Optimal implementation of morphological operations on neighborhood-connected parallel computers

To efficiently perform morphological operations on neighborhood-processing-based parallel image computers, we need to decompose structuring elements larger than the neighborhood that can be directly handled into neighborhood subsets. In the special case that the structuring element is a convex polygon, there are known decomposition algorithms in the literature. In this paper, we give an algorithm for the optimal decomposition of arbitrarily shaped structuring elements, enabling an optimal implementation of morphological operations on neighborhood-connected parallel computers in the general case.     

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.     

Inhibition of microtubule assembly in tumor cells by 3-bromoacetylamino benzoylurea, a new cancericidal compound

We have synthesized a new compound, 3-bromoacetylamino benzoylurea (3-BAABU), which showed strong cancericidal activity by inducing irreversible mitotic arrest and subsequently apoptosis in human T cell leukemic cells (CEM), human biphenotypic leukemic cells (SP), a human prostate cancer cell line (PC-3), murine melanoma cells (B-16), and murine lymphoma/leukemia cells (EL4) in vitro with an ID50 in the range of 0.013-0.07 microg/ml (0.04-0.22 microM). Treatment of tumor cells for 12-24 h with 3-BAABU resulted in mitotic arrest at prometaphase/metaphase/anaphase, with separation and dispersion of chromosomes and with the absence of mitotic spindle apparatus in cytoplasm. Treatment with 3-BAABU had no cytotoxic and mitotic blocking effect in normal human lymphocytes, proliferating fibroblast cells (3T3), or proliferating myocardial cells (MOT). Cell cycle analyses showed that most treated leukemic cells accumulated at M phase 12 h after treatment. By the end of 48 h of treatment, the cells underwent apoptosis with DNA fragmentation. 3-BAABU inhibited the assembly of microtubules from tubulin but did not interfere with the disassembly of microtubules. The presence and the position of bromine and urea groups on the benzoic ring are the determining factors for its inhibition of microtubule assembly. Replacing bromine with chlorine yielded much less mitotic blocking activity and increased the ID50 40-fold. Substitution of the urea group with ethyl ester abrogated the activity of blocking mitosis but induced apoptosis. Moving the bromoacetylamino group from the 3-position to the 4-position removed blocking activity for mitosis but induced necrosis. These results suggest that 3-BAABU possesses a unique and functional structure and is a potential agent for cancer chemotherapy.     

Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice

Many lines of evidence have suggested that angiotensin II (AngII) plays an important role in the development of cardiac hypertrophy through AngII type 1 receptor (AT1). To determine whether AngII is indispensable for the development of mechanical stress-induced cardiac hypertrophy, we examined the activity of mitogen-activated protein kinase (MAPK) family and the expression of the c-fos gene as hypertrophic responses after stretching cultured cardiac myocytes of AT1a knockout (KO) mice. When cardiac myocytes were stretched by 20% for 10 min, extracellular signal-regulated protein kinases (ERKs) were strongly activated in KO cardiomyocytes as well as wild type (WT) myocytes. Both basal and stimulated levels of ERKs were higher in cardiomyocytes of KO mice than in those of WT mice. Activation of another member of the MAPK family, p38(MAPK), and expression of the c-fos gene were also induced by stretching cardiac myocytes of both types of mice. An AT1 antagonist attenuated stretch-induced activation of ERKs in WT cardiomyocytes but not in KO cardiomyocytes. Down-regulation of protein kinase C inhibited stretch-induced ERK activation in WT cardiomyocytes, whereas a broad spectrum tyrosine kinase inhibitor (genistein) and selective inhibitors of epidermal growth factor receptor (tyrphostin, AG1478, and B42) suppressed stretch-induced activation of ERKs in KO cardiac myocytes. Epidermal growth factor receptor was phosphorylated at tyrosine residues by stretching cardiac myocytes of KO mice. These results suggest that mechanical stretch could evoke hypertrophic responses in cardiac myocytes that lack the AT1 signaling pathway possibly through tyrosine kinase activation.     

Reduction by cefodizime of the pulmonary inflammatory response induced by heat-killed Streptococcus pneumoniae in mice

It has recently become apparent that overwhelming inflammatory reactions contribute to the high mortality rate associated with pneumococcal infection in immunocompetent hosts. Cefodizime (CEF) is an antibiotic that seems to be endowed with immunomodulating properties. To investigate the influence of CEF on the pulmonary inflammatory response induced by Streptococcus pneumoniae, we infected mice with repeated intranasal inoculations of 10(7) CFU of heat-killed fluorescein isothiocyanate-labeled bacteria, which are insensitive to the killing properties of the drug. CEF downregulated but did not abolish the strong polymorphonuclear leukocyte (PMN) recruitment induced by S. pneumoniae. PMN recruitment was not primarily mediated by leukotriene B4 in this model. The drug did not interfere with intrinsic mechanisms of phagocytosis by PMNs and alveolar macrophages. CEF totally abrogated the pneumococcus-induced tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) secretion in bronchoalveolar lavage fluid. The drug also prevented IL-6 release in lung homogenates and partly inhibited TNF-alpha, but it did not interfere with IL-1alpha secretion in the lungs of infected mice. The fractional and selective downregulation of inflammatory cells and cytokines by CEF suggests cell-specific and intracellular specific mechanisms of interaction of the drug. The immunomodulatory properties of CEF may help restrain excessive inflammatory reactions, thus contributing to the reported good clinical efficacy of the drug against lower respiratory tract infections.     

The elimination of hepatitis B virus infection: changing seroepidemiology of hepatitis A and B virus infection in Okinawa, Japan over a 26-year period

Serial changes in hepatitis A virus (HAV) and B virus (HBV) markers were determined from 1970 to 1996 in healthy Japanese residents of a rural area of Okinawa, Japan. All 190 serum samples taken in 1970, 791 in 1980, 708 in 1988, and 523 in 1996 from residents 0 to more than 60 years of age were tested for antibody to HAV (anti-HAV), antibody to hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg). The age-adjusted prevalences of anti-HAV and anti-HBc decreased significantly from 83.9% and 74.9%, respectively, in 1970 to 39.7% and 36.6%, respectively, in 1996. In residents < or = 29 years of age, the prevalences of anti-HAV and anti-HBc decreased significantly from 65.3% and 83.8%, respectively, in 1970 to 0.7% and 8.2%, respectively, in 1996. The age-adjusted HBsAg prevalence decreased significantly from 8.2% in 1980 to 4.1% in 1988. These results indicate that exposure to HAV and HBV infections among Okinawa residents less than 29 years of age is decreasing, probably because of improvements in socioeconomic conditions since 1970. Infection with HBV may be eliminated there in the near future.     

Myositis caused by hydroxyurea in a patient with chronic myelogenous leukemia

A 59-year-old man with chronic myelogenous leukemia (CML) had a white-blood-cell (WBC) count of 55,400/microliter when admitted in July 1997, and was placed on oral hydroxyurea (HU) of 1,500 mg/day. Treatment with 600 MU/day of interferon alpha (IFN alpha) was started on August 5. HU was discontinued when the patient's WBC count dropped to 8,100/microliter on August 18. However, HU was resumed about a month later, after his WBC count increased to 10,100/microliter, but discontinued when the patient started to complain of chills, high fever, and bilateral femoral pain. HU treatment was initiated again one week later, after the patient's WBC count had begun rising but ceased again after he experienced chills, high fever, and bilateral femoral pain. The patient's myogenetic enzymes were found to be increasing the following day, and a lymphocyte stimulation test (LST) with HU showed a high stimulation index of 41.7%. The elevation of myogenetic enzymes and the results of the LST suggested that myositis due to HU was the cause of the patient's clinical manifestations. His myositis spontaneously disappeared after HU was discontinued. Although the patient is no longer receiving HU, IFN alpha has brought his CML under control. To our knowledge, this is the first reported case of myositis caused by HU.     

Inhibition of angiotensin-converting enzyme increases the nitric oxide levels in canine ischemic myocardium

Since angiotensin-converting enzyme (ACE) produces angiotensin II in the heart, ACE inhibitors may prevent coronary vasoconstriction and increase coronary blood flow. On the other hand, since ACE inhibitors also inhibit kininase II which results in reduced degradation of bradykinin, ACE inhibitors may increase cardiac nitric oxide (NO) levels via stimulation of bradykinin receptors. This study was undertaken to test whether ACE inhibitors increase the cardiac NO levels and coronary blood flow in the ischemic myocardium. In 34 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When either imidaprilat or cilazaprilat of 3 microg/kg/min was infused into the bypass tube for 10 min after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 31 +/- 1 to either 45 +/- 5 or 43 +/- 4 ml/100 g/min despite no changes in coronary perfusion pressure (43 +/- 2 mmHg). During an infusion of either imidaprilat or cilazaprilat, bradykinin and the end-products of NO (nitrate + nitrite) concentrations of coronary venous blood were markedly increased, which were attenuated by either HOE-140 (an inhibitor of bradykinin receptors) or by N(omega)-nitro-L-arginine methyl ester (an inhibitor of NO synthase). We also observed increases in cardiac bradykinin and NO levels due to either imidaprilat or cilazaprilat in the low constant coronary blood flow condition. It is concluded that ACE inhibitors can increase cardiac NO levels via the accumulation of bradykinin in the ischemic myocardium.     

The DEAH-box splicing factor Prp16 unwinds RNA duplexes in vitro

BACKGROUND: During pre-mRNA splicing, dynamic rearrangement of RNA secondary structure within the spliceosome is crucial for intron recognition and formation of the catalytic core. Splicing factors belonging to the DExD/DExH-box family of RNA-dependent ATPases are thought to have a central role in directing these rearrangements by unwinding RNA helices. Proof of this hypothesis has, however, been conspicuously lacking. RESULTS: Prp16 is a DEAH-box protein that functions in the second step of splicing in vitro. Using various RNA duplexes as substrate, we have shown that Prp16 has an ATP-dependent RNA unwinding activity. This activity is independent of sequence in either the single-stranded or duplexed regions of the RNA substrate. A mutation (prp16-1) near the ATP-binding motif of Prp16 inhibits both the RNA-dependent ATPase activity and the ATP-dependent RNA unwinding activity. CONCLUSIONS: Our findings provide strong biochemical evidence that Prp16 can disrupt a duplexed RNA structure on the spliceosome. Because the purified protein lacks sequence specificity in unwinding RNA duplexes, targeting of the unwinding activity of Prp16 in the spliceosome is likely to be determined by other interacting protein factors. The demonstration of unwinding activity will also help our understanding of how the fidelity of branchpoint recognition is controlled by Prp16.