Testing the GlaaS algorithm for dose measurements on low- and high-energy photon beams using an amorphous silicon portal imager

The GLAaS algorithm for pretreatment intensity modulation radiation therapy absolute dose verification based on the use of amorphous silicon detectors, as described in Nicolini et al. [G. Nicolini, A. Fogliata, E. Vanetti, A. Clivio, and L. Cozzi, Med. Phys. 33, 2839-2851 (2006)], was tested under a variety of experimental conditions to investigate its robustness, the possibility of using it in different clinics and its performance. GLAaS was therefore tested on a low-energy Varian Clinac (6 MV) equipped with an amorphous silicon Portal Vision PV-aS500 with electronic readout IAS2 and on a high-energy Clinac (6 and 15 MV) equipped with a PV-aS1000 and IAS3 electronics. Tests were performed for three calibration conditions: A: adding buildup on the top of the cassette such that SDD-SSD = d(max) and comparing measurements with corresponding doses computed at d(max), B: without adding any buildup on the top of the cassette and considering only the intrinsic water-equivalent thickness of the electronic portal imaging devices device (0.8 cm), and C: without adding any buildup on the top of the cassette but comparing measurements against doses computed at d(max). This procedure is similar to that usually applied when in vivo dosimetry is performed with solid state diodes without sufficient buildup material. Quantitatively, the gamma index (gamma), as described by Low et al. [D. A. Low, W. B. Harms, S. Mutic, and J. A. Purdy, Med. Phys. 25, 656-660 (1998)], was assessed. The gamma index was computed for a distance to agreement (DTA) of 3 mm. The dose difference deltaD was considered as 2%, 3%, and 4%. As a measure of the quality of results, the fraction of field area with gamma larger than 1 (%FA) was scored. Results over a set of 50 test samples (including fields from head and neck, breast, prostate, anal canal, and brain cases) and from the long-term routine usage, demonstrated the robustness and stability of GLAaS. In general, the mean values of %FA remain below 3% for deltaD equal or larger than 3%, while they are slightly larger for deltaD = 2% with %FA in the range from 3% to 8%. Since its introduction in routine practice, 1453 fields have been verified with GLAaS at the authors' institute (6 MV beam). Using a DTA of 3 mm and a deltaD of 4% the authors obtained %FA = 0.9 +/- 1.1 for the entire data set while, stratifying according to the dose calculation algorithm, they observed: %FA = 0.7 +/- 0.9 for fields computed with the analytical anisotropic algorithm and %FA = 2.4 +/- 1.3 for pencil-beam based fields with a statistically significant difference between the two groups. If data are stratified according to field splitting, they observed %FA = 0.8 +/- 1.0 for split fields and 1.0 +/- 1.2 for nonsplit fields without any significant difference.

Drug targeting using OX7-immunoliposomes: correlation between Thy1.1 antigen expression and tissue distribution in the rat

OX7 monoclonal antibody F((ab')2) fragments directed against Thy1.1 antigen can be used for drug targeting by coupling to the surface of drug-loaded liposomes. Such OX7-conjugated immunoliposomes (OX7-IL) were used recently for drug delivery to rat glomerular mesangial cells, which are characterized by a high level of Thy1.1 antigen expression. In the present study, the relationship between OX7-IL tissue distribution and target Thy1.1 antigen localization in different organs in rat was investigated. Western blot and immunohistofluorescence analysis revealed a very high Thy1.1 expression in brain cortex and striatum, thymus and renal glomeruli. Moderate Thy1.1 levels were observed in the collecting ducts of kidney, lung tissue and spleen. Thy1.1 was not detected in liver and heart. There was a poor correlation between Thy1.1 expression levels and organ distribution of fluorescence- or (14)C-labeled OX7-IL. The highest overall organ density of OX7-IL was observed in the spleen, followed by lung, liver and kidney. Heart and brain remained negative. With respect to intra-organ distribution, a localized and distinct signal was observed in renal glomerular mesangial cells only. As a consequence, acute pharmacological (i.e. toxic) effects of doxorubicin-loaded OX7-IL were limited to renal glomeruli. The competition with unbound OX7 monoclonal antibody F((ab')2) fragments demonstrated that the observed tissue distribution and acute pharmacological effects of OX7-IL were mediated specifically by the conjugated OX7 antibody. It is concluded that both the high target antigen density and the absence of endothelial barriers are needed to allow for tissue-specific accumulation and pharmacological effects of OX7-IL. The liposomal drug delivery strategy used is therefore specific toward renal glomeruli and can be expected to reduce the risk of unwanted side effects in other tissues.

Perivascular spaces and the two steps to neuroinflammation

Immune cells enter the central nervous system (CNS) from the circulation under normal conditions for immunosurveillance and in inflammatory neurologic diseases. This review describes the distinct anatomic features of the CNS vasculature that permit it to maintain parenchymal homeostasis and which necessitate specific mechanisms for neuroinflammation to occur. We review the historical evolution of the concept of the blood-brain barrier and discuss distinctions between diffusion/transport of solutes and migration of cells from the blood to CNS parenchyma. The former is regulated at the level of capillaries, whereas the latter takes place in postcapillary venules. We summarize evidence that entry of immune cells into the CNS parenchyma in inflammatory conditions involves 2 differently regulated steps: transmigration of the vascular wall into the perivascular space and progression across the glia limitans into the parenchyma.

Visual and spectral analysis of sleep EEG in acute hemispheric stroke

BACKGROUND: Reports on the effects of focal hemispheric damage on sleep EEG are rare and contradictory. PATIENTS AND METHODS: Twenty patients (mean age +/- SD 53 +/- 14 years) with a first acute hemispheric stroke and no sleep apnea were studied. Stroke severity [National Institute of Health Stroke Scale (NIHSS)], volume (diffusion-weighted brain MRI), and short-term outcome (Rankin score) were assessed. Within the first 8 days after stroke onset, 1-3 sleep EEG recordings per patient were performed. Sleep scoring and spectral analysis were based on the central derivation of the healthy hemisphere. Data were compared with those of 10 age-matched and gender-matched hospitalized controls with no brain damage and no sleep apnea. RESULTS: Stroke patients had higher amounts of wakefulness after sleep onset (112 +/- 53 min vs. 60 +/- 38 min, p < 0.05) and a lower sleep efficiency (76 +/- 10% vs. 86 +/- 8%, p < 0.05) than controls. Time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep and total sleep time were lower in stroke patients, but differences were not significant. A positive correlation was found between the amount of SWS and stroke volume (r = 0.79). The slow-wave activity (SWA) ratio NREM sleep/wakefulness was lower in patients than in controls (p < 0.05), and correlated with NIHSS (r = -0.47). CONCLUSION: Acute hemispheric stroke is accompanied by alterations of sleep EEG over the healthy hemisphere that correlate with stroke volume and outcome. The increased SWA during wakefulness and SWS over the healthy hemisphere contralaterally to large strokes may reflect neuronal hypometabolism induced transhemispherically (diaschisis).

Effects of gender and dementia severity on Alzheimer's disease caregivers' sleep and biomarkers of coagulation and inflammation

BACKGROUND: Being a caregiver for a spouse with Alzheimer's disease is associated with increased risk for cardiovascular illness, particularly for males. This study examined the effects of caregiver gender and severity of the spouse's dementia on sleep, coagulation, and inflammation in the caregiver. METHODS: Eighty-one male and female spousal caregivers and 41 non-caregivers participated (mean age of all participants 70.2 years). Full-night polysomnography (PSG) was recorded in each participants home. Severity of the Alzheimer's disease patient's dementia was determined by the Clinical Dementia Rating (CDR) scale. The Role Overload scale was completed as an assessment of caregiving stress. Blood was drawn to assess circulating levels of D-dimer and Interleukin-6 (IL-6). RESULTS: Male caregivers who were caring for a spouse with moderate to severe dementia spent significantly more time awake after sleep onset than female caregivers caring for spouses with moderate to severe dementia (p=.011), who spent a similar amount of time awake after sleep onset to caregivers of low dementia spouses and to non-caregivers. Similarly, male caregivers caring for spouses with worse dementia had significantly higher circulating levels of D-dimer (p=.034) than females caring for spouses with worse dementia. In multiple regression analysis (adjusted R(2)=.270, p<.001), elevated D-dimer levels were predicted by a combination of the CDR rating of the patient (p=.047) as well as greater time awake after sleep onset (p=.046). DISCUSSION: The findings suggest that males caring for spouses with more severe dementia experience more disturbed sleep and have greater coagulation, the latter being associated with the disturbed sleep. These findings may provide insight into why male caregivers of spouses with Alzheimer's disease are at increased risk for illness, particularly cardiovascular disease.

Effects of depressive and anxious symptoms on norepinephrine and platelet P-selectin responses to acute psychological stress among elderly caregivers

BACKGROUND: Caring for a spouse with Alzheimer's disease is associated with increased psychological distress, impaired immunity, and heightened cardiovascular risk. Hyperreactivity of sympathetic and platelet activation responses to acute psychological stress, or the failure to recover quickly from stressful events, may constitute an important pathway linking stress and negative affect with cardiovascular disease (CVD). OBJECTIVES: (1) To evaluate associations between negative affect (i.e., depressive and anxious symptoms) with increased norepinephrine and P-selectin responses to an acute psychological stress task. (2) To establish whether these associations are augmented among elderly spousal caregivers (CG) compared to non-caregivers (NC). METHODS: Depressive (DEP) and anxious (ANX) symptoms from the Brief Symptom Inventory were assessed among 39 CG and 31 NC. Plasma norepinephrine levels (NE) and percent platelet P-selectin (PSEL) expression were assayed at three time-points: rest, immediately following a laboratory speech test (reactivity), and after 14 min of recovery. Results: Among CG, but not NC, increased symptoms of depression and anxiety were associated with delayed NE recovery (DEP: beta=.460, p=.008; ANX: beta=.361, p=.034), increased PSEL reactivity (DEP: beta=.703, p<.001; ANX: beta=.526, p=.002), and delayed PSEL recovery (DEP: beta=.372, p=.039; ANX: beta=.295, p=.092), while controlling for age, gender, aspirin use, antidepressant use, and preexisting CVD. Bivariate correlations showed delayed NE recovery was also associated with increased PSEL reactivity (r=.416) and delayed PSEL recovery (r=.372; all ps<.05) among CG but not NC. DISCUSSION: Among chronically stressed caregivers, increased levels of depressive and anxious symptoms are associated with prolonged sympathetic activation and pronounced platelet activation. These changes may represent one pathway linking caregiving stress to cardiovascular risk.

Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects

Decreased heart rate variability (HRV) has been associated with an increased risk of atherosclerosis. We hypothesized that a decrease in frequency domains of resting HRV would be associated with elevated plasma levels of interleukin (IL)-6 and soluble tissue factor (sTF) both previously shown to prospectively predict atherothrombotic events in healthy subjects. Subjects were 102 healthy and unmedicated black and white middle-aged men and women. We determined IL-6 and sTF antigen in plasma and HRV measures from surface electrocardiogram data using spectral analysis. All statistical analyses controlled for age, gender, ethnicity, smoking status, blood pressure, and body mass index. Low amounts of low frequency (LF) power (beta=-0.31, p=0.007) and high frequency (HF) power (beta=-0.36, p=0.002) were associated with increased amounts of IL-6, explaining 7% and 9% of the variance, respectively. Interactions between LF power and IL-6 (p=0.002) and between HF power and IL-6 (p=0.012) explained 8% and 5%, respectively, of the variance in sTF. Post hoc analyses showed associations between IL-6 and sTF when LF power (beta=0.51, p<0.001) and HF power (beta=0.48, p<0.001) were low but not when LF power and high HF power were high. The findings suggest that systemic low-grade inflammatory activity is associated with a decrease in HRV. Furthermore, there was a positive relationship between plasma levels of IL-6 and sTF antigen when HRV was low. Inflammation and related hypercoagulability might particularly contribute to atherothrombotic events in a setting of decreased HRV.

A new surgical approach for exclusion of renal artery aneurysms avoiding organ ischemia

INTRODUCTION: Surgical treatment of renal artery aneurysms is inevitably associated with temporary renal artery occlusion and risk of ischemic injury. We present a technique for renal artery grafting and aneurysm exclusion without interrupting renal blood flow. REPORT: A symptomatic renal artery aneurysm was bypassed with a venous graft between the abdominal aorta and the very distal renal artery utilizing a distal anastomotic device without interruption of renal blood flow. The aneurysm was then excluded by means of hemostatic clips. CONCLUSION: The presented surgical technique offers the major advantage of avoiding organ ischemia and accelerating the surgical procedure.

Sudden cardiac death in patients with silent myocardial ischemia after myocardial infarction (from the Swiss Interventional Study on Silent Ischemia Type II [SWISSI II])

The occurrence of sudden cardiac death (SCD) in patients with silent ischemia after myocardial infarction (MI) and the factors facilitating SCD are unknown. This study aimed to determine the factors facilitating SCD in patients with silent ischemia after MI. In the Swiss Interventional Study on Silent Ischemia Type II (SWISSI II), 201 patients with silent ischemia after MI were randomized to percutaneous coronary intervention (PCI) or medical management. The main end point of the present analysis was SCD. Multivariable regression models were used to detect potential associations between baseline or follow-up variables and SCD. During a mean follow-up of 10.3 +/- 2.6 years, 12 SCDs occurred, corresponding to an average annual event rate of 0.6%. On multivariate regression analysis, the decline in the left ventricular ejection fraction (LVEF) during follow-up was the only independent predictor of SCD (p = 0.011), other than age; however, the baseline LVEF was not. The decline in LVEF was greater in patients receiving medical management than in those who had received PCI (p <0.001), as well as in patients with residual myocardial ischemia or recurrent MI compared with patients without these findings (p = 0.038 and p <0.001, respectively). Compared with medical management, PCI reduced the rate of residual myocardial ischemia (p <0.001) and recurrent MI (p = 0.001) during follow-up. In conclusion, patients with silent ischemia after MI are at a substantial risk of SCD. The prevention of residual myocardial ischemia and recurrent MI using PCI resulted in better long-term LVEF and a reduced SCD incidence.

Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK

In adults, glioblastomas are the most lethal and most frequent malignant brain tumors, and the poor prognosis despite aggressive treatment indicates the need to establish novel targets for molecular intervention. The secreted growth factor pleiotrophin (PTN, HB-GAM, HBNF, OSF-1) shows mitogenic, chemotactic, and transforming activity. Whereas PTN expression is tightly regulated during embryogenesis and is very limited in normal adult tissues, a marked PTN up-regulation is seen in tumors including glioblastomas. Likewise, the PTN receptor anaplastic lymphoma kinase (ALK) has been shown previously to be upregulated and functionally relevant in glioblastoma. In this study, we explore the antitumorigenic effects of the simultaneous ribozyme-mediated knockdown of both receptor and ligand. Various glioblastoma cell lines are analyzed for PTN and ALK expression. Beyond the individual efficacies of several specific ribozymes against PTN or ALK, respectively, antiproliferative and proapoptotic effects of a single gene targeting approach are strongly enhanced on double knockdown of both genes in vitro. More importantly, this results in the abolishment of tumor growth in an in vivo subcutaneous tumor xenograft model. Finally, the analysis of various downstream signaling pathways by antibody arrays reveals a distinct pattern of changes in the activation of signal transduction molecules on PTN/ALK double knockdown. Beyond the already known ones, it identifies additional pathways relevant for PTN/ALK signaling. We conclude that double targeting of PTN and ALK leads to enhanced antitumorigenic effects over single knockdown approaches, which offers novel therapeutic options owing to increased efficacy also after prolonged knockdown.

Bone-marrow derived progenitor cells are associated with psychosocial determinants of health after controlling for classical biological and behavioral cardiovascular risk factors

BACKGROUND: Circulating progenitor cells have been implicated with maintaining vascular integrity. Low counts are found in adults with high cardiovascular risk and are associated with impaired endothelial function. It remains unknown whether psychosocial risk factors are independently related to counts of circulating progenitor cells. METHODS: We investigated a random sample of 468 adult industrial employees (mean age 41.2 years, 89% men) of Caucasian origin. Cardiovascular risk factors (blood pressure, LDL, HDL and C-reactive protein), health behavior (smoking, alcohol and physical exercise), psychological variables (effort-reward imbalance social support, negative affectivity) and interaction terms served as predictors of circulating progenitor cells (CD34+ CD31dim) as enumerated by flow-cytometry. FINDINGS: Psychosocial variables were independently associated with progenitor cell counts. The association with risk factors increased with age (explained variance in 18-36 year olds R(2)=0.17, p=0.55; age 36.1-46 R(2)=0.32, p=0.001; age>46 R(2)=0.27, p<0.001). Data revealed a shift from a larger association between behavioral and psychosocial variables and cell counts to a stronger association between biological variables and cell counts in older individuals. A significant interaction was observed between smoking and effort-reward imbalance in middle-aged subjects, those with both risk factors present had lower cell counts. In older employees, the interaction between biological risk factors and smoking was related to lower cell counts. INTERPRETATION: In working middle-aged and older men, psychosocial risk factors were related to circulating counts of progenitor cells. Smoking interacted negatively with psychosocial risk factors (middle-aged men) or with biological risk factors (older employees).

Diminished prefrontal brain function in adults with psychopathology in childhood related to attention deficit hyperactivity disorder

The aim of the present study was to investigate prefrontal brain function and cognitive response control in patients with personality disorders who either suffered or did not suffer from psychopathology related to attention deficit hyperactivity disorder (ADHD) during childhood. For this purpose, 36 psychiatric out-patients with personality disorders--24 of whom showed ADHD-related psychopathology during childhood assessed by the German short form of the Wender Utah Rating Scale--and 24 healthy controls were investigated electrophysiologically by means of a cued Go-NoGo task (Continuous Performance Test). Topographical analyses were conducted to individually quantify the NoGo anteriorisation (NGA), a neurophysiological correlate of prefrontal response control that has been suggested to reflect activation of the anterior cingulate cortex. ADHD patients exhibited a significantly reduced mean NGA and diminished amplitudes of the Global Field Power, as well as a reduced increase of fronto-central P300 amplitudes, in NoGo-trials compared with the healthy controls, whereas patients with personality disorders alone did not differ from the control group in any of the electrophysiological parameters. The results indicate that ADHD-related psychopathology is associated with prefrontal brain dysfunction, probably related to processes of response inhibition and/or cognitive response control.

A Stereoscopic Volume Rendered Brain Atlas

The anatomy of the human brain is organized as a complex arrangement of interrelated structures in three dimensional space. To facilitate the understanding of both structure and function, we have created a volume rendered brain atlas (VRBA) with an intuitive interface that allows real-time stereoscopic rendering of brain anatomy. The VRBA incorporates 2-dimensional and 3-dimensional texture mapping to display segmented brain anatomy co-registered with a T1 MRI. The interface allows the user to remove and add any of the 62 brain structures, as well as control the display of the MRI dataset. The atlas also contains brief verbal and written descriptions of the different anatomical regions to correlate structure with function. A variety of stereoscopic projection methods are supported by the VRBA and provide an abstract, yet simple, way of visualizing brain anatomy and 3-dimensional relationships between different nuclei.

Smell and taste of chewing gum affect frequency domain EEG source localizations

We investigated brain electric field signatures of subjective feelings after chewing regular gum or gum base without flavor. 19-channel eyes-closed EEG from 20 healthy males before and after 5 minutes of chewing the two gum types in random sequence was source modeled in the frequency domain using the FFT-Dipole-Approximation. 3-dimensional brain locations and strengths (Global Field Power, GFP) of the equivalent sources of five frequency bands were computed as changes from pre-chewing baseline. Gum types differed (ANOVA) in pre-post changes of source locations for the alpha-2 band (to anterior and right after regular gum, opposite after gum base) and beta-2 band (to anterior and inferior after regular gum, opposite after gum base), and of GFP for delta-theta, alpha-2 and beta-1 (regular gum: increase, gum base: decrease). Subjective feeling changed to more positive values after regular gum than gum base (ANOVA).—Thus, chewing gum with and without taste-smell activates different brain neuronal populations.

Mammalian iron transporters: Families SLC11 and SLC40

This review is focused on the mammalian SLC11 and SLC40 families and their roles in iron homeostasis. The SLC11 family is composed of two members, SLC11A1 and SLC11A2. SLC11A1 is expressed in the lysosomal compartment of macrophages and in the tertiary granules of neutrophils, playing a key role in innate resistance against infection by intracellular microbes. SLC11A2 is a key player in iron metabolism and is ubiquitously expressed, most notably in the proximal duodenum, immature erythroid cells, brain, placenta and kidney. Intestinal iron absorption is mediated by SLC11A2 at the apical membrane of enterocytes, followed by basolateral exit via SLC40A1. To meet the daily requirement for iron, approximately 80% of the iron comes from the breakdown of hemoglobin following macrophage phagocytosis of senescent erythrocytes (iron recycling). Both SLC11A1 and SLC11A2 play an important role in macrophage iron recycling. SLC11A2 also transports iron into the cytosol across the membrane of endocytotic vesicles of the transferrin receptor-cycle. SLC40A1 is the sole member of the SLC40 family and is involved in the only cellular iron efflux mechanism described. SLC40A1 is highly expressed in several tissues and cells that play a critical role in body iron homeostasis. The signaling pathways that regulate SLC11A2 and SLC40A1 expression at transcriptional, post-transcriptional and post-translational levels are discussed. The roles of SLC11A2 and/or SLC40A1 in iron-associated disorders such as hemochromatosis, neurodegenerative diseases, and breast cancer are also summarized.