Role of selenium addition to CdZnTe matrix for room-temperature radiation detector applications.

Because of its ideal band gap, high density and high electron mobility-lifetime product, cadmium zinc telluride (CdZnTe or CZT) is currently the best room-temperature compound-semiconductor X- and gamma-ray detector material. However, because of its innate poor thermo-physical properties and above unity segregation coefficient for Zn, the wide spread deployment of this material in large-volume CZT detectors is still limited by the high production cost. The underlying reason for the low yield of high-quality material is that CZT suffers from three major detrimental defects: compositional inhomogeneity, high concentrations of dislocation walls/sub-grain boundary networks and high concentrations of Te inclusions/precipitates. To mitigate all these disadvantages, we report for the first time the effects of the addition of selenium to the CZT matrix. The addition of Se was found to be very effective in arresting the formation of sub-grain boundaries and its networks, significantly reducing Zn segregation, improving compositional homogeneity and resulting in much lower concentrations of Te inclusions/precipitates. Growth of the new quaternary crystal Cd1-xZnxTe1-ySey (CZTS) by the Traveling Heater Method (THM) is reported in this paper. We have demonstrated the production of much higher yield according to its compositional homogeneity, with substantially lower sub-grain boundaries and their network, and a lower concentration of Te inclusions/precipitates.

Stability of the Baseline Holder in Readout Circuits For Radiation Detectors.

Baseline holder (BLH) circuits are used widely to stabilize the analog output of application-specific integrated circuits (ASICs) for high-count-rate applications. The careful design of BLH circuits is vital to the overall stability of the analog-signal-processing chain in ASICs. Recently, we observed self-triggered fluctuations in an ASIC in which the shaping circuits have a BLH circuit in the feedback loop. In fact, further investigations showed that methods of enhancing small-signal stabilities cause an even worse situation. To resolve this problem, we used large-signal analyses to study the circuit's stability. We found that a relatively small gain for the error amplifier and a small current in the non-linear stage of the BLH are required to enhance stability in large-signal analysis, which will compromise the properties of the BLH. These findings were verified by SPICE simulations. In this paper, we present our detailed analysis of the BLH circuits, and propose an improved version of them that have only minimal self-triggered fluctuations. We summarize the design considerations both for the stability and the properties of the BLH circuits.

Novel ZnO:Al contacts to CdZnTe for X- and gamma-ray detectors.

CdZnTe (CZT) has made a significant impact as a material for room-temperature nuclear-radiation detectors due to its potential impact in applications related to nonproliferation, homeland security, medical imaging, and gamma-ray telescopes. In all such applications, common metals, such as gold, platinum and indium, have been used as electrodes for fabricating the detectors. Because of the large mismatch in the thermal-expansion coefficient between the metal contacts and CZT, the contacts can undergo stress and mechanical degradation, which is the main cause for device instability over the long term. Here, we report for the first time on our use of Al-doped ZnO as the preferred electrode for such detectors. The material was selected because of its better contact properties compared to those of the metals commonly used today. Comparisons were conducted for the detector properties using different contacts, and improvements in the performances of ZnO:Al-coated detectors are described in this paper. These studies show that Al:ZnO contacts to CZT radiation detectors offer the potential of becoming a transformative replacement for the common metallic contacts due to the dramatic improvements in the performance of detectors and improved long-term stability.

An array of virtual Frisch-grid CdZnTe detectors and a front-end application-specific integrated circuit for large-area position-sensitive gamma-ray cameras.

We developed a robust and low-cost array of virtual Frisch-grid CdZnTe detectors coupled to a front-end readout application-specific integrated circuit (ASIC) for spectroscopy and imaging of gamma rays. The array operates as a self-reliant detector module. It is comprised of 36 close-packed 6 × 6 × 15 mm(3) detectors grouped into 3 × 3 sub-arrays of 2 × 2 detectors with the common cathodes. The front-end analog ASIC accommodates up to 36 anode and 9 cathode inputs. Several detector modules can be integrated into a single- or multi-layer unit operating as a Compton or a coded-aperture camera. We present the results from testing two fully assembled modules and readout electronics. The further enhancement of the arrays' performance and reduction of their cost are possible by using position-sensitive virtual Frisch-grid detectors, which allow for accurate corrections of the response of material non-uniformities caused by crystal defects.

Test of a 32-channel Prototype ASIC for Photon Counting Application.

A new low-power application-specific integrated circuit (ASIC) for Cadmium Zinc Telluride (CZT) detectors for single-photon emission computed tomography (SPECT) application is being developed at BNL. As the first step, a 32-channel prototype ASIC was designed and tested recently. Each channel has a preamplifier followed by CR-RC3 shaping circuits and three independent energy bins with comparators and 16-bit counters. The ASIC was fabricated with TSMC 0.35-µm complementary metal-oxide-semiconductor (CMOS) process and tested in laboratories. The power consumption is around 1 mW/ch with a 2.5-V supply. With a gain of 400 mV/fC and the peaking time of 500 ns, the equivalent noise charge (ENC) of 360 e- has been measured in room temperature while the crosstalk rate is less than 0.3%. The 10-bit DACs for global thresholds have an integral nonlinearity (INL) less than 0.56% and differential nonlinearity (DNL) less than 0.33%. In the presentation, we will report the detailed test results with this ASIC.

The chemokine CXCL13 (BCA-1) inhibits FGF-2 effects on endothelial cells.

Several chemokines, belonging to both the CXC and CC classes, act as positive or negative regulators of angiogenesis. We sought to investigate the role of CXCL13, B cell-attracting chemokine 1 (BCA-1), also known as B-lymphocyte chemoattractant (BLC), on endothelial cell functions. We tested the effect of CXCL13 on HUVEC chemotaxis and proliferation in the presence of fibroblast growth factor (FGF)-2 and found that such chemokine inhibits FGF-2-induced functions, while is not active by itself. To test whether other FGF-2-mediated biological activities may be affected, we evaluated the ability of CXCL13 to rescue HUVEC from starvation-induced apoptosis, as FGF-2 is a survival factor for endothelial cells, and found that CXCL13 partially inhibits such rescue. Multiple mechanisms may be responsible for these biological activities as CXCL13 displaces FGF-2 binding to endothelial cells, inhibits FGF-2 homodimerization, and induces the formation of CXCL13-FGF-2 heterodimers. Our data suggest that CXCL13 may modulate angiogenesis by interfering with FGF-2 activity.

I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo.

Several chemokines have been shown to act as angiogenic molecules or to modulate the activity of growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelial growth factor (VEGF). The detection of the CC chemokine receptor (CCR) 8 message in human umbilical vein endothelial cells (HUVECs) by reverse transcription- polymerase chain reaction (RT-PCR) and RNase protection assay (RPA), prompted us to investigate the potential role exerted by the CC chemokine I-309, a known ligand of such receptor, in both in vitro and in vivo angiogenesis assays. We show here that I-309 binds to endothelial cells, stimulates chemotaxis and invasion of these cells, and enhances HUVEC differentiation into capillary-like structures in an in vitro Matrigel assay. Furthermore, I-309 is an inducer of angiogenesis in vivo in both the rabbit cornea and the chick chorioallantoic membrane assay (CAM).

Nef protein induces differential effects in CD8+ cells from HIV-1-infected patients.

BACKGROUND: The Nef protein of HIV-1 is suspected to play a role in the depletion of uninfected CD4+ lymphocytes that leads to AIDS. By contrast its effect on CD8+ cells, whose functions are also deregulated during HIV-1 infection, is presently unclear. Here we describe a number of derangements induced in vitro by Nef in CD8+ cells from HIV-1-infected patients. DESIGN: Peripheral lymphocytes from 16 HIV-1+ subjects and 9 uninfected individuals were cultivated on a Nef-transfected mouse fibroblast layer exposing the carboxyl-terminal region of the viral protein on cell membrane. The cultures were then measured for both apoptosis and proliferation by subdiploid DNA content and Ki67 expression, respectively, whereas the molecular analysis of purified CD8+ cells investigated the Fas-L mRNA levels in Nef-treated CTLs. In addition, we evaluated the Nef-induced variation in the extent of CD8+/HLA-DR+ subset, which includes non cytotoxic cells secreting T-cell antiviral factor (CAF) and a soluble factor inhibiting the HIV-1 replication. RESULTS: The viral protein induced in peripheral blood lymphocytes (PBL) a moderate tendency to proliferate, as measured by the increment of Ki67 antigen, particularly on the CD8+ subset of HIV-1 infected individuals (P < 0.05). This profile was particularly evident in cultures from patients with severe CD4+ lymphopenia and paralleled an apparent expansion of the CD8+/CD57+ suppressor cell subset. Molecular analysis of purified CD8+ cells revealed a defective expression of Fas-L mRNA in Nef-cultured CTLs, whereas the viral protein exerted a down modulatory effect on the CD8+/HLA-DR+ subset (P < 0.05), thus suggesting a potential inhibition of CAF. CONCLUSIONS: These results support a potential role of Nef in the progression of HIV-1 infection as a number of cellular functions are affected in the CD8+ subset. In particular, the defective functions of CD8+ cells induced by the viral protein could contribute, at least partly, to the escape of HIV-1 from the immune control of these cells.

The equine herpesvirus 2 E1 open reading frame encodes a functional chemokine receptor.

Several herpesviruses contain open reading frames (ORFs) that encode potential homologs of eucaryotic genes. Equine herpesvirus 2 (EHV-2) is a gammaherpesvirus related to other lymphotropic herpesviruses such as herpesvirus saimiri and Epstein-Barr virus. The E1 ORF of EHV-2, a G protein-coupled receptor homolog, shows 31 to 47% amino acid identity with known CC chemokine receptors. To investigate whether E1 may encode a functional receptor, we cloned the E1 ORF and expressed it in stably transfected cell lines. We report here the identification of the CC chemokine eotaxin as a functional ligand for the EHV-2 E1 receptor. Chemokines are likely to play a role in the regulation of immune functions in equine hosts during EHV-2 infection and, via interaction with E1, may affect viral replication and/or escape from immune responses.

Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells.

IL-6 is a growth factor which interferes in the apoptosis of malignant plasma cells. Here we explore its role in the spontaneous and Fas/FasL-regulated apoptosis of seven myeloma cell clones (MCC). MCC-2 and -7 were constitutively defective in Fas antigen in the presence of large membrane exposure of FasL, and showed a high rate of cell proliferation irrespective of the presence of IL-6. Cytofluorimetric analysis following propidium iodide (PI) staining revealed a minimal extent of spontaneous apoptosis, as in other IL-6-insensitive, though Fas-positive MCC, namely MCC-3 and -5. By contrast, a regular amplitude of apoptosis occurred in the remaining IL-6-dependent clones. Their propensity to cell death, as well as their FasL membrane expression, were promptly down-modulated by the cytokine, whereas no substantial effect was detected in IL-6-independent MCC. Furthermore, we investigated the quantitative secretion of FasL. Both [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) cytotoxicity assay and PI staining of WC8 lymphoblasts from a Fas-transfected mouse lymphoma, incubated with supernatants from MCC, showed a variable cytocidal property, thus confirming the cellular release of FasL. However, a significant elevation of FasL secretion occurred in both Fas- MCC, whereas molecular cloning and sequencing of Fas revealed the presence of a splicing variant, namely Fas Exo4,6Del, in the cDNA from both MCC-3 and -5, which were previously demonstrated to be unresponsive to Fas stimulation. Taken together, these data provide evidence that concurrence of IL-6 insensitivity and deregulation of apoptosis in myeloma cells reflects a high malignancy grade. It is suggested that the secretion of Fas splicing variants in Fas+ plasma cells, as well as the over-production of FasL in Fas- myelomas, are differential mechanisms by which myeloma cells escape host immune surveillance.

Functional Fas-ligand expression on T cells from HIV-1-infected patients is unrelated to CD4+ lymphopenia.

Recent studies have demonstrated that the expression of Fas by peripheral T cells from HIV-1+ patients is deregulated and increases the susceptibility of these cells to undergo apoptosis. Here, we show that secretion of Fas-ligand (L), the complementary agonist of Fas, is abnormally upregulated in CD4+ cells from HIV-1-infected individuals, particularly during the non-lymphopenic stages of the disease. An increase of soluble Fas-L occurred in T cell cultures from 26 patients with a number of CD4+ cells higher than 400/microliter, whereas it was almost undetectable in cultures from 21 severely lymphopenic patients (CD4+ < 200/microliter). The MTT test, cytofluorimetric analysis of cellular DNA, cytotoxicity, and proliferative assays using the Fas-transfected WC8 mouse lymphoma confirmed the cytocidal capability of T cell supernatants from non-lymphopenic patients. Double-fluorescence analysis revealed that the majority of CD4+ cells (approximately 90%) in these cultures secreted Fas-L in the presence of high intracellular gamma-interferon and low Bcl-2. In contrast, the CD8+/Fas-L+ population was comparably decreased (approximately 55%). Molecular cloning of Fas-L revealed a substantial expression of Fas-L mRNA in cells from non-lymphopenic patients compared with patients with advanced disease and healthy controls. Since CD4+ cells of Th1 phenotype are impaired during HIV-1 infection and show high cellular expression of Fas-L, it is conceivable that excess Fas-L during the early or non-lymphopenic phase of the disease increases the extent of apoptosis in these cells by the Fas/Fas-L pathway. The defective expression of the ligand in severely lymphopenic stages could be explained by exhaustion of this mechanism as the disease progresses.

Intra- and interindividual variation in flank gland secretions of free-ranging shrewsCrocidura russula.

Individual differences in flank gland secretions were examined among males of the monogamous shrewCrocidura russula during the breeding and nonbreeding seasons. Gas chromatography was used to measure intra- and interindividual variation of flank gland secretions of free-ranging shrews from different populations. The number of compounds detected by gas Chromatographic analyses was correlated with body mass, flank gland size, and the presence of blood parasites in individual shrews. Very few compounds were detected from the flank gland area of juvenile males. After they reached sexual maturity, however, the number of compounds detected from the flank gland secretions increased significantly. At the beginning of the reproductive season 48 different compounds were detected from male flank gland secretions. In the middle of the breeding season 70 compounds were detected, while only 11 compounds were detected during the nonbreeding season. Few compounds were common to all males. There were more volatile compounds in the flank gland secretions of males in the beginning of the breeding season than later in the breeding season. Males from the same population had fewer differences in the elution profile of compounds than males from different populations indicating that individuals from a distinct population have similar elution profiles of compounds and that each population has its own type of elution profile. No correlations were found between the number of compounds detected by gas chromatography for each male and the male's body mass or flank gland size. Blood parasites (trypanosomes,Trypanosoma crocidurae) were found in only three of 30 males investigated.

Multiple pathways originate at the Fas/APO-1 (CD95) receptor: sequential involvement of phosphatidylcholine-specific phospholipase C and acidic sphingomyelinase in the propagation of the apoptotic signal.

The early signals generated following cross-linking of Fas/APO-1, a transmembrane receptor whose engagement by ligand results in apoptosis induction, were investigated in human HuT78 lymphoma cells. Fas/APO-1 cross-linking by mAbs resulted in membrane sphingomyelin hydrolysis and ceramide generation by the action of both neutral and acidic sphingomyelinases. Activation of a phosphatidylcholine-specific phospholipase C (PC-PLC) was also detected which appeared to be a requirement for subsequent acidic sphingomyelinase (aSMase) activation, since PC-PLC inhibitor D609 blocked Fas/APO-1-induced aSMase activation, but not Fas/APO-1-induced neutral sphingomyelinase (nSMase) activation. Fas/APO-1 cross-linking resulted also in ERK-2 activation and in phospholipase A2 (PLA2) induction, independently of the PC-PLC/aSMase pathway. Evidence for the existence of a pathway directly involved in apoptosis was obtained by selecting HuT78 mutant clones spontaneously expressing a newly identified death domain-defective Fas/APO-1 splice isoform which blocks Fas/APO-1 apoptotic signalling in a dominant negative fashion. Fas/APO-1 cross-linking in these clones fails to activate PC-PLC and aSMase, while nSMase, ERK-2 and PLA2 activates are induced. These results strongly suggest that a PC-PLC/aSMase pathway contributes directly to the propagation of Fas/APO-1-generated apoptotic signal in lymphoid cells.

Methylation state of the human HLA-DRA gene in T-lymphocytes and B-lymphocytes of transgenic mice. Lack of methylation at one 5'-GCGC site is not required for gene expression.

A consistent lack of DNA methylation at one or both of two GCGC (Hha I) restriction sites in the 5' region of the HLA-DRA gene has been previously documented by the use of methyl-sensitive restriction enzymes in human cells and tissues, irrespectively of their expression of DR alpha products. Evidence presently available, however, does not exclude that a lack of methylation in this region, although not sufficient, might be necessary for gene expression. In this report, we show that only one of the 5'-GCGC sites is protected, although less efficiently than in man, from CG-->mCG modifications in tissues and cells of transgenic mice carrying an expressed single copy of the HLA-DRA gene/diploid genome. We demonstrate that the two 5' GCGC sites of the HLA-DRA transgene are fully methylated in DR alpha- splenocytes (more than 80% T-lymphocytes), while one of them (the most 5' site) is not methylated in a fraction of DR alpha+ splenocytes (more than 95% B-lymphocytes). These results provide evidence that absence of DNA methylation in the 5' region is not necessary for, but might be associated with and possibly secondary to the expression of the DRA gene.

[Use and effect of simvastin in patients with type II diabetes]. / Uso ed effetto della simvastatina in pazienti diabetici di tipo II.

Ten non insulin-dependent diabetics in satisfactory metabolic control but with high cholesterol levels were treated with simvastatin. A significant reduction of total cholesterol and LDL-cholesterol was obtained together with an increase in HDL-cholesterol, thus documenting the efficacy of this agent.

[Evaluation of the effect of enalapril in hypertensive patients with non-insulin-dependent diabetes mellitus]. / Valutazione dell'effetto dell'enalapril in pazienti ipertesi con diabete mellito non insulino-dipendente.

We selected 15 hypertensive non insulin-dependent diabetics in reasonable metabolic control, treated for 6 months with enalapril 20 mg/die. The results showed a significant reduction of mean arterial blood pressure and triglycerides without interference on the metabolic control.