Search

Regrettably the authors have made several mistakes relating to the European guidelines for the diagnosis and management of syncope (1), which suggest that the reported results (many additional diagnostic procedures, low diagnostic yield) were achieved by using guideline conform treatment. They claim that the recommended basic diagnostic criteria for the emergency department were carried out for nearly all patients with syncope. Basic diagnostic procedures include a careful medical history, physical examination including blood pressure and pulse measurements taken in a supine position and for a minimum of 3 minutes while standing up (“orthostatic testing”), and a 12-lead ECG. Orthostatic testing was used in only 14.5% of cases. A careful history would have prompted for characteristics preceding the syncope—such as vegetative signs (sweating, sensation of warmth) or circumstances that might act as triggers, such as standing in warm rooms—which reliably enable the conclusion of a vasovagal mechanism. The guidelines include this type of “signposting” information from the medical history, enabling a diagnosis of vasovagal syncope often even without further tests. Taking a thorough history would certainly have diagnosed more than just 10.4% of cases of vasovagal syncope. Furthermore, specific additional diagnostic tests that are indicated in suspected vasovagal syncope without confirmatory basic diagnostic criteria (tilt table test, carotid sinus massage) were not carried out at all (or not mentioned in the article). They would probably have helped clarify further cases of syncope. The European guidelines list only three categories of syncope: vasovagal syncope (referred to as reflex syncope), orthostatic hypotension, and cardiac syncope. Guldner and colleagues refer to these guidelines, but, without offering any further explanation, they describe two further categories: neurological syncope and psychogenic syncope. This will inevitably cause confusion in those who believe themselves on safe ground, in firm knowledge of the guidelines. Perhaps the authors meant epileptic, cataplectic, or dissociative (psychogenic) attacks. These are, however, by definition not the same as syncope.

Intracellular transport is supported by enzymes called motor proteins that are often coupled to the same cargo and function collectively. Recent experiments and theoretical advances have been able to explain certain behaviors of multiple motor systems by elucidating how unequal load sharing between coupled motors changes how they bind, step, and detach. However, non-mechanical interactions are typically overlooked despite several studies suggesting that microtubule-bound kinesins interact locally via short-range non-mechanical potentials. This work develops a new stochastic model to explore how these types of interactions influence multiple kinesin functions in addition to mechanical coupling. Non-mechanical interactions are assumed to affect kinesin mechanochemistry only when the motors are separated by less than three microtubule lattice sites, and it is shown that relatively weak interaction energies (~2 kBT) can have an appreciable influence over collective motor velocities and detachment rates. In agreement with optical trapping experiments on structurally-defined kinesin complexes, the model predicts that these effects primarily occur when cargos are transported against loads exceeding single-kinesin stalling forces. Overall, these results highlight the inter-dependent nature of factors influencing collective motor functions, namely, that the way the bound configuration of a multiple motor system evolves under load determines how local non-mechanical interactions influence motor cooperation.

Air pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood.To determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution.Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations.C-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure.Concentrations of particulate and gaseous pollutants decreased substantially (-13% to -60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by -34.0% (95% CI, -38.4% to -29.2%; P.001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by -13.1% (95% CI, -18.6% to -7.5%; P.001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥ 0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and sCD40L concentrations.Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.

In traumatic brain injury, the hypocapnic effects on blood pressure autoregulation may vary from beneficial to detrimental. The consequences of moderate hypocapnia (HC) on the autoregulation of cerebral perfusion pressure (CPP) have not been monitored so far.Thirty head injured patients requiring sedation and mechanical ventilation were studied during normocapnia (5.1 ± 0.4 kPa) and moderate HC (4.4 ± 3.0 kPa). Transcranial Doppler flow velocity (Fv) of the middle cerebral arteries (MCA), invasive arterial blood pressure, and intracranial pressure were monitored. CPP was calculated. The responsiveness of Fv to slow oscillations in CPP was assessed by means of the moving correlation coefficient, the Mx autoregulatory index. Hypocapnic effects on Mx were increasing with its deviation from normal baseline (left MCA: R (2) = 0.67; right MCA: R (2) = 0.51; p0.05). Mx indicating normal autoregulation (left: -0.23 ± 0.23; right: -0.21 ± 0.24) was not significantly changed by moderate HC. Impaired Mx autoregulation, however, (left: 0.37 ± 0.13; right: 0.33 ± 0.26) was improved (left: 0.12 ± 0.25; right: -0.0003 ± 0.19; p0.01) during moderate HC. Mx was adjusted to normal despite no significant change in CPP levels. Our study showed that short-term moderate HC may optimize the autoregulatory response to spontaneous CPP fluctuations with only a small CPP increase. Patients with impaired autoregulation seemed to benefit the most.

In traumatic brain injury, the hypocapnic effects on blood pressure autoregulation may vary from beneficial to detrimental. The consequences of moderate hypocapnia (HC) on the autoregulation of cerebral perfusion pressure (CPP) have not been monitored so far.

The etiology and genetic susceptibility of Moyamoya angiopathy (MMA) (Moyamoya disease, Moyamoya syndrome and unilateral type of MMA) still remain unclear. In Asian patient cohorts several HLA markers were described to be associated with MMA, but in Caucasians very little is known about genetic susceptibility of this angiopathy.We analysed DNA of 33 Caucasian patients with MMA for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 markers, respectively. HLA frequencies of all 33 patients with MMA were compared with HLA-frequencies of Caucasian controls. Additionally, subgroup analysis of 22 patients with Moyamoya disease (MMD) and 11 patients with unilateral type of MMA was performed.Significant association was observed for HLA-DRB1*03 and HLA-DRB1*13 in all 33 patients (P (c) 0.001 and P (c) 0.001, respectively). Moreover, HLA-A*02 (P (c) = 0.009); HLA-B*08 (P (c) = 0.009), and HLA-DQB1*03 (P (c) = 0.003) frequencies were higher in all patients with MMA when compared with the controls. In addition, in 22 patients with MMD a higher frequency of HLA-DRB1*03 (P (c) 0.001) was observed when compared with controls.The results of this study indicate a putative association of HLA markers with MMA in Caucasian patients. Further studies are needed to elucidate the role of human MHC in the pathogenesis of this angiopathy.

Background and Aims. Associations between air pollution and cardio-respiratory health have been well established; but direct human data to support biological mechanisms are limited. We investigated...

Subcellular cargos are often transported by teams of processive molecular motors, which raises questions regarding the role of motor cooperation in intracellular transport. Although our ability to characterize the transport behaviors of multiple-motor systems has improved substantially, many aspects of multiple-motor dynamics are poorly understood. This work describes a transition rate model that predicts the load-dependent transport behaviors of multiple-motor complexes from detailed measurements of a single motor's elastic and mechanochemical properties. Transition rates are parameterized via analyses of single-motor stepping behaviors, load-rate-dependent motor-filament detachment kinetics, and strain-induced stiffening of motor-cargo linkages. The model reproduces key signatures found in optical trapping studies of structurally defined complexes composed of two kinesin motors, and predicts that multiple kinesins generally have difficulties in cooperating together. Although such behavior is influenced by the spatiotemporal dependence of the applied load, it appears to be directly linked to the efficiency of kinesin's stepping mechanism, and other types of less efficient and weaker processive motors are predicted to cooperate more productively. Thus, the mechanochemical efficiencies of different motor types may determine how effectively they cooperate together, and hence how motor copy number contributes to the regulation of cargo motion.

Purpose: Epstein–Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families. Experimental Design: We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated. Results: A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4–16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5–61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker. Conclusions: Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity. Clin Cancer Res; 17(7); 1906–14. ©2011 AACR.

A transient loss of consciousness (TLOC) may have different causes. The term syncope is restricted to an underlying sudden decrease in cerebral perfusion. In most cases, syncopes or other causes of TLOC are recognizable by a basic diagnostic evaluation (history taking, physical examination, ECG, and supine and upright blood pressure measurements). Cues for epileptic seizures, e.g., delayed recovery, should prompt an extended search for an epileptic focus. Unusual features of the attacks without any hint for a syncopal or an epileptic origin require the psychiatric inspection of suspected dissociative (psychogenic) seizures. Neurogenic orthostatic hypotension results from sympathetic failure. The underlying disease (Parkinson's disease, pure autonomic failure, autonomic neuropathy, etc.) has to be identified by neurological examinations.

In the "Special Report on Schizophrenia" published in the Schizophrenia Bulletin in 1987, the genetic basis of schizophrenia was reviewed. Here, we provide our perspective on the current status of this area of investigation, focusing largely but not exclusively on recent findings. Methodologically rigorous family studies have now clearly shown that schizophrenia substantially aggregates in families. Familial factors that predispose to schizophrenia also increase the risk for certain schizophrenia-related personality disorders and probably for some forms of non-schizophrenic nonaffective psychosis. Results from one new twin study and updates from two ongoing adoption studies continue to support the hypothesis that genetic factors play a major role in the etiology of schizophrenia. Little is known about how genetic liability to schizophrenia is transmitted, although statistical models suggest that transmission is probably not due solely to a single major gene. Schizophrenia is clearly a complex disorder in that gene carriers need not manifest the illness (incomplete penetrance), affected individuals need not have the gene (environmental forms of phenocopies), diagnostic uncertainties cannot be avoided, and different families may carry different susceptibility genes (genetic heterogeneity). Therefore, segregation or linkage analyses are far more difficult to perform with schizophrenia than with Mendelian genetic disorders. Given this complexity, it is not too surprising that no replicated positive evidence for linkage to schizophrenia has been reported to date. However, just as linkage analysis of schizophrenia should not be excessively embraced as the only form of viable genetic research in schizophrenia, it also shouldn't be prematurely spurned. If one or several genes of major effect exist for schizophrenia, large samples using new statistical and laboratory methodologies have a good chance of detecting them. The authors thus recommend a balanced research approach to the genetics of schizophrenia that includes traditional methods of family, twin, and adoption studies as well as a major effort in large-sample linkage studies.

An artificial motor protein with loosely coordinated subunits can travel at high speed and over long distances.

Standard therapy for acute ischaemic stroke is the intravenous thrombolysis with rtPA. A combined therapy with intravenous bridging and consecutive intraarterial thrombolysis and mechanical thrombectomy is a relatively new option in patients with proximal vessel occlusion.10 Patients with a CTA proven proximal vessel occlusion in the anterior circulation (ACI, carotis bifurcation, MCA) in CTA were treated with a combined therapy with i. v. and i. a. thrombolysis and thrombectomy with a Solitaire FR stent device.All Patients were recanalized, the NIHSS changed from 15.6 to 3.3. 8 out of 10 patients had nearly no symptoms when dismissed. There were no direct therapeutic complications.Combined therapy with i. v. and i. a. thrombolysis and thombectomy with the Solitaire FR stent device is a promising option in patients with acute proximal vessel occlusion in the anterior circulation.

Transport of intracellular cargos by multiple microtubule motor proteins is believed to be a common and significant phenomenon in vivo, yet signatures of the microscopic dynamics of multiple motor systems are only now beginning to be resolved. Understanding these mechanisms largely depends on determining how grouping motors affect their association with microtubules and stepping rates, and hence, cargo run lengths and velocities. We examined this problem using a discrete state transition rate model of collective transport. This model accounts for the structural and mechanical properties in binding/unbinding and stepping transitions between distinct microtubule-bound configurations of a multiple motor system. In agreement with previous experiments that examine the dynamics of two coupled kinesin-1 motors, the energetic costs associated with deformations of mechanical linkages within a multiple motor assembly are found to reduce the system's overall microtubule affinity, producing attenuated mean cargo run lengths compared to cases where motors are assumed to function independently. With our present treatment, this attenuation largely stems from reductions in the microtubule binding rate and occurs even when mechanical coupling between motors is weak. Thus, our model suggests that, at least for a variety of kinesin-dependent transport processes, the net 'gains' obtained by grouping motors together may be smaller than previously expected.

The number of microtubule motors attached to vesicles, organelles, and other subcellular commodities is widely believed to influence their motile properties. There is also evidence that cells regulate intracellular transport by tuning the number and/or ratio of motor types on cargos. Yet, the number of motors responsible for cargo motion is not easily characterized, and the extent to which motor copy number affects intracellular transport remains controversial. Here, we examined the load-dependent properties of structurally defined motor assemblies composed of two kinesin-1 molecules. We found that a group of kinesins can produce forces and move with velocities beyond the abilities of single kinesin molecules. However, such capabilities are not typically harnessed by the system. Instead, two-kinesin assemblies adopt a range of microtubule-bound configurations while transporting cargos against an applied load. The binding arrangement of motors on their filament dictates how loads are distributed within the two-motor system, which in turn influences motor-microtubule affinities. Most configurations promote microtubule detachment and prevent both kinesins from contributing to force production. These results imply that cargos will tend to be carried by only a fraction of the total number of kinesins that are available for transport at any given time, and provide an alternative explanation for observations that intracellular transport depends weakly on kinesin number in vivo.

Light scattering by individual particulates is used in a multiple-detector system to categorize the composition of suspended solids in terms of broad particulate categories. The scattering signatures of red clay and taconite tailings, the two primary particulate contaminants in western Lake Superior, along with two types of asbestiform fibers, amphibole and chrysotile, were studied in detail. A method was developed to predict the concentration of asbestiform fibers in filtration plant samples for which electron microscope analysis was done concurrently. Fiber levels as low as 5 x 10(4) fibers/liter were optically detectable. The method has application in optical categorization of samples for remote sensing purposes and offers a fast, inexpensive means for analyzing water samples from filtration plants for specific particulate contaminants.

Highly polymorphic microsatellite loci offer great promise for gene mapping studies, but fulfillment of this potential will require substantial improvements in methods for accurate and efficient genotyping. Here, we report a genotyping method based on fluorescently labeled PCR primers and size characterization of PCR products using an automated DNA fragment analyzer. We capitalize on the availability of three distinct fluorescent dyes to label uniquely loci that overlap in size, and this innovation increases by threefold the number of loci that can be analyzed simultaneously. We label size standards with a fourth dye and combine these with the microsatellite PCR products in each gel lane. Computer programs provide very rapid and accurate sizing of microsatellite alleles and efficient data management. In addition, fluorescence signals are linear over a much greater range of intensity than conventional autoradiography. This facilitates multiplexing of loci (since signal intensities often vary greatly) and helps distinguish major peaks from artifacts, thereby improving genotyping accuracy.

Tumor cell lines derived from malignant schwannomas removed from patients with neurofibromatosis type 1 (NF1) have been examined for the level of expression of NF1 protein. All three NF1 lines examined expressed lower levels of NF1 protein than control cells, and the level in one line was barely detectable. The tumor lines expressed normal levels of p120GAP and p21ras. Although the p21ras proteins isolated from the tumor cells had normal (nonmutant) biochemical properties in vitro, they displayed elevated levels of bound GTP in vivo. The level of total cellular GAP-like activity was reduced in extracts from the tumor line that expresses very little NF1 protein. Introduction of the catalytic region of GAP into this line resulted in morphological reversion and lower in vivo GTP binding by endogenous p21ras. These data implicate NF1 protein as a tumor suppressor gene product that negatively regulates p21ras and define a "positive" growth role for ras activity in NF1 malignancies.

Visual stimulation of the occipital cortex results in an increased cerebral blood flow velocity (CBFV) in the posterior cerebral artery, as measured by transcranial Doppler in 10 normal subjects. The increase was greater for visual stimuli with a higher degree of complexity than for stimuli with a lower degree of complexity (movie with 30.1% maximal amplitude, checkerboard with 21%, and diffuse light with 16.3%). Endexpiratory carbon dioxide pressures (PCO2) influenced the visual-induced changes of CBFV: Hypercapnia induced a reduction of maximal response amplitude from 30% (normocapnia) to 15% (mild hypercapnia) or 8% (severe hypercapnia) as did hypocapnia (19.6%), indicating a nonlinear interaction between the vasomotor effects of PCO2 and physiological activation. Ischemic lesions of the visual cortex studied in 7 patients also strongly reduced the CBFV responses evoked on the affected side, depending on the degree of infarcted tissue.

Several studies have provided evidence supporting the inheritance of juvenile periodontitis (JP) in a Mendelian fashion, and both X-linked and autosomal modes of transmission have been proposed. Re-examination of the evidence for the X-linked dominant hypothesis reveals that two assumptions were crucial in favoring the X-linked rather than an autosomal hypothesis of JP transmission. The first assumption was that females are more likely than males to have JP by ratios of approximately 2.5:1. The second key observation was the reported lack of father to son transmission of the trait. However, the data that these assumptions were based on may be interpreted differently. Although the number of females reported to be affected by JP is greater than the number of affected males, this is probably a reflection of the greater number of females incorporated into these studies. When the proportions of affected males and females are examined, rather than total numbers of affected individuals, the proportion of affected males and females is similar. Additionally, the reported lack of father to son transmission for JP appears to be the result of incomplete family data. The female ascertainment bias inherent in many JP studies, compounded by the lack of male participation in such studies, appears to have resulted in the perception of a lack of male to male transmission of JP. This lack of observed father to son transmission of JP in incomplete data sets has been regarded as proof of no male to male transmission for the trait. Studies of more complete family data, however, do document father to son transmission of JP.(ABSTRACT TRUNCATED AT 250 WORDS)

A young man had two dangerous episodes of transient loss of consciousness during apnea diving in a swimming pool. Medical and neurologic examination results were normal. Standard autonomic test results (including heart rate variability, baroreflex sensitivity, tilt-table test, and Valsalva ratio) were unremarkable, with the exception of an increased blood pressure decrease during early phase II of the Valsalva maneuver. Syncope with arrhythmic myoclonic jerks could be evoked by a strong straining maneuver. Simultaneous physiologic recordings showed extreme blood pressure and cerebral blood flow velocity decreases and electroencephalographic slowing during syncope. The electrocardiogram showed a continuous sinus rhythm with a progressive tachycardia. The authors' findings were not compatible with baroreflex failure or vasovagal mechanisms (Bezold-Jarisch reflex activation) as the underlying causes. The authors concluded that mechanical factors (strong reduction of blood reflux to the heart) in combination with a reduced threshold of the brain for developing ischemia-related arrhythmic myoclonic jerks were responsible for Valsalva-induced syncope in the patient.

The assembly of molecular motor proteins into multi-unit protein complexes plays an important role in determining the intracellular transport and trafficking properties of many subcellular commodities. Yet, it is not known how proteins within these complexes interact and function collectively. Considering the established ties between motor transport and diseases, it has become increasingly important to investigate the functional properties of these essential transport 'motifs'. Doing so requires that the composite motile and force-generating properties of multi-unit motor assemblies are characterized. However, such analyses are typically confounded by a lack of understanding of the links between the structural and mechanical properties of many motor complexes. New experimental challenges also emerge when one examines motor cooperation. Distributions in the mechanical microstates available to motor ensembles must be examined in order to fully understand the transport behavior of multi-motor complexes. Furthermore, mechanisms by which motors communicate must be explored to determine whether motor groups can move cargo together in a truly cooperative fashion. Resolving these issues requires the development of experimental methods that allow the dynamics of complex systems of transport proteins to be monitored with the same precision available to single-molecule biophysical assays. Herein, we discuss key fundamental principles governing the function of motor complexes and their relation to mechanisms that regulate intracellular cargo transport. We also outline new experimental strategies to resolve these essential features of intracellular transport.

Motor proteins play an essential role in regulating the internal organization of the cytoplasm by maneuvering a wide variety of vesicles and organelles. Many of these transport processes depend on the ability of motors to function collectively, in groups that contain more than one motor molecule. Utilizing protein engineering and DNA-self-assembly techniques, we have created experimental models of these multi-motor systems. Our synthetic assemblies afford precise control over the number of coupled motors in a construct, as well as their relative positions and the mechanical compliance of the linkage between each motor and the solid support to which it is anchored. Furthermore, the molecular architecture of these assemblies has been characterized using both bulk methods and single-molecule microscopy techniques. Our initial optical trapping experiments revealed rich behavior in a system of two coupled kinesin motors; the force-velocity relationship for individual constructs reveals that coupled kinesin motors can move at higher-than-predicted velocities when under high loads. Additionally, the system's stepping dynamics appears to vary significantly with applied load. Here, we discuss our efforts to characterize the effect of mechanical compliance and inter-motor separation upon these behaviors. Understanding these structure-activity relationships is critical to our broader goal of a comprehensive, mechanistic model of collective motor protein transport. Such a model would provide important insight into the process by which a cell controls its internal order.

Vasovagal response (VVR) is provoked by a reduced venous blood return to the heart as a reaction to orthostatic stress and to haemorrhage. Recently, two cases were reported showing elevated plasma concentration of von-Willebrand-factor (VWF) and factor VIII (FVIII) after VVR due to venapuncture. Although the effect of epinephrine as trigger for VWF liberation is known, a connection between VVR and activation of the coagulation system has not been studied systematically. We examined 21 subjects with lower body negative pressure. We measured the plasma concentration of von-Willebrand-factor-antigen (VWF:Ag), the activity of von-Willebrand-factor-Ristocetin-Cofactor (VWF:RiCo) and FVIII at several stress-levels and consecutively split up the different VWF-multimers. In 16 of 21 subjects VVR could be induced. These subjects showed a significant increase of VWF:Ag concentration in plasma and an increase of FVIII and VWF:RiCo activity. The five individuals who experienced all stress-levels without VVR did not show any changes in their clotting factor levels. VVR leads to measurable changes in the coagulation system. This might be a further diagnostic tool in treating patients with syncope.

One of the scientific objectives of NASA’s Fermi Gamma‐ray Space Telescope is the study of Gamma‐Ray Bursts (GRBs). The Fermi Gamma‐Ray Burst Monitor (GBM) was designed to detect and localize bursts for the Fermi mission. By means of an array of 12 NaI(Tl) (8 keV to 1 MeV) and two BGO (0.2 to 40 MeV) scintillation detectors, GBM extends the energy range (20 MeV to >300 GeV ) of Fermi’s main instrument, the Large Area Telescope (LAT), into the traditional range of current GRB databases. The physical detector response of the GBM instrument to GRBs is determined with the help of Monte Carlo simulations, which are supported and verified by on‐ground individual detector calibration measurements. We present the principal instrument properties, which have been determined as a function of energy and angle, including the channel‐energy relation, the energy resolution and the effective area.

The Fermi Gamma‐ray Space Telescope launched on June 11, 2008 carries two experiments onboard—the Large Area Telescope (LAT) and the Gamma‐ray Burst Monitor (GBM). The primary mission of the GBM instrument is to support the LAT in observing γ‐ray bursts (GRBs) by providing low‐energy measurements with high temporal and spectral resolution as well as rapid burst locations over a large field‐of‐view (⩾8 sr). The GBM will complement the LAT measurements by observing GRBs in the energy range 8 keV to 40 MeV, the region of the spectral turnover in most GRBs. The GBM detector signals are processed by the onboard digital processing unit (DPU). We describe some of the hardware features of the DPU and its expected limitations during intense triggers.

Juvenile periodontitis (JP) is generally recognized to exist in 2 clinical forms: localized and generalized. Historically, females have been reported to be affected by both forms of JP at rates of 2 to 10 times greater than males. However, evidence suggests that females are more likely than males to seek dental care. If this is true, females will be diagnosed with JP more often than males even if juvenile periodontitis is equally prevalent among males and females in the general population. Thus, previous reports of a female predominance for JP may simply reflect this selection bias. The purpose of this study was to test our hypothesis that juvenile periodontitis occurs with equal frequency in males and females after correcting for selection bias. Twenty-four juvenile periodontitis probands were ascertained from the VCU/MCV dental clinics. The families of these individuals were examined to determine the relative prevalence of JP among male and female relatives of these probands. Our results indicate that while females are 3 times more likely than males to be initially ascertained as juvenile periodontitis probands, among relatives of probands the proportion of affected males and females is equal.

A psychophysical method of measuring interocular delay based on dynamic random-dot stereograms is presented. The measurement requires only about 2 min. The sensitivity of this method to detect differences in the transmission times of the two optic nerves is demonstrated in patients with multiple sclerosis and in healthy subjects in whom interocular delays were produced by using different luminance levels for each eye. This new method may be a useful and economic method for monitoring the time course of optic neuritis.

Spontaneous oscillations in cerebral blood flow velocity (CBFV) in normals and in patients with stenoses or occlusions of the internal cerebral artery were measured using transcranial Doppler sonography. In normal subjects, large oscillations of up to ±30% from the mean CBFV were found with low frequencies between 0.4 and 9 cycles/min. No correlations between CBFV oscillations and systemic circulatory parameters were detected. In patients with carotid artery obstructions the CBFV oscillations were significantly reduced in the middle cerebral artery ipsilaterally to a hemodynamically significant lesion, but not contralaterally. Our results support the hypothesis that spontaneous oscillations (B-waves) of small pial vessels are responsible for the CBFV fluctuations.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder, which shows extensive genetic heterogeneity and is mostly inherited in an autosomal recessive fashion. There are four genes with a proven pathogenetic role in PCD. DNAH5 and DNAI1 are involved in 28 and 10% of PCD cases, respectively, while two other genes, DNAH11 and TXNDC3, have been identified as causal in one PCD family each. We have previously identified a 3.5cM (2.82 Mb) region on chromosome 15q linked to Kartagener syndrome (KS), a subtype of PCD characterized by the randomization of body organ positioning. We have now refined the KS candidate region to a 1.8Mb segment containing 18 known genes. The coding regions of these genes and three neighboring genes were subjected to sequence analysis in seven KS probands, and we were able to identify 60 single nucleotide sequence variants, 35 of which resided in mRNA coding sequences. However, none of the variations alone could explain the occurrence of the disease in these patients.

The GLAST Burst Monitor (GBM) is designed to provide wide field of view observations of gamma‐ray bursts and other fast transient sources in the energy range 10 keV to 30 MeV. The GBM is composed of several unshielded and uncollimated scintillation detectors (twelve NaI and two BGO) that are widely dispersed about the GLAST spacecraft. As a result, reconstructing source locations, energy spectra, and temporal properties from GBM data requires detailed knowledge of the detectors' response to both direct radiation as well as that scattered from the spacecraft and Earth's atmosphere. This full GBM instrument response will be captured in the form of a response function database that is derived from computer modeling and simulation. The simulation system is based on the GEANT4 Monte Carlo radiation transport simulation toolset.

The possible role of endogenous PGE2 in corpus luteum function during the estrous cycle of the pig was examined. A catheter was placed in an ovarian vein of each of three sows and in the posterior vena cava of six gilts. Blood samples were collected twice daily. Blood was also collected every 10 min for 6 h from the sows and for 12 h from the gilts during early, mid and late estrous cycle. In the sows, average serum PGE2 levels tended to be higher on days 2 and 9 than on day 16 postestrus (P < 0.1). Average PGE2 levels in the gilts were higher during the late phase than during the early and mid phases of the cycle (P < 0.05). Average progesterone levels in both the sows and the gilts were several fold higher during the mid phase than during the early and late phases of the cycle. Results from this study do not support the hypothesis that endogenous PGE2 is antiluteolytic because the average PGE2 levels in the gilts and sows were either higher or not lower during the regression phase of the corpus luteum than during earlier stages of the cycle.

Cyclic voltammetry (CV), flotation response, evolved-gas analysis (EGA), and X-ray photoelectron spectroscopy (XPS) were employed to evaluate the major differences in the surface property and surface reactivity of a selected coal pyrite and a mineral pyrite. Surface properties of pyrite were evaluated in terms of flotation response in the presence of both an anionic fluorosurfactant and sodium hydrosulfide. The charge transfer adsorption and oxidation potential of sodium hydrosulfide were evaluated using cyclic voltammetry. Drastic differences in the flotation response have been observed between the coal pyrite and the mineral pyrite. Significant differences in the cyclic voltammograms at pyrite surfaces of these two sources were also observed. Measurements by XPS and EGA were used to determine the oxidation products and the rate of oxidation of the coal-pyrite and the mineral-pyrite surfaces.

This is the final report for the year one effort to improve RUSTIC for Coastal, Ocean and Rolling/Rough Terrain Areas. RUSTIC, developed by ITT, is a quasi-CFD wind field modeling software intended for urban domains limited to 2 km x 2 km. This effort produced RUSTIC-CR in order to incorporate physics that are more appropriate to domains on the order of 60 km x 60 km. For larger domains, it was necessary to incorporate new terms into the governing equations as well as treat the turbulence in different ways. The effort focused on incorporating the appropriate planetary boundary layer (PBL) model for these applications. With regards to these improvements, an upgrade to the model thermodynamics was completed, physics for moist boundary layers was added, and the previous turbulence model was replaced with a second-order-closure (SOC) boundary layer model. In addition, the initial surface boundary conditions in RUSTIC-CR were improved by incorporating land use and land cover, sensible and latent heat fluxes, albedo and boundary layer height. The new product model was tested mainly in three different scenarios: Seattle, Colorado Springs, and Oklahoma City.

Background and Purpose— Cerebral blood flow is coupled to brain metabolism by means of active modulation of cerebrovascular resistance. This homeostatic vasogenic activity is reflected in slow waves of cerebral blood flow velocities (FV) which can also be detected in intracranial pressure (ICP). However, effects of increased ICP on the modulation of cerebral blood flow are still poorly understood. This study focused on the question whether ICP has an independent impact on slow waves of FV within the normal cerebral perfusion pressures range. Methods— Twenty patients presenting with communicating hydrocephalus underwent a diagnostic intraventricular constant-flow infusion test. Blood flow velocities in the middle cerebral artery and posterior cerebral arteries were measured using Transcranial Doppler. Pulsatility index, FV variability of slow vasogenic waves (3 to 9 bpm), ICP, and arterial blood pressure were simultaneously monitored. Results— During the test, ICP increased from a baseline of 11 (6) mm Hg to a plateau value of 21 (6) mm Hg ( P =0.00005). Although the infusion did not induce significant changes in cerebral perfusion pressures, FV, pulsatility index, or index of autoregulation, the magnitude of FV vasogenic waves at plateau became inversely correlated to ICP (middle cerebral artery: r =−0.58, P r =−0.54, P Conclusions— This study shows that even moderately increased ICP can limit the modulation of cerebral blood flow in both vascular territories within the autoregulatory range of cerebral perfusion pressures. The exhaustion of cerebrospinal fluid volume buffering reserve during infusion studies elicits a direct interaction between the cerebrospinal fluid space and the cerebrovascular compartment.

Background It has been proposed that the PST and PerioPredict genetic tests that are based on polymorphisms in interleukin 1 (IL-1) genes identify a subset of patients who experience fewer tooth extractions if provided with 2 annual preventive visits. Economic analyses indicate rationing preventive care to only “high-risk” genotypes, smokers, patients with diabetes, or combinations of these risk factors would reduce the cost of dental care by $4.8 billion annually in the United States. Methods Data presented in the study that claimed clinical utility for the PST and PerioPredict tests were obtained for reanalysis using logistic regression to assess whether the PST genetic test, smoking, diabetes, or number of preventive visits were risk factors for tooth extraction during a span of 16 years. Consistency of risk classification by the PST (version 1) and PerioPredict (version 2) genetic tests was evaluated in different ethnic groups from the 1000 Genomes database. Results Multivariate analyses revealed association of tooth extraction with diabetes ( P P P = .004), but no support for the PST genetic test ( P = .96) nor indication that the benefit of 2 preventive visits was affected by this genetic test ( P = .58). Classification of risk was highly inconsistent between the PST (version 1) and PerioPredict (version 2) genetic tests. Conclusions Two annual preventive visits were supported as beneficial for all patients, and there was no evidence that the IL-1 PST genetic test has any effect on tooth extraction risk or influences the benefits of 2 annual preventive visits. Practical Implications Neither IL-1 PST nor PerioPredict genetic tests are useful for rationing preventive dental care. Further research is needed to identify genetic biomarkers with robust clinical validity and clinical utility to effectively personalize the practice of dentistry.

Factor XIII deficiency is an uncommon inherited disorder which is characterized by umbilical cord bleeding and an unusually high incidence of intracranial hemorrhage. We report here a case of Factor XIII deficiency in a child that presented a caput. succedaneum as the first manifestation of the disease and then an umbilical cord bleeding. The importance of performing a quantitative FXIII assay in the presence of strong clinical suspicion is strengthened because of the normality of the standard screening tests and the important therapeutic consequences.

Up till now, the presence of wave reflection of pressure and flow waves was not considered in studies on the cerebral circulation. This study tested the hypothesis whether the typical changes in cerebral blood flow velocity (CBFV) seen in patients during vasovagal syncope can be explained by the emergence of a wave reflection site in the cerebrovascular vessels. Continuous recordings of peripheral blood pressure (ABP, by Finapres) and CBFV (by transcranial Doppler) of 20 control subjects and 10 patients with syncope during tilt table testing were analyzed. Wave reflection analysis (WRA) consisted of a multivariate regression analysis with CBFV as dependent variable and simultaneous ABP as well as delayed ABP (by systematically varied time lags) as independent variables. The time delay yielding the best prediction of CBFV was interpreted as the reflection time. A univariate regression analysis with only simultaneous ABP as independent variable served as control method. In patients and controls CBFV during supine position could be explained sufficiently (explained variance=88-90%) by univariate regression without improvement by WRA. During syncope, multivariate regression improved the prediction of CBFV (explained variance=58% with univariate and 77% with multivariate regression) in 9 of 10 patients. The mean reflection time was 160 ms. The results can be explained by a collapse of the distal bridging veins during systemic hypotension giving rise to a pressure wave moving backward with a resulting distortion of the flow wave. In particular, the WRA model could account for the characteristic changes in the diastolic flow shape during syncope.

A biosynthetic approach was developed to control and probe cooperativity in multiunit biomotor assemblies by linking molecular motors to artificial protein scaffolds. This approach provides precise control over spatial and elastic coupling between motors. Cooperative interactions between monomeric kinesin-1 motors attached to protein scaffolds enhance hydrolysis activity and microtubule gliding velocity. However, these interactions are not influenced by changes in the elastic properties of the scaffold, distinguishing multimotor transport from that powered by unorganized monomeric motors. These results highlight the role of supramolecular architecture in determining mechanisms of collective transport.

Das autonome Nervensystem (ANS) ist ein funktionelles System, das im Wesentlichen dichotom (parasympathisches und sympathisches System) organisiert und anatomisch im zentralen und im peripheren Nervensystem lokalisiert ist. Das ANS steuert vorwiegend unbewusste, unwillkurliche Korperfunktionen im Dienste der Konstanz des inneren Milieus (Homoostase). Neben den seltenen primaren autonomen Erkrankungen fuhren viele Erkrankungen des zentralen und peripheren Nervensystems zu z. T. klinisch relevanten vegetativen Defiziten. Zu den haufigsten Krankheitsbildern, mit denen Neurologen und Internisten konfrontiert sind, gehoren die neurokardiogenen Synkopen, andere reflektorisch (vasovagal) oder orthostatisch bedingte Kreislaufregulationsstorungen sowie die diabetische autonome Neuropathie. Diese fuhrt bei einem Grosteil der Diabetiker zu einer kardialen autonomen Neuropathie mit erhohter Morbiditat und Mortalitat. Dies unterstreicht exemplarisch die klinische Relevanz autonomer Erkrankungen, welche nach einer validen autonomen Funktionsdiagnostik einer moglichst kausalen Therapie zugefuhrt werden sollten.

Posture changes may cause hemodynamic ischemic events, particularly in severe vertebrobasilar artery disease. It may be difficult and not without risk to prove this vulnerability to changes in posture during angiography. Therefore, TCD monitoring with passive tilting (PT) was used to evaluate cerebral hemodynamics distally to severe bilateral vertebral artery disease (BVAD). PCA flow velocity changes and dynamic cerebral autoregulation (DCA) were analyzed in supine and upright position. Despite a significant autoregulatory deficit distally to BVAD, the posterior cerebral blood supply seemed to be sufficiently maintained as long as systemic blood pressure changes were within normal limits. Posterior cerebral flow velocities, however, were significantly diminished when PT detected a systemic hypotension in upright position. This study proves the feasibility to combine PT and TCD monitoring of the PCA in patients with BVAD. In vertebrobasilar artery disease, the examination of spontaneous and tilt-induced autoregulatory responses could support the evaluation of a risk for hemodynamic ischemia.

As a sensitive and convenient means for the cerebral hemodynamic monitoring, dynamic cerebral autoregulation testing could be especially useful in medical conditions where less invasive diagnostics and therapies are preferred. This study analysed the effect of carotid stenting on dynamic autoregulation in elderly patients focussing on the relation between blood pressure and cerebral blood flow velocity.We examined 20 patients age 69 +/- 8 years with coexisting cerebrovascular and medical risk factors before and at least six month after stenting of severe carotid stenoses. Data were compared to 24 age-matched healthy controls. Slow spontaneous oscillations were studied in continuous recordings of Transcranial Doppler and beat-to-beat blood pressure. Analysis was based on the "high-pass filter model", which predicts a positive phase relationship between these oscillations.Whereas phase shift angles were diminished (20.4 +/- 14.1 degrees ) before stenting, after stenting these values were significantly increased to normal (48.1 +/- 16.6 degrees ), to the level of controls (46.7 +/- 15.9 degrees ). Medical conditions such as coronary artery disease, arterial hypertension, and dyslipidemia did not diminish this recovery. The level of increase was inversely correlated with the initial autoregulatory deficit (r = -0.68) which was largest with insufficient collateral blood supply and symptomatic carotid stenoses.The study showed that an impaired cerebral autoregulation may recover after stent-guided carotid angioplasty even in the elderly with co-existing medical conditions. In this respect to regain vasomotor capability, patients with cerebrovascular risk factors seemed to benefit particularly.

Background: Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity. Methods: In a genome-wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction-only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow-up study, 65 additional microsatellite markers encompassing D15S205 were analysed. Results: A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24–25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families. Conclusions: Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.