of the osteocyte markers dentin matrix protein 1, sclerostin, and fibroblast growth factor 23. Histochemical analysis indicated that bone formation by osteoblasts and bone resorption by osteoclasts occurred at the bone formation side and the bone resorption side, respectively. Osteocyte marker immunoreactivity of osteocytes at the surface of the bone close to the periodontal ligament differed at the bone formation and bone resorption sides. We also showed different specific features of osteocytic lacunar canalicular systems at the bone formation and bone resorption sides by using silver staining. This study suggests that the alveolar bone is different in the osteocyte nature between the bone formation side and the bone resorption side due to physiological distal movement of the mouse molar.

High-resolution computer simulation of the dynamics of isoelectric focusing using carrier ampholytes: focusing with concurrent electrophoretic mobilization is an isotachophoretic process

Focusing of four hemoglobins with concurrent electrophoretic mobilization was studied by computer simulation. A dynamic electrophoresis simulator was first used to provide a detailed description of focusing in a 100-carrier component, pH 6-8 gradient using phosphoric acid as anolyte and NaOH as catholyte. These results are compared to an identical simulation except that the catholyte contained both NaOH and NaCl. A stationary, steady-state distribution of carrier components and hemoglobins is produced in the first configuration. In the second, the chloride ion migrates into and through the separation space. It is shown that even under these conditions of chloride ion flux a pH gradient forms. All amphoteric species acquire a slight positive charge upon focusing and the whole pattern is mobilized towards the cathode. The cathodic gradient end is stable whereas the anodic end is gradually degrading due to the continuous accumulation of chloride. The data illustrate that the mobilization is a cationic isotachophoretic process with the sodium ion being the leading cation. The peak height of the hemoglobin zones decreases somewhat upon mobilization, but the zones retain a relatively sharp profile, thus facilitating detection. The electropherograms that would be produced by whole column imaging and by a single detector placed at different locations along the focusing column are presented and show that focusing can be commenced with NaCl present in the catholyte at the beginning of the experiment. However, this may require detector placement on the cathodic side of the catholyte/sample mixture interface.

Novel mutation in the ceruloplasmin gene causing a cognitive and movement disorder with diabetes mellitus

In a Chinese woman who had diabetes mellitus, undetectable ceruloplasmin, hand tremor, neck dystonia, and cognitive disturbances, genetic analyses revealed a novel homozygous mutation (848G > C or W283S) in exon 5 in the ceruloplasmin gene. Another member with a milder phenotype was also affected by this mutation. The healthy sister was heterozygous at the same position. Aceruloplasminemia has not yet been reported in China. This case suggests that increased awareness should be paid to this disorder in the presence of the typical symptoms.

Movement control of manipulative tasks in patients with Gilles de la Tourette syndrome

When a hand-held object is moved, grip and load force are accurately coordinated for establishing grasp stability. In the present work, the question was raised whether patients with Gilles de la Tourette syndrome (TS), who show tic-like movements, are impaired in grip-load force control when executing a manipulative task. To this end, we assessed force regulation during action patterns that required rhythmical unimanual or bimanual (iso-directional/anti-directional) movements. Results showed that the profile of grip-load force ratio was characterized by maxima and minima that were realized at upward and downward hand positions, respectively. TS patients showed increased force ratios during unimanual and bimanual movements, compared with control subjects, indicative of an inaccurate specification of the precision grip. Functional imaging data complemented the behavioural results and revealed that secondary motor areas showed no (or greatly reduced) activation in TS patients when executing the movement tasks as compared with baseline conditions. This indicates that the metabolic level in the secondary motor areas was equal during rest and task performance. At the neuronal level, this observation suggests that these cortical areas were continuously involved in movement preparation. Based on these data, we conclude that the ongoing activation of secondary motor areas may be explained by the TS patients' involuntary urges to move. Accordingly, interference will prevent an accurate planning of voluntary behaviour. Together, these findings reveal modulations in movement organization in patients with TS and exemplify degrading consequences for manual function.

Esophagus imaging for catheter ablation of atrial fibrillation: comparison of two methods with showing of esophageal movement

This study aims to evaluate whether visualization and integration of the computed tomography (CT) scan of the left atrium (LA) and the esophagus into the three-dimensional (3D) electroanatomical map the day before ablation is accurate compared with integration of an esophagus tag into the electroanatomic LA map visualizing the anatomic relationship during the radiofrequency ablation or whether esophagus movement prohibits esophagus visualization the day before ablation.

Saccadic eye movement changes in Parkinson's disease dementia and dementia with Lewy bodies.

Neurodegeneration in Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) affect cortical and subcortical networks involved in saccade generation. We therefore expected impairments in saccade performance in both disorders. In order to improve the pathophysiological understanding and to investigate the usefulness of saccades for differential diagnosis, saccades were tested in age- and education-matched patients with PDD (n = 20) and DLB (n = 20), Alzheimer's disease (n = 22) and Parkinson's disease (n = 24), and controls (n = 24). Reflexive (gap, overlap) and complex saccades (prediction, decision and antisaccade) were tested with electro-oculography. PDD and DLB patients had similar impairment in all tasks (P > 0.05, not significant). Compared with controls, they were impaired in both reflexive saccade execution (gap and overlap latencies, P < 0.0001; gains, P < 0.004) and complex saccade performance (target prediction, P < 0.0001; error decisions, P < 0.003; error antisaccades: P < 0.0001). Patients with Alzheimer's disease were only impaired in complex saccade performance (Alzheimer's disease versus controls, target prediction P < 0.001, error decisions P < 0.0001, error antisaccades P < 0.0001), but not reflexive saccade execution (for all, P > 0.05). Patients with Parkinson's disease had, compared with controls, similar complex saccade performance (for all, P > 0.05) and only minimal impairment in reflexive tasks, i.e. hypometric gain in the gap task (P = 0.04). Impaired saccade execution in reflexive tasks allowed discrimination between DLB versus Alzheimer's disease (sensitivity > or =60%, specificity > or =77%) and between PDD versus Parkinson's disease (sensitivity > or =60%, specificity > or =88%) when +/-1.5 standard deviations was used for group discrimination. We conclude that impairments in reflexive saccades may be helpful for differential diagnosis and are minimal when either cortical (Alzheimer's disease) or nigrostriatal neurodegeneration (Parkinson's disease) exists solely; however, they become prominent with combined cortical and subcortical neurodegeneration in PDD and DLB. The similarities in saccade performance in PDD and DLB underline the overlap between these conditions and underscore differences from Alzheimer's disease and Parkinson's disease.

Saccadic eye movement disturbances in whiplash patients with persistent complaints.

In order to analyse the possible basis of subjective complaints following whiplash injury, horizontal eye movements were examined in subjects with persistent complaints ('symptomatic group') and subjects who had completely recovered ('recovered group'). The results for the symptomatic and recovered groups were compared with those for age-matched, healthy volunteers (control group). A battery of different saccade paradigms was employed: two were reflexive saccade tasks including a gap and an overlap task, and two were intentional saccade tasks consisting of an antisaccade and a memory-guided saccade task. In addition, the symptomatic and recovered groups also underwent psychiatric evaluation in a structured clinical interview, and all groups were assessed for emotional functioning using the Beck Depression Inventory (BDI). The recovered group did not differ significantly from the control group in saccade performance and emotional functioning. The symptomatic group showed dissociation of their performances of reflexive and intentional saccade tasks: performance in reflexive saccade tasks was normal, but in intentional saccade tasks the symptomatic group showed significantly impaired inhibition of unwanted reflexive saccades, impaired saccade triggering (i.e. increased latency) and a higher percentage error in amplitude in memory-guided saccades. Based on clinical interviews, no signs of major depression or dysthymia were found in any of the groups. Compared with the other two groups, the symptomatic group had significantly higher overall BDI scores, but these resulted from BDI dimensions that were non-specific to depression, viz. 'physiological manifestations' (e.g. fatigue, sleep disturbance) or 'performance difficulty' (e.g. work inhibition). In summary, in the symptomatic group the pattern of eye movement disturbances together with normal performance in reflexive saccade tasks and impaired performance in the intentional saccade tasks, especially impaired inhibitory function, suggests dysfunction of prefrontal and frontal cortical structures.