Genetics of subcortical vascular dementia

Subcortical vascular dementia or cerebral small vessel disease is a common cause of disability in the elderly. On magnetic resonance imaging the disease is manifested as white matter lesions, lacunes and microbleeds. Its etiology is complex, with age and hypertension as established risk factors. The heritability of white matter lesions is constantly high over different populations. Linkage studies identified several loci for these lesions however no genes responsible for the linkage signals had been identified so far. Results from genetic association studies using the candidate gene approach support the role of APOE, the renin–angiotensin system, as well as the Notch3 signaling pathway in the development of subcortical vascular dementia. The recent genomegenome wide association study on white matter lesions identified a novel locus on chromosome 17q25 harboring several genes such as TRIM65 and TRIM47 which pinpoints to possible novel mechanisms leading to these lesions.     

Stability of event-related (de-) synchronization during brain–computer interface-relevant mental tasks

ObjectiveThe aim of this study was to examine the temporal stability of event-related desynchronization/synchronization (ERD/S) patterns over several sessions as a function of mental task, frequency band, brain region and time interval during the imagery period.MethodsNine volunteers participated in four sessions within 2 weeks of multi-channel EEG recordings. They performed seven mental tasks (i.e. mental rotation, word association, auditory imagery, mental subtraction, spatial navigation, imagery of familiar faces, motor imagery) during 7-s imagery periods. Cronbach’s alpha coefficients were calculated over sessions to evaluate the stability of ERD/S values.ResultsThe word association, mental subtraction and spatial navigation task showed highest stability. Cronbach’s alpha coefficients were highest in the alpha bands (7–10, 10–13 Hz), poorer in the beta bands (13–20, 20–30 Hz) and poorest in the theta band (4–7 Hz). In the majority of tasks, the first time interval and posterior left regions showed highest stability and strongest ERD in the alpha and beta bands.ConclusionStability of ERD/S is strongly dependent on the specific task and differs between time intervals of the imagery period. Furthermore, stability was related to ERD in the alpha and beta bands.SignificanceThe reliability of brain activation patterns is highly relevant for brain–computer interface developments.     

NKG2C deletion is a risk factor of HIV infection

NK cell function is important in the immune response to HIV infection. NKG2C and NKG2A are activating and inhibitory NK cell receptors, respectively, and their only known ligand, HLA-E, demonstrates increased expression in HIV infection and presents at least one HIV-derived peptide. A variation in chromosome 12 exists in which the 16-kb section of DNA encompassing the nkg2c gene is completely absent. DNA samples of 433 HIV-1-infected patients and 280 controls were genotyped by PCR, and revealed an association of the absence variation with a higher risk of HIV infection, as well as faster progression and higher pretreatment viral loads (p<0.05, respectively). Surface NKG2C expression, analyzed by FACS, on the freshly isolated lymphocytes of 20 control and 19 HIV-infected donors revealed that NKG2C expression is genotype dependent in both populations: no NKG2C expression in the -/- groups, intermediate expression in the +/- groups, and highest expression in the +/+ groups. The comparison of NKG2C and NKG2A expression in HIV and control groups (+/- and +/+ included) indicates an increased NKG2C expression on HIV patient NK cells (p<0.05) and decreased inhibitory NKG2A expression on CD8 T cells (p<0.001), and both these effects are more striking in the +/+ genotype (p<0.005). Furthermore, a positive correlation was found between HIV viral load and the proportion of NKG2C(+) NK cells. The increased expression of NKG2C in HIV patients, in combination with the genetic association of the absence variation with an increased susceptibility to HIV infection, higher HIV viral set point, and a faster progression, indicate that NKG2C is important in the defense against HIV infection and progression.     

Ultrasound-guided versus computed tomography-controlled periradicular injections in the middle and lower cervical spine: a prospective randomized clinical trial

Purpose

We conducted this study to evaluate accuracy, time saving, radiation doses, safety, and pain relief of ultrasound (US)-guided periradicular injections versus computed tomography (CT)-controlled interventions in the cervical spine in a prospective randomized clinical trial.

Methods

Forty adult patients were consecutively enrolled and randomly assigned to either a US or a CT group. US-guided periradicular injections were performed on a standard ultrasound device using a broadband linear array transducer. By basically following the osseous landmarks for level definition in “in-plane techniques”, a spinal needle was advanced as near as possible to the intended, US-depicted nerve root. The respective needle tip positioning was then verified by CT. The control group underwent CT-guided injections, which were performed under standardized procedures using the CT-positioning laser function.

Results

The accuracy of US-guided interventions was 100 %. The mean time to final needle placement in the US group was 02:21 ± 01:43 min:s versus 10:33 ± 02:30 min:s in the CT group. The mean dose-length product radiation dose, including CT confirmation for study purposes only, was 25.1 ± 16.8 mGy cm for the US group and 132.5 ± 78.4 mGy cm for the CT group. Both groups showed the same significant visual analog scale decay (p < 0.05) without “inter-methodic” differences of pain relief (p > 0.05).

Conclusions

US-guided periradicular injections are accurate, result in a significant reduction of procedure expenditure under the avoidance of radiation and show the same therapeutic effect as CT-guided periradicular injections.     

Nitric Oxide Administration Restores the Hepatic Artery Buffer Response During Porcine Endotoxemia

The hepatic artery buffer response, which is lost during endotoxemia, plays a central role in the autoregulation of liver perfusion. A temporarily decreased synthesis of nitric oxide during early endotoxemia might be responsible for this dysfunction; hence exogenous administration of nitric oxide could reestablish the autoregulation of hepatic blood flow and help prevent hepatic damage later in septic shock. Fifteen pigs were treated with lipopolysaccharide +/? the nitric oxide donor nitroprusside-sodium via the portal vein. Hemodynamics were measured, and serum chemistry and liver biopsies for nitric oxide synthase expression were obtained. Lipopolysaccharide decreased arterial liver perfusion after 5 hours by 38% (p =. 012), which was reversed by addition of nitroprusside (8%). Administration of nitroprusside preserved an increase of 28% in hepatic arterial upon portal vein flow reduction (p <. 001). Nitroprusside maintained mRNA levels of constitutive nitric oxide synthase in liver tissue which were decreased by lipopolysaccharide (p =. 026 vs. p =. 114) and tempered the burst in inducible nitric oxide synthase expression at t = 3 hours. The early administration of the nitric oxide donor sodium nitroprusside during endotoxemia is able to reestablish the autoregulatory response of the hepatic artery following reduction of hepatic blood flow. This beneficial effect might help to prevent subsequent hepatic damage in the course of abdominal sepsis.     

Transcatheter Arterial Embolization of Spontaneous Soft Tissue Hematomas: A Systematic Review

CardioVascular and Interventional Radiology - Severe spontaneous soft tissue hematomas (SSTH) are usually treated with transcatheter arterial embolization (TAE) although only limited retrospective...     

Dichotomous effects of C-C chemokines in HIV-1 pathogenesis

Whilst many physiological functions of nitric oxide (NO) have been revealed so far, recent evidence proposes an essential role for NO in T lymphocyte activation and signal transduction. NO acts as a second messenger, activating soluble guanyl cyclase and participating in signal transduction pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial biogenesis in many cell types, including lymphocytes. Several studies undertaken on patients with RA and SLE have documented increased endogenous NO synthesis, although the effects of NO may be distinct. Here, we discuss recent evidence that NO contributes to T cell dysfunction in both SLE and RA by altering multiple signaling pathways in T cells. Although NO may play a physiological role in lymphocyte cell signaling, its overproduction may perturb T cell activation, differentiation and effector responses, each of which may contribute in different ways to the pathogenesis of autoimmunity.     

Multibeam tomotherapy: a new treatment unit devised for multileaf collimation, intensity-modulated radiation therapy

A fully integrated system for treatment planning, application, and verification for automated multileaf collimator (MLC) based, intensity-modulated, image-guided, and adaptive radiation therapy (IMRT, IGRT and ART, respectively) is proposed. Patient comfort, which was the major development goal, will be achieved through a new unit design and short treatment times. Our device for photon beam therapy will consist of a new dual energy linac with five fixed treatment heads positioned evenly along one plane but one electron beam generator only. A minimum of moving parts increases technical reliability and reduces motion times to a minimum. Motion is allowed solely for the MLCs, the robotic patient table, and the small angle gantry rotation of +/- 36 degrees. Besides sophisticated electron beam guidance, this compact setup can be built using existing modules. The flattening-filter-free treatment heads are characterized by reduced beam-on time and contain apertures restricted in one dimension to the area of maximum primary fluence output. In the case of longer targets, this leads to a topographic intensity modulation, thanks to the combination of "step and shoot" MLC delivery and discrete patient couch motion. Owing to the limited number of beam directions, this multislice cone beam serial tomotherapy is referred to as "multibeam tomotherapy." Every patient slice is irradiated by one treatment head at any given moment but for one subfield only. The electron beam is then guided to the next head ready for delivery, while the other heads are preparing their leaves for the next segment. The "Multifocal MLC-positioning" algorithm was programmed to enable treatment planning and optimize treatment time. We developed an overlap strategy for the longitudinally adjacent fields of every beam direction, in doing so minimizing the field match problem and the effects of possible table step errors. Clinical case studies show for the same or better planning target volume coverage, better organ-at-risk sparing, and comparable mean integral dose to the normal tissue a reduction in treatment time by more than 50% to only a few minutes in comparison to high-quality 3-D conformal and IMRT treatments. As a result, it will be possible to incorporate features for better patient positioning and image guidance, while sustaining reasonable overall treatment times at the same time. The virtual multibeam tomotherapy design study TOM'5-CT contains a dedicated electron beam CT (TOM'AGE) and an objective optical topometric patient positioning system (TOPOS). Thanks to the wide gantry bore of 120 cm and slim gantry depths of 70 cm, patients can be treated very comfortably, in all cases tumor-isocentrically, as well as with noncoplanar beam arrangements as in stereotactic radiosurgery with a couch rotation of up to +/- 54 degrees. The TOM'5 treatment unit on which this theoretical concept is based has a stand-alone depth of 40 cm and an outer diameter of 245 cm; the focus-isocenter distance of the heads is 100 cm with a field size of 40 cm x 7 cm and 0.5 cm leaves, which operate perpendicular to the axis of table motion.     

The diabetogenic, insulin-specific CD8 T cell response primed in the experimental autoimmune diabetes model in RIP-B7.1 mice

Type 1 diabetes mellitus can result from the specific destruction of pancreatic beta cells by autoreactive T cells. As shown here, experimental autoimmune diabetes (EAD) is efficiently induced in RIP-B7.1 mice by preproinsulin (ppins)-encoding DNA vaccines. EAD develops in RIP-B7.1 mice within 3-4 wk after a single immunization with ppins-encoding plasmid DNA. RIP-B7.1 mice develop insulitis, insulin deficiency and hyperglycemia after vaccination with plasmids encoding murine ppins-I or murine ppins-II or human hu-ppins. EAD induction critically depends on CD8 T cells and is independent of CD4 T cells. To be diabetogenic, ppins-specific CD8 T cells had to express IFN-gamma. Neither expression of perforin nor signaling through the type I IFN receptor is an essential component of this pathogenic CD8 T cell phenotype. Using plasmids encoding truncated ppins variants, we show that EAD is only induced by DNA vaccines encoding the insulin A-chain. Diabetogenic CD8 T cells specifically recognize the Kb-restricted A12-21 epitope of the insulin A-chain. The RIP-B7.1 model hence represents an attractive model for the characterization of cellular and molecular events involved in the CD8 T cell-mediated immune pathogenesis of diabetes.