Dark Matter Search Results from the PICO-60 C_{3}F_{8} Bubble Chamber.

New results are reported from the operation of the PICO-60 dark matter detector, a bubble chamber filled with 52 kg of C_{3}F_{8} located in the SNOLAB underground laboratory. As in previous PICO bubble chambers, PICO-60 C_{3}F_{8} exhibits excellent electron recoil and alpha decay rejection, and the observed multiple-scattering neutron rate indicates a single-scatter neutron background of less than one event per month. A blind analysis of an efficiency-corrected 1167-kg day exposure at a 3.3-keV thermodynamic threshold reveals no single-scattering nuclear recoil candidates, consistent with the predicted background. These results set the most stringent direct-detection constraint to date on the weakly interacting massive particle (WIMP)-proton spin-dependent cross section at 3.4×10^{-41} cm^{2} for a 30-GeV c^{-2} WIMP, more than 1 order of magnitude improvement from previous PICO results.

A precise method to determine the activity of a weak neutron source using a germanium detector.

A standard high purity germanium (HPGe) detector was used to determine the previously unknown neutron activity of a weak americium-beryllium (AmBe) neutron source. γ rays were created through (27)Al(n,n'), (27)Al(n,γ) and (1)H(n,γ) reactions induced by the neutrons on aluminum and acrylic disks, respectively. These γ rays were measured using the HPGe detector. Given the unorthodox experimental arrangement, a Monte Carlo simulation was developed to model the efficiency of the detector system to determine the neutron activity from the measured γ rays. The activity of our neutron source was determined to be 307.4±5.0n/s and is consistent for the different neutron-induced γ rays.

A Study to Investigate the Role of GULP/ CED 6 Gene in "Eat Me" Signaling in Cellular Efferocytosis and Immunosurveillance.

In this report, investigations were done to study human GULP/ CED 6 genes role in presenting cancer cells to scavenger cells. CED 6 SiRNA was used to knock out the gene in Astrocytoma (HTB-12) cell lines to study its effects on expression of various "eat me" signals on these cells including Phosphatidyl serine (PtdSer) expression, nitric oxide (NO) signaling and Leukotrine B4 (LTB4) expression and Caspase 3 activation. Investigations were done by fluorescence microscopy techniques, ELISA assay and colorimetric assays using a standard microplate reader and spectrophotometer. Initial results showed all the above mentioned "eat me" signals were significantly decreased in CED 6 knock out cell lines. Therefore CED 6 gene must have a role in cancer cell clearance, pathway involved in the cross talk between CED 6 and other genes in this process is a matter of farther investigation.

Dark Matter Search Results from the PICO-2L C3F8 Bubble Chamber.

New data are reported from the operation of a 2 liter C3F8 bubble chamber in the SNOLAB underground laboratory, with a total exposure of 211.5 kg days at four different energy thresholds below 10 keV. These data show that C3F8 provides excellent electron-recoil and alpha rejection capabilities at very low thresholds. The chamber exhibits an electron-recoil sensitivity of <3.5×10(-10) and an alpha rejection factor of >98.2%. These data also include the first observation of a dependence of acoustic signal on alpha energy. Twelve single nuclear recoil event candidates were observed during the run. The candidate events exhibit timing characteristics that are not consistent with the hypothesis of a uniform time distribution, and no evidence for a dark matter signal is claimed. These data provide the most sensitive direct detection constraints on WIMP-proton spin-dependent scattering to date, with significant sensitivity at low WIMP masses for spin-independent WIMP-nucleon scattering.

Identification of the Transmembrane Glucose Regulated Protein 78 as a Biomarker for the Brain Cancer Glioblastoma Multiforme by Gene Expression and Proteomic Studies.

The prognosis of patients with Glioblastoma Multiforme (GBM), the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of GBM warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis (2D-DIGE) followed by spot picking and analysis of proteins/peptides by Mass Spectrometry. We report Glucose Regulated Protein 78 (GRP78) as a differentially expressed protein in the GBM cell line compared to human normal Astrocyte cells. In addition to proteomic studies, we performed microarray analysis which further confirmed up regulation of GRP78 in GBM cells compared to human normal Astrocyte cells. GRP78 has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found in cell plasma membrane, cytoplasm, mitochondria, nucleus and other cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor micro environmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which senses and facilitates the adaptation to the tumor microenvironment. Our findings showed differential expression of this gene in brain cancer GBM and thus confirm similarities in findings in existing transcriptional and translational studies. Thus, these findings could be of further importance for diagnostic, therapeutic and prognostic approaches for dealing with this highly malignant cancer.

TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer.

BACKGROUND: Clinicopathologic stage is still the main parameter to evaluate the prognosis of newly diagnosed colorectal cancer (CRC) patients. Although molecular markers have been suggested for follow up of treated CRC patients, their complete clinical application is still under evaluation. MATERIALS AND METHODS: To evaluate the association of immune-related genes with CRC prognosis and survival, a total of 19 single nucleotide polymorphisms (SNPs) were genotyped in 614 German patients within the Kiel cohort (POPGEN). RESULTS: A promoter variant (rs1800872) in the Interleukin-10 (IL-10) gene was associated with an increased lymph node metastasis involvement [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.03-4.2, for carriers of the TT genotype]. More importantly, among 582 followed up patients the SNP rs3775291 in the toll-like receptor 3 (TLR-3) gene was associated with CRC specific survival (150 events). Patients carrying the TT genotype had a 93% increased risk of death compared with the CC carriers [hazard ratio (HR) = 1.93, 95% CI 1.14-3.28]. The observed effect of the TLR-3 variant was restricted to stage II patients (HR = 4.14, 95% CI 1.24-13.84) and to patients who did not receive adjuvant therapy (HR = 3.2, 95% CI 1.4-7.7). CONCLUSIONS: Our results may provide additional candidates for risk assessment in stage II CRC patients for treatment decision. Further validation of the presented findings is warranted.

Comparison of the performance of SAPS II, SAPS 3, APACHE II, and their customized prognostic models in a surgical intensive care unit.

BACKGROUND: The Simplified Acute Physiology Score (SAPS) 3 has recently been developed, but not yet validated in surgical intensive care unit (ICU) patients. We compared the performance of SAPS 3 with SAPS II and the Acute Physiology and Chronic Health Evaluation (APACHE) II score in surgical ICU patients. METHODS: Prospectively collected data from all patients admitted to a German university hospital postoperative ICU between August 2004 and December 2005 were analysed. The probability of ICU mortality was calculated for SAPS II, APACHE II, adjusted APACHE II (adj-APACHE II), SAPS 3, and SAPS 3 customized for Europe [C-SAPS3 (Eu)] using standard formulas. To improve calibration of the prognostic models, a first-level customization was performed, using logistic regression on the original scores, and the corresponding probability of ICU death was calculated for the customized scores (C-SAPS II, C-SAPS 3, and C-APACHE II). RESULTS: The study included 1851 patients. Hospital mortality was 9%. Hosmer and Lemeshow statistics showed poor calibration for SAPS II, APACHE II, adj-APACHE II, SAPS 3, and C-SAPS 3 (Eu), but good calibration for C-SAPS II, C-APACHE II, and C-SAPS 3. Discrimination was generally good for all models [area under the receiver operating characteristic curve ranged from 0.78 (C-APACHE II) to 0.89 (C-SAPS 3)]. The C-SAPS 3 score appeared to have the best calibration curve on visual inspection. CONCLUSIONS: In this group of surgical ICU patients, the performance of SAPS 3 was similar to that of APACHE II and SAPS II. Customization improved the calibration of all prognostic models.

Simulation of special bubble detectors for PICASSO.

The PICASSO project is a cold dark matter (CDM) search experiment relying on the superheated droplet technique. The detectors use superheated freon liquid droplets (active material) dispersed and trapped in a polymerised gel. This detection technique is based on the phase transition of superheated droplets at about room temperature and ambient pressure. The phase transition is induced by nuclear recoils when an atomic nucleus in the droplets interacts with incoming subatomic particles. This includes CDM particles candidate as the neutralino (a yet-to-discover particle predicted in extensions of the standard model of particle physics). Simulations performed to understand the detector response to neutrons and alpha particles are presented along with corresponding data obtained at the Montreal Laboratory.

Direct dark matter search using large-mass superheated droplet detectors in the PICASSO experiment.

The PICASSO experiment investigates the presence and nature of dark matter in the Universe. The experiment is based on the detection of acoustic signals generated in explosive phase transitions induced by dark matter particles. This technique is an alternative more traditional detection technique like scintillation and ionisation, which are largely employed for dark matter search. One of the main advantages of this technique, besides its sensitivity to very low nuclear recoil energies (few keV), is its excellent background suppression features. A pilot experiment consisting of six superheated droplet detectors (40 g of active mass) is presently taking data at the Sudbury Neutrino Observatory (SNO) at a depth of 2000 m. We discuss the operation, calibration and data acquisition of the experiment and also the ongoing work to increase the sensitivity and the active mass of the detectors.

Comparison of peripheral bone and body axis skeleton in a rat model of mild-to-moderate renal failure in the presence of physiological serum levels of calcitropic hormones.

The skeleton is characterized by anatomic heterogeneity of metabolic turnover. Site-dependent differences in hormonal effects seem likely. Hyporesponsiveness of osteoclasts to parathyroid hormone (PTH) and probably calcitriol was recently demonstrated in the fifth lumbar vertebra of a rat model with moderate renal failure. We compared histomorphometric findings of the tibial head to these data. Histomorphometric measurements were carried out in sections of the right tibial head of pair-fed male Sprague-Dawley rats. Subtotally nephrectomized (SNx), parathyroidectomized (PTx), rats, which received either solvent or rat PTH(1-34) (100 ng/kg per hour) + calcitriol (5 pmol/kg per hour) via osmotic minipumps were compared with sham-operated controls. Results were compared with data from the fifth lumbar vertebra reported recently. Osteoclast numerical density and osteoclast surface density were lower in the tibial head and the lumbar vertebra of solvent-treated SNxPTx rats than in sham-operated controls (p < 0.05), and could not be returned to normal by the substitution of PTH + calcitriol (p < 0.05). On the other hand, there were differences between interventional effects on the tibial head and on the lumbar vertebra concerning parameters describing osteoblasts and trabecular bone volume. In the tibial head, osteoblast surface density was nearly unchanged in both interventions. Nevertheless, bone volume increased after SNxPTx without substitution of PTH + calcitriol (p < 0.05), and no further changes occurred after hormonal replacement. In contrast, osteoblast surface density in the lumbar vertebra was decreased slightly compared with values in sham-operated rats; a clear but nonsignificant increase occurred after the administration of calcitropic hormones. This was accompanied by unchanged trabecular bone volume after SNxPTx. Hormonal replacement, however, caused an increase in trabecular bone volume (p < 0.05), which represents an anabolic effect, which contrasts with findings from the tibial head. The different interventional effects on the lumbar spine and on peripheral bone, regarding the parameters reflecting the condition of osteoblasts, may be intrinsic to the uremic syndrome itself as well as to dissimilar growth manner, function, and mechanical requirements. The findings substantiate the site dependence of bone surface cell metabolism in renal failure and should be the subject of further study. Corresponding results with regard to bone resorption argue for a bone-site-independent, diminished response of osteoclasts to calcitropic hormones.

C242T polymorphism of the p22 phox gene is not associated with peripheral arterial occlusive disease.

Formation of reactive oxygen metabolites is vital for the microbicidal activity of phagocytes. As an unwanted side effect, these metabolites may contribute to oxidative stress in the vasculature and thus lead to arteriosclerosis. p22 phox, a component of the NADH/NADPH oxidase in phagocytes and vascular smooth muscle cells, is essential for production of reactive oxygen metabolites. Recently, a C/T polymorphism at position 242 of the p22 phox gene has been associated with coronary artery disease (CAD), suggesting a protective effect of the 242 T allele on the vasculature. In the present study, we analysed the relation of this polymorphism to peripheral arterial occlusive disease (PAOD). C242T polymorphism was determined by restriction fragment polymorphism (RFLP) analysis in 324 patients with documented PAOD and 295 control subjects without any known arterial disease. p22 phox 242 T allele frequencies and genotype distributions were not significantly different between patients and controls; the adjusted relative risk associated with the 242 T allele was 1.14 (95% CI 0.84-1.54, P=0.39), assuming an additive effect of the T allele. C242T polymorphism was not associated with the age of patients at the onset of the disease. Our data indicate that C242T polymorphism of the p22 phox gene is not associated with PAOD.

Prenatal diagnosis of inverted duplicated 8p.

The phenotype of inverted duplicated 8p, region 8p11.2-p23, reported in children and adults, includes: severe mental retardation, minor facial anomalies, agenesis of corpus callosum, and other malformations including those of heart and kidneys. We report on the prenatal diagnosis of 2 cases of inverted duplication 8p. Both cases were ascertained by abnormal level 2 ultrasound findings. Case 1 presented at 16.5 weeks of gestation with massive distention of the fetal bladder, bilateral hydronephrosis, abnormality of the lower lumbar spine, absence of the sacral spine and a Dandy-Walker variant (interhemispheric cyst and enlarged third ventricle). Case 2 presented at 30 weeks of gestation with agenesis of corpus callosum, slightly enlarged lateral ventricles, interhemispheric cyst and enlarged third ventricle, and possible coarctation of the aorta. The intracranial and cardiac anomalies were confirmed and further defined after delivery. Cytogenetic analysis in both cases showed additional material on 8p. In both cases, fluorescence in situ hybridization (FISH) defined the abnormal chromosome, as a pseudodicentric chromosome with duplication of the short arm from centromere to p23 and deletion from p23 to pter. Our findings support those of prior reports of the inverted duplicated 8p chromosome with multiple anomalies and add prenatal findings to our knowledge.

[Diagnosis-oriented diagnosis, therapy and fee schedules in oncology. A model trial]. / Diagnose-orientierte Diagnostik, Therapie und Kostenerstattung in der operativen Onkologie. Ein Modellversuch.

In 1996 the project "operative oncology" was initiated by the Department of Surgery University of Kiel in order to guarantee a solid and longterm financing of surgical oncological interventions with a high quality standard. First step was to determine the detailed costs of the diagnostic and different surgical procedures in order to calculate flat rates per case. Covered by these comprehensive prices per case are also the psychooncological support, prospective evaluation of quality of life and molecular-oncological diagnostics (determination of micrometastasis). The development of project was primarily financed by the AOK health insurance company of Schleswig-Holstein. It was calculated by the GSbG and is supported since April, 1st, 1998 by all health insurance companies of the region.

Prenatal detection and mapping of a distal 8p deletion associated with congenital heart disease.

We report the prenatal diagnosis, at 18 weeks' gestational age of a del(8)(p23.1-->pter) in a fetus with an atrio-ventricular canal, persistent left superior vena cava and hypoplastic right ventricle detected by sonographic imaging. We further refine the breakpoints associated with this defect using fluorescent in situ hybridization analysis (FISH). Our findings correlate with recent reports of the localization and importance of GATA4 (a zinc finger transcription factor) in cardiac development. Though microcephaly, mental retardation and typical behavioural features are well described in various deletions in 8p, the absence of notable microcephaly in this case raises the possibility for a separate genetic aetiology for some of these features. Indeed, primary autosomal recessive microcephaly (MCPH1) was recently mapped to a nearby region and may be the cause for this frequent observation in some cases of 8p deletions. These observations illustrate the role of FISH in prenatal diagnosis and refinement of chromosomal breakpoints. In addition, mappings of loci significant for cardiac development are presented. Our findings suggest that some features of the 8p deletion syndrome may ultimately be uncoupled from one another, and underscore the need for further study of this region of chromosome 8, in order to achieve adequate information for genetic counselling.

Jarcho-Levin syndrome: prenatal diagnosis, perinatal care, and follow-up of siblings.

Jarcho-Levin syndrome (JLS), spondylothoracic or spondylocostal dysostosis, is a rare entity with variable clinical severity. This syndrome is usually diagnosed in individuals with short neck, short trunk, and short stature with multiple vertebral anomalies at all levels of the vertebral column, including "butterfly vertebrae," hemivertebrae, and fused, hypoplastic vertebrae. The small size of the thorax in newborns frequently leads to respiratory compromise and death in infancy. We report a family in which the diagnosis of JLS in a 1-year-old led to prenatal ultrasound diagnosis of JLS in a sibling. Aggressive neonatal care of the sibling, who developed respiratory failure soon after birth, led to an excellent outcome. This case confirms the utility of the prenatal ultrasound diagnosis of JLS and suggests that when the diagnosis of JLS is known prenatally, appropriate preparations can be made for specialized prenatal and postnatal care that may improve survival.

Is fetal hyperechoic bowel on second-trimester sonogram an indication for amniocentesis?

OBJECTIVE: To determine the clinical significance of hyperechoic bowel seen sonographically in second-trimester fetuses. METHODS: Fifty fetuses (0.6%) with echogenic bowel were identified sonographically from a population of 8680 consecutive second-trimester fetuses over 21 months. The fetal bowel was considered hyperechoic if its echogenicity was similar to that of surrounding bone. Follow-up was obtained through medical record review. RESULTS: Twenty-nine of 50 fetuses (58%) were normal; eight (16%) were aneuploid, including six Down syndrome, one trisomy 13, and one Turner syndrome. All eight fetuses with aneuploidy had sonographic anomalies in addition to the echogenic bowel. Eight of 50 fetuses (16%) were growth-retarded, and five others (10%) had normal karyotypes but are still undelivered. Among the eight growth-retarded fetuses, there were five intrauterine or neonatal deaths, one elective abortion, and two survivors. In addition, the six fetuses with Down syndrome and echogenic bowel represented 12.5% of all second-trimester Down syndrome fetuses karyotyped in our laboratory during the study period. Combining results from the present study (six Down syndrome fetuses) with three studies from the literature (21 additional Down syndrome fetuses), a total of 27 fetuses with echogenic bowel and Down syndrome were identified, 11 (40.7%) of whom had no other sonographic findings. We calculate that if 1,000,000 second-trimester fetuses were scanned, 5105 would have hyperechoic bowel as the only finding, of whom 71 would have Down syndrome and 5034 would not. The risk of Down syndrome in fetuses with isolated hyperechoic bowel is, therefore, 71 in 5105 or 1.4%. CONCLUSION: The finding of isolated hyperechoic bowel in the second trimester should prompt genetic counseling and consideration of karyotypic analysis.

Physical mapping of the holoprosencephaly critical region on chromosome 7q36.

Holoprosencephaly (HPE) is a developmental field defect involving the brain and face. Cytogenetic deletions in patients with HPE have localized one of the HPE genes to chromosomal region 7q36. We have characterized the 7q deletions in thirteen HPE patients. The result is the construction of a high resolution physical map of 7q32-qter. As a first step towards cloning an HPE gene crucial for normal brain development, we have defined the HPE minimal critical region in 7q36 between D7S292 and D7S392.

Familial holoprosencephaly associated with a translocation breakpoint at chromosomal position 7q36.

A familial balanced t(7;9) (q36;q34) was reported recently. Analysis of the craniofacial features of 3 of the sibs showed signs of holoprosencephaly. Two of the sibs have an unbalanced derivative chromosome leading to del(7) (q36) and dup(9) (q34), while the other has a cytogenetically balanced translocation. These findings, together with several reports associating holoprosencephaly with terminal 7q deletions, indicate that a putative locus for holoprosencephaly resides at or near 7q36. It should now be feasible to clone this locus.

Ultrasound detection of fetal aneuploidy in patients with elevated maternal serum alpha-fetoprotein.

Increasing confidence in the ability of high-resolution ultrasound to detect neural tube and ventral wall defects has enabled us to offer a revised risk estimate to the patient with an elevated maternal serum alpha-fetoprotein (MSAFP) level, such that amniocentesis may not be necessary. Recent authors have suggested that a reduced emphasis on follow-up amniocentesis fails to consider an increased risk for chromosomal anomalies in pregnancies with an elevated MSAFP, and that amniocentesis should still be performed. We reviewed our ultrasound findings from patients who underwent amniocentesis for evaluation of an elevated MSAFP and who had a karyotype prepared from the amniotic fluid sample. Four abnormal karyotypes were detected among 313 amniocenteses, and three of these were correctly predicted based on an abnormal ultrasound. The risk of an unexpected fetal aneuploidy after a normal consultative ultrasound in our series was one in 310. This is comparable to the risk of detecting abnormal chromosomes in the fetus of a 32-year-old woman, an age at which amniocentesis is not routinely offered.