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Biomedical subjects

C George

Publications and source records attributed to C George.

At least 73 records · Page 4Linked to original sources
PubMed1997

X-ray structure of Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP-NH2), a highly potent mu-receptor selective opioid agonist. Comparison with proposed model structures.

Tyr-D-Tic-Phe-Phe-NH2 (D-TIPP), a linear tetrapeptide containing the conformationally restricted Tic residue (tetrahydroisoquinoline-3-carboxylic acid), is an opioid agonist which exhibits high affinity and selectivity for the mu-receptor. Its conformational features have been studied using a combination, a solid-state (X-ray) and modeling (molecular mechanics and Monte Carlo simulations) methods. The results of the X-ray study showed two distinct conformers for D-TIPP, with the main differences lying in the orientation of the Tyr side-chain and the presence of both D-Tic(+) and D-Tic(-) conformations for the D-Tic residue. The peptide backbone is folded and stabilized by the formation of one intramolecular hydrogen bond. The modeling results also indicated a folded backbone for the peptide and both cis and trans conformers for the D-Tic residue are found in the lowest-energy structures. Comparison of the X-ray and modeling results shows many similarities especially around the D-Tic residue.

Crystallography, X-Ray↗
PubMed1997

Epidemiology and aetiological diagnosis of corneal ulceration in Madurai, south India.

AIMS/BACKGROUND: To determine the epidemiological characteristics and risk factors predisposing to corneal ulceration in Madurai, south India, and to identify the specific pathogenic organisms responsible for infection. METHODS: All patients with suspected infectious central corneal ulceration presenting to the ocular microbiology and cornea service at Aravind Eye Hospital, Madurai, from 1 January to 31 March 1994 were evaluated. Sociodemographic data and information pertaining to risk factors were recorded, all patients were examined, and corneal cultures and scrapings were performed. RESULTS: In the 3 month period 434 patients with central corneal ulceration were evaluated. A history of previous corneal injury was present in 284 patients (65.4%). Cornea cultures were positive in 297 patients (68.4%). Of those individuals with positive cultures 140 (47.1%) had pure bacterial infections, 139 (46.8%) had pure fungal infections, 15 (5.1%) had mixed bacteria and fungi, and three (1.0%) grew pure cultures of Acanthamoeba. The most common bacterial pathogen isolated was Streptococcus pneumoniae, representing 44.3% of all positive bacterial cultures, followed by Pseudomonas spp (14.4%). The most common fungal pathogen isolated was Fusarium spp, representing 47.1% of all positive fungal cultures, followed by Aspergillus spp (16.1%). CONCLUSIONS: Central corneal ulceration is a common problem in south India and most often occurs after a superficial corneal injury with organic material. Bacterial and fungal infections occur in equal numbers with Streptococcus pneumoniae accounting for the majority of bacterial ulcers and Fusarium spp responsible for most of the fungal infections. These findings have important public health implications for the treatment and prevention of corneal ulceration in the developing world.

Adolescent↗
PubMed1997

Multiple pigmented cutaneous papules associated with a novel canine papillomavirus in an immunosuppressed dog.

Cutaneous papillomavirus infection was diagnosed in a 6-year-old female Boxer dog that was under long-term corticosteroid therapy for atopic dermatitis. Multiple black, rounded papules were present on the ventral skin. Spontaneous regression occurred within 3 weeks after cessation of corticosteroids. Histologically, the lesions consisted of well-demarcated cup-shaped foci of epidermal endophytic hyperplasia with marked parakeratosis. In the upper stratum spinosum and in the stratum granulosum, solitary or small collections of enlarged keratinocytes were observed with basophilic intranuclear inclusion bodies and a single eosinophilic fibrillar cytoplasmic inclusion. Ultrastructurally, viruslike particles (40-45 nm in diameter) were observed within the nucleus, free or aggregated in crystalline arrays. Undulating fibrillar material, thought to be a modified keratin protein, was observed in the cytoplasmic inclusion. Immunohistochemistry, restriction enzyme analysis, and molecular hybridization experiments indicated that these distinctive clinical, histologic, and cytologic features were associated with a novel canine papillomavirus.

Adrenal Cortex Hormones↗
PubMed1996

Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Adrenergic alpha-Agonists↗
PubMed1996

[D-Ala2,D-Leu5]-enkephalin hydrochloride.

The title compound, L-tyrosyl-D-alanyl-glycyl-L-phenyl-alanyl-D-leucine hydrochloride (C29H40N5O7+. Cl-), co-crystallizes with 2-butanone (C4H8O). The structure determination reveals a slightly distorted type I' beta-bend conformation stabilized by one intramolecular hydrogen bond. This conformation is similar to that observed for other [Leu]-enkephalin analogues.

Amino Acid Sequence↗
PubMed1996

A diacetylmorphine polymorph.

The title compound, 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diyl diacetate, C21H23NO5, was crystallized from a solution of its hydrochloride and sodium acetate. Unlike prior reports in which crystals were hexagonal shaped (orthorhombic) and in space group P2(1)2(1)2(1), the crystals in the present determination grew as large prisms (monoclinic) and were in space group P2(1).

Crystallography, X-Ray↗
PubMed1996

Conformationally constrained analogues of diacylglycerol. 12. Ultrapotent protein kinase C ligands based on a chiral 4,4-disubstituted heptono-1,4-lactone template.

Conformationally constrained analogues of diacylglycerol (DAG) built on a 5(-)[(acyloxy)methyl]-5-(hydroxymethyl)tetrahydro-2-furanone template (1, Chart 1) were shown previously to bind tightly to protein kinase C alpha (PK-C alpha) in a stereospecific manner. These compounds, however, racemized readily through rapid acyl migration and lost biological potency. In order to circumvent this problem, the "reversed ester" analogues were designed as a new set of PK-C ligands. This reversal of the ester function produced some new DAG mimetics that are embedded in a C-4 doubly-branched heptono-1,4-lactone template. The reversed ester analogues were impervious to racemization, and their chemically distinct branches facilitated the enantiospecific syntheses of all targets. Compound 2, the simplest reversed ester analogue of 1 (Chart 1), exhibited a 3.5-fold reduction in binding affinity toward PK-C alpha which we attributed to the loss of a stabilizing gauche interaction that caused the ester branch in 2 to be more disordered than in the normal ester 1. However, conversion of the propanoyl branch of 2 into a propenoyl branch restored binding affinity (3 versus 5). As expected, the compounds bound to the enzyme with strict enantioselectivity (3 and 5 versus 4 and 6). Functionalization of the propenoyl-branched compounds as alpha-alkylidene lactones, in a manner which proved successful with the 5(-)[(acyloxy)methyl]-5-(hydroxymethyl)tetrahydro-2-furanone template (9 and 10), produced stable compounds with equivalent ultrapotent binding affinities for PK-C alpha (7 and 8). The additional incorporation of the propenoyl-branched carbonyl into a gamma-lactone ring was performed (11-14) not only to derive a possible additional entropic advantage but also to confirm the spatial disposition of this carbonyl function in the ligand-enzyme complex. Although no additional entropic advantage was derived, the high binding affinities displayed by compounds 11 and 12 helped to establish the correct orientation of the equivalent carbonyl group in PK-C-bound DAG. As expected, these DAG analogues activated PK-C alpha. The most potent agonist, compound 8, stimulated phosphorylation of the alpha-pseudosubstrate peptide, and in primary mouse keratinocytes it caused inhibition of binding of epidermal growth factor with an ED50 of approximately 1 microM. In contrast to the phorbol esters, compound 8 did not induce acute edema or hyperplasia in skin of CD-1 mice, and its pattern of downregulation with several PK-C isozymes was different from that of phorbol 12-myristate 13-acetate (PMA).

4-Butyrolactone↗
PubMed1996

Structural studies of opioid peptides: a review of recent progress in x-ray diffraction studies.

The solid state structures of many opioid peptide agonists have been elucidated by x-ray diffraction analysis. Recently, the first structure of an opioid peptide antagonist has been determined. Theoretically, linear peptides can have many different backbone conformations, yet early x-ray studies (1983-1987) on enkephalin and its analogues showed only two different backbone conformations: extended and single beta-bend. In 1989 enkephalin was observed in a third conformation, a double beta-bend. Since that time diffraction studies have been completed on the rationally designed linear opioid peptide agonists DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) and DADLE (D-Ala2,D-Leu5-enkephalin) as well as on several cyclic enkephalin analogues including DPDPE (Tyr-[D-Pen-Gly-Phe-D-Pen]) and JOM-13 (Tyr-[D-Cys-Phe-D-Pen]). The most recent review of the x-ray studies on this class of compounds was written in 1988. This paper will update that review to include the results of studies completed since that time.

Amino Acid Sequence↗
PubMed1996

A representational perspective of child abuse and prevention: internal working models of attachment and caregiving.

Attachment theory provides a rich theoretical framework for research and intervention in child abuse. This paper examines the central role of internal working models in the development of child-parent relationships. Mental representations of child attachment (in infancy and middle childhood), adult attachment and parental caregiving are discussed in light of the adaptational deficits that researchers have found to be associated with attachment insecurity. A reconceptualization of the link between insecurity and child abuse is described, highlighting disorganized attachment. Implications for child abuse intervention are discussed.

Child↗
PubMed1996

Crystallographic characterization of geometry and conformation of TOAC, a nitroxide spin-labelled C alpha,alpha-disubstituted glycine, in simple derivatives and model peptides.

The molecular and crystal structures of one derivative and two oligopeptides of TOAC, a nitroxide spin-labelled C alpha, alpha-disubstituted glycine, have been determined by X-ray diffraction. The derivative is the 5(4H)-oxazolone from Piv-TOAC-OH; the oligopeptides are Z-TOAC-(L-Ala)2-NHtBu sesquihydrate and pBrBz-TOAC-(L-Ala)2-TOAC-L-Ala-NHtBu hemihydrate. Incipient and fully developed right-handed 3(10)-helical conformations are formed by both independent molecules in the asymmetric unit of the terminally blocked tripeptide amide and the terminally blocked pentapeptide amide, respectively. The average geometry and preferred conformation for the piperidine ring of the TOAC residues are also discussed in detail.

Cyclic N-Oxides↗
PubMed1996

Fatal transplacental neosporosis in a deer (Cervus eldi siamensis).

Neospora caninum tissue cysts were found in sections of the brain from a full-term stillborn deer of Eld (Cervus eldi siamensis) from a zoo in France. There was N. caninum-associated nonsuppurative encephalitis and the diagnosis was confirmed in immunohistochemical staining with antibodies specific to N. caninum.

Animals↗
PubMed1995

Novel 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors.

A series of 4'-substituted and 4',4"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter. These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters. All of these compounds monophasically displaced [3H]WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM. The most potent compound in this series was 4',4"-difluoro 3 alpha-(diphenylmethoxy)tropane 7c with a Ki = 11.8 nM. All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter. None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM) transporters. Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter. Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake. The present data coupled with the observed differences from cocaine in structure-activity relationships suggested that the 3 alpha-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.

Animals↗
PubMed1995

Conformationally constrained phosphotyrosyl mimetics designed as monomeric Src homology 2 domain inhibitors.

Inhibitors of specific src homology 2 (SH2) domain binding interactions could potentially afford new therapeutic approaches toward a variety of diseases, including several cancers. To date SH2 domain inhibitors have been confined to small phosphotyrosyl (pTyr)-containing peptides that appear to bind along the surface of SH2 domains with specific recognition features protruding into the protein. Among these protrusions is the pTyr residue itself, which is inserted into a well-formed binding pocket. In the present study monomeric pTyr mimetics were prepared having key aspects of their structure constrained to conformations of the bound pTyr residue observed in the previously reported X-ray structure of a pTyr-peptide bound to the Lck SH2 domain. The resulting constrained pTyr mimetics were examined for inhibitory potency in six SH2 domain constructs: Lck, Src, Grb2, and the C-terminal SH2 domains of PLC gamma (PLC gamma-C) and the p85 subunit of PI-3 kinase (p85-C), as well as the N-terminal SH2 domain of SH PTP2. Although inhibition constants were in the millimolar range, it was observed that capping pTyr as its N alpha-acetyl carboxamide [(L)-1] provided a roughly 2-3-fold increase in potency relative to free pTyr. Diastereomeric indanylglycine-based analogues (+/-)-3a,b were essentially inactive. Of note was methanobenzazocine (+/-)-2. While being racemic and a partial pTyr structure, this analogue retained full binding potency of the enantiomerically pure N alpha-acetyl pTyr amide (L)-1. Modification and elaboration of 2 could potentially result in small molecule inhibitors having greater potency.

Amino Acid Sequence↗
PubMed1995

Intranuclear binding of nucleoplasmin.

Many proteins--including not only structural proteins, but also enzymes, hormone receptors, and other transcription factors--accumulate to much higher nuclear than cytoplasmic concentrations. Nuclear localization sequences or signals (NLSs) within their primary structures entrain specific transport of these proteins through the nuclear pore complexes. This transport process is energy-dependent, but evidence for a true active transport mechanism is not conclusive. An alternative mechanism--facilitated transport of NLS proteins followed by their intranuclear binding--has been implicated by experiments with oil-isolated nuclei. However, there has been no agreement as to a role for binding in the in vivo nuclear accumulation of NLS-containing proteins. We demonstrate herein that a prototypical NLS protein, nucleoplasmin (Np), binds within the nucleus of the living Xenopus oocyte and that this binding accounts for its nuclear accumulation.

Animals↗
PubMed1995

The management of bereavement on intensive care units.

OBJECTIVE: To investigate the management of the bereaved on Intensive Care Units (ICU) throughout the United Kingdom, and to identify inadequacies that may exist either in the provision of staff training in dealing with bereavement or in the facilities or support available for the bereaved. DESIGN: Questionnaires were sent to the senior nurse and senior doctor in all general ICUs with more than four beds nationwide. The questions asked about nursing and medical practice around the time of a patient's death, as well as about staff attitudes towards, and training in, dealing with bereavement and the support they received for this role. RESULTS: We obtained a 68% (293/430) response rate. Most ICUs had facilities for relatives, but little for the specific needs of the bereaved. Only 6% of doctors and 21% of nurses had training in dealing with bereavement and grieving. A staff support group was available in 23% of ICUs, and 75% of the remainder thought it would be useful to have one. Lack of staff training and poor facilities for relatives were identified as the major concerns of ICU staff. CONCLUSION: Many doctors and nurses working in Intensive Care Units feel inadequately trained to deal confidently with the bereaved. A minority of ICUs have support mechanisms available for their staff, inspite of the perceived need for them. Furthermore, many ICU staff feel the facilities they are able to offer the bereaved are inadequate. We have identified the major inadequacies and the needs of ICU staff for improved training. Meeting these needs would play a significant role not only in reducing staff stress but also minimising the morbidity in surviving relatives.

Bereavement↗
PubMed1995

Laparoscopic Swenson pull-through procedure for congenital megacolon.

Constipation that is unresponsive to conventional remedies is the primary symptom of congenital megacolon (ie, Hirschsprung's disease). The cause of congenital megacolon is lack of ganglion cells in the bowel. The laparoscopic Swenson pull-through procedure involves removing the aganglionic segment of the colon, bringing the normally decompressed bowel through the pelvic floor, and anastomosing the bowel to the anorectal verge. Advantages of the laparoscopic approach include shorter lengths of hospital stay and fewer complications resulting from disruption of skin integrity.

Anastomosis, Surgical↗