Ammonia tolerance of the bivalve Mulinia lateralis sublethal sediment toxicity test.
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Ammonia↗
Biomedical subjects
M Huber
Publications and source records attributed to M Huber.
Prevention of supraventricular tachyarrhythmias after open heart operation by low-dose sotalol: a prospective, double-blind, randomized, placebo-controlled study.
BACKGROUND: The aim of this prospective, double-blind, placebo-controlled trial was to assess the preventive effect and safety of low-dose sotalol after heart operation. METHODS: Two hundred fifty-five consecutive patients referred for elective coronary artery bypass grafting (n = 220) or aortic valve operation (n = 35) were randomized to receive either 80 mg of sotalol twice daily (n = 126) or matching placebo (n = 129) for 3 months, with the first dose given 2 hours before operation. RESULTS: There were no significant baseline differences between the groups. Overall, supraventricular tachyarrhythmias occurred in 36% of patients (82% atrial fibrillation). Hospital stay was 11.6 +/- 5 days in patients with supraventricular arrhythmias, versus 9.5 +/- 2.4 days in patients without it (p < 0.0001). Low-dose sotalol reduced the rate of supraventricular arrhythmias from 46% (placebo) to 26% (sotalol; p = 0.0012), or by 43%. On the fourth postoperative day, heart rate was lower in the sotalol group (74 +/- 12 beats/min versus 85 +/- 15 beats/min; p < 0.0001) but the QT interval corrected for the heart rate was not prolonged (sotalol group, 0.44 +/- 0.03 second; placebo group, 0.43 +/- 0.03 second; p = not significant). Study medication had to be discontinued because of side effects in 5.6% of sotalol and 3.9% of placebo patients (p = not significant), with one possible proarrhythmic event occurring in a patient receiving sotalol. CONCLUSIONS: Because more than 90% of supraventricular arrhythmic episodes occurred within 9 days after operation and 70% of all possibly sotalol related side effects occurred after day 9, the findings in this study imply that prophylactic treatment with sotalol may be limited to the first 9 postoperative days.
Aged↗
Chinese hamster ovary cells are non-permissive towards infection with coxsackievirus B3 despite functional virus-receptor interactions.
Viral infection is a complex process which includes binding and interaction of the virus with specific cell surface receptors, uptake and uncoating of the virus, and finally replication. Chinese hamster ovary (CHO) cells are non-permissive towards infection with coxsackieviruses of group B (CVB), although they do express a putative CVB-specific receptor protein. In order to localize the block of infection in CHO cells, these cells were tested for binding of radiolabelled CVB3, receptor-mediated transformation of virions into A-particles, and replication of the viral genome. Binding of CVB3 to CHO cells was found to be comparable to the binding of this virus to permissive cell lines. Detergent-solubilized membrane proteins of CHO cells were tested in virus overlay protein-binding assays (VOPBAs) and shown to express a 100 kDa CVB-binding membrane protein similar to the CVB receptor protein which we recently described for permissive HeLa cells. Incubation of CVB3 with intact CHO cells resulted in transformation of cell-bound virions into non-infectious A-particles (deprived of capsid protein VP4), demonstrating the functional activity of the CVB receptor protein on CHO hamster cells. Transfection of recombinant CVB3 cDNA or viral RNA into CHO cells resulted in the production of infectious CVB3 virions, implying that the failure of CVB to infect CHO cells is not caused by a defect in virus replication but results from a block in the uptake of virus particles into the cell after the initial steps of virus-receptor interactions.
Animals↗
[Determination of cartilage thickness in the ankle joint. an MRT (1.5)-anatomical comparative study].
PURPOSE: The aim of this study was to evaluate the accuracy of MRI in the measurement of cartilage thickness of the ankle joint in comparison to pathologic and histologic specimens. PATIENTS AND METHODS: The ankle joints of four fresh cadaver feet were imaged on a 1.5T MR-unit in the coronal plane. Standard T1-weighted spin echo (SE) and a T1-weighted 3D-GE (FLASH-3D) sequence with fat saturation were applied. Following MR imaging, the talus was explanted and cut parallel to the MR images for macroscopic evaluation and histologic specimens were prepared. MRI measurements of the cartilage thickness of the talus were carried out in two ways: without and with consideration of a transition zone of intermediate signal intensity between hyperintense cartilage and hypointense cortical bone. The data were compared with the anatomic specimens as the gold standard expressing the difference as a percentage value. On histologic specimens thickness of deep calcified cartilage layer was measured. RESULTS: Measurements without the transition zone showed a mean underestimation of talus cartilage thickness of 46.8% (41.3-52.1) for T1-SE and 47.5% (43.1-52.1) for fat saturated FLASH-3D images. Considering the transition zone the mean values were 25.0% (23.1-26.2) and 14.1% (6.7-21.5). The histologic specimens showed a three-fold increase of thickness of deep calcified cartilage layer. CONCLUSIONS: Measurements of the cartilage layer of the ankle joint on MR images are only accurate if the transition zone (calcified cartilage layer) is considered and the optimal pulse sequence (FLASH-3D-fat-sat) is applied.
Aged↗
Massive and persistent anterograde amnesia in the absence of detectable brain damage: anterograde psychogenic amnesia or gross reduction in sustained effort?
The case of a young patient with severe and persistent anterograde amnesia of no known cause is reported. Anterograde amnesia arose within a 1-month period and has persisted for more than 1 year. Although a wide variety of neurological and neuroradiological assessments were completed (EEG, evoked potential recordings, Doppler sonography, MRI, PET), no evidence of brain damage was detected. Neuropsychologically, the patient was of high intelligence, had average to above-average short-term memory, and normal retrograde memory abilities, but severe and persistent anterograde amnesia in both verbal and nonverbal domains. Furthermore, he demonstrated grossly reduced long-term concentration. It is likely that a complex chain of interacting variables can produce a syndrome that appears phenomenologically as anterograde amnesia without organically measurable correlates.
Adult↗
Performance of elderly White and African American community residents on the abbreviated CERAD Boston Naming Test.
Differences in the responses of an elderly biracial group of cognitively normal subjects to a 15-item short version of the Boston Naming Test developed for the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) were examined. The subjects consisted of 103 Whites and 136 African Americans who were 70 years of age and older and living in a five-county urban and rural area of North Carolina. They were drawn from the Duke University site of the Established Populations for Epidemiologic Studies of the Elderly (EPESE). All were cognitively normal. With gender, years of education, and age controlled, White subjects performed significantly better than did African American subjects. The items in this test were selected to represent words with a high, medium, and low frequency of occurrence in English. They did not, however, show the expected gradation for either racial group. Medium and low frequency items were of comparable difficulty for the two races. Hierarchical ordering of difficulty would be improved with minor rearrangement of items.
Aged↗
Mineral oil material in canned foods.
Mineral oil material was determined in canned foods by on-line LC-LC-GC-FID. In the edible oil phase of 90 samples of sea foods, concentrations were mostly around 100 mg/kg, but reached 820 mg/kg. The predominant source of this mineral oil material was lubricating oil used for can manufacturing. Mineral oil contamination of the fish was usually a minor source, but cannot be neglected.
Chromatography, Gel↗
A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma.
Annular epidermolytic ichthyosis has recently been delineated as a distinct clinical phenotype within the spectrum of epidermolytic keratinization disorders. The pattern of inheritance of the disorder is consistent with an autosomal dominant mode of transmission. Here we report a second incidence of this disorder in a family with two affected generations. The proband suffered from bullous ichthyosis and had bouts of disease activity associated with the development of numerous annular and polycyclic erythematous, hyperkeratotic plaques on the trunk and the proximal extremities. Histologic examination showed the typical pathology of epidermolytic hyperkeratosis, and ultrastructural analysis revealed abnormal keratin filament networks and tonofilament clumping with a perinuclear distribution. Molecular analysis revealed a novel tandem CG to GA 2-bp mutation in the same allele of keratin 10 in affected individuals, resulting in an arginine to glutamate substitution at residue 83 (R83E) of the 2B helical segment. We conclude that annular epidermolytic ichthyosis should be considered a variant of bullous congenital ichthyosiform erythroderma.
Adult↗
Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex.
Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias in which the main phenotypic characteristic is hypertrophic nail dystrophy. In the Jackson-Lawler form (PC-2), pachyonychia is accompanied by multiple pilosebaceous cysts, natal teeth, and hair abnormalities. By direct sequencing of genomic PCR products, we report heterozygous K17 missense mutations in the same conserved protein motif in a further five PC-2 families (K17 N92S in one familial and three sporadic cases; K17 Y98D in one familial case) confirming that mutations in this gene are a common cause of PC-2. We also show heterozygous missense mutations in K17 (N92H and R94H) in two families diagnosed as steatocystoma multiplex. Mild nail defects were observed in some but not all of these patients on clinical re-evaluation of these families. All the K17 mutations reported here were shown to co-segregate with the disease in the pedigrees analyzed and were excluded from 100 unaffected, unrelated chromosomes by restriction enzyme analysis of K17 genomic PCR products. We conclude that phenotypic variation is observed with K17 mutations, as is the case with other keratin disorders.
Cysts↗
Tyrosine phosphorylation events during coxsackievirus B3 replication.
In order to study cellular and viral determinants of pathogenicity, interactions between coxsackievirus B3 (CVB3) replication and cellular protein tyrosine phosphorylation were investigated. During CVB3 infection of HeLa cells, distinct proteins become phosphorylated on tyrosine residues, as detected by the use of antiphosphotyrosine Western blotting. Two proteins of 48 and 200 kDa showed enhanced tyrosine phosphorylation 4 to 5 h postinfection (p.i.), although virus-induced inhibition of cellular protein synthesis had already occurred 3 to 4 h p.i. Subcellular fractionation experiments revealed distinct localization of tyrosine-phosphorylated proteins of 48 and 200 kDa in the cytosol and membrane fractions of infected cells, respectively. In addition, in Vero cells infected with CVB3, echovirus (EV)11, or EV12, increased tyrosine phosphorylation of a 200-kDa protein was detected 6 h p.i. Herbimycin A, a specific inhibitor of Src-like protein tyrosine kinases, was shown to inhibit virus-induced tyrosine phosphorylations and to reduce the production of progeny virions. In contrast, in cells treated with the inhibitors staurosporine and calphostin C, the synthesis of progeny virions was not affected. Immunoprecipitation experiments suggested that the tyrosine-phosphorylated 200-kDa protein in CVB3-infected cells is of cellular origin. In summary, these investigations have begun to unravel the effect of CVB3 as well as EV11 and EV12 replication on cellular tyrosine phosphorylation and support the importance of tyrosine phosphorylation events for effective virus replication. Such cellular phosphorylation events triggered in the course of enterovirus infection may enhance virus replication.
Animals↗
Phase I clinical and pharmacological study of liposome-entrapped NDDP administered intrapleurally in patients with malignant pleural effusions.
cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (NDDP) is a lipophilic non-cross-resistant platinum compound formulated in large multilamellar liposomes (1-3 micrometer). The maximum tolerated dose (MTD) of liposomal-entrapped NDDP (L-NDDP) administered i.v. in humans is 300 mg/m2, and myelosuppresion is the dose-limiting toxicity. L-NDDP administered i.p. is absorbed slowly from the peritoneal cavity of rats. Recently, i.p. cisplatin has been shown to be superior to i.v. cisplatin in improving the survival of patients with ovarian carcinoma and minimal residual disease. We conducted a Phase I study to determine the MTD, side effects, kinetics of absorption into the systemic circulation, and preliminary antitumor activity of L-NDDP administered intrapleurally in patients with free-flowing malignant pleural effusions. Twenty-one patients were treated with escalating doses of L-NDDP by intrapleural administration over 30 min every 21 days. Fourteen patients had adenocarcinoma of the lung, 5 patients had malignant pleural mesothelioma (MPM), and 2 patients had ovarian carcinoma. The dose-limiting toxicity of L-NDDP was chest pain secondary to chemical pleuritis, which was severe in three of four patients treated at 550 mg/m2. The MTD was 450 mg/m2. At this dose, the only toxicity observed was grade 1-2 nausea and vomiting presenting 6-8 h after drug administration. Neither myelosuppression nor nephrotoxicity was observed. Loculation of residual pleural fluid with continued decrease over a period of weeks to months was observed in seven patients; in one of these patients (MPM), the pleural effusion disappeared without evidence of recurrence for 19 + months, and in six patients (three adenocarcinoma of the lung, two MPM, and one ovarian carcinoma), the pleural effusion was reduced by >50% for 5+, 10+, 18+, 8, 5+, and 2+ months. Plasma pharmacokinetic studies showed that the absorption of L-NDDP from the pleural cavity was rapid during the first 2 h, with levels becoming steady (bioavailable or free platinum) or increasing slowly (total plasma platinum) between 6 and 24 h after administration. Urinary excretion was negligible (1-3%). We conclude that: (a) the MTD of intrapleural L-NDDP is 50% higher than the MTD after i.v. administration; (b) intrapleural L-NDDP causes mild nausea and vomiting and no myelosuppression at the MTD; and (c) the absorption of L-NDDP into the systemic circulation is much slower than that of the parent compound cisplatin. Because of the favorable depot effect, lack of systemic toxicity, and control of the pleural effusion in three of five patients with MPM, a disease similar to ovarian carcinoma in that it tends to remain confined to a body cavity, a Phase II study of intrapleural L-NDDP administered in patients with MPM is in progress.
Adenocarcinoma↗
Production of a novel polyketide through the construction of a hybrid polyketide synthase.
The lactone rings of the polyketides platenolide and tylactone are synthesized by condensation of acetate-, proprionate-, and butyrate-derived precursors. A hybrid tylactone/platenolide synthase was constructed to determine if the choice of substrate is programmed by the polyketide synthase and to ascertain if a substrate different than that normally used in the first step of platenolide synthesis could be incorporated into the final polyketide. In this work, we report the successful incorporation of a propionate in place of the acetate normally used in the first step of platenolide synthesis. This result demonstrates that polyketide synthases choose a particular substrate at defined steps and provides strong evidence that substrate choice is programmed by the acyl transferase domain of a large, multifunctional polyketide synthase.
Acyl Coenzyme A↗
2,2'-Dithiobis(N-ethyl-spermine-5-carboxamide) is a high affinity, membrane-impermeant antagonist of the mammalian polyamine transport system.
We have synthesized 2,2'-dithiobis(N-ethyl-spermine-5-carboxamide) (DESC), its thiol monomer (MESC), and the mixed MESC-cysteamine disulfide (DEASC) as potential inhibitors of polyamine transport in mammalian cells. DESC was the most potent antagonist of spermine transport in ZR-75-1 human breast cancer cells, with Ki values of 5. 0 +/- 0.7, 80 +/- 31, and 16 +/- 3 microM for DESC, MESC, and DEASC, respectively. DESC also strongly blocked putrescine and spermidine uptake in ZR-75-1 cells (Ki = 1.6 +/- 0.5 and 2.7 +/- 1.1 microM, respectively). While DESC and MESC were purely competitive inhibitors of putrescine transport, DEASC was a mixed competitive/noncompetitive antagonist. Remarkably, DESC was virtually impermeant in ZR-75-1 cells despite its low Ki toward polyamine transport. The marked difference in affinity between DESC and MESC was essentially due to the tail-to-tail juxtaposition of two spermine-like structures, suggesting that dimeric ligands of the polyamine transporter might simultaneously interact with more than one binding site. While DESC strongly decreased the initial rate of [3H]spermidine transport, even a 40-fold molar excess of antagonist could not completely abolish intracellular spermidine accumulation. Moreover, as little as 0.3 microM spermidine fully restored growth in ZR-75-1 cells treated with an inhibitor of polyamine biosynthesis in the presence of 50 microM DESC, thus emphasizing the importance of uptake of trace amounts of exogenous polyamines. Thus, reducing the exogenous supply of polyamines with a potent competitive inhibitor may be kinetically inadequate to block replenishment of the polyamine pool in polyamine-depleted tumor cells that display high transport capacity. These results demonstrate that polyamine analogues cross-linked into a dimeric structure such as DESC interact with high affinity with the mammalian polyamine carrier without being used as substrates. These novel properties provide a framework for the design of specific irreversible inhibitors of the polyamine transporter, which should present advantages over competitive antagonists for an efficient blockade of polyamine transport in tumor cells.
Animals↗
Growth-independent induction of spermidine transport by IL-4 and IL-13 in ZR-75-1 human breast cancer cells.
Polyamine transport is strongly induced by insulin and estradiol (E2) in ZR-75-1 human breast cancer cells. Because signal transduction mechanisms of insulin and interleukin-4 (IL-4) partly overlap, we have compared the ability of these agents as well as that of interleukin-13 (IL-13), a cytokine that often mimics IL-4, to modulate spermidine transport in these cells. In the presence of E2, insulin increased DNA content and the rate of [3H]spermidine uptake by 2.1- and 3.7-fold, respectively, after an 8-day incubation, whereas the sole addition of IL-4 caused a quantitatively similar induction of [3H]spermidine uptake while leaving cell growth unaffected. No comparable induction of spermidine transport was observed with interleukins-1 alpha and -6, and the effect of IL-4 was not additive to that elicited by insulin plus E2. IL-4 and IL-13 stimulated [3H]spermidine uptake to a comparable extent, with half-maximal effects observed at 80 and 400 pg/ml, respectively. Interferon-gamma inhibited IL-4- and IL-13-dependent spermidine uptake to a much greater extent than basal or insulin-induced transport of the polyamine. IL-4 and IL-13 increased the Vmax and K(m) of [3H]spermidine uptake by about 4- and 2.5-fold, respectively. Na(+)-dependent amino acid uptake was increased by insulin but not by IL-4 or IL-13, indicating that the cytokines do not induce a general increase in membrane transport activity. IL-4 and IL-13 did not interfere with feedback inhibition of polyamine uptake, and only modestly decreased polyamine content after prolonged incubation, suggesting that these cytokines stimulate spermidine uptake by increasing total transport capacity rather than by repressing and endogenous inhibitor.
Biological Transport↗
Understanding the P1' specificity of the matrix metalloproteinases: effect of S1' pocket mutations in matrilysin and stromelysin-1.
Matrilysin (MAT) prefers leucine over residues that have aromatic side chains at the P1' position of peptide and protein substrates, while stromelysin (HFS) has a broader specificity. The X-ray structures of these enzymes show that their respective S1' subsites differ primarily due to the amino acids present at positions 214 and 215. To examine the role that these residues play in determining P1' specificity, the amino acids at these positions in matrilysin have been replaced by those found in stromelysin (MAT: Y214L, MAT:A215V, and MAT:Y214L/A215V). The specificity and activity of MAT:A215V are similar to those of wild type matrilysin. Both MAT:Y214L and MAT:Y214L/A215V, however, have P1' specificities that are more similar to stromelysin than matrilysin. Specifically, these enzymes exhibit an 8- to 9-fold reduction in kcat/KM toward a peptide substrate with Leu in subsite P1' relative to wild type matrilysin. This is predominantly the result of an approximate 5-fold decrease in kcat. The KM values only partially increase toward the value observed for stromelysin. Studies of the pre-steady-state reaction of wild type and mutant matrilysin with substrates with Leu and Tyr residues in the P1' position confirm that the KM values for these reactions reflect KD values for substrate binding. Thus, replacement of a single tyrosine residue in the S1' pocket of matrilysin by leucine alters its P1' specificity to resemble that of stromelysin. In contrast, alteration of the S1' subsite of stromelysin (HFS:L214Y/V215A) to resemble matrilysin increases activity (i.e., higher kcat/KM) toward peptide substrates with both leucine and residues with aromatic side chains in the P1' position with only a partial increase in specificity for Leu. These increases in activity are the result of decreases in the KM values for these reactions.
Amino Acid Sequence↗
[Prognosis of depression].
Contrary to classical psychopathological assessment of the phenomenology of depressive states, modern diagnosis tools like the DSM-III-R or DSM-IV rely upon the distinction between major depression, dysthymia and depressive symptoms during the course of other psychiatric diseases. Within each category, the degree of severity is determined and by using a multiaxial approach, different aspects of global social functioning, accompanying diseases, and characteristics of personality are assessed. Few long-term studies concerning outcome of the depressions exist. At least the following factors can be assumed to indicate a favorable outcome: minor extent of depressive symptoms at the beginning, no severe personality disorder, absence of psychotic symptoms, no alcohol dependency or major physical illness, reliable social background, intellectual functions not being impaired, and skillful choice of antidepressant drug therapy regimes.
Depressive Disorder↗
Post-translational cooperativity of ornithine decarboxylase induction by estrogens and peptide growth factors in human breast cancer cells.
Mutual interactions between 17 beta-estradiol (E2) and insulin or insulin-like growth factor-I (IGF-1) in the regulation of ornithine decarboxylase (ODC) expression were examined in estrogen-responsive MCF-7 human breast cancer cells. Whereas E2 only retarded the rapid decay of ODC activity observed upon mitogen withdrawal, both insulin and IGF-1 led to a rapid (< 4 h), net increase in ODC activity that was mediated, at least in part, through their cognate receptors. E2 synergistically potentiated the induction of ODC by IGF-1, resulting in a 170-fold elevation of enzyme activity after 48 h, as compared with 23- and 70-fold increases caused by E2 and IGF-1 alone, respectively. Cooperativity was more pronounced at suboptimal peptide concentrations due to a decrease in the half-maximal concentration of insulin or IGF-1 required for ODC induction. Phorbol-12-myristate-13-acetate (PMA) also strongly induced ODC activity in a transient manner, and additively to the effect of IGF-1. IGF-1 and PMA additively increased ODC mRNA level, whereas E2 alone had no effect on ODC mRNA abundance. IGF-1 increased the half-life of ODC activity by 60%, whereas E2 or PMA alone had no significant effect on enzyme stability. On the other hand, the simultaneous addition of IGF-1 and either E2 or PMA cooperatively reduced ODC turnover, resulting in 3.5- and 2-fold increases, respectively, in the half-life of ODC activity. Thus, ODC expression in breast cancer cells is primarily regulated by tyrosine kinase- and protein kinase C-dependent pathways, whereas estrogens increase ODC activity through a novel type of synergistic interaction with growth factors that results in a decreased rate of enzyme turnover.
Breast Neoplasms↗
Use of a modified surgical approach to the right atrium for retrieval of heartworms in a dog.
A 2-year-old 2-kg female Maltese dog was referred for treatment of dirofilariosis and mild caval syndrome characterized by hemolysis and lethargy. Ultrasonography revealed worms within the caudal vena cava, right auricle, right ventricle, and pulmonary artery. Because of the mild clinical signs and small size of the dog, jugular venotomy was not performed, and treatment with sodium caparsolate was instituted. A markedly adverse reaction was noticed on initial injection, characterized by cardiac and respiratory arrest. Further treatment with sodium caparsolate was discontinued. Because of progression of the dog's condition surgical removal of heartworms was elected. A modified surgical approach to the right atrium was performed, using a cannula introduced through a pursestring placed in the wall of the right auricle. This technique allowed almost complete removal of heartworms with minimal blood loss. Postoperative ultrasonography revealed a single heart-worm remaining in the distal portion of the left pulmonary artery, but it was subsequently absorbed.
Animals↗