bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin Augmentation of 17α-Hydroxylase Activity Is Mediated by Phosphatidyl Inositol 3-Kinase But Not Extracellular Signal-Regulated Kinase-1/2 in Human Ovarian Theca Cells
Authors: Munir Iqbal , Yen Hui-Wen , Geller David H. , Torbati Donna , Bierden Rebecca M. , Weitsman Stacy R. , Agarwal Sanjay K. , Magoffin Denis A.
Published: September 2003

Polycystic ovary syndrome, characterized by hyperandrogenism and chronic anovulation, is frequently associated with insulin resistance. Ample evidence implicates a role for insulin in the genesis of ovarian hyperandrogenism. The objective of this study was to begin to define the intracellular signaling pathway(s) that mediates insulin regulation of 17α-hydroxylase activity in human ovarian theca cells. Third-passage theca cells, isolated from the ovaries of regularly cycling premenopausal women, were used. Insulin alone had no effect on 17α-hydroxylase activity or CYP17 mRNA expression but required costimulation with forskolin. At the insulin concentration used (10 ng/ml), a neutralizing antibody to the insulin receptor (but not an antibody to the type I IGF receptor) blocked the insulin stimulation of 17α-hydroxylase activity, demonstrating that the effects were mediated by the insulin receptor. Insulin stimulated both phosphatidylinositol-3-kinase (PI3-kinase) and extracellular signal-regulated kinase-1/2 (MAPK) pathways. Specific inhibition of MAPK kinase (MEK) with PD98059 or I0126 did not decrease the 17α-hydroxylase activity stimulated by forskolin or forskolin plus insulin. In contrast, the PI3-kinase inhibitor LY294002 completely blocked insulin-stimulated 17α-hydroxylase activity. Our data demonstrate that insulin stimulates PI3-kinase and extracellular signal-regulated kinase-1/2 activities in human theca cells, but only PI3-kinase mediates the insulin augmentation of forskolin-stimulated 17α-hydroxylase activity.
Investigation of the physical properties of spray-dried stabilised lysozyme particles
Authors: Liao Yong-Hong , Brown Marc B , Quader Abdul , Martin Gary P
Published: September 2003

The aim of this study was to investigate the effect of the composition of formulations on the physical properties, including glass-transition temperatures (Tg) and aerodynamic-related characteristics, of spray-dried lysozyme particles. The Tg, as determined by differential scanning calorimetry, of spray-dried lysozyme formulations was found to be dependent upon the type and amount of excipient(s) included in the formulation. In addition, the Tg of sucrose-containing particles appeared to be raised markedly by the inclusion of trehalose, but not by dextran. The surfaces of all spray-dried particles were shown by scanning electron microscopy to be smooth with some containing characteristic dimples, typical of spray-dried material, and the morphology appeared to be independent of variation in excipient composition. However, the volume median diameters (VMD) of spray-dried powders, as determined by laser diffraction, were found to depend upon the amounts of excipients. The fine particle fraction of enzyme delivered to the lower stage of a twin-stage impinger from lysozyme–trehalose 1:1 powders appeared to be greater than that from lysozyme–sucrose 1:1 particles (22.5% vs 15.9%) when dispersed via a Rotahaler although a similar dispersibility of the two formulations (39.6% vs 36.7%) was found from a glass inhaler. In general, spray-drying was demonstrated to be feasible to produce respirable particles of the stabilised model protein, with Tg of the formulations being >30°C higher than room temperature.
Induction of apoptosis of RAW 264.7 cells by the cytostatic macrolide apicularen A
Authors: Hong JangJa , Yamaki Kouya , Ishihara Kenji , Ahn Jong Woong , Zee OkPyo , Ohuchi Kazuo
Published: September 2003

In RAW 264.7 cells, a mouse leukaemic monocyte cell line, apicularen A decreased cell growth and survival as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in a concentration-dependent manner at 10–1000 nM. Apicularen B, an N-acetyl-glucosamine glycoside of apicularen A, was 10–100-fold less effective than apicularen A. Apicularen A induced a DNA ladder, an increase in the percentage of sub-G1 cells and annexin V-binding cells, and promoted the activation of caspase as revealed by the cleavage of poly(ADP-ribose) polymerase, indicating that apicularen A induced apoptosis in RAW 264.7 cells. In addition, apicularen A phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK. The p44/42 MAPK inhibitor PD98059 rescued the cells from apicularen-induced decrease in cell growth and survival as determined by the MTT assay, while the p38 MAPK inhibitor SB203580 augmented the effect of apicularen A. This suggested the activation of p44/42 MAPK to be pro-apoptotic and the activation of p38 MAPK anti-apoptotic in apicularen A-treated RAW 264.7 cells.
Nanoparticle formulation enhances the delivery and activity of a vascular endothelial growth factor antisense oligonucleotide in human retinal pigment epithelial cells
Authors: Aukunuru Jithan V , Ayalasomayajula Surya P , Kompella Uday B
Published: September 2003

The objective of this study was to investigate the delivery and activity of a vascular endothelial growth factor (VEGF) antisense oligonucleotide in a human retinal pigment epithelial cell line (ARPE-19) using a biodegradable nanoparticulate delivery system. A 19-mer antisense phosphorothioate oligonucleotide (PS-ODN) complementary to bases 6–24 relative to the translational start site of the VEGF mRNA, a sense PS-ODN and a mismatch PS-ODN were examined for the inhibition of secretion and mRNA expression of VEGF using an enzyme-linked immunosorbent assay and reverse transcription–polymerase chain reaction, respectively. Nanoparticles of the antisense oligonucleotides were formulated using a poly(lactide-co-glycolide) (50:50) copolymer using a double emulsion solvent evaporation method. After preparing nanoparticles, drug loading, encapsulation efficiency and particle size were determined. The cells were exposed to either plain solution of oligonucleotide or nanoparticles of oligonucleotide from Day 3 through Day 6. Alternatively, the cells were incubated with PS-ODNs and lipofectin for 4h on Day 4. In all studies, VEGF secretion and mRNA expression were determined on Day 6. The particle size, drug loading and encapsulation efficiency were 252 nm, 5.5% and 16.5%, respectively. The antisense PS-ODN inhibited VEGF mRNA and protein secretion when delivered using nanoparticles or lipofectin but not in its free form. This was consistent with the ability of nanoparticles and lipofectin to elevate the cellular uptake of the oligonucleotide by 4-fold and 13-fold, respectively. Neither mismatch nor sense oligonucleotides inhibited VEGF secretion. In conclusion, biodegradable nanoparticles enhance cellular delivery of a VEGF antisense oligonucleotide and inhibit VEGF secretion and mRNA expression in a human retinal pigment epithelial cell line.
Therapeutic effect of Semecarpus anacardium Linn. nut milk extract on carbohydrate metabolizing and mitochondrial TCA cycle and respiratory chain enzymes in mammary carcinoma rats
Authors: Arathi G , Sachdanandam P
Published: September 2003

Semecarpus anacardium Linn. of the family Anacardiaceae has many applications in the Ayurvedic and Siddha systems of medicine. We have evaluated the effect of S. anacardium nut milk extract on carbohydrate metabolizing enzymes and mitochondrial tricarboxylic acid cycle and respiratory enzymes in liver and kidney mitochondria of dimethyl benzanthracene-induced mammary carcinoma in Sprague–Dawley rats. Mammary carcinoma-bearing rats showed a significant rise in glycolytic enzymes (hexokinase, phosphoglucoisomerase and aldolase) and a simultaneous fall in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase). The activities of mitochondrial enzymes isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH-dehydrogenase and cytochrome C oxidase were significantly lowered in mammary carcinoma-bearing rats when compared with control rats. S. anacardium nut extract administration to tumour-induced animals significantly lowered the glycolytic enzyme activities (hexokinase, phosphoglucoisomerase and aldolase) and there was a rise in gluconeogenic enzymes (glucose-6-phosphatase and fructose 1,6-diphosphatase), which indicated an antitumour and anticancer effect. Comparison of normal control rats and rats administered S. anacardium only as drug control animals showed no significant variations in enzyme activities. S. anacardium nut extract administration to dimethyl benzanthracene-tumour-induced animals significantly increased the activities of mitochondrial enzymes, thereby suggesting its role in mitochondrial energy production.
Synthesis and evaluation of 5-arylated 2(5H)-furanones and 2-arylated pyridazin-3(2H)-ones as anti-cancer agents
Authors: Lattmann Eric , Ayuko Washington O , Kinchinaton Derek , Langley Christopher A , Singh Harjit , Karimi Leila , Tisdale Michael J
Published: September 2003

Bis-cyclic butenolides, 5-arylated 2(5H)-furanones 6a–c, 7a, b and the 3(2H)-pyridazones 9a–d were prepared by using the aldehyde form of muco halogen acids in electrophilic substitution reactions and in an aldol-like condensation reaction. The cytotoxicity of these simple and bis-cyclic butenolides have been evaluated in tissue culture studies on MAC 13 and MAC 16 murine colon cancer cell lines. The butyl furanone 3 displayed the highest cytotoxicity of 3 μM, as one selected example of a series of dichlorinated pseudoesters. The 5-arylated 2(5H)-furanones 6 and 7 did not show a structure–activity relationship (SAR) depending on the substitution pattern of the aromatic system. An IC50 (concentration inhibiting growth by 50%) was found within a range of 30–50 and 40–50 μM for the MAC 13 and MAC 16 cell lines, respectively. The pyridazine series 9 showed a maximum in-vitro activity for the p-methoxydrivative 9b, having an IC50 of 17 in MAC 13 and 11 μM in MAC 16 cell lines. Selected examples of each series and further novel 2(5H)-furanones such as the hydrazone 5 and the hydantoin 8 have been screened in-vivo in mice and the data are presented. For the pyridazines 9a–d, the in-vitro cytotoxicity correlated with an in-vivo inhibition of tumour growth. The ring expansion of the 5-membered 2(5H)-furanone ring system such as 6a into the 6-membered 3(2H)-pyridazone 9b led to an agent with improved antineoplastic properties. On the resistant MAC 16 cell line the pyridazone 9b displayed 52% tumour inhibition in mice at a dose of 50 mg kg−1 compared with 27% for the 5-FU standard.
Analgesic effects of intra-nasal enkephalins
Authors: Gwak H S , Cho Y M , Chun I K
Published: September 2003

The analgesic effects of intranasal delivery of leucine enkephalin (Leu-Enk) and its synthetic analogue [D-ala2]-leucine enkephalinamide (YAGFL) with or without enzyme inhibitors and/or absorption enhancers were investigated using the acetic acid-induced writhing test in mice. The analgesic activity was significantly affected by the time delay after the administration of Leu-Enk; the inhibition rates for the groups administered with acetic acid 5 min and 30 min after the administration of Leu-Enk were 56.40 + 8.54 and 17.98 + 7.07%, respectively. The addition of enzyme inhibitors and absorption enhancers markedly increased the inhibition rate of Leu-Enk and YAGFL; their inhibition rates were about four times and twice those without any enzyme inhibitor or absorption enhancer, respectively. The enzyme inhibitors and absorption enhancers that produced the highest inhibition rates of Leu-Enk and YAGFL were azelaic acid (1%), thimerosal (0.5% mM, TM), ethylenediamine-tetraacetic acid (5 mM, EDTA) and L-α-lysophosphatidylcholine (0.5%, LPC), and TM (0.5 mM), EDTA (5 mM), LPC (0.5%) and povidone (5%), respectively. The ED50 value of both enkephalins was also determined and found to be about 13 μg kg−1, which is 850 and 60 times more potent than literature values for ketoprofen and morphine, respectively. Based on these results it was concluded that Leu-Enk or YAGFL could exert very high analgesic activity when administered nasally with a combination of inhibitors and absorption enhancers as compared with other analgesics.
Hepatocyte hollow-fibre bioreactors: design, set-up, validation and applications
Authors: Planchamp Corinne , Vu Thanh L , Mayer Joachim M , Reist Marianne , Testa Bernard
Published: September 2003

Hepatocytes carry out many vital biological functions, such as synthetic and catabolic reactions, detoxification and excretion. Due to their ability to restore a tissue-like environment, hollow-fibre bioreactors (HFBs) show great potential among the different systems used to culture hepatocytes. Several designs of HFBs have been proposed in which hepatocytes or hepatocyte-derived cell lines can be cultured in suspensions or on a solid support. Currently the major use of hepatocyte HFBs is as bioartificial livers to sustain patients suffering from acute liver failure, but they can also be used to synthesize cell products and as cellular models for drug metabolism and transport studies. Here, we present an overview of the set-up of hepatocyte HFBs and aim to provide potential users with the basic knowledge necessary to develop their own system. First, general information on HFBs is given, including basic principles, transport phenomena, designs and cell culture conditions. The importance of the tests necessary to assess the performance of the HFBs, i.e. the viability and functionality of hepatocytes, is underlined. Special attention is paid to drug metabolism studies and to adequate analytical methods. Finally, the potential uses of hepatocyte HFBs are described.
GBP binds kinesin light chain and translocates during cortical rotation inXenopuseggs
Authors: Weaver Carole , Farr Gist H. , Pan Weijun , Rowning Brian A. , Wang Jiyong , Mao Junhao , Wu Dianqing , Li Lin , Larabell Carolyn A. , Kimelman David
Published: September 2003

In Xenopus, axis development is initiated by dorsally elevated levels of cytoplasmic β-catenin, an intracellular factor regulated by GSK3 kinase activity. Upon fertilization, factors that increase β-catenin stability are translocated to the prospective dorsal side of the embryo in a microtubule-dependent process. However, neither the identity of these factors nor the mechanism of their movement is understood. Here, we show that the GSK3 inhibitory protein GBP/Frat binds kinesin light chain (KLC), a component of the microtubule motor kinesin. Upon egg activation, GBP-GFP and KLC-GFP form particles and exhibit directed translocation. KLC, through a previously uncharacterized conserved domain, binds a region of GBP that is required for GBP translocation and for GSK3 binding, and competes with GSK3 for GBP. We propose a model in which conventional kinesin transports a GBP-containing complex to the future dorsal side, where GBP dissociates and contributes to the local stabilization of β-catenin by binding and inhibiting GSK3.
The isthmic organizer links anteroposterior and dorsoventral patterning in the mid/hindbrain by generating roof plate structures
Authors: Alexandre Paula , Wassef Marion
Published: September 2003

During vertebrate development, an organizing signaling center, the isthmic organizer, forms at the boundary between the midbrain and hindbrain. This organizer locally controls growth and patterning along the anteroposterior axis of the neural tube. On the basis of transplantation and ablation experiments in avian embryos, we show here that, in the caudal midbrain, a restricted dorsal domain of the isthmic organizer, that we call the isthmic node, is both necessary and sufficient for the formation and positioning of the roof plate, a signaling structure that marks the dorsal midline of the neural tube and that is involved in its dorsoventral patterning. This is unexpected because in other regions of the neural tube, the roof plate has been shown to form at the site of neural fold fusion, which is under the influence of epidermal ectoderm derived signals. In addition, the isthmic node contributes cells to both the midbrain and hindbrain roof plates, which are separated by a boundary that limits cell movements. We also provide evidence that mid/hindbrain roof plate formation involves homeogenetic mechanisms. Our observations indicate that the isthmic organizer orchestrates patterning along the anteroposterior and the dorsoventral axis.
Tgfβ signaling acts on a Hox response element to confer specificity and diversity to Hox protein function
Authors: Grienenberger Aurélie , Merabet Samir , Manak John , Iltis Isabelle , Fabre Aurélie , Bérenger Hélène , Scott Matthew P. , Pradel Jacques , Graba Yacine
Published: September 2003

Hox proteins play fundamental roles in generating pattern diversity during development and evolution, acting in broad domains but controlling localized cell diversification and pattern. Much remains to be learned about how Hox selector proteins generate cell-type diversity. In this study, regulatory specificity was investigated by dissecting the genetic and molecular requirements that allow the Hox protein Abdominal A to activate wingless in only a few cells of its broad expression domain in the Drosophila visceral mesoderm. We show that the Dpp/Tgfβ signal controls Abdominal A function, and that Hox protein and signal-activated regulators converge on a wingless enhancer. The signal, acting through Mad and Creb, provides spatial information that subdivides the domain of Abdominal A function through direct combinatorial action, conferring specificity and diversity upon Abdominal A activity.
Retrograde Gbb signaling through the Bmp type 2 receptor Wishful Thinking regulates systemic FMRFa expression inDrosophila
Authors: Marqués Guillermo , Haerry Theodore E. , Crotty M. Lisa , Xue Mingshan , Zhang Bing , O'Connor Michael B.
Published: September 2003

Amidated neuropeptides of the FMRFamide class regulate numerous physiological processes including synaptic efficacy at the Drosophilaneuromuscular junction (NMJ). We demonstrate here that mutations in wishful thinking (wit) a gene encoding a DrosophilaBmp type 2 receptor that is required for proper neurotransmitter release at the neuromuscular junction, also eliminates expression of FMRFa in that subset of neuroendocrine cells (Tv neurons) which provide the systemic supply of FMRFa peptides. We show that Gbb, a Bmp ligand expressed in the neurohemal organ provides a retrograde signal that helps specify the peptidergic phenotype of the Tv neurons. Finally, we show that supplying FMRFa in neurosecretory cells partially rescues the witlethal phenotype without rescuing the primary morphological or electrophysiological defects of wit mutants. We propose that Wit and Gbb globally regulate NMJ function by controlling both the growth and transmitter release properties of the synapse as well as the expression of systemic modulators of NMJ synaptic activity.
Egfr signalling defines a protective function for ommatidial orientation in theDrosophilaeye
Authors: Brown Katherine E. , Freeman Matthew
Published: September 2003

Ommatidial rotation in the Drosophila eye provides a striking example of the precision with which tissue patterning can be achieved. Ommatidia in the adult eye are aligned at right angles to the equator, with dorsal and ventral ommatidia pointing in opposite directions. This pattern is established during disc development, when clusters rotate through 90°, a process dependent on planar cell polarity and rotation-specific factors such as Nemo and Scabrous. Here, we demonstrate a requirement for epidermal growth factor receptor (Egfr) signalling in rotation, further adding to the manifold actions of this pathway in eye development. Egfr is distinct from other rotation factors in that the initial process is unaffected, but orientation in the adult is greatly disrupted when signalling is abnormal. We propose that Egfr signalling acts in the third instar imaginal disc to `lock' ommatidia in their final position, and that in its absence, ommatidial orientation becomes disrupted during the remodelling of the larval disc into an adult eye. This lock may be achieved by a change in the adhesive properties of the cells:cadherin-based adhesion is important for ommatidia to remain in their appropriate positions. In addition, we have evidence that there is an error-correction mechanism operating during pupal stages to reposition inappropriately orientated ommatidia. Our results suggest that initial patterning events are not sufficient to achieve the precise architecture of the fly eye, and highlight a novel requirement for error-correction, and for an Egfr-dependent protection function to prevent morphological disruption during tissue remodelling.
Novel roles ofFgfr2in AER differentiation and positioning of the dorsoventral limb interface
Authors: Gorivodsky Marat , Lonai Peter
Published: September 2003

The epithelial b variant of Fgfr2 is active in the entire surface ectoderm of the early embryo, and later in the limb ectoderm and AER,where it is required for limb outgrowth. As limb buds do not form in the absence of Fgfr2, we used chimera analysis to investigate the mechanism of action of this receptor in limb development. ES cells homozygous for a loss-of-function mutation of Fgfr2 that carry aβ-galactosidase reporter were aggregated with normal pre-implantation embryos. Chimeras with a high proportion of mutant cells did not form limbs,whereas those with a moderate proportion formed limb buds with a lobular structure and a discontinuous AER. Where present, the AER did not contain mutant cells, although mutant cells did localize to the adjacent surface ectoderm and limb mesenchyme. In the underlying mesenchyme of AER-free areas,cell proliferation was reduced, and transcription of Shh and Msx1 was diminished. En1 expression in the ventral ectoderm was discontinuous and exhibited ectopic dorsal localization, whereas Wnt7a expression was diminished in the dorsal ectoderm but remained confined to that site. En1 and Wnt7a were not expressed in non-chimeric Fgfr2-null mutant embryos, revealing that they are downstream of Fgfr2. In late gestation chimeras, defects presented in all three limb segments as bone duplications, bone loss or ectopic outgrowths. We suggest that Fgfr2 is required for AER differentiation, as well as for En1 and Wnt7a expression. This receptor also mediates signals from the limb mesenchyme to the limb ectoderm throughout limb development, affecting the position and morphogenesis of precursor cells in the dorsal and ventral limb ectoderm, and AER.
Including a 'no active intervention' arm in surgical trials is possible: evidence from the CLasP randomised trial
Authors: Brookes Sara , Peters Tim , Campbell Rona , Featherstone Katie , Neal David , Abrams Paul , Donovan Jenny
Published: September 2003

Objectives: To examine the impact of including a 'no active intervention' arm (called 'conservative management') in a randomised controlled trial comparing treatments (including surgery) for men with lower urinary tract symptoms related to benign prostatic enlargement.

Methods: Outcomes 7.5 months after randomisation were acceptability of randomisation, overall acceptability of and satisfaction with conservative management, impact on quality of life, perceived need for further treatment and treatment failure (defined a priori).

Results: In total, 177 (out of 755) patients refused randomisation, including 31% who did not want surgery and 22% who wanted surgery. Most men randomised to conservative management were willing to undertake it as part of a trial but at the end of the trial they were divided between those who wanted to continue with it and those who expected surgery. At follow-up, 39% of conservative management patients requested surgery, and interference of symptoms with life and an unsuccessful outcome were more commonly reported in this arm. There were no appreciable differences between treatment groups in terms of treatment failures.

Conclusions: Including a 'no active intervention' arm did not appear to have a detrimental effect on patient recruitment or the completion of this trial in the short-term; overall, conservative management was successfully completed by the majority of patients during the trial period, suggesting that researchers need not avoid including a no-intervention arm in surgical trials as long as they take care with its presentation.
Changing the lens: widening the approach to primary care research
Authors: Checkland Kath
Published: September 2003

After years of being shielded from most of the managerial and organisational changes in health care, primary care is going through a period of change in many countries. Much of the research that has been done in primary care, in common with that in secondary care, puts at the centre of its methodology the concept of professionalism. However, there are other ways of theorising medical work, and using a wider range of theoretical 'lenses' when planning research into the impact of change will enhance and enrich that research. Viewing primary care physicians as 'workers', concerned, like other workers, with constructing understanding of what they do that helps them cope with pressures and uncertainties, shifts the focus of research questions away from issues of professional status towards the practical ways in which they deal with change in their local contexts. Research using this theoretical approach may be able to explain phenomena that other, more broad-brush approaches cannot.
Carbamazepine-Induced Pseudo Mycosis Fungoides
Authors: Gül Ülker , Kiliç Arzu , Dursun Ayşe
Published: September 2003

Objective

To report a case of pseudo mycosis fungoides due to carbamazepine.

Case Summary

A 54-year-old man experienced a skin lesion resembling mycosis fungoides without any systemic symptoms or signs 2 months after he had begun carbamazepine treatment for his seizures. Skin-punch biopsy specimens revealed mycosis fungoides–like histopathologic appearance. After drug discontinuation, the patient experienced complete remission of the clinical and pathologic findings. This suggests a diagnosis of pseudo mycosis fungoides due to carbamazepine.

Discussion

Mycosis fungoides is the cutaneous T-cell lymphoma of the skin that needs aggressive chemotherapy and radiation treatment. Pseudo mycosis fungoides is a condition caused by certain drugs that has a similar clinical and histopathologic appearance to mycosis fungoides. When the causative drug is discontinued, the lesions resolve completely.

Conclusions

An objective causality assessment revealed that carbamazepine was highly probable as the cause of the adverse reaction. Patients who are diagnosed with mycosis fungoides should be asked about any drug use, and clinicians should recognize signs of pseudo mycosis fungoides.
Oxidation and Degradation Products of Papaverine, Part II[1]: Investigations on the Photochemical Degradation of Papaverine Solutions
Authors: Girreser Ulrich , Hermann Tadeusz W. , Piotrowska Karolina
Published: September 2003

The structure of the final degradation product formed in papaverine solutions in either water or chloroform was found to be a 2, 3, 9, 10‐tetramethoxy‐12‐oxo‐12H‐indolo [2, 1‐a] isoquinolinylium salt (a dibenzo [b, g] pyrrocolonium derivative). Its formation from papaverine oxidation products that is papaverinol, papaveraldine, and papaverine‐N‐oxide chloroformsolutions under the influence of UV light, was investigated and possible reaction pathways are discussed.
Synthesis and Effects on the COX‐1 and COX‐2 Activity in Human Whole Blood ex vivo of Derivatives Containing the [1]Benzothienol‐[3, 2‐d]pyrimidin‐4‐one Heterocyclic System
Authors: Santagati Andrea , Granata Giuseppe , Marrazzo Agostino , Santagati Maria
Published: September 2003

Methyl and phenyl derivatives containing the [1]Benzothieno [3, 2‐d]pyrimidin‐4‐one system have been synthesized and tested as inhibitors of COX‐1 and COX‐2 activities in human whole blood (HWB) ex vivo; all compounds turned out to be weak inhibitors of COX‐1 activity, as deduced from the TXB2 (thromboxane B) generation; the acid phenyl derivative 11 b was an interesting inhibitor of COX‐2 activity, as deduced from the PGE2 (prostaglandine E) generation.
Synthesis and Evaluation of Pharmacological Activities of 3, 5‐Dialkyl 1, 4‐Dihydro‐2, 6‐Dimethyl‐4‐Nitroimidazole‐3, 5‐Pyridine Dicarboxylates
Authors: Miri Ramin , Javidnia K. , Kebriaie‐Zadeh A. , Niknahad H. , Shaygani N. , Semnanian S. , Shafiee A.
Published: September 2003

New analogues of nifedipine, in which the 2‐nitrophenyl group at position 4 is replaced by a 1‐methyl‐5‐nitro‐2‐imidazolyl substituent, were synthesized. The symmetrical dialkyl 1, 4‐dihydro‐2, 6‐dimethyl‐4‐(1‐methyl‐5‐nitro‐2‐imidazolyl)‐3, 5‐pyridinedicarboxylates were prepared by a classical Hantzsch condensation. The asymmetrical analogues were synthesized using a procedure reported by Iwanami that involved the condensation of alkylacetoacetate with methyl‐, ethyl‐ or isopropyl3‐aminocrotonate and 1‐methyl‐5‐nitroimidazole‐2‐carboxaldehyde. Calcium channel antagonist activities were determined in vitro using a guinea pig ileum longitudinal smooth muscle (GPILSM)assay. Many compounds exhibited superior, or equipotent, calcium antagonist activity (IC50 = 10—10 to 10—13 M range) relative to the reference drug nifedipine (IC50 = 1.09 ± 0.12 × 10—11 M). Antinociceptive effects of some compounds were evaluated by the mouse tail‐flick assay in vivo. Results demonstrate that some of the compounds were active as an antinociceptive.
Investigations of New Pyridazinone Derivatives for the Synthesis of Potent Analgesic and Anti‐Inflammatory Compounds with Cyclooxygenase Inhibitory Activity
Authors: Ökçelik Berna , Ünlü Serdar , Banoglu Erden , Küpeli Esra , Yeşilada Erdem , Şahin M. Fethi
Published: September 2003

In this study we describe the synthesis of two novel 4‐phenyl‐and 4‐(2‐chlorophenyl)‐6‐(5‐chloro‐2‐oxo‐3H‐benzoxazol‐7‐yl)‐3(2H)‐pyridazinone derivatives (compounds 8a and b) and their testing as inhibitors of cyclooxygenases (COX‐1 and COX‐2). Both compounds inhibited COX‐1 (by 59 % and 61 % for compounds 8a and 8b respectively and COX‐2 (by 37 % and 28 % for compounds 8a and 8b spectively) at a concentration of 10 μM. Furthermore, we tested the analgesic and anti‐inflammatory activities of the synthesized compounds in vivo by using the pbenzoquinone‐induced writhing test and the carrageenan‐induced hind paw edema model, respectively. Compounds 8a and 8b showed potent analgesic and anti‐inflammatory activities without causing gastric lesions in the tested animals.
Geometrically Constrained Analogues of N‐Benzylindolylglyoxylylamides: [1, 2, 4]Triazino[4, 3‐a]benzimidazol‐4(10H)‐one Derivatives as Potential New Ligands at the Benzodiazepine Receptor
Authors: Primofiore Giampaolo , Da Settimo Federico , Taliani Sabrina , Marini Anna Maria , Simorini Francesca , Novellino Ettore , Greco Giovanni , Trincavelli Letizia , Martini Claudia
Published: September 2003

A series of 3‐benzylamino‐and 3‐arylalkylaminocarbonyl [1, 2, 4]triazino [4, 3‐a]benzimidazoles 1—12 were synthesized and biologically assayed as geometrically constrained analogues of N‐benzylindolylglyoxylylamides II, which are high affinity ligands at the benzodiazepine receptor (BzR). The intermediate 3‐ethoxycarbonyl [1, 2, 4]triazino [4, 3‐a]benzimidazol‐4(10H)‐one 14 and its N(10)‐methyl analogue 15 closely related to 3‐alkoxycarbonyl‐β‐carbolines I were also investigated. The title compounds exhibited a lower affinity compared with the corresponding indolylglyoxylylamide derivatives II. Attempts were made to rationalize these results taking into account the possible tautomeric equilibria involving these ligands.
Completeness of state administrative databases for surveillance of congenital heart disease
Authors: Cronk Christine E. , Malloy Marsha E. , Pelech Andrew N. , Miller Richard E. , Meyer Sally A. , Cowell Melissa , McCarver D. Gail
Published: September 2003

BACKGROUND

Tracking birth prevalence of cardiac defects is essential to determining time and space clusters, and identifying potential associated factors. Resource limitations on state birth defects surveillance programs sometimes require that databases already available be used for ascertaining such defects. This study evaluated the data quality of state administrative databases for ascertaining congenital heart defects (CHD) and specific diagnoses of CHD.

METHODS

Children's Hospital of Wisconsin (CHW) medical records for infants born 1997–1999 and treated for CHD (n = 373) were abstracted and each case assigned CHD diagnoses based on definitive diagnostic reports (echocardiograms, catheterizations, surgical or autopsy reports). These data were linked to state birth and death records, and birth and postnatal (<1 year of age) hospital discharge summaries at the Wisconsin Bureau of Health Information (WBHI). Presence of any code/checkbox indicating CHD (generic CHD) and exact matches to abstracted diagnoses were evaluated.

RESULTS

Fifty‐eight percent of cases with generic CHD were identified by state databases. Postnatal hospital discharge summaries identified 48%, birth hospital discharge summaries 27%, birth certificates 9% and death records 4% of these cases. Exact matches were found for 52% of 633 specific diagnoses. Postnatal hospital discharge summaries provided most matches.

CONCLUSION

State databases identified 60% of generic CHD and exactly matched about half of specific CHD diagnoses. The postnatal hospital discharge summaries performed best in both in identifying generic CHD and matching specific CHD diagnoses. Vital records had limited value in ascertaining CHD. Birth Defects Research (Part A) 67:597–603, 2003. © 2003 Wiley‐Liss, Inc.
Estimating prevalence of fetal alcohol syndrome (FAS): Effectiveness of a passive birth defects registry system
Authors: Fox Deborah J. , Druschel Charlotte M.
Published: September 2003

BACKGROUND

Fetal alcohol syndrome (FAS) is a preventable birth defect, easiest to recognize in children two through eleven years and more difficult to recognize in newborns. In New York State, two systems ascertain FAS cases, the statewide birth defects registry and the Fetal Alcohol Syndrome Surveillance Network (FASSNet) system. The accuracy of FAS reports to the birth defects registry was assessed through a comparison with the FASSNet system.

METHODS

The birth defects registry mandates reporting up to age two, including FAS with an ICD‐9 code of 760.71. FASSNet is a population‐based, multi‐source surveillance and uses a standard definition to determine FAS case status.

RESULTS

Among 33 children reported to the registry with FAS, 19 (58%) met FASSNet criteria for FAS. FASSNet identified 24 additional children with FAS facial features documented before the child's second birthday that should have been reported to the birth defects registry. FAS prevalence rate for the birth defects registry was 0.28 per 1,000 live births but would have been 0.37 if all children diagnosed before age two were included.

CONCLUSIONS

Almost 60% of children reported to a birth defects registry with FAS from 1995 to 1998 were confirmed as FAS based on a more intensive surveillance. Additional children with FAS were not reported to the CMR. FAS prevalence calculated from birth defects registries, relying on the ICD‐9 code 760.71, include false positives and underestimate the true prevalence. Age limits for reporting FAS to registries further contribute to under ascertainment. Birth Defects Research (Part A) 67:604–608, 2003. © 2003 Wiley‐Liss, Inc.
Random error and undercounting in birth defects surveillance data: Implications for inference
Authors: Correa‐Villaseñor Adolfo , Satten Glen A. , Rolka Henry , Langlois Peter , Devine Owen
Published: September 2003

BACKGROUND

There has been an ongoing debate among birth defects investigators about whether or not to publish estimates of rates of birth defects with confidence intervals to allow for comparisons of rates across regions and time. A major impediment in resolving this debate has been the lack of a framework for quantifying uncertainties in the data that can be applied uniformly to birth defects surveillance programs. This report presents an overview of random error and ascertainment bias in birth defects surveillance data, and of the implications of these errors for estimation and comparisons of birth defects rates.

METHODS

We consider when confidence intervals can be used as part of a strategy to make inference on rates, as well as ratios of or differences between two rates. Worth noting is that confidence intervals only address random error in the data. In the presence of undercounting of cases, estimation of rates and confidence intervals requires knowledge or an estimate of the extent of underascertainment. Rate estimates and confidence intervals that ignore such bias can be misleading. However, if it is reasonable to assume that the ascertainment bias is constant over time (or across regions), then it is possible to make valid comparisons of rates over time (or across regions) using ratio or difference estimators, even when lack of knowledge of the extent of undercounting makes estimating the absolute rate and its confidence interval problematic. Finally, sensitivity analyses can use confidence limits to determine the difference in ascertainment bias necessary to explain an apparent difference in rates.

CONCLUSION

Because birth defects surveillance systems have evolved in the absence of agreed upon standards to guide the process, it is difficult to determine the extent to which the variability in rates of birth defects across programs or over time is real or due to differences in surveillance methods. Efforts to develop standards for birth defects surveillance may help to minimize the variability in prevalence of birth defects due to differences in case ascertainment methods and allow for evaluations of real temporal and spatial variations in environmental effects. In the meantime, if comparisons of rates need to be made to address public health concerns, it would be prudent to conduct only such comparisons between regions or across time when the degree of case ascertainment can be assumed to be relatively constant across regions and time. Birth Defects Research (Part A) 67:610–616, 2003. Published 2003 Wiley‐Liss, Inc.
The Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the centers for disease control and prevention
Authors: Correa‐Villaseñor Adolfo , Cragan Janet , Kucik James , O'Leary Leslie , Siffel Csaba , Williams Laura
Published: September 2003

BACKGROUND

The Metropolitan Atlanta Congenital Defects Program (MACDP) is a population‐based birth defects surveillance program administered by the Centers for Disease Control and Prevention (CDC) that has been collecting, analyzing, and interpreting birth defects surveillance data since 1967. This paper presents an overview of MACDP current methods and accomplishments over the past 35 years.

METHODS

MACDP actively monitors major birth defects among infants born to residents of five counties of metropolitan Atlanta, an area with approximately 50,000 annual births. Cases are ascertained from multiple sources, coded using a modified British Pediatric Association six‐digit code, and reviewed and classified by clinical geneticists.

RESULTS

MACDP has monitored trends in birth defects rates and has served as a case registry for descriptive, risk factor, and prognostic studies of birth defects, including studies of Agent Orange exposure among Vietnam War veterans, maternal use of multivitamins, diabetes, febrile illnesses, and survival of children with neural tube defects. MACDP has served as a data source for one of the centers participating in the National Birth Defects Prevention Study, and for developing and evaluating neural tube defects prevention strategies related to the periconceptional use of folic acid supplements.

CONCLUSIONS

Since its inception, MACDP has served as a resource for the development of uniform methods and approaches to birth defect surveillance across the United States and in many other countries, monitoring birth defects rates, and as a case registry for various descriptive, etiologic, and survival studies of birth defects. MACDP has also served as a training ground for a large number of professionals active in birth defects epidemiology. Birth Defects Research (Part A) 67:617–624, 2003. Published 2003 Wiley‐Liss, Inc.
Maternal age‐specific Down syndrome rates by maternal race/ethnicity, Hawaii, 1986–2000
Authors: Forrester Mathias B. , Merz Ruth D.
Published: September 2003

BACKGROUND

Published maternal age‐specific rates for Down syndrome are based mostly on populations of predominately European origin. Down syndrome rates have been reported to vary by race/ethnicity. The objective of this study was to calculate maternal age‐specific Down syndrome rates for various racial/ethnic groups and to compare the rates between the racial/ethnic groups.

METHODS

Data were obtained from a population‐based birth defects registry and included all Down syndrome cases delivered in Hawaii during 1986–2000 with maternal race/ethnicity of white, Far East Asian, Pacific Islander, or Filipino. Maternal age‐specific Down syndrome rates were calculated for each race/ethnicity, and the rates were compared.

RESULTS

The pattern of maternal age‐specific Down syndrome rates among Far East Asians and Filipinos was similar to that among whites ‐ Down syndrome rates increased with maternal age, with the increase in rate being most obvious for maternal age groups of 35 years or greater. However, for maternal age of 35 years or greater, the Down syndrome rate was lower for Pacific Islanders than whites, with the difference between the two racial/ethnic groups being significant for maternal age of 40 years or greater (rate ratio 0.13, 95% confidence interval 0.02–0.48).

CONCLUSIONS

All racial/ethnic groups do not appear to demonstrate the same maternal age pattern of Down syndrome rates as whites. This is important because maternal age‐specific Down syndrome rates are used to calculate expected Down syndrome rates in a population and to estimate a woman's risk of having an infant with Down syndrome given her age. Birth Defects Research (Part A) 67:625–629, 2003. © 2003 Wiley‐Liss, Inc.
Omphalocele and gastroschisis in the state of New York, 1992–1999
Authors: Salihu Hamisu M. , Pierre‐Louis Bosny J. , Druschel Charlotte M. , Kirby Russell S.
Published: September 2003

BACKGROUND

Variations in the temporal distribution and risk factors for omphalocele and gastroschisis have been suggested although results have not been conclusive. This study examines the trend and risk factors for both conditions among live births in New York State.

METHODS

Analysis of surveillance data from the New York Congenital Malformation Registry for the years 1992–1999.

RESULTS

Five hundred and ninety‐five (595) infants with either omphalocele (287) or gastroschisis (308) were identified. It appeared that the prevalence of gastroschisis was rising from 1992–1999, while prevalence of omphalocele was decreasing. Cases of gastroschisis were clustered among younger mothers while the maternal age distribution among omphalocele infants was U‐shaped. As compared to Whites, Black infants were more likely to present with omphalocele (OR = 1.73; 95% confidence interval = 1.28–2.33) and Hispanic infants with gastroschisis (OR = 1.50; 95% CI = 1.12–2.00). For both anomalies, residents of rural New York were significantly at higher risk than those living in urban New York. Twenty‐three chromosomal aberrations were detected, all among omphalocele babies. Infant survival was substantially greater among gastroschisis (92%) as compared to omphalocele newborn (81%)[p < 0.0001].

CONCLUSIONS

Prevalence of gastroschisis has been on the rise while that of omphalocele has been declining in New York State. Geographical and racial/ethnic variations were observed, further confirming the notion of different etiologies for the two congenital anomalies. Birth Defects Research (Part A) 67:630–636, 2003. © 2003 Wiley‐Liss, Inc.
Orofacial cleft malformations: Associations with maternal and infant characteristics in Washington State
Authors: DeRoo Lisa A. , Gaudino James A. , Edmonds Larry D.
Published: September 2003

BACKGROUND

To characterize the prevalence of orofacial cleft malformations and investigate variations in prevalence according to maternal and infant characteristics, we analyzed a cohort of 298,138 live births delivered between 1987 and 1990 to residents of Washington State.

METHODS

Infants with cleft defects were identified using a statewide, population‐based birth defects registry. Information on infant and maternal characteristics was obtained from Washington State birth certificates. Multiple logistic regression analysis was used to measure the association between potential risk factors and orofacial clefts. Cleft lip with or without cleft palate (CL±CP) and cleft palate (CP) were analyzed separately, depending on the presence or absence of other defects.

RESULTS

We identified 608 infants with cleft defects. The prevalences of isolated and non‐isolated CL±CP were 0.87 and 0.30 per 1,000 live births, respectively. The prevalences of isolated and non‐isolated CP were 0.34 and 0.54 per 1,000 live births, respectively. Compared with mothers aged 25‐29 years, mothers aged < 20 years were twice as likely to have an infant with isolated CL±CP (RR=2.0; 95% CI 1.3, 2.9). Compared to white mothers, black mothers were more likely to have an infant with non‐isolated CL±CP (RR=2.8; 95% CI 1.2, 6.6).

CONCLUSIONS

The prevalences of orofacial clefts in Washington State in 1987‐90 were similar to those of other states. This study is among the first to report a greater relative risk for isolated CL±CP among the infants of mothers < 20 years compared to older mothers. Birth Defects Research (Part A) 67:637–642, 2003. © 2003 Wiley‐Liss, Inc.
Treatment of oralfacial clefts by state‐affiliated craniofacial centers and cleft palate clinics
Authors: Williams Charles A. , Mardon Russell E. , Grove Douglas , Wharton Paul , Hauser Kimberlea W. , Frías Jaime L.
Published: September 2003

BACKGROUND

Oralfacial clefting (OFC) disorders require expedient evaluation and treatment to obtain optimal outcome. In Florida, there is a statewide program targeted to the care of infants with OFC. We therefore sought to determine statewide referral and treatment patterns of children born with OFC identified through the Florida Birth Defects Registry.

METHODS

Using data for 1996 and 1997 and ICD‐9 CM codes 749.00 ‐ 749.25, we identified 539 OFC cases. All cases were matched with the evaluation and treatment records of the statewide Children's Medical Services' (CMS) craniofacial centers (CFC) and cleft palate clinics (CPC). The likelihood of CMS contact was examined with respect to demographic and other descriptive data characterizing the OFC cases.

RESULTS

42% (227/539) of OFC cases were evaluated at or known to the CFC or CPC. Children with cleft lip and palate were more likely to have had contact than were those with cleft lip or cleft palate alone. The CFC and CPC programs were most likely to provide evaluation between age 2 months and 3 years. Of 12 counties with occurrences of more than 15 OFC cases, 2 had significantly lower contact rates, suggesting possible problems in accessibility or reporting of services.

CONCLUSIONS

Statewide Birth Defect Registry data can be used in collaboration with statewide treatment programs to gain insight into referral patterns and provision of services. Factors influencing access to services and quality of care, though not addressed by this study, could be prospectively incorporated into such a project. Birth Defects Research (Part A) 67:643–646, 2003. © 2003 Wiley‐Liss, Inc.