Congenital goitrous primary hypothyroidism in two German families caused by novel thyroid peroxidase (TPO) gene mutations.

Congenital hypothyroidism occurs with a prevalence of approximately 1:3 500. Defects in thyroid hormone synthesis which lead to goitrous hypothyroidism account for 10-15% of these cases. Several genetic defects have been characterized and mutations in the thyroid peroxidase (TPO) gene are the most common cause for dyshormonogenesis.So far, more than 80 mutations in the TPO gene have been described, resulting in a variable decrease in TPO bioactivity. Clinically TPO defects manifest with congenital primary goitrous hypothyroidism.We here present 2 children with congenital primary hypothyroidism, who were identified to have compound heterozygous TPO mutations. They both shared the same novel mutation in the TPO gene (C756R) in exon 13. One case presented with an apparently dominant inheritance of thyroid dyshormonogenesis.

Dynamic multimode analysis of Q-switched solid state laser cavities.

We derive a new model and simulation technique called "Dynamic Multimode Analysis (DMA)" to simulate the 3-dimensional dynamic behavior of a laser. A Gaussian mode analysis is used to obtain resonator eigenmodes taking into account thermal aberrations. These modes are coupled by a set of rate equations to describe the dynamic behavior of the individual modes for cw and Q-switched lasers. Our approach analyzes mode competition and provides a detailed description of the laser beam in terms of output power, beam quality factor M(2), and pulse shape. Comparison of experimental data with our simulation results provides new insight into the effect of mode competition and the operation of Q-switched lasers.

Resorcylic acid lactone L-783,277 inhibits the growth of the human adrenal cancer cell line H295R in vitro.

The resorcylic acid lactone L-783,277, isolated from a Phoma sp. (ATCC 74403), is a potent and specific inhibitor of MEK (Map kinase kinase) that exerts very interesting pharmacological activities including anti-neoplastic properties. However, the role of this compound in the regulation of endocrine-related cancer cell growth and tumor progression remains unknown. In the present study we have evaluated the effect of L-783,277 on the viability, proliferation and cell cycle of the human adrenocortical carcinoma cell line H295R. L-783,277 inhibited viability (IC50 of 22 microM) and cell proliferation (IC50 of 21 microM) of H295R. At concentrations of 10(-6)-10(-8)M this effect was associated with the accumulation of H295R cells in S-phase, whereas at concentrations of 10(-9)-10(-10)M a prolonged G1-phase and reduced transition into S-phase were observed. Our findings demonstrate for the first time the anti-proliferative action of L-783,277 on the human adrenocortical H295R cell line.

Macrolide-based microtubule-stabilizing agents - chemistry and structure-activity relationships.

This article provides an overview on the chemistry and structure-activity relationships of macrolide-based microtubule-stabilizing agents. The primary focus will be on the total synthesis or examples thereof, but a brief summary of the current state of knowledge on the structure-activity relationships of epothilones, laulimalide, dictyostatin, and peloruside A will also be given. This macrolide class of compounds, over the last decade, has become the subject of growing interest due to their ability to inhibit human cancer cell proliferation through a taxol-like mechanism of action.

Bidirectional cavopulmonary anastomosis: impact on diastolic ventricular function indices.

Systolic ventricular function has been demonstrated to remain unchanged following bidirectional cavopulmonary anastomosis (BCPA). The effects of BCPA on diastolic ventricular performance have not been critically assessed. The objective of this study was to evaluate the changes in diastolic ventricular function indices early after BCPA. Nineteen patients were enrolled prospectively. Transthoracic echocardiograms were performed at a median of 4 days prior to and 5 days subsequent to BCPA. Diastolic and systolic echocardiographic indices of ventricular performance were measured for the dominant ventricle. End diastolic volume decreased postoperatively (71.1 +/- 21.1 vs 68.08 +/- 17.9 ml/m2, p = 0.05). Tei index increased postoperatively (0.51 +/- 0.2 vs 0.62 +/- 0.1, p = 0.002), whereas inflow Doppler E velocity (70.3 +/- 13 vs 56.3 +/- 24.7 cm/sec, p = 0.04), E/A ratio (1.18 +/- 0.52 vs 0.84 +/- 0.2, p = 0.02), tissue Doppler E' velocity (9.5 +/- 2.5 vs 6.4 +/- 3.2 cm/sec, p = 0.03) and diastolic flow propagation velocity (56.5 +/- 12 vs 52.8 +/- 11 cm/sec, p = 0.04) all decreased. There was no change in ventricular mass, area change fraction, heart rate, or inflow Doppler A or tissue Doppler A' and S' velocities. This study demonstrated that diastolic indices of ventricular performance are altered indicating decreased diastolic function early following BCPA. Whether this observation is a result of a change in ventricular mass:volume ratio, loading conditions of the ventricle, ventricular geometry, or the effects of cardiopulmonary bypass remains to be determined.

Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.

PURPOSE: The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice. METHODS: Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment. RESULTS: As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib (P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups. CONCLUSION: Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.

Fractional band filling in an atomic chain structure.

A new chain structure of Au is found on stepped Si(111) which exhibits a 1/4-filled band and a pair of > or =1/2-filled bands with a combined filling of 4/3. Band dispersions and Fermi surfaces for Si(553)-Au are obtained by photoemission and compared to that of Si(557)-Au. The dimensionality of both systems is determined using a tight binding fit. The fractional band filling makes it possible to preserve metallicity in the presence of strong correlations.

The biology and medicinal chemistry of epothilones.

Epothilones are naturally occurring 16-membered macrolides with the ability to promote tubulin polymerization in vitro and to stabilize preformed microtubules against Ca(2+)- or cold-induced depolymerization. At the cellular level, interference with microtubule functionality results in potent inhibition of cancer cell proliferation at nM to even sub-nM concentrations. Most significantly, epothilones, unlike paclitaxel (Taxol), are equally active against drug-sensitive and multidrug-resistant cell lines in vitro and epothilone B has also shown potent in vivo antitumor activity in Taxol-resistant human tumor models. Epothilone B is currently undergoing Novartis-sponsored Phase II clinical trials. In addition to naturally occurring epothilones, numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. These studies have generated a wealth of SAR data in a remarkably short period of time, given the complexity of the synthetic targets pursued. One of these analogs, BMS-247550, is presently in Phase II clinical trials by Bristol-Myers Squibb. In a first part this review is intended to provide a summary of the basic features of the in vitro biological profile of epothilones A and B, including emerging data on potential cellular epothilone resistance mechanisms. The second and third part will feature a comprehensive discussion of the epothilone SAR as it has emerged from the work of various (industrial and academic) laboratories across the world, including our own, with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity.

Effect of magnetic doping on the electronic states of Ni.

Angle-resolved photoemission is used to determine the change in the electronic states of Ni induced by doping with Fe and Cr. Well-defined spin and k states are selected using high energy and k resolution combined with single crystal alloys. Iron suppresses the mean free path of minority spins only, while chromium suppresses both spins and decreases the magnetic splitting. The strong variation of these effects from one impurity to the other supports the concept of magnetic doping.

Studies of a chemically modified oligodeoxynucleotide containing a 5-atom amide backbone which exhibits improved binding to RNA.

Chimeric oligodeoxyribonucleotides where the phosphodiester linkage -C3'-O-PO2--O-CH2-C4'- of DNA is substituted by the amide linkage -C3'-CH2-CH*(CH3)-CO-NH-CH2-C4' (*either R or S stereochemistry) have been prepared and their binding to RNA targets have been investigated. Incorporation of a single amide unit increases the Tm by approximately 1.4-1.9 degrees C. Circular dichroic spectra of these modified duplexes are similar to the wildtype DNA/RNA.

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

Microtubule-stabilizing agents: a growing class of important anticancer drugs.

Microtubule-stabilizing agents continue to play an important role in anticancer drug discovery and development. New agents were again discovered in the past year, including small synthetic molecules. At least three new taxanes and two compounds of the epothilone class of natural products underwent clinical trials in 2000. Unexpected new findings about synergistic effects between different microtubule-stabilizing agents in vitro raise new prospects for combination chemotherapy.

Band splitting for Si(557)-Au: is it spin-charge separation?

It has been proposed that the Si(557)-Au surface exhibits spin-charge separation in a one-dimensional electron liquid. Two narrowly spaced bands are found which exhibit a well-defined splitting at the Fermi level. That is incompatible with the assignment to a spinon-holon pair in a Luttinger liquid. Instead, we propose that the two bands are associated with two nearly degenerate atomic chains, or a chain of step atoms with two broken bonds. Such an assignment explains why the surface is metallic despite an even number of electrons per unit cell.

Bulboventricular foramen resection: hemodynamic and electrophysiologic results.

BACKGROUND: The two major surgical approaches to the relief of bulboventricular foramen (BVF) obstruction in patients with single left ventricle (LV) are the Damus-Kaye-Stansel (DKS) procedure or direct BVF resection. Theoretical advantages of the DKS include better out-flow gradient relief, lower potential incidences of postoperative heart block and lower incidences of reoperation. Potential disadvantages of this approach include increased semilunar valvar insufficiency, lack of feasibility when attempting septation-type operations for univentricular hearts, and a technically more difficult operation. We report the results of direct surgical BVF resection. METHODS: From June 1990 to June 1999, 9 patients had direct BVF resection performed at our institution. The median age at surgery was 16.5 years (range 1 month to 27 years). Diagnoses in these patients were [S,L,L] single LV (n = 8) and [S,D,D] single LV tricuspid atresia (n = 1). Eight of 9 patients had pulmonary artery bands placed either before BVF resection or at the same time as this procedure. Three patients required reoperation for reobstruction at the BVF (12 total operations in 9 patients). RESULTS: Median preoperative peak systolic gradient across the BVF measured at cardiac catheterization was 47 mm Hg (range 10 to 63 mm Hg). The median peak gradient measured by Doppler echocardiography was 44 mm Hg (range 5 to 125 mm Hg). Eight of 9 patients survived the operation to discharge from the hospital and 7 of 9 are alive at follow-up. At a median follow-up of 22 months (range 5 to 76 months), 8 of 8 surviving patients had an unobstructed BVF as determined by qualitative two-dimensional echocardiography and Doppler color flow imaging. There was one perioperative and one late death 5 months postoperatively (secondary to fungal sepsis). No patient developed new or worsened aortic insufficiency after BVF resection. Eight of 9 patients had no change in AV nodal conduction after surgery. One patient developed Mobitz II heart block requiring postoperative implantation of a pacemaker. CONCLUSIONS: Direct resection of an obstructive BVF can be performed with total relief of obstruction although reoperation may be required. Atrioventricular nodal function can be preserved in most patients with this operative approach, including those with [S,L,L] segmental anatomy.

Chemical synthesis and biological properties of pyridine epothilones.

BACKGROUND: Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors. RESULTS: A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus. CONCLUSIONS: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.

Two-dimensional echocardiographic assessment of right ventricular function as a predictor of outcome in hypoplastic left heart syndrome.

This study was undertaken to assess the importance of right ventricular function at the time of initial presentation on early and intermediate outcome in patients with hypoplastic left heart syndrome (HLHS). Several studies have attempted to define physiologic risk factors for poor early outcome following the Norwood palliation for HLHS. No clinical or hemodynamic factors including right ventricular function have been found to reliably predict Norwood I operative survival. The relation between initial ventricular function and later survival has not been investigated. To assess the importance of right ventricular (RV) function at the time of initial presentation on outcome in patients with HLHS, systolic function was determined by qualitative and quantitative methods in 60 consecutive patients before surgical intervention. The effects on stage I operative survival, survival to stage II, and overall survival were analyzed. Initial RV function did not impact on stage I survival. However, analysis of later outcome of the stage I survivors showed that those with prestage I RV dysfunction had significantly greater mortality before stage II. Actuarial survival 18 months after Norwood surgery was 93% for patients with initially normal RV function compared with 47% for those with abnormal function (p = <0.005). The relative risk for later mortality was approximately 11 times greater for patients with initial RV dysfunction. Thus, RV dysfunction identifiable soon after initial presentation does not impact on early survival after Norwood I operation for HLHS. Intermediate and overall survival, however, is significantly decreased in patients with initially diminished RV function.

Estimating vaccine coverage by using computer algebra.

The approach of N Gay for estimating the coverage of a multivalent vaccine from antibody prevalence data in certain age cohorts is complemented by using computer aided elimination theory of variables. Hereby, Gay's usage of numerical approximation can be replaced by exact formulae which are surprisingly nice, too.

New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.

Synthesis and hybridization properties of polyamide based nucleic acid analogues incorporating pyrrolidine-derived nucleoamino acids.

Ndelta-Fmoc protected nucleoamino acids of type I (Base = T, C, A) have been synthesized and employed as building blocks for the construction of novel polyamide based nucleic acid analogues. Homopyrimidine oligomer A binds to complementary RNA with significant affinity and in a sequence-specific fashion, while no binding was observed to complementary DNA.