Umbilical Cord Diseases Affecting Obstetric and Perinatal Outcomes.

BACKGROUND: (1) The aim of this article is to describe the physiopathology underlying umbilical cord diseases and their relationship with obstetric and perinatal outcomes. (2) Methods: Multicenter case series of umbilical cord diseases with illustrations from contributing institutions are presented. (3) Results: Clinical presentations of prenatal ultrasound findings, clinical prenatal features and postnatal outcomes are described. (4) Conclusions: Analysis of our series presents and discusses how umbilical cord diseases are associated with a wide variety of obstetric complications leading to a higher risk of poor perinatal outcomes in pregnancies. Knowing the physiopathology, prenatal clinical presentations and outcomes related to umbilical diseases allow for better prenatal counseling and management to potentially avoid severe obstetric and perinatal complications.

The impact of artisanal gold mining, ore processing and mineralization on water quality in Marmato, Colombia.

Marmato, Colombia, has been an important centre of gold mining since before the first Spanish colonizers arrived in 1536. The Marmato deposit is hosted in a dacite and andesite porphyry stock as sheeted sulphide-rich veinlet systems. The district is currently experiencing a surge in both major mining projects and artisanal mining, driven by sustained high gold prices. Ore from small-scale and artisanal gold mining is processed in numerous small mills (entables) around Marmato, which impact surface water quality through the discharge of milled waste rock slurry, highly alkaline cyanide-treated effluent, and high dissolved metal loads. To investigate the impact of artisanal mining and ore processing, water samples were collected in January 2012 from streams around Marmato. The average dissolved metal concentrations in impacted streams were Zn, 78 mg L-1; Pb, 0.43 mg L-1; Cu, 403 µg L-1 Cd, 255 µg L-1; As, 235 µg L-1; Ni, 67 µg L-1; Co, 55 µg L-1; Sb, 7 µg L-1; and Hg, 42 ng L-1, exceeding World Health Organization drinking water guidelines. In addition, arsenic speciation was conducted in-situ and indicated that 91-95% of inorganic arsenic species is in the form of As(V). Spatial analysis of the data suggests that entables processing ore for artisanal miners are the main contributor to water pollution, with high sediment loads, alkalinity and elevated concentrations of dissolved arsenic, cadmium, mercury and lead, caused by the processing of gold-bearing sulphides in the entables. Geochemical data from surface water were compared to a comprehensive data set of whole rock analyses from drill core and channel samples from the deposit, indicating that the deposit is significantly enriched in gold, silver, lead, zinc, arsenic, antimony, and cadmium compared to crustal averages, which is reflected in the surface water geochemistry. However, elevated mercury levels in surface water cannot be explained by enrichment of mercury in the deposit and strongly suggest that mercury is being added to concentrates during ore processing to amalgamate fine gold.

Pharmacotherapy of Down's Syndrome: When and Which?

Down Syndrome (DS) is an essential genetic disease that involves many other body systems along with cerebral functions. The postnatal approach to treat this genetic disease includes intervention on various related disorders (e.g., heart failure, respiratory, oral, ear, and hearing disorders). However, different proposed treatments do not significantly improve the quality of life of these subjects. Another approach to the treatment of DS considering the possibility to intervene on the embryo was recently introduced. As of this, the current study has reviewed different outcomes regarding DS treatment in an animal model, namely the Ts65Dn mouse. The obtained results encouraged spending more time, efforts, and resources in this field. Besides, various treatment strategies were tried to include genetic modification, treatment with vasoactive intestinal peptide derivatives or fluoxetine. However, the main obstacle to the use of these possible treatments is the ethical issues it raises. The progression of the pregnancy in spite of awareness that DS affects the unborn and prenatal treatment of DS injured embryo are relevant dilemmas. Thus, talented researchers should spend more efforts to improve the quality of life for people affected by DS, which will allow probably a better approach to the ethical issues.

Polycyclic Sulfoximines as New Scaffolds for Drug Discovery.

The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory.

Fetal Intra-abdominal Umbilical Vein Aneurysm.

IMPORTANCE: Fetal umbilical vein aneurysm is an uncommon anomaly that accounts for approximately 4% of umbilical cord abnormalities. The rate of intrauterine fetal death is reported to be approximately 4% to 5%, higher than the background rate of 0.7% that is generally reported during pregnancy. OBJECTIVE: The aim of this study was to review the pathophysiology, diagnosis, and clinical management of fetal umbilical vein aneurysm. EVIDENCE ACQUISITION: Advances in high-resolution ultrasound combined with color Doppler and 3-dimensional rendering have contributed to an increased understanding of the fetal venous circulation in recent years. RESULTS: When the diagnosis of umbilical vein aneurysm is made, the patient should undergo a detailed ultrasound evaluation of the fetal anatomy, including fetal echocardiography, to exclude associated anomalies. Amniocentesis should be offered when other anomalies are found. Patients should be informed about the potential for an unfavorable outcome of pregnancy and should undergo close ultrasound surveillance to assess the size of the aneurysm, as well as any evidence of thrombosis or signs of hydrops. CONCLUSIONS: The main prognostic feature associated with a poor outcome of umbilical vein aneurysm seems to be the presence of other anomalies. Early diagnosis is associated with a somewhat worse prognosis, and most fetal deaths have been observed between 27 and 30 weeks of gestation. In the third trimester, it is reasonable to perform serial ultrasound examinations to assess fetal growth, the size of the aneurysm, and the blood flow pattern within the aneurysm.

An innovative fast track solution for food bolus impaction due to Jackhammer esophagus in an emergency department: the "Nitro-Push Blind Technique" case report.

BACKGROUND: In the medical literature are described only few clinical cases of esophageal food bolus impaction due to esophageal motility disorders. Moreover, the management of this condition is highly variable with no evidence in the literature to strongly support a clear defined intervention. CASE PRESENTATION: In this paper we describe for the first time a case of 53-year-old male with food bolus impaction due to Jackhammer esophagus referred to emergency department. On the basis of the known esophageal past medical history as well as the absence of bones in the bolus, the patient was submitted to a new conservative treatment, the "Nitro-Push Blind Technique". CONCLUSIONS: The new technique performed with naso-gastric tube thrust after nitrates medication in definite clinical case supported by known functional disease, represents a safe and successful method, with short observational period to minimize exposure to potential morbidity and reduce the inpatient stay in emergency department. It should be recommended, once validated in a larger cohort, as the initial treatment of choice in the selected patients with food boneless bolus impaction in the emergency settings. Indeed, this management provides only minimal deviation from the current practice and is hence technically easy to learn and perform.

Vagus nerve stimulation during pregnancy: an instructive case.

BACKGROUND: Little is known about the safety of vagus nerve stimulation during pregnancy. CASE REPORT: Herein we report the case of a young woman affected by childhood-onset partial epilepsy, obesity, and depression in which a malfunctioning of VNS was detected during pregnancy. Although device functioning was not optimal during the critical period of organogenesis, no morphological abnormalities of the fetus were detected. CONCLUSION: A confirmation of VNS safety may increase its use during pregnancy, thus reducing possible systemic effects of antiepileptic drugs and antidepressants on the women and the baby.

Ureido-substituted sulfamates show potent carbonic anhydrase IX inhibitory and antiproliferative activities against breast cancer cell lines.

A series of 50 sulfamates were obtained by reacting 4-aminophenol with isocyanates followed by sulfamoylation. Most of the new compounds were nanomolar inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII, whereas they inhibited less cytosolic offtarget isoforms CA I and II. Some of these sulfamates showed significant antiproliferative activity in several breast cancer cell lines, such as SKBR3, MCF10A, ZR75/1, MDA-MB-361 and MCF7, constituting interesting anticancer leads.

Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.

Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.

Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma.

Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.

Dissecting the inhibition mechanism of cytosolic versus transmembrane carbonic anhydrases by ESR.

Spin-labeled sulfonamides incorporating TEMPO moieties showed efficient activity as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and, in particular, of the physiologically relevant isoenzymes hCA II, hCA IX, and hCA XIV. Here we report a detailed analysis of this class of inhibitors by means of ESR and X-ray crystallography, in comparison with inhibition tests against all mammalian CA isoforms, CA I-XIV. Local dynamics and structure were manifested in the ESR signal through modulation of internal magnetic anisotropies. Analysis and fitting of the ESR spectra of several spin-labeled sulfonamides with isoforms CA II (cytosolic), CA IX (catalytic domain and full length transmembrane, tumor-associated isoform) and CA XIV (transmembrane isozyme) provided information about polarity and dynamics of specific microenvironments sensed by the nitroxyl group within the active site cavity of these isozymes. The comparison of ESR and crystallographic data of hCA II complexed with one of these inhibitors constitutes a useful tool for the understanding of molecular hindrance and ordering within the enzyme active site, and provides theoretical bases to use these inhibitors for imaging purposes of hypoxic tumors overexpressing the transmembrane isozyme CA IX. Combining the sulfonamide zinc-binding group with the TEMPO moiety thus allowed to dissect the selective inhibition mechanism of different cytosolic and transmembrane carbonic anhydrases.

Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-ray crystal structures in adducts with isozyme II: when three water molecules and the keto-enol tautomerism make the difference.

Thiazide diuretics inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a different profile as compared to classical inhibitors. Acting as moderate-weak inhibitors of CA II and CA I, chlorthalidone and indapamide considerably inhibit other isozymes among the 16 CAs present in vertebrates. These compounds show a different behavior against CAs I and II, with chlorthalidone being 18.3 times more potent against CA II and 150 times more potent against CA I, as compared to indapamide. In the X-ray crystal structures of the CA II-chlorthalidone adduct three active site water molecules interacting with the inhibitor scaffold were observed that lack in the corresponding indapamide adduct. Chlorthalidone bound within the active site is in an enolic tautomeric form, with the OH moiety participating in two strong hydrogen bonds with Asn67 and a water molecule. This binding mode may be exploited for designing better CA II inhibitors.

Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.

Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.

Ligand-based and structure-based virtual screening to identify carbonic anhydrase IX inhibitors.

A three-dimensional pharmacophore model of CA IX inhibitors was generated and used to screen the ZINC database of commercially available compounds. The hits were docked in a CA IX homology model. By visualizing the binding mode and score of these compounds, six derivatives were selected and evaluated for their inhibitory potency against CA IX. A highly active CA IX inhibitor was identified which may be used as a lead to design novel such derivatives.

Carbonic anhydrase inhibitors. Cloning, characterization and inhibition studies of the cytosolic isozyme III with anions.

The cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozyme III (hCA III) has been cloned and purified by the GST-fusion protein method. Recombinant pure hCA III had the following kinetic parameters for the CO(2) hydration reaction at 20 degrees C and pH 7.5: k(cat) of 1.3 x 10(4) s(- 1) and k(cat)/K(M) of 2.5.10(5) M(- 1) s(- 1). The first detailed inhibition study of this enzyme with anions is reported. Inhibition data of the cytosolic isozymes hCA I - hCA III with a large number of anions (halides, pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrosulfide, sulfate, sulfamic acid, sulfamide, etc.), were determined and these values are comparatively discussed for these three cytosolic isoforms. Fluoride, nitrate, nitrite, phenylboronic acid and phenylarsonic acid (as anions) were weak hCA III inhibitors (K(I)s of 21-78.5 mM), whereas bicarbonate, chloride, bromide, sulfate and several other simple anions showed K(I)s around 1 mM. The best hCA III inhibitors were carbonate, cyanide, thiocyanate, azide and hydrogensulfide, which showed K(I)s in the range of 10-90 microM. It is difficult to explain the inhibitory activity of carbonate (K(I) of 10 microM) against hCA III, also considering the fact that this ion has an affinity of 15-73 mM for hCA I and II and is in equilibrium with one of the substrates of this enzyme, i.e., bicarbonate, which is a much weaker inhibitor (K(I) of 0.74 mM against hCA III, of 12 mM against hCA I and of 85 mM against hCA II).

Carbonic anhydrase inhibitors. Biphenylsulfonamides with inhibitory action towards the transmembrane, tumor-associated isozymes IX possess cytotoxic activity against human colon, lung and breast cancer cell lines.

Reaction of 4,4-biphenyl-disulfonyl chloride with aromatic/heterocyclic sulfonamides also incorporating a free amino group, such as 4-aminobenzenesulfonamide, 4-aminoethyl-benzenesulfonamide, 6-chloro-4-aminobenzene-1,3-disulfonamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded bis-sulfonamides which have been tested as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4..2.1.1). The compounds were rather modest inhibitors of isozymes CA I and XII, but were more efficient as inhibitors of the cytosolic CA II and transmembrane, tumor-associated CA IX (inhibition constants in the range of 21-129 nM gainst hCA II, and 23-79 nM against hCA IX, respectively). The new bis-sulfonamides also showed inhibition of growth of several tumor cell lines (ex vivo), with GI(50) values in the range of 0.74-10.0 microg/mL against the human colon cancer cell line HCT116, the human lung cancer cell line H460 and the human breast cancer cell line MCF-7.

Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic isozymes I and II.

An approach for the synthesis of carbonic anhydrase (CA, EC 4.2.1.1) inhibitor coated gold nanoparticles is reported. This nanomaterial selectively inhibited the tumor-associated isoform CA IX overexpressed in hypoxic cancers over the ubiquitous, cytosolic housekeeping isozymes CA I and II and was membrane impermeant. As CA IX has an extracellular active site, the new nanomaterial which is confined to the extracellular space may be useful for imaging and treatment of hypoxic tumors.

Carbonic anhydrase inhibitors: design of membrane-impermeant copper(II) complexes of DTPA-, DOTA-, and TETA-tailed sulfonamides targeting the tumor-associated transmembrane isoform IX.

The synthesis and carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of two series of aromatic sulfonamides and their Cu(II) derivatives, incorporating metal-complexing moieties of the DTPA, DOTA, and TETA type are reported. The new compounds were designed in such a way as to possess high affinity for Cu(II) ions, exploiting four pendant carboxylate moieties in the DTPA derivatives, as well as the cyclen/cyclam macrocyles, and three pendant acetate moieties in the DOTA and TETA derivatives. The new derivatives showed modest inhibition of the cytosolic isoform CA I (K(I) values in the range of 66-2130 nM), were better CA II inhibitors (K(I) values in the range of 21-360 nM), and excellent inhibitors of the tumor-associated isoform CA IX (K(I) values in the range of 4.1-110 nM), with selectivity ratios for the inhibition of the tumor (CA IX) over the cytosolic (CA II) isozyme in the range of 10.74-20.88 for the best derivatives. Copper complexes were more inhibitory than the corresponding ligand sulfonamides, and showed membrane impermeability, thus, having the possibility to specifically target the transmembrane CA IX that has an extracellular active site. Incorporation of radioactive copper isotopes in this type of CA inhibitor may lead to interesting diagnostic/therapeutic applications for such compounds.

Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?

Sulfonamide diuretics such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide were tested as inhibitors of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). These drugs were discovered in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. We prove here that although acting as moderate to weak inhibitors of CA II, all these drugs considerably inhibit other isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar/subnanomolar inhibitors against such isoforms were detected, such as among others metolazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also resolved at high resolution, and the binding of this sulfonamide to the enzyme was compared to that of dichlorophenamide, sulpiride and a pyridinium containing sulfonamide. Indapamide binds to CA II in a manner not seen earlier for any other CA inhibitor, which might be important for the design of compounds with a different inhibition profile.

Carbonic anhydrase inhibitors: design of spin-labeled sulfonamides incorporating TEMPO moieties as probes for cytosolic or transmembrane isozymes.

A series of spin-labeled sulfonamides incorporating TEMPO moieties were synthesized by a procedure involving the formation of a thiourea functionality between the benzenesulfonamide and free radical fragment of the molecules. The new compounds were tested as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and showed efficient inhibition of the physiologically relevant isozymes hCA II and hCA IX (hCA IX being predominantly found in tumors) and moderate to weak inhibitory activity against hCA I. Some derivatives were also selective for inhibiting the tumor-associated isoform over the cytosolic one CA II, and presented significant changes in their ESR signals when complexed to the enzyme active site, being interesting candidates for the investigation of hypoxic tumors overexpressing CA IX by ESR techniques, as well as for imaging/treatment purposes.