Deep gray matter atrophy in multiple sclerosis: a tensor based morphometry.

Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r=-0.51, p=3.85 x 10(-7); caudate nucleus: r=-0.43, p=2.35 x 10(-5); putamen: r=-0.36, p=6.12 x 10(-6)). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r=-0.56, p=9.96 x 10(-9); caudate nucleus: r=-0.31, p=3.10 x 10(-3); putamen: r=-0.50, p=6.06 x 10(-7)), 2) T1 hypointense lesion volumes (thalamus: r=-0.61, p=2.29 x 10(-10); caudate nucleus: r=-0.35, p=9.51 x 10(-4); putamen: r=-0.43, p=3.51 x 10(-5)), and 3) normalized CSF volume (thalamus: r=-0.66, p=3.55 x 10(-12); caudate nucleus: r=-0.52, p=2.31 x 10(-7), and putamen: r=-0.66, r=2.13 x 10(-12)). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS.

Plasma DNA is Elevated in Patients with Deep Vein Thrombosis

OBJECTIVE To investigate if plasma DNA is elevated in patients with deep vein thrombosis (DVT) and to determine whether there is a correlation with other biomarkers of DVT. BACKGROUND Leukocytes release DNA to form extracellular traps (ETs), which have recently been linked to experimental DVT. In baboons and mice, extracellular DNA co-localized with von Willebrand factor (VWF) in the thrombus and DNA appeared in circulation at the time of thrombus formation. ETs have not been associated with clinical DVT. SETTING From December 2008 to August 2010, patients were screened through the University of Michigan Diagnostic Vascular Unit and were divided into three distinct groups: 1) the DVT positive group, consisting of patients who were symptomatic for DVT, which was confirmed by compression duplex ultrasound (n=47); 2) the DVT negative group, consisting of patients that present with swelling and leg pain but had a negative compression duplex ultrasound, (n=28); and 3) a control group of healthy non-pregnant volunteers without signs or symptoms of active or previous DVT (n=19). Patients were excluded if they were less than 18 years of age, unwillingness to consent, pregnant, on an anticoagulant therapy, or diagnosed with isolated calf vein thrombosis. METHODS Blood was collected for circulating DNA, CRP, D-dimer, VWF activity, myeloperoxidase (MPO), ADAMTS13 and VWF. The Wells score for a patient's risk of DVT was assessed. The Receiver Operating Characteristic (ROC) curve was generated to determine the strength of the relationship between circulating DNA levels and the presence of DVT. A Spearman correlation was performed to determine the relationship between the DNA levels and the biomarkers and the Wells score. Additionally the ratio of ADAMTS13/VWF was assessed. RESULTS Our results showed that circulating DNA (a surrogate marker for NETs) was significantly elevated in DVT patients, compared to both DVT negative patients (57.7±6.3 vs. 17.9±3.5ng/mL, P<.01) and controls (57.7±6.3 vs. 23.9±2.1ng/mL, P<.01). There was a strong positive correlation with CRP (P<.01), D-dimer (P<.01), VWF (P<.01), Wells score (P<.01) and myeloperoxidase (MPO) (P<.01), along with a strong negative correlation with ADAMTS13 (P<.01) and the ADAMTS13/VWF ratio. The logistic regression model showed a strong association between plasma DNA and the presence of DVT (ROC curve was determined to be 0.814). CONCLUSIONS Plasma DNA is elevated in patients with deep vein thrombosis and correlates with biomarkers of DVT. A strong correlation between circulating DNA and MPO suggests that neutrophils may be a source of plasma DNA in patients with DVT.

Uptake And Metabolism Of 5’-AMP In The Erythrocyte Play Key Roles In The 5’-AMP Induced Model Of Deep Hypometabolism

UPTAKE AND METABOLISM OF 5’-AMP IN THE ERYTHROCYTE PLAY KEY ROLES IN THE 5’-AMP INDUCED MODEL OF DEEP HYPOMETABOLISM Publication No. ________ Isadora Susan Daniels, B.A. Supervisory Professor: Cheng Chi Lee, Ph.D. Mechanisms that initiate and control the natural hypometabolic states of mammals are poorly understood. The laboratory developed a model of deep hypometabolism (DH) initiated by uptake of 5’-adenosine monophosphate (5’-AMP) into erythrocytes. Mice enter DH when given a high dose of 5’-AMP and the body cools readily. Influx of 5’-AMP appears to inhibit thermoregulatory control. In a 15°C environment, mice injected with 5’-AMP (0.5 mg/gw) enter a Phase I response in which oxygen consumption (VO2) drops rapidly to 1/3rd of euthermic levels. The Phase I response appears independent of body temperature (Tb). This is followed by gradual body temperature decline that correlates with VO2 decline, called Phase II response. Within 90 minutes, mouse Tb approaches 15°C, and VO2 is 1/10th of normal. Mice can remain several hours in this state, before gradually and safely recovering. The DH state translates to other mammalian species. Our studies show uptake and metabolism of 5’-AMP in erythrocytes causes biochemical changes that initiate DH. Increased AMP shifts the adenylate equilibrium toward ADP formation, consequently decreasing intracellular ATP. In turn, glycolysis slows, indicated by increased glucose and decreased lactate. 2,3-bisphosphoglycerate levels rise, allosterically reducing oxygen affinity for hemoglobin, and deoxyhemoglobin rises. Less oxygen transport to tissues likely triggers the DH model. The major intracellular pathway for AMP catabolism is catalyzed by AMP deaminase (AMPD). Multiple AMPD isozymes are expressed in various tissues, but erythrocytes only have AMPD3. Mice lacking AMPD3 were created to study control of the DH model, specifically in erythrocytes. Telemetric measurements demonstrate lower Tb and difficulty maintaining Tb under moderate metabolic stress. A more dramatic response to lower dose of 5’-AMP suggests AMPD activity in the erythrocyte plays an important role in control of the DH model. Analysis of adenylates in erythrocyte lysate shows 3-fold higher levels of ATP and ADP but similar AMP levels to wild-type. Taken together, results indicate alterations in energy status of erythrocytes can induce a hypometabolic state. AMPD3 control of AMP catabolism is important in controlling the DH model. Genetically reducing AMP catabolism in erythrocytes causes a phenotype of lower Tb and compromised ability to maintain temperature homeostasis.

Safety and Feasibility of a Diagnostic Algorithm Combining Clinical Probability, d-Dimer Testing, and Ultrasonography for Suspected Upper Extremity Deep Venous Thrombosis: A Prospective Management Study.

BACKGROUND Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE None.

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis.

Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the post-thrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute ilio-femoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 ± 21 years, 60% women) were included. At 15 hours, thrombolysis success ≥50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 ± 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0-6%) and 6 minor bleedings (7%; 95%CI, 3-14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74-94%) and 96% (95% CI, 88-99%), respectively. At three months, 88% (95% CI, 78-94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81-99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with ilio-femoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS.

Clutter elimination for deep clinical optoacoustic imaging using localised vibration tagging (LOVIT)

This paper investigates a novel method which allows clutter elimination in deep optoacoustic imaging. Clutter significantly limits imaging depth in clinical optoacoustic imaging, when irradiation optics and ultrasound detector are integrated in a handheld probe for flexible imaging of the human body. Strong optoacoustic transients generated at the irradiation site obscure weak signals from deep inside the tissue, either directly by propagating towards the probe, or via acoustic scattering. In this study we demonstrate that signals of interest can be distinguished from clutter by tagging them at the place of origin with localised tissue vibration induced by the acoustic radiation force in a focused ultrasonic beam. We show phantom results where this technique allowed almost full clutter elimination and thus strongly improved contrast for deep imaging. Localised vibration tagging by means of acoustic radiation force is especially promising for integration into ultrasound systems that already have implemented radiation force elastography.

Softening the Lower Crust: Modes of Syn-Transport Transposition Around and Adjacent to a Deep Crustal Granulite Nappe, Parry Sound Domain, Grenville Province, Ontario, Canada

The Parry Sound domain is a granulite nappe-stack transported cratonward during reactivation of the ductile lower and middle crust in the late convergence of the Mesoproterozoic Grenville orogeny. Field observations suggest the following with respect to the ductile sheath: (1) Formation of a carapace of transposed amphibolite facies gneiss derived from and enveloping the western extremity of the Parry Sound domain and separating it from high-strain gneiss of adjacent allochthons. This ductile sheath formed dynamically around the moving granulite nappe through the development of systems of progressively linked shear zones. (2) Transposition initiated by hydration (amphibolization) of granulite facies gneiss by introduction of fluid along cracks accompanying pegmatite emplacement. Shear zones nucleated along pegmatite margins and subsequently linked and rotated. The source of the pegmatites was most likely subjacent migmatitic and pegmatite-rich units or units over which Parry Sound domain was transported. Comparison of gneisses of the ductile sheath with high-strain layered gneiss of adjacent allochthons show the mode of transposition of penetratively layered gneiss depended on whether or not the gneiss protoliths were amphibolite or granulite facies tectonites before initiation of transposition, resulting in, e.g., folding before shearing, no folding before shearing, respectively. Meter-scale truncation along high-strain gradients at the margins of both types of transposition-related shear zones observed within and marginal to Parry Sound domain mimic features at kilometer scales, implying that apparent truncation by transposition originating in a manner similar to the ductile sheath may be a common feature of deep crustal ductile reworking. Citation: Culshaw, N., C. Gerbi, and J. Marsh (2010), Softening the lower crust: Modes of syn-transport transposition around and adjacent to a deep crustal granulite nappe, Parry Sound domain, Grenville Province, Ontario, Canada, Tectonics, 29, TC5013, doi:10.1029/2009TC002537.

Surface Deformations as Indicators of Deep Ebullition Fluxes in a Large Northern Peatland

Peatlands deform elastically during precipitation cycles by small (+/- 3 cm) oscillations in surface elevation. In contrast, we used a Global Positioning System network to measure larger oscillations that exceeded 20 cm over periods of 4 - 12 hours during two seasonal droughts at a bog and fen site in northern Minnesota. The second summer drought also triggered 19 depressuring cycles in an overpressured stratum under the bog site. The synchronicity between the largest surface deformations and the depressuring cycles indicates that both phenomena are produced by the episodic release of large volumes of gas from deep semi-elastic compartments confined by dense wood layers. We calculate that the three largest surface deformations were associated with the release of 136 g CH4 m(-2), which exceeds by an order of magnitude the annual average chamber fluxes measured at this site. Ebullition of gas from the deep peat may therefore be a large and previously unrecognized source of radiocarbon depleted methane emissions from northern peatlands.

Directional deep brain stimulation: an intraoperative double-blind pilot study.

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional stimulation could increase the efficacy of such therapies. This has never been demonstrated in humans. In the present study, we assess the effect of directional stimulation compared to omnidirectional stimulation. Three different directions of stimulation as well as omnidirectional stimulation were tested intraoperatively in the subthalamic nucleus of 11 patients with Parkinson's disease and in the nucleus ventralis intermedius of two other subjects with essential tremor. At the trajectory chosen for implantation of the definitive electrode, we assessed the current threshold window between positive and side effects, defined as the therapeutic window. A computed finite element model was used to compare the volume of tissue activated when one directional electrode was stimulated, or in case of omnidirectional stimulation. All but one patient showed a benefit of directional stimulation compared to omnidirectional. A best direction of stimulation was observed in all the patients. The therapeutic window in the best direction was wider than the second best direction (P = 0.003) and wider than the third best direction (P = 0.002). Compared to omnidirectional direction, the therapeutic window in the best direction was 41.3% wider (P = 0.037). The current threshold producing meaningful therapeutic effect in the best direction was 0.67 mA (0.3-1.0 mA) and was 43% lower than in omnidirectional stimulation (P = 0.002). No complication as a result of insertion of the directional electrode or during testing was encountered. The computed model revealed a volume of tissue activated of 10.5 mm(3) in omnidirectional mode, compared with 4.2 mm(3) when only one electrode was used. Directional deep brain stimulation with a reduced electrode size applied intraoperatively in the subthalamic nucleus as well as in the nucleus ventralis intermedius of the thalamus significantly widened the therapeutic window and lowered the current needed for beneficial effects, compared to omnidirectional stimulation. The observed side effects related to direction of stimulation were consistent with the anatomical location of surrounding structures. This new approach opens the door to an improved deep brain stimulation therapy. Chronic implantation is further needed to confirm these findings.

A new rechargeable device for deep brain stimulation: a prospective patient satisfaction survey

Background: Deep brain stimulation (DBS) is highly successful in treating Parkinson's disease (PD), dystonia, and essential tremor (ET). Until recently implantable neurostimulators were nonrechargeable, battery-driven devices, with a lifetime of about 3-5 years. This relatively short duration causes problems for patients (e.g. programming and device-use limitations, unpredictable expiration, surgeries to replace depleted batteries). Additionally, these batteries (relatively large with considerable weight) may cause discomfort. To overcome these issues, the first rechargeable DBS device was introduced: smaller, lighter and intended to function for 9 years. Methods: Of 35 patients implanted with the rechargeable device, 21 (including 8 PD, 10 dystonia, 2 ET) were followed before and 3 months after surgery and completed a systematic survey of satisfaction with the rechargeable device. Results: Overall patient satisfaction was high (83.3 ± 18.3). Dystonia patients tended to have lower satisfaction values for fit and comfort of the system than PD patients. Age was significantly negatively correlated with satisfaction regarding process of battery recharging. Conclusions: Dystonia patients (generally high-energy consumption, severe problems at the DBS device end-of-life) are good, reliable candidates for a rechargeable DBS system. In PD, younger patients, without signs of dementia and good technical understanding, might have highest benefit.

Adaption of cardio-respiratory balance during day-rest compared to deep sleep—An indicator for quality of life?

Heart rate and breathing rate fluctuations represent interacting physiological oscillations. These interactions are commonly studied using respiratory sinus arrhythmia (RSA) of heart rate variability (HRV) or analyzing cardiorespiratory synchronization. Earlier work has focused on a third type of relationship, the temporal ratio of respiration rate and heart rate (HRR). Each method seems to reveal a specific aspect of cardiorespiratory interaction and may be suitable for assessing states of arousal and relaxation of the organism. We used HRR in a study with 87 healthy subjects to determine the ability to relax during 5 day-resting periods in comparison to deep sleep relaxation. The degree to which a person during waking state could relax was compared to somatic complaints, health-related quality of life, anxiety and depression. Our results show, that HRR is barely connected to balance (LF/HF) in HRV, but significantly correlates to the perception of general health and mental well-being as well as to depression. If relaxation, as expressed in HRR, during day-resting is near to deep sleep relaxation, the subjects felt healthier, indicated better mental well-being and less depressive moods.