Fibrin glue obliteration is safe, effective and minimally invasive as first line treatment for pilonidal sinus disease in children.

BACKGROUND / PURPOSE: Sacrococcygeal pilonidal sinus disease (PSD) has an incidence of 1.2-2.5/1000 in children. Onset is around puberty. Symptoms of recurrent abscess and chronic suppuration may interfere with education and social integration. Treatments should cause minimal disruption while having good cure and recurrence rates. Curettage and Fibrin glue obliteration (FGO) show promising results in adults. We present our experience of its use in children. METHODS: Review of all pediatric patients receiving FGO of pilonidal sinus performed by a single surgeon from September 2014 to February 2018. RESULTS: Eighteen patients were identified. Median age was 16 (range 15-17), 55.6% were male. All procedures were completed as day cases. Median operative duration was 14 .1 (6-29) min. Twelve patients required only 1 procedure, 4 required 2 procedures, 1 required 5 procedures and 1 elected for formal excision after 2 FGO treatments. Median return to normal activities was 3 days, with 1 day school absence. Two patients developed minor surgical site infections. Median follow-up was 52 weeks (17-102), during which time there was 1 recurrence (5.6%). CONCLUSION: This study demonstrates FGO is a safe, effective procedure for pediatric PNS, with results comparable to off-midline flap techniques and without the need for extensive tissue excision and the associated morbidity. LEVEL OF EVIDENCE: IV.

Fibrin glue is a quick and effective treatment for primary and recurrent pilonidal sinus disease.

BACKGROUND: Pilonidal sinus disease (PSD) is a common, chronic inflammatory condition involving hair follicles within the natal cleft. It mainly affects young males and creates a significant health, social and economic burden. Traditional surgery is often radical resulting in pain, wound complications, long recovery times and poor cosmesis. The aim of our study was to evaluate fibrin glue as a primary treatment for PSD. METHODS: Fibrin glue procedures for a single surgeon at our institution were identified from operative coding databases and the logbook from January 2011 to January 2016. Patients had curettage of the sinus with fibrin glue obliteration. Recurrence data was collected retrospectively. RESULTS: One hundred and forty-six patients were identified; (115 (79%) males, mean age 30 (range 16-78 years). One hundred and forty-four (99%) were discharged the same day. Four (2.7%) were treated conservatively for wound discharge. Median operating time was 9 (range 4-28) min. There were 40 (27%) recurrences after one glue application. Median time to recurrence was 4 (range 0.25-36) months. Twenty-four (60%) of the recurrences had repeat glue treatment with 4 (16.6%) recurrences. After 2 rounds of treatment with glue alone, 126 out of 130 (96.9%) patients had healed. CONCLUSIONS: Fibrin glue application following curettage of the sinus is a quick and effective procedure for first and second line treatment of PSD.

Experimental and theoretical charge density distribution in a host-guest system: synthetic terephthaloyl receptor complexed to adipic acid.

The experimental charge density distributions in a host-guest complex have been determined. The host, 1,4-bis[[(6-methylpyrid-2-yl)amino]carbonyl]benzene (1) and guest, adipic acid (2). The molecular geometries of 1 and 2 are controlled by the presence in the complex of intermolecular hydrogen bonding interactions and the presence in the host 1 of intramolecular hydrogen bonding motifs. This system therefore serves as an excellent model for studying noncovalent interactions and their effects on structure and electron density, and the transferability of electron distribution properties between closely related molecules. For the complex, high resolution X-ray diffraction data created the basis for a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) against extensive low-temperature (T = 100 K) single-crystal X-ray diffraction data and compared with a selection of theoretical DFT calculations on the same complex. The molecules crystallize in the noncentrosymmetric space group P2(1)2(1)2(1) with two independent molecules in the asymmetric unit. A topological analysis of the resulting density distribution using the atoms in molecules methodology is presented along with multipole populations, showing that the host and guest structures are relatively unaltered by the geometry changes on complexation. Three separate refinement protocols were adopted to determine the effects of the inclusion of calculated hydrogen atom anisotropic displacement parameters on hydrogen bond strengths. For the isotropic model, the total hydrogen bond energy differs from the DFT calculated value by ca. 70 kJ mol(-1), whereas the inclusion of higher multipole expansion levels on anisotropic hydrogen atoms this difference is reduced to ca. 20 kJ mol(-l), highlighting the usefulness of this protocol when describing H-bond energetics.

An evaluation of the potential of linear and nonlinear skin permeation models for the prediction of experimentally measured percutaneous drug absorption.

UNLABELLED: OBJECTIVES The developments in combinatorial chemistry have led to a rapid increase in drug design and discovery and, ultimately, the production of many potential molecules that require evaluation. Hence, there has been much interest in the use of mathematical models to predict dermal absorption. Therefore, the aim of this study was to test the performance of both linear and nonlinear models to predict the skin permeation of a series of 11 compounds. METHODS: The modelling in this study was carried out by the application of both quantitative structure permeability relationships and Gaussian process-based machine learning methods to predict the flux and permeability coefficient of the 11 compounds. The actual permeation of these compounds across human skin was measured using Franz cells and a standard protocol with high performance liquid chromatography analysis. Statistical comparison between the predicted and experimentally-derived values was performed using mean squared error and the Pearson sample correlation coefficient. KEY FINDINGS: The findings of this study would suggest that the models failed to accurately predict permeation and in some cases were not within two- or three-orders of magnitude of the experimentally-derived values. However, with this set of compounds the models were able to effectively rank the permeants. CONCLUSIONS: Although not suitable for accurately predicting permeation the models may be suitable for determining a rank order of permeation, which may help to select candidate molecules for in-vitro screening. However, it is important to note that such predictions need to take into account actual relative drug candidate potencies.

Cell surface rescue of kidney anion exchanger 1 mutants by disruption of chaperone interactions.

Mutations in the human kidney anion exchanger 1 (kAE1) membrane glycoprotein cause impaired urine acidification resulting in distal renal tubular acidosis (dRTA). Dominant and recessive dRTA kAE1 mutants exhibit distinct trafficking defects with retention in the endoplasmic reticulum (ER), Golgi, or mislocalization to the apical membrane in polarized epithelial cells. We examined the interaction of kAE1 with the quality control system responsible for the folding of membrane glycoproteins and the retention and degradation of misfolded mutants. Using small molecule inhibitors to disrupt chaperone interactions, two functional, dominant kAE1 mutants (R589H and R901stop), retained in the ER and targeted to the proteasome for degradation by ubiquitination, were rescued to the basolateral membrane of Madin-Darby canine kidney cells. In contrast, the Golgi-localized, recessive G701D and the severely misfolded, ER-retained dominant Southeast Asian ovalocytosis (SAO) mutants were not rescued. These results show that functional dRTA mutants are retained in the ER due to their interaction with molecular chaperones, particularly calnexin, and that disruption of these interactions can promote their escape from the ER and cell surface rescue.

The synthesis and coordination chemistry of a tris-8-aminoquinoline tripodal ligand.

A tripodal tris-8-aminoquinoline ligand was synthesised in high yield via the Bucherer reaction. The septa-dentate ligand was found to give isolable complexes when coordinated with transition metals. Complexes of zinc(ii), cadmium(ii) and cobalt(iii) were isolated and their solid state structures were determined by single crystal X-ray diffraction. The solid state structures of these complexes were compared to the solution (1)H NMR data which was obtained for each complex. The two first row metals both gave octahedral six coordinate structures, although the two metals were coordinated by a differing donor set of heteroatoms. The cadmium complex was found to contain a seven coordinate cadmium centre in the solid state. DFT calculations were carried out in order to give an indication as to why the two different six coordinate binding modes were encountered.

Loss of specific chaperones involved in membrane glycoprotein biosynthesis during the maturation of human erythroid progenitor cells.

The production of erythrocytes requires the massive synthesis of red cell-specific proteins including hemoglobin, cytoskeletal proteins, as well as membrane glycoproteins glycophorin A (GPA) and anion exchanger 1 (AE1). We found that during the terminal differentiation of human CD34(+) erythroid progenitor cells in culture, key components of the endoplasmic reticulum (ER) protein translocation (Sec61alpha), glycosylation (OST48), and protein folding machinery, chaperones BiP, calreticulin (CRT), and Hsp90 were maintained to allow efficient red cell glycoprotein biosynthesis. Unexpected was the loss of calnexin (CNX), an ER glycoprotein chaperone, and ERp57, a protein-disulfide isomerase, as well as a major decrease of the cytosolic chaperones, Hsc70 and Hsp70, components normally involved in membrane glycoprotein folding and quality control. AE1 can traffic to the cell surface in mouse embryonic fibroblasts completely deficient in CNX or CRT, whereas disruption of the CNX/CRT-glycoprotein interactions in human K562 cells using castanospermine did not affect the cell-surface levels of endogenous GPA or expressed AE1. These results demonstrate that CNX and ERp57 are not required for major glycoprotein biosynthesis during red cell development, in contrast to their role in glycoprotein folding and quality control in other cells.

Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis.

Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.

Quantum-Chemical Design of Cryptand-like Ditopic Salt Binders.

Hartree-Fock, density functional, and MP2 methods are applied to the problem of designing neutral, bicyclic C3-symmetric cages incorporating interacting anion- and cation-binding sites which strongly bind NaCl as an ion contact pair. A large number of trial ligands L and their complexes L:NaCl are tested, with the focus on maximizing binding by (i) optimizing the cavity size and shape and (ii) varying the nature of the anion- and cation-binding functionalities. The corresponding complexes L:Cl(-) and L:Na(+) are also studied in some detail. An analysis of their structures and charge distributions helps to build a consistent picture of the requirements for a successful NaCl binding. The 'best' candidate ligand utilizes a tripodal triether-substituted amine N(CH2CH2OR-)3 to bind the sodium cation; three thiourea groups in a tripodal arrangement with a 1,3,5-trisubstituted benzyl spacer group {C6H3(CH2NHC [Formula: see text] XNH-)3 X=O,S} to bind chloride; and a -CH2CH2- spacer linking the two binding sites. A simple Quantitative Structure-Property analysis suggests that the binding cavity shape and size is near to the optimal one for this system.

Conformations, energies, and intramolecular hydrogen bonds in dicarboxylic acids: implications for the design of synthetic dicarboxylic acid receptors.

The various conformers of the dicarboxylic acids HO2C--(CH2)n--CO2H, n = 1-4, were obtained using density functional methods (DFT), both in the gas phase and in the aqueous phase using a polarized continuum model (PCM). Several new conformers were identified, particularly for the two larger molecules glutaric (n = 3) and adipic acid (n =4). The PCM results show that the stability of most conformers were affected, many becoming unstable in the aqueous phase; and the energy ordering of conformers is also different. The results suggest that conformational preferences could be important in determining the design and stability of appropriate synthetic receptors for glutaric and adipic acid. Geometry changes between gas and aqueous phases were most marked in those conformers containing an intramolecular hydrogen bond. Additional calculations have probed the strength of intramolecular hydrogen bonds in these dicarboxylic acids. In the cases of glutaric and adipic acid, the strength of the intramolecular hydrogen bond were estimated to be around 28-29 kJ/mol, without any vibrational energy correction. The intramolecular hydrogen bond energies in malonic and succinic acid were also estimated from the calculated H-bond distances using an empirical relationship. Intramolecular H-bond redshifts of 170-250 cm(-1) have been estimated from the results of the harmonic frequency analyses.

AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer.

Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.

Experimental charge density of a potential DHO synthetase inhibitor: dimethyl-trans-2-oxohexahydro-pyrimidine-4,6-dicarboxylate.

The experimental charge density distribution of dimethyl-trans-2-oxohexahydro-pyrimidine-4,6-dicarboxylate 1 has been determined using single-crystal X-ray diffraction data measured at 100 K, in terms of the rigid-pseudoatom formalism. Multipole refinement converged at R(F) = 0.034 for 7283 reflections with I > 3 sigma (I) and sin theta/lambda < or = 1.13 A(-1). Covalent and hydrogen bonding interactions are analyzed using a topological analysis of the Laplacian of the charge density. The experimentally derived electrostatic potential mapped onto the reactive surface of the molecule reveals the potential binding sites of 1.

A new orbital-based model for the analysis of experimental molecular charge densities: an application to (Z)-N-methyl-C-phenylnitrone.

An alternative to the usual atom-centred multipole expansion is presented for the analysis of high resolution, low-temperature X-ray scattering data. The molecular electron density is determined in a fixed basis of molecular orbitals with variable orbital occupation numbers, i.e. the same form which is used to represent the density in ab initio electron-correlated calculations. The advantages of such an approach include linear scaling (in the sense that the number of parameters to be determined by fitting varies linearly with system size) and ease of property calculation. The method is applied to experimental high-resolution structure factors for a phenylnitrone, and compared to the results of a multipole model of the same data. Finally, the model is critically compared with several related, published orbital-based models.

Bond energy, aromatic stabilization energy and strain in IPR fullerenes.

Various models applied to DFT structures and energies of 2-D and 3-D aromatic molecules shed new light on the effects of strain and aromaticity in these systems. The cyclic pi electron delocalisation does not stabilize the fullerene C60 formation; and 5-6 and 6-6 CC bonds have near-identical bond stretch potentials.

Intramolecular C-H...Ccarbene hydrogen bonds and competing interactions in monoprotonated tripodal carbenes.

The anionic tripodal N-heterocyclic carbene (C3N2H3)3BH- first prepared by Fehlhammer, together with three neutral variants, (C3N2H3)3CH, (C3N2H3)3P, and (C3N2H3)3SiH, have been studied using quantum chemical methods. Isodesmic reactions are used to deduce that the phosphine-bridgehead species in particular has a large-resonance stabilization energy. All the podands undergo substantial conformational change on excitation to the lowest triplet electronic state, with effective localization of the excitation on one of the heterocyclic rings, dearomatizing it. On monoprotonation of the ground states, three of these species display intramolecular C-H...Ccarbene hydrogen bonding: The nature and strength of these interactions is explored using model (intermolecularly hydrogen-bonded) complexes, isodesmic reactions, and GIAO calculations of chemical shifts. One surprising result is that C-H...Ccarbene hydrogen bonds involving ethenic hydrogens can be almost as strong as those involving the imidazolium proton (first identified by Arduengo). The case of the monoprotonated carbon bridgehead species is in particular intriguing. It is stabilized by a competitive Ccarbene...N interaction of sufficient strength to override the C-H...Ccarbene bonding motif observed in the other structures.

Determination of estrogens in river water by gas chromatography-negative-ion chemical-ionization mass spectrometry.

A method for the determination of estrogens (17alpha-estradiol, 17beta-estradiol, estrone, ethynyl estradiol, and estriol) as pentafluorobenzyl-trimethylsilyl (PFB-TMS) derivatives by gas chromatography-mass spectrometry (GC-MS) with negative-ion chemical-ionization (NICI) is described. The NICI of all the derivatives produced an intense [M-PFB]- ion as the base peak. The reagent gas (methane) flow-rate and the ion source temperature were determined to be 2.0 ml/min and 240 degrees C, respectively, for the optimized NICI-selected ion monitoring (SIM) conditions. The sensitivities of the PFB-TMS derivatives in the NICI mode were 8.0-130 times higher than those of the PFB-TMS derivatives in electron ionization (EI) mode, and 12-25 times higher than those of all the TMS derivatives in the EI mode. This method was applied to the analysis of estrogens in river water using a solid-phase extraction as the sample preparation. The recoveries of the target chemicals from a river-water sample spiked with standards at 2 ng/l level were 85.8-126.5% (RSD, 6.2-13.0%). The methodical detection limits ranged from 0.10 to 0.28 ng/l.