Marked Lengthening Research Articles

Mycobacterial and Human Ferrous Nitrobindins: Spectroscopic and Reactivity Properties.

Structural and functional properties of ferrous Mycobacterium tuberculosis (Mt-Nb) and human (Hs-Nb) nitrobindins (Nbs) were investigated. At pH 7.0 and 25.0 °C, the unliganded Fe(II) species is penta-coordinated and unlike most other hemoproteins no pH-dependence of its coordination was detected over the pH range between 2.2 and 7.0. Further, despite a very open distal side of the heme pocket (as also indicated by the vanishingly small geminate recombination of CO for both Nbs), which exposes the heme pocket to the bulk solvent, their reactivity toward ligands, such as CO and NO, is significantly slower than in most hemoproteins, envisaging either a proximal barrier for ligand binding and/or crowding of H2O molecules in the distal side of the heme pocket which impairs ligand binding to the heme Fe-atom. On the other hand, liganded species display already at pH 7.0 and 25 °C a severe weakening (in the case of CO) and a cleavage (in the case of NO) of the proximal Fe-His bond, suggesting that the ligand-linked movement of the Fe(II) atom onto the heme plane brings about a marked lengthening of the proximal Fe-imidazole bond, eventually leading to its rupture. This structural evidence is accompanied by a marked enhancement of both ligands dissociation rate constants. As a whole, these data clearly indicate that structural–functional relationships in Nbs strongly differ from what observed in mammalian and truncated hemoproteins, suggesting that Nbs play a functional role clearly distinct from other eukaryotic and prokaryotic hemoproteins.

Role of Diffusion Weighted MRI in Characterization of Ovarian Tumors

Background: Ovarian masses present a special diagnostic challenge when imaging findings cannot be categorized into benign or malignant pathology. Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) are currently used to evaluate ovarian tumors.Functional imaging by means of diffusion weighted magnetic resonance imaging (DW-MRI) is now part of the standard imaging protocols for evaluation of the female pelvis. DW-MRI is important MR imaging technique which enable the radiologist to move from morphological to functional assessment of diseases of the female pelvis. Aim of the Study: The aim of the current study is to evaluate the diffusion-weighted MR imaging in prediction of the nature of suspicious ovarian masses which are detected previously by conventional ultrasound. Patients and Methods: MRI Unit, radiodiagnosis department, Ain Shams University hospital. The study is prospective, included thirty women who presented with suspicious adnexal masses on previous ultrasound examination and referred for further assessment and characterization by DW-MRI. Patients with contraindications to MRI (e.g. claustrophobia, cardiac prosthesis and metallic plates) are excluded. Results: The study included 30 women ranging in age between 24 and 61 years with mean age 43.22±11.15. Out of 30 cases, 12 had of benign ovarian tumors while 18 had malignant tumors. Conclusion: Thus, combination of DWI and conventional MRI implies using a completely noninvasive technique with no radiation exposure. It is cost effective (no additional cost to MRI examination), and easily added to the MR study protocols with no marked lengthening of examination time. It improves the specificity of MRI and thus increasing radiologist’s confidence in image interpretation which will finally reflect on patient’s outcome and prognosis.

MR Imaging of the Achilles Tendon after Surgical Repair.

Achilles tendon tear is common and increasingly frequent. Magnetic resonance imaging (MRI) is the modality of choice for radiological evaluation. It is accurate to assess the status and integrity of the tendon with well documented features. In this article, the MR findings of a normal Achilles tendon as well as common diseases like insertional and noninsertional tendinosis, chronic tendinosis with marked lengthening, tendon rupture are illustrated. After a torn Achilles tendon receives surgical repair, it undergoes different stages of healing process including inflammatory, reparative and remodeling phases. Acute scar tissue in the surgical bed may share similar MR features of tendon re-rupture especially in the early healing phase because both are T2W hyperintense. The size of the gap may even appear larger than expected on T2W images possibly due to tendon remodeling. Understanding of the healing process in post-operative period may prevent overestimation of tendon gap and misdiagnosis of re-tear. We describe the MR features of the post-operative changes with serial studies in different months after surgery. The MR findings with the highlights of the expected sequential changes in normal healing process are illustrated in different cases. A case with surgical repair on a partial tear of Achilles tendon is also included.

Effects of neuropeptide Y on coronary artery vasomotion in patients with microvascular angina

BackgroundPatients with microvascular angina (exertional angina, positive exercise tests and normal coronary arteriograms) usually have a reduced coronary blood flow reserve. Neuropeptide Y (NPY) is a potent endogenous vasoconstrictor involved in modulation of coronary vasomotor tone and may play a role in microvascular angina. MethodsWe compared the effects of NPY (0.2–1.0pmol/kg, intracoronary) on the vasomotor response of proximal and distal segments of the coronary arteries in 7 patients with microvascular angina, 9 with chronic stable angina, and 9 control individuals. The coronary response to the administration of ergonovine was also assessed in 9 other patients with microvascular angina. Computerized coronary artery diameter measurements were carried out before (baseline) and after the administration of the vasoactive agents. ResultsMean baseline coronary lumen diameters were similar in control, microvascular angina, and coronary artery disease patients. NPY constricted proximal coronary segments by 8±2%, 5±2% and 6±3% and distal segments by 14±2%, 11±2% and 10±2% in control, microvascular angina, and coronary artery disease patients, respectively (p=NS between groups). In patients with microvascular angina, ergonovine constricted proximal coronary segments by 7±1.5% and distal segments by 12.5±3% (p=NS vs. NPY). During NPY administration four microvascular angina patients developed chest pain, ST segment depression, and a marked lengthening of the contrast medium run off, in the absence of epicardial coronary artery spasm. Control individuals and coronary artery disease patients did not experience chest pain, ST segment shifts, or lengthening of the run off during NPY administration. Ergonovine administration caused chest pain and lengthening of the contrast run-off, in the absence of epicardial coronary artery spasm, in one microvascular angina patient. ConclusionsExogenous NPY causes mild epicardial coronary artery constriction which is similar in patients with non-cardiac chest pain, microvascular angina and coronary artery disease. Myocardial ischemia and marked lengthening of the contrast run off in response to NPY occurred in microvascular angina patients but not in control or coronary artery disease patients. An abnormal constrictor response to NPY at the microcirculation level could be the mechanism underlying the ischemic manifestations observed in patients with microvascular angina. Condensed abstract (table of contents)The vasomotor response of proximal and distal coronary artery segments was studied in twenty five patients: 7 microvascular angina, 9 chronic stable angina, and 9 control subjects. Computerized measurements of coronary diameters were carried out before and after the intracoronary administration of neuropeptide Y (NPY) and ergonovine. Constriction of epicardial arteries in response to NPY was mild and not significantly different in control, microvascular angina and coronary artery disease patients. Ergonovine-induced epicardial coronary artery constriction was similar to that of NPY. However, NPY caused transient myocardial ischemia in patients with microvascular angina (probably through constriction of the small intramyocardial vessels), but not in control subjects or coronary artery disease patients.

Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.

Effectiveness of the Consecutive Alternating Administration Course of a Triple Antiviral Combination in Coxsackievirus B3 Infections in Mice.

Anti-enteroviral chemotherapeutics for clinical use are not registered so far, mainly due to the rapid development of drug-resistance. One of the possible approaches to overcome this problem is the use of combined chemotherapy. However, its application consisting of simultaneously given drugs, is not efficacious because of the development of multiple resistance. Here we present a novel approach for combined application of anti-enteroviral compounds, consisting of a consecutive alternating administration (CAA) course. CAA was tested on 2 in vivo models of Coxsackievirus B3 infection in newborn mice at inoculation dose of 20 MLD50 (50% mouse lethal dose): neurotropic (Nancy strain) and cardiotropic (Woodruff strain) infections. Compounds partnering in a triple combination were selected as enterovirus (EV) replication inhibitors with different mode of action - disoxaril (a VP1 blocker), guanidine.HCl (targeting 2C protein) and oxoglaucine (attacking 3A coding region). The application of this combination by CAA course resulted in around 40 and 60% survival rate in mice infected with Nancy and Woodruff virus, respectively, accompanied by a marked lengthening of the mean survival time (MST). The results obtained are proofs for the prospect of the treatment course by a triple combination through the CAA scheme as an approach interfering the occurrence of drug resistance at EV infections.

Suprachiasmatic nucleus as the site of androgen action on circadian rhythms

Androgens act widely in the body in both central and peripheral sites. Prior studies indicate that in the mouse, suprachiasmatic nucleus (SCN) cells bear androgen receptors (ARs). The SCN of the hypothalamus in mammals is the locus of a brain clock that regulates circadian rhythms in physiology and behavior. Gonadectomy results in reduced AR expression in the SCN and in marked lengthening of the period of free-running activity rhythms. Both responses are restored by systemic administration of androgens, but the site of action remains unknown. Our goal was to determine whether intracranial androgen implants targeted to the SCN are sufficient to restore the characteristic free-running period in gonadectomized male mice. The results indicate that hypothalamic implants of testosterone propionate in or very near the SCN produce both anatomical and behavioral effects, namely increased AR expression in the SCN and restored period of free-running locomotor activity. The effect of the implant on the period of the free-running locomotor rhythm is positively correlated with the amount of AR expression in the SCN. There is no such correlation of period change with amount of AR expression in other brain regions examined, namely the preoptic area, bed nucleus of the stria terminalis and premammillary nucleus. We conclude that the SCN is the site of action of androgen effects on the period of circadian activity rhythmicity.

Cellular Clocks in AVP Neurons of the SCN Are Critical for Interneuronal Coupling Regulating Circadian Behavior Rhythm

The suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, is a network structure composed of multiple types of neurons. Here, we report that mice with a Bmal1 deletion specific to arginine vasopressin (AVP)-producing neurons showed marked lengthening in the free-running period and activity time of behavior rhythms. When exposed to an abrupt 8-hr advance of the light/dark cycle, these mice reentrained faster than control mice did. In these mice, the circadian expression of genes involved in intercellular communications, including Avp, Prokineticin 2, and Rgs16, was drastically reduced in the dorsal SCN, where AVP neurons predominate. In slices, dorsal SCN cells showed attenuated PER2::LUC oscillation with highly variable and lengthened periods. Thus, Bmal1-dependent oscillators of AVP neurons may modulate the coupling of the SCN network, eventually coupling morning and evening behavioral rhythms, by regulating expression of multiple factors important for the network property of these neurons.

Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: Evidence from sleep–wake EEG in rodents

Accumulating data continue to support the therapeutic potential of glutamate metabotropic (mGluR2) receptors for treatment of psychiatric disorders such as depression, anxiety and schizophrenia. Glutamate neurotransmission is an integral component of sleep–wake mechanisms, which have translational relevance to assess on-target activity of drugs. Here, we investigated the influence of mGluR2 inactivation upon sleep–wake electroencephalogram (EEG) in rodents. Rats were administered with vehicle, the specific mGluR2 antagonist LY341495 (2.5, 5, 10mg/kg) or negative allosteric modulator (NAM) Ro-4491533 (2.5, 10 and 40mg/kg) at lights onset. mGluR2 (−/−) mice were used to confirm the selectivity of functional response. Both LY341495 and Ro-4491533 induced an immediate and endured desynchronized cortical activity during 3–6h associated with enhanced theta and gamma oscillations and depressed slow oscillations during sleep. The arousal-promoting effect is consistent with the marked lengthening of sleep onset latency, an increased number of state transitions from light sleep to waking and the gradual increase in homeostatic compensatory sleep. The arousal response to mGluR2 blockade was not accompanied by sharp rebound hypersomnolence as found with the classical psycho-stimulant amphetamine. mGluR2 (−/−) mice and their WT littermates exhibited similar sleep–wake phenotype, while Ro-4491533 (40mg/kg) enhanced waking associated with increased locomotor activity and body temperature in WT but not in mGluR2 (−/−) mice, which confirm the role of mGluR2 inactivation in the arousal response. Our results lend support for a role of mGluR2 blockade in promoting cortical arousal associated with theta/gamma oscillations as well as high thresholds transitions from sleep to waking.

Neuropeptide-S Evoked Arousal with Electroencephalogram Slow-Wave Compensatory Drive in Rats

Objectives: Neuropeptide S (NPS) exerts a dual arousal and anxiolytic effect in rodents, which may indicate the potential of a novel class of therapeutic agents in psychiatry. The purpose of this study is to fully describe the nature of electroencephalogram (EEG)-defined waking that mediates these arousal effects. Methods: Effects of the intracerebroventricular infusion of NPS at 2 different doses were characterized over 20 h on sleep-wake architecture and EEG spectral components in rats that were chronically implanted with epidural electrodes for continuous measurement of sleep polygraphic and EEG variables. Results: NPS (1 and 10 nmol) increased active waking (+88 and +87%, respectively), decreased light slow-wave sleep (lSWS) (–84 and –68%, respectively), deep slow-wave sleep (dSWS) (–47 and –33%, respectively) and rapid-eye-movement sleep (–71 and –70%, respectively) during the first 2 h after infusion. The wake-promoting effect of NPS is consistent with a marked lengthening in latency to sleep onset, a decrease in the number of state transitions from wakefulness to lSWS, and a delayed lSWS compensatory response. Interestingly, NPS significantly enhanced waking EEG theta oscillations and slow wave activity during dSWS. Conclusion: The findings suggest that NPS enhanced a consolidated waking associated with a subsequent compensatory EEG slow-wave homeostatic drive rather than rebound sleep duration. The characteristics of NPS-induced waking coupled with enhanced EEG theta oscillations without rebound in sleep are desirable therapeutic features in wake-promoting agents.

The effects of submergence on anatomical, morphological and biomass allocation responses of tropical grasses Chloris gayana and Panicum coloratum at seedling stage

Submergence is a major factor affecting seedling recruitment in lowland grassland ecosystems. Our aim was to evaluate the tolerance to increasing flooding intensity of the seedlings of tropical grasses Chloris gayana K. and Panicum coloratum L., whose use as a forage species is increasing in humid grasslands. For this purpose, 2-week-old seedlings of C. gayana and P. coloratum were subjected to control, partial submergence (PS) and complete submergence (CS) in clear water for 14 days and allowed to grow for a subsequent 12-day period to assess their recovery. The following responses were assessed: generation of root aerenchyma, morphological changes and emergence from water, biomass allocation in relation to plant size, and biomass accumulation. Results showed that constitutive root aerenchyma was high in both species. Under PS and CS, root aerenchyma increased by up to 50–55% in C. gayana and up to 40–48% in P. coloratum. Under PS, the increase in seedling height for both species was the same as for controls. Under CS, C. gayana further increased its height and emerged more quickly from water; P. coloratum was not able to increase its height, and therefore the seedlings always remained underwater. The escape-from-water response of C. gayana was associated with preferential biomass allocation towards shoots and with a marked lengthening of leaf blades. By contrast, there was no change in allocation in P. coloratum, and its leaves were shorter under CS. The final biomass of C. gayana under CS was similar to that under PS, and equivalent to 54% of its controls. In P. coloratum, biomass under PS and CS were 64 and 21% of its controls (respectively), which indicates that injury caused by CS persisted during the post-submergence period. In conclusion, both species are tolerant to PS at the seedling stage. However, when flood depth increases by submerging the seedlings, C. gayana is able to escape from water while P. coloratum is not, thus strongly affecting its recovery. Therefore, C. gayana appears to be a more promising species for cultivation in lowland grasslands prone to flooding of unpredictable intensity.

Functional effects of a missense mutation in HERG associated with type 2 long QT syndrome

Long QT syndrome (LQTS) is characterized by a prolonged QT interval that can lead to severe ventricular arrhythmias (torsades de pointes) and sudden death. Congenital LQTS type 2 (LQT2) is due to loss-of-function mutations in the KCNH2 gene encoding Kv11.1 channels responsible for the rapid component of the delayed rectifier current. The purpose of this study was to determine the functional properties of the LQT2-associated mutation p.E637G found in a Spanish family. Wild-type (WT) and p.E637G Kv11.1 channels were transiently transfected in Chinese hamster ovary cells, and currents were recorded using the patch-clamp technique. The p.E637G channels lost inward rectification and K(+) selectivity, generating small but measurable slowly activating, noninactivating currents. These important alterations were corrected neither by cotransfection with WT channels nor by incubation at low temperatures or with pharmacological chaperones. As a consequence of its effects on channel gating, the mutation significantly reduced the outward repolarizing current during the action potential (AP), resulting in a marked lengthening of the duration of a simulated human ventricular AP. We have identified and characterized an LQT2-associated mutation that through removal of C-type inactivation and reduction of K(+) selectivity causes the QT prolongation observed in the patients carrying the mutation. Moreover, the results obtained demonstrate the importance of the glutamic acid at position 637 for the inactivation process and K(+) selectivity of Kv11.1 channels.

TESTING FOR UNEQUAL RATES OF MORPHOLOGICAL DIVERSIFICATION IN THE ABSENCE OF A DETAILED PHYLOGENY: A CASE STUDY FROM CHARACIFORM FISHES

This study develops the random phylogenies rate test (RAPRATE), a likelihood method that simulates morphological evolution along randomly generated phylogenies, and uses it to determine whether a considerable difference in morphological diversity between two sister clades of South American fishes should be taken as evidence of differing rates of morphological change or lineage turnover. Despite identical ages of origin, similar species richness, and sympatric geographic distributions, the morphological and ecological diversity of the superfamily Anostomoidea exceeds that of the Curimatoidea. The test shows with 90% confidence (using variance among species as the measure of morphological diversity) or 99% confidence (using volume of occupied morphospace) that the rate of morphological change per unit time in the Anostomoidea likely exceeded that of the Curimatoidea. Variation in the rate of lineage turnover (speciation and extinction rates) is not found to affect greatly the morphological diversity of simulated clades and is not a likely explanation of the observed difference in morphological diversity in this case study. Though a 17% or greater delay in the onset of diversification in the Curimatoidea remains a possible alternative explanation of unequal morphological diversification, further simulations suggest that two clades drawn from the possible treespace of the Anostomoidea and Curimatoidea will rarely differ so greatly in the onset of diversification. Several uniquely derived morphological and ecological features of the Anostomoidea and Curimatoidea may have accelerated or decelerated their rate of morphological change, including a marked lengthening of the quadrate that may have relaxed structural constraints on the evolution of the anostomoid jaw.

Liver transplantation: evolving patient selection criteria.

The widespread recognition of the success of liver transplantation as a treatment for most types of acute and chronic liver failure has led to increased referrals for transplantation in the setting of a relatively fixed supply of cadaver donor organs. These events have led to a marked lengthening of the waiting time for liver transplantation, resulting in increased deaths of those on the waiting list and sicker patients undergoing transplantation. Nearly 5000 liver transplantations were performed in the United States in 2000, while the waiting list grew to over 17,000 patients. The mounting disparity between the number of liver transplant candidates and the limited supply of donor organs has led to reassessment of the selection and listing criteria for liver transplantation, as well as revision of organ allocation and distribution policies for cadaver livers. The development of minimal listing criteria for patients with chronic liver disease based on a specific definition for decompensation of cirrhosis has facilitated the more uniform listing of patients at individual centres across the United States. The United Network for Organ Sharing, under pressure from transplant professionals, patient advocacy groups and the federal government, has continuously revised allocation and distribution policies based on the ethical principles of justice for the individual patient versus optimal utility of the limited organ supply available annually. Beginning in 2002, it is likely that the Model for End-stage Liver Disease (MELD) score will be implemented to determine disease severity and direct donor organs to the sickest patients rather than to those with the longest waiting times.

Quantitative effects of functional bundle branch block in patients with atrioventricular reentrant tachycardia

Changes in the retrograde conduction time (ventriculoatrial [VA]) interval during functional bundle branch block (BBB) have been used to separate septal from free wall accessory pathways (APs), but different values of the VA interval prolongation (ΔVA) have been described in different reports. A total of 95 patients with single nondecremental APs who developed BBB during atrioventricular reentrant tachycardia were studied. Free wall APs were found in 60 patients, and 35 had septal APs. For patients with free wall APs, complete and incomplete BBB ipsilateral to the atrial insertion site of APs were observed in 39 of 60 patients (65%) and 31 of 60 patients (52%), respectively. For patients who had both complete (QRS ≥120 ms) and incomplete (QRS <120 ms) BBB during atrioventricular reentrant tachycardia, ΔVA for patients with complete BBB was significantly greater than in those with incomplete BBB, 59 ± 19 ms versus 30 ± 11 ms, p <0.001. For patients with septal APs and complete and incomplete BBB during tachycardia, the mean ΔVA for those with complete BBB was 31 ± 20 ms and was significantly longer than in patients with incomplete BBB (14 ± 6 ms), p <0.001. There was no significant difference in ΔVA between those with free wall APs and incomplete BBB compared with those with septal APs and complete BBB. The criteria of QRS ≥120 ms associated with ΔVA ≥40 ms served to best separate free wall from septal APs with a sensitivity of 88% and a specificity of 89%. Left anterior fascicular block was associated with marked lengthening of ΔVA for those with left free wall APs, whereas a left posterior fascicular block pattern resulted in a marked increase in the ΔVA for patients with posteroseptal APs. In the absence of fascicular block patterns, a ΔVA ≥40 ms provides strong evidence of a free wall AP, with a sensitivity of 95% and a specificity of 100%. The left posterior fascicle appears to provide predominant innervation of the posterior septum.

Preceding stimulus frequency-dependent potentiation of the postrest shortening of the action potential duration in rabbits.

Action potential duration (APD) in rabbit ventricular myocardium shortens after a rest period (postrest shortening). However, the effects of preceding stimulus frequency on the postrest shortening have not been elucidated. We recorded transmembrane action potentials (TAPs) and monophasic action potentials (MAPs) from the rabbit ventricle. In in vitro experiments. repetitive regular stimuli (S1) at cycle lengths ranging between 500 to 3000 ms were followed by a single extrastimulus (S2) at a coupling interval of 5000 ms. A decrease in S1S1 interval resulted in a progressive shortening of the duration of TAP (TAPD) elicited by S2 (S2-TAPD), which was potentiated by increasing extracellular calcium concentration ([Ca2+]o) or application of ouabain and was inhibited by lowering [Ca2+]o or verapamil. Application of ryanodine was most effective in lengthening S2-TAPD following a short S1S1 interval. 4-aminopyridine and E4031 caused marked lengthening of S2-TAPD when S1S1 was long. However, the lengthening effect was attenuated and disappeared with a shorter S1S1 interval. In in vivo experiments, regular ventricular pacing (S1) at cycle lengths ranging between 250 to 1000 ms was followed by a single extrastimulus (S2) with a coupling interval (S1S2) of 1500 ms. A decrease in the S1S1 interval also resulted in progressive shortening of the duration of MAP elicited by S2. Our results indicate that the postrest shortening is potentiated by an increase in the preceding stimulus frequency in the rabbit ventricle, in which the function of sarcoplasmic reticulum may play a significant role.

Structural studies on iminophosphine ligands and their palladium complexes

The crystal and molecular structures of the iminophosphine o-(Ph2P)C6H4CH=NC6H4OMe-4 (1) and its palladium complexes [Pd(η3-C3H5){o-(Ph2P)C6H4CH=NC6H4OMe-p}]BF4 (2) and [Pd(η2-fn){o-(Ph2P)C6H4CH=NC6H4OMe-4}] [fn = fumaronitrile, (3)] have been determined by X-ray analysis. In the free ligand (1), the planar imino group of E configuration is oriented, relative to the PPh2 unit, so that the CH=N hydrogen atom points towards phosphorus, with the nitrogen atom on the opposite side. In (2) and (3) the iminophosphine behaves as a P,N-chelate ligand, this coordination mode being achieved by the imino group rotation of 169.3 ° and 145.3 °, respectively, around its bond with the ortho disubstituted phenyl ring. Complex (2) shows a structural disorder with two different orientations of the allyl ligand. The trigonal planar coordination around the central metal in complex (3) involves the P- and N-donor atoms of (1) and the η2-bound olefin, with a marked lengthening of the olefinic carbon-carbon bond. In both the complexes, the chelate six-membered ring of the iminophosphine with palladium is not coplanar with the N-Pd-P coordination plane, the imino carbon atom and the ortho disubstituted phenyl group lying on the same side out of the N-Pd-P plane, whereas the N-substituent and one of the PPh2 groups are on the opposite side. The 1H-n.m.r. spectra at low temperatures of (2) and (3), and of [Pd(η2-tmetc){o-(Ph2P)C6H4CH=NCMe3}] [tmetc = tetramethyl ethylenetetracarboxylate, (4)] are interpreted on the basis of a non-rigid conformation of the chelate iminophosphine, which undergoes a fast dynamic process whereby the N- and P-substituents move above and below the coordination plane.

Structural and Photophysical Properties of Mononuclear and Dinuclear Lanthanide(III) Complexes of Multidentate Podand Ligands Based on Poly(pyrazolyl)borates

Lanthanide(III) complexes have been prepared with [L1]- [the tetradentate chelating ligand bis{3-(2-pyridyl)pyrazolyl}dihydroborate], [L2]- [the tetradentate chelating ligand bis{3-(2-pyrazinyl)pyrazolyl}dihydroborate], [L3]- [the hexadentate chelating ligand bis[3-{6‘-(2,2‘-bipyridyl)}pyrazol-1-yl]dihydroborate], and [L4]2- [the 12-dentate compartmental ligand hexakis{3-(2-pyridyl)pyrazol-1-yl}diboran(IV)ate, which has two hexadentate tris(pyrazolyl)borate-based cavities linked “back-to-back” by a B−B bond]. [Ln(L1)2(NO)3] are 10-coordinate with two tetradentate N-donor ligands and one bidentate nitrate. [Ln(L2)2(NO)3] have 10-coordinate structures similar to those of the [L1]- complexes except that the coordinated N1 of the pyrazine rings is not such a good donor as the pyridine rings in the [L1]- complexes, leading to marked lengthening of these Ln−N bonds. [Ln(L3)(NO3)2] are also 10-coordinate from one hexadentate chelating ligand which has a pseudoequatorial coordination mode and two pseudoaxial bidentate nitrate ligands; the hexadentate ligand has a shallow helical twist to prevent steric interference between its ends. Finally [{Ln(NO3)2(L4)] are dinuclear, with each metal center being 10-coordinate from a tripodal hexadentate ligand cavity and two bidentate nitrates. Five complexes were structurally characterized: [Tb(L2)2(NO3)]·dmf is monoclinic (P21/c) with a = 14.881(3) Å, b = 15.5199(12) Å, c = 15.845(2) Å, β = 92.387(12)°, and Z = 4. [Gd(L2)2(NO3)]·dmf is monoclinic (P21/c) with a = 14.926(2) Å, b = 15.465(2) Å, c = 15.878(2) Å, β = 92.698(11)°, and Z = 4. [Eu(L3)(NO3)2]·dmf·0.5Et2O is triclinic (P1̄) with a = 10.020(3) Å, b = 13.036(3) Å, c = 14.740(3) Å, α = 70.114(14)°, β = 71.55(2)°, γ = 79.66(2)°, and Z = 2. [{La(NO3)(dmf)2}2(L4)](NO3)2·dmf is orthorhombic (Pbca) with a = 18.813(2) Å, b = 15.241(2) Å, c = 27.322(2), and Z = 4. [{Gd(NO3)2}2(L4)]·2.4dmf is tetragonal (P42/n) with a = 16.622(6), c = 24.19(5) Å, and Z = 4. Detailed photophysical studies have been performed on the free ligands and their complexes with Gd(III), Eu(III), and Tb(III) in several solvents. The results show a wide range in the emission properties of the complexes which can be rationalized in terms of subtle variations in the steric and electronic properties of the ligands. In particular the dinuclear Tb(III) complex of [L4]2- has an emission quantum yield of ca. 0.5 in D2O and MeOD.

Post-partum prolongation of the atrial repolarization in rabbit.

Female sexual steroids are known to modify the expression of various K+ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1-3 days) post-partum and late (2-3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1-3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2-3 post-partum. 4-aminopyridine (1 mmol L(-1)). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 micromol L(-1)) or glibenclamide (5 micromol L(-1)) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K+ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.

Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice.

Smooth muscle cells (SMC) of the vascular wall, bladder, myometrium, and gastrointestinal and respiratory tracts retain the ability to proliferate postnatally, which enables adaptive responses to injury, hormonal, or mechanical stimulation. SMC growth is regulated by a number of mesenchymal growth factors, including insulin-like growth factor I (IGF-I). To explore the function of IGF-I on SMC in vivo, the mouse SMC alpha-actin promoter fragment SMP8 (-1074 bp, 63 bp of 5'UT and 2.5 kb of intron 1) was cloned upstream of rat IGF-I cDNA, and the fusion gene microinjected to fertilized eggs of the FVB-N mouse strain. Mating of hemizygous mice with controls produced about 50% transgenic offspring, with equal sex distribution. Transgenic IGF-I mRNA expression was confined to SMC-containing tissues, with the following hierarchy: bladder > stomach > aorta = uterus > intestine. There was no transgene expression in skeletal muscle, heart, or liver. Radioimmunoassayable IGF-I content was increased by 3.5- to 4-fold in aorta, and by almost 10-fold in bladder of transgenic mice at 5 and 10 wk, with no change in plasma IGF-I levels. Wet weight of bladder, stomach, intestine, uterus, and aorta was selectively increased, with no change in total body or carcass weight of transgenic animals. In situ hybridization showed that transgene expression was exquisitely targeted to the smooth muscle layers of the arteries, veins, bladder, ureter, stomach, intestine, and uterus. Paracrine overproduction of IGF-I resulted in hyperplasia of the muscular layers of these tissues, manifesting in remarkably different phenotypes in the various SMC beds. Whereas the muscular layer of the bladder and stomach exhibited a concentric thickening, the SMC of the intestine and uterus grew in a longitudinal fashion, resulting in a marked lengthening of the small bowel and of the uterine horns. This report describes the first successful targeting of expression of any functional protein capable of modifying the phenotype of SMC in transgenic mice. IGF-I stimulates SMC hyperplasia, leading to distinct patterns of organ remodeling in the different tissue environments.