Increased thrombin inhibition in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS). Activated coagulation factors are associated with inflammation and are elevated in the plasma of animals with EAE. Thrombin is a key coagulation factor and its major endogenous inhibitors are antithrombin III (ATIII) in the plasma and protease nexin 1 (PN-1) in the brain. We measured the capacity of brain homogenates to inhibit exogenous thrombin and the CNS levels of ATIII and PN-1 during the course of EAE. Acute EAE was induced in SJL/J mice by immunization with mouse spinal cord homogenates. On Days 8, 13, and 22 post-immunization, inhibition of exogenous thrombin activity was measured by a recently developed fluorimetric assay. PN-1 and ATIII were assayed both by immunohistochemistry and by immunoblots in the brain and spinal cord. Total brain thrombin inhibitory activity increased (32%) in EAE mice at the peak of clinical disease (Day 13, P=0.04 compared to controls). Brain ATIII also increased at the peak of disease (2.5-fold higher than controls, P=0.0001), and correlated significantly with clinical scores at all stages of disease (r=0.72, P=0.0068). In contrast, PN-1 elevations were more pronounced at the preclinical stage on Day 8 (3-fold higher than controls, P=0.01) than on Day 13 (1.4-fold higher, P=0.005). Increased brain thrombin inhibition at the clinical peak of EAE probably reflects increased influx of plasma thrombin inhibitors. Early PN-1 changes represent a potential target for thrombin modulating drugs in EAE and MS.     

Advance preparation and stimulus-induced interference in cued task switching: further insights from BOLD fMRI

To switch from one cognitive task to another is thought to rely on additional control effort being indicated by performance costs relative to repeating the same task. This switch cost can be reduced by advance task preparation. In the present experiment the nature of advance preparation was investigated by comparing a situation where an explicit task cue was presented 2000 ms in advance of the target stimulus (CTI-2000) with a situation where cue and target were presented in close succession (CTI-100). We mapped the blood-oxygenation-level-dependent (BOLD) activation correlates of switch-related control effort and advance task preparation to test alternative explanations why advance preparation is reducing switch costs. A previously reported control-related cortical network of frontal and parietal brain areas emerged that was more strongly activated for switching between tasks. However, this was true exclusively for CTI-100 where no advance task preparation was possible. At CTI-2000 these same brain areas were equally engaged in both switch and repeat trials. For some of these areas, this common activation was time-locked to the presentation of both the cue as well as the target. Other areas were exclusively associated with target processing. The overall pattern of results suggests that advance task preparation is a common process of pre-activating (cue-locked activation) the currently relevant task set which does not face interference from a persisting N - 1 task set. During target processing the same brain areas are re-engaged (subsequent target-locked activation) to apply the pre-activated task set. Though being common to repeat and switch trials, advance preparation has a differential benefit for switch trials. This is because the instructed task set has time to settle into a stable state, thus becoming resistant against disruption from the previous task set, which is retrieved by the current target stimulus.     

The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa

Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664-1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals, no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit.     

Correlation and overlapping between nuchal translucency and triple test among Down syndrome-affected pregnancies

OBJECTIVES: To examine the correlation and extent of overlapping between first-trimester nuchal translucency (NT) and second-trimester triple test (TT) results in Down syndrome (DS)-affected pregnancies. METHODS: Results of both tests were obtained in 28 cases with DS. Inter-test correlation was performed by comparing the likelihood ratios (LRs). Screen-positive rates (risk >1:380) were calculated for different age groups by adjusting age-dependent background risk and tests' LRs. Overlapping referred to ratio between screen-positive cases by both tests simultaneously and total screen-positive cases by either one or both tests. RESULTS: No correlation was found between the tests' LRs (Pearson correlation test, r = 0.0487). The overlapping between the tests was 25% and 38.5% among young patients of 20 and 35 years of age, respectively. The average overlapping among patients between 25 and 35 years of age was approximately 33%. Only 3 of the 28 DS cases demonstrated LRs <1 by both tests and moreover none exhibited LRs <0.2 by both tests. CONCLUSIONS: The degree of overlapping of one third, between NT and TT, confirms the assumption that both tests utilized together improves DS detection. Screen- negative result, by both tests simultaneously, may reassure low-risk population and aid to reduce the number of non-indicated invasive tests.     

Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid

We report a case of Dubin-Johnson Syndrome in a neonate presenting with severe direct hyperbilirubinemia, which failed to respond to phenobarbital treatment. Ursodeoxycholic Acid added to therapy was well tolerated, and resulted in declining bilirubin concentration. We suggest ursodeoxycholic acid in treatment for Dubin-Johnson Syndrome with severe direct hyperbilirubinemia presenting in the neonatal age.     

Cardiovascular nursing in Israel

Cardiovascular (CV) nursing as an entity in Israel dates back to 1952, when the nurses in Tel-Hashomer hospital took care of postoperative heart surgery patients. The first intensive cardiac care units (ICCUs) were established in 1971. In 1982, the first ICCU course was established in Tel-Hashomer hospital nursing school. Today, most of the nursing staff in Israels ICCUs are graduates of ICCU courses. The nurses professional society, the Society for Nursing of Israel, was established in 1947. In 1989 the Society for Advancement of Cardiac Nursing in Israel (SACN) was established. The main goals of the society were: the exchange of CV nursing knowledge, CV nursing research, CV nursing education in nursing schools, education of nurses in other departments in the care of the cardiac patient, and CV nursing education in the community. The CV nurse takes a large role in the total care of the cardiac patient, which includes rehabilitation within the hospital and in the ambulatory setting and coordination of nursing in national and international multicenter clinical trials. In collaboration with the Ministry of Health Nursing Division, Israeli CV nurses participate in national and international projects to: develop and upgrade nursing education; train new CV nurses; develop, review, and revise nursing protocols and guidelines; and establish new, more advanced ICCUs in underdeveloped areas within Israel and around the world. Our vision for the future development of CV nursing in Israel includes coordination and management roles in the hospital setting, and the establishment and management of home-care programs.     

Effect of second-formant transitions on the perception of Hebrew voiced stop consonants

Studies in English, Dutch, Danish and French show that of the possible acoustic cues that listeners use for the perception of place of articulation, the transition of the second formant (F2) appears to be a very important cue. Although the Hebrew language shares some similarities with the above languages, one cannot assume that it either has similar acoustic-articulatory patterns or uses the same cues for perception. The general goal of the present study was, therefore, to investigate the effect of the starting frequency of F2 transition on the perception of place of articulation of Hebrew voiced plosives in initial position. Sixteen Hebrew-speaking young normal-hearing adults served as subjects. Stimuli were generated by re-synthesizing a naturally spoken /ba/ syllable into 17 test syllables by varying only the starting frequency of F2. Listeners heard each stimulus six times (total of 102) at random and were required to label the stimuli as /ba/, /da/ or /ga/. Results showed that varying only F2 transitions caused a perceptual change of place of articulation for all listeners. There was, however, large inter-subject variability in the perceived category: 75% of the subjects identified /ba/ and /da/, half of them also identified /ga/, and 25% of the subjects were able to identify /ba/ and /ga/ only. These data suggest that while F2 transitions are important for perceiving place of articulation of Hebrew voiced stops, they cannot predict the perceived category. It also supports the notion that normal-hearing listeners differ in the relative importance they assign to the cues for the perception of place of articulation.     

Progression of mouse mammary tumors: MCP-1-TNFalpha cross-regulatory pathway and clonal expression of promalignancy and antimalignancy factors

The progression of breast cancer is affected by multiple cellular and microenvironmental components. The monocyte chemoattractant MCP-1, IL-6 and matrix metalloproteinases (MMP) were suggested to promote, each on its own, breast cancer progression. We recently demonstrated that the high-tumorigenicity phenotype of the DA3 and CSML murine mammary adenocarcinoma cells is correlated with a high expression of MCP-1, IL-6 and MMP. This raised the possibility that common intrinsic tumor-derived factors regulate the concordant expression of these 3 components. The aim of the present study was to gain insight into the mode by which the secretion of MCP-1, IL-6 and MMP from murine mammary adenocarcinoma cells is regulated. This was investigated in cellular clones established from a highly malignant variant of the DA3 tumor (DA3-high). We also determined the secretion of the antimalignancy chemokine IP-10 from these cells. The results indicate that the secretion levels of IL-6, MMP and IP-10 varied between the clones. In contrast, all the clones secreted uniformly high levels of MCP-1, suggesting that MCP-1 constitutes an important feature of the malignancy phenotype of mammary carcinoma. In most of the clones, elevated levels of 1 of the 3 promalignancy factors did not correlate with a high expression of the other 2 factors and vice versa. These findings indicate that the 3 promalignancy factors are not coregulated by a common intrinsic tumor-derived factor. Rather, these results suggest that the individual capacities of the different clones to secrete these factors are summed up in the high-malignancy DA3 parental tumor population, which secretes relatively high levels of MCP-1, IL-6 and MMP as compared to DA3 cells expressing a low-malignancy phenotype. In contrast to the lack of coordinated intrinsic regulation of MCP-1, IL-6 and MMP, it was found that recombinant TNFalpha, a product of tumor-associated macrophages contributing to breast cancer progression, upregulated the secretion of MCP-1, IL-6 and MMP from all the clones. These results suggest a key role for this microenvironmental, monocyte-derived cytokine in the coordinated regulation of these 3 molecules. Furthermore, additional results demonstrated that monocytic cell-derived TNFalpha upregulated MCP-1 secretion from the tumor cells and that MCP-1 in turn promoted the secretion of TNFalpha from monocytic cells. This may result in a positive feedback loop, whereby the tumor cells and the monocytic cells at tumor site promote each other's ability to express and secrete promalignancy factors. We next attempted to assess the contribution of the promalignancy factors MCP-1, IL-6 and MMP and of the antimalignancy factor IP-10 to mammary adenocarcinoma progression. To this end, a preliminary formula was developed in which the net balance between secretion levels of the promalignancy factors and that of the antimalignancy IP-10 chemokine from different clones was related to their in vivo tumorigenicity profile. This formula suggests that a balance between the secretion levels of these factors plays an important role in determining the malignancy phenotype of mammary carcinomas. In all, our findings demonstrate that the mammary tumor cell population is composed of a heterogeneous assortment of clones whose individual characteristics are averaged in the whole population. The malignancy potential of such tumors is thus determined, inter alia, by a combinatorial effect of several promalignancy and antimalignancy factors secreted from each of the clones comprising these tumors. Our results also suggest that the expression of such factors is determined by several nonmutually exclusive regulatory mechanisms.     

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells

Northern blotting confirmed previous results indicating that the mitogen-activated protein kinase (MAPK) phosphatase Pyst2-L was highly expressed in leukocytes obtained from acute myeloid leukemia (AML) patients. High levels of Pyst2-L mRNA were expressed in bone marrow (BM) and peripheral leukocytes from nine AML and acute lymphoblastic leukemia (ALL) patients. BM from healthy individuals expressed very low levels of Pyst2-L. Whereas high levels of Pyst2-L mRNA and protein were detected in several leukemia cell lines, Pyst2-L mRNA was detected neither in 33/34 samples of normal peripheral blood mononuclear cells (PBMC) nor in leukocyte fractions enriched with CD34+ cells. Certain solid tumor and lymphoblastoid cell lines expressed high levels of Pyst2-L mRNA. In view of the association of Pyst2-L to MAPK signaling cascades, we tested if cell activation, a process involving MAPK signaling, influences Pyst2-L expression. Indeed, activation of T cells and endothelial cells increased Pyst2-L in these cells. Furthermore, TPA, a known MAPK activator, induces the expression of both Pyst2-L mRNA as well as the Pyst2-L protein in leukemia cells. This induction was partially inhibited by PD098059, an Mek1/2-specific inhibitor. Based on the results of this and previous studies, we hypothesize that the high levels of Pyst2-L detected in the active state of AML and ALL diseases and in other types of cancer reflect an altered MAPK signaling pathway in such malignant processes. This alteration may be the result of a failed attempt to counter the constitutive activation of MAPK in transformed cells or alternatively, may represent the activated state of such cells.