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PubMed2003

Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control.

BACKGROUND: The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to update cancer rates and trends in the United States. This report updates statistics on lung, female breast, prostate, and colorectal cancers and highlights the uses of selected surveillance data to assist development of state-based cancer control plans. METHODS: Age-adjusted incidence rates from 1996 through 2000 are from state and metropolitan area cancer registries that met NAACCR criteria for highest quality. Death rates are based on underlying cause-of-death data. Long-term trends and rates for major racial and ethnic populations are based on NCI and CDC data. Incidence trends from 1975 through 2000 were adjusted for reporting delays. State-specific screening and risk factor survey data are from the CDC and other federal and private organizations. RESULTS: Cancer incidence rates for all cancer sites combined increased from the mid-1970s through 1992 and then decreased from 1992 through 1995. Observed incidence rates for all cancers combined were essentially stable from 1995 through 2000, whereas the delay-adjusted trend showed an increase that had borderline statistical significance (P =.05). Increases in the incidence rates of breast cancer in women and prostate cancer in men offset a long-term decrease in lung cancer in men. Death rates for all cancer sites combined decreased beginning in 1994 and stabilized from 1998 through 2000, resulting in part from recent revisions in cause-of-death codes. Death rates among men continued to decline throughout the 1990s, whereas trends in death rates among women were essentially unchanged from 1998 through 2000. Analysis of state data for the leading cancers revealed mixed progress in achieving national objectives for improving cancer screening, risk factor reduction, and decreases in mortality. CONCLUSIONS: Overall cancer incidence and death rates began to stabilize in the mid- to late 1990s. The recent increase in the delay-adjusted trend will require monitoring with additional years of data. Further reduction in the burden of cancer is possible but will require the continuation of strong federal, state, local, and private partnerships to increase dissemination of evidence-based cancer control programs to all segments of the population.

Age Distribution↗

PubMed2004

Analysis of functional motions in Brownian molecular machines with an efficient block normal mode approach: myosin-II and Ca2+ -ATPase.

The structural flexibilities of two molecular machines, myosin and Ca(2+)-ATPase, have been analyzed with normal mode analysis and discussed in the context of their energy conversion functions. The normal mode analysis with physical intermolecular interactions was made possible by an improved implementation of the block normal mode (BNM) approach. The BNM results clearly illustrated that the large-scale conformational transitions implicated in the functional cycles of the two motor systems can be largely captured with a small number of low-frequency normal modes. Therefore, the results support the idea that structural flexibility is an essential part of the construction principle of molecular motors through evolution. Such a feature is expected to be more prevalent in motor proteins than in simpler systems (e.g., signal transduction proteins) because in the former, large-scale conformational transitions often have to occur before the chemical events (e.g., ATP hydrolysis in myosin and ATP binding/phosphorylation in Ca(2+)-ATPase). This highlights the importance of Brownian motions associated with the protein domains that are involved in the functional transitions; in this sense, Brownian molecular machines is an appropriate description of molecular motors, although the normal mode results do not address the origin of the ratchet effect. The results also suggest that it might be more appropriate to describe functional transitions in some molecular motors as intrinsic elastic motions modulating local structural changes in the active site, which in turn gets stabilized by the subsequent chemical events, in contrast with the conventional idea of local changes somehow getting amplified into larger-scale motions. In the case of myosin, for example, we favor the idea that Brownian motions associated with the flexible converter propagates to the Switch I/II region, where the salt-bridge formation gets stabilized by ATP hydrolysis, in contrast with the textbook notion that ATP hydrolysis drives the converter motion. Another useful aspect of the BNM results is that selected low-frequency normal modes have been identified to form a set of collective coordinates that can be used to characterize the progress of a significant fraction of large-scale conformational transitions. Therefore, the present normal mode analysis has provided a stepping-stone toward more elaborate microscopic simulations for addressing critical issues in free energy conversions in molecular machines, such as the coupling and the causal relationship between collective motions and essential local changes at the catalytic active site where ATP hydrolysis occurs.

Algorithms↗

PubMedDate not supplied

Reconstruction of the anterior cruciate ligament with the tendons of the semitendinosus and gracilis doubled: a comparison with reconstruction using the patellar tendon.

A total of sixty consecutive cases of anterior chronic laxity of the knee the pre- and intraoperative features of which corresponded to the criteria of inclusion considered, hospitalized in our institute between September and December 1998 and submitted to reconstruction of the ACL were reviewed at a follow-up of 74 months. The series was made up of two groups that were homogeneous in terms of sex, age, degree of preoperative laxity and number and type of associated meniscal lesions; in the first group (20 cases) reconstruction was carried out using the patellar tendon (BPTB) and in the other (40 cases) the doubled semitendinosus and gracilis tendons (DGST) were used with the association in cases with greater rotatory laxity (20 cases) of peripheral reinforcement reconstruction. An accelerated rehabilitation protocol was used in the first group, a more prudent one with immobilization in extension for two weeks was used in the second group. The results, evaluated based on the IKDC form, appeared to be better in the DGST group, with a statistically significant difference; joint stability, evaluated at follow-up with a KT1000 arthrometer also proved to be better in the DGST group, with a difference that was not statistically significant. The present study seems to show that reconstruction of the ACL with DGST, a prudent rehabilitation protocol and peripheral reinforcement reconstruction in selected cases is capable of providing better long-term results as compared to standard reconstruction with the patellar tendon and accelerated rehabilitation protocol. Among methods used to reconstruct the anterior cruciate ligament (ACL), those that utilize the central third of the patellar tendon (BPTB) or the semitendinosus and gracilis tendons (DGST) continue to be those used most frequently. Although the debate between orthopedics is still going on as to which of the two methods is to be preferred, studies that compare the two methods do not seem to report essential differences in medium-term results. In a recent meta-analysis of the most important international literature, to this regard Freedman et al. concluded that despite a significant major presence of anterior pain reconstruction with BPTB is capable of guaranteeing better joint stability and patient satisfaction, with a minor incidence of transplant failure. Nonetheless, if methods of reconstruction with BPTB seem to be rather standardized in terms of the method used to obtain the specimen and that used for stabilization (with very few differences between interference screws and transverse stabilization), and in postoperative rehabilitation (so-called accelerated), when DGST is used there are many technical variables capable of influencing the final results (choice of methods of stabilization, postoperative rehabilitation in particular). For this reason we still cannot obtain an absolute comparison of the two methods, but can only compare reconstruction with BPTB and a particular method used with DGST. It is the purpose of this study to present the medium-term results not so much of ACL reconstruction with the semitendinosus and gracilis doubled, but as a more articulate approach to the pathology of the ACL, so that DGST is only one phase, even if it is the most important one. Because we wished to verify whether it is possible, even in terms of joint stability and patient satisfaction, to improve the results of the so-called gold standard for reconstruction of the ACL, reconstruction by BPTB with transverse femoral reconstruction and accelerated postoperative rehabilitation protocol was chosen as a term of paragon.

Adult↗

PubMed1987

Metal protein interactions.

Proteins associated with metals serve many important biological functions. The amino acid residues provide the functional groups in a protein which are the potential ligands for a metallic cation. Metals impart various effects on protein structure and bring about overall structural stability. These effects are seen in quarternary, secondary and tertiary structures of the protein. There are varieties of approaches to study metal protein interactions. The earliest technique being the equilibrium dialysis which is still used extensibly to determine the binding strength and the number of metals bound per protein molecule. There are a number of other techniques available which provide precise information about the nature of metal binding sites. They include electron spin resonance, UV and visible spectoscopy, nuclear magnetic resonance, resonance Raman, X-ray crystallography, X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (XAFS), etc. Selected metal protein interactions are discussed in this review. Albumin is the major plasma protein in blood which transports a number of metals. Detailed studies of Cu(II) and Ni(II) binding to albumin suggests that both metals have the same specific binding site at the NH2-terminal tripeptide sequence (Asp1-Ala2-His3...) involving the Asp alpha-NH2, His3 N (1) imidazole, two deprotonated peptide nitrogens (Ala2NH and His3NH), and Asp1 COO- group. Transferrin transports Fe(III) in blood. The protein possesses two metal-binding sites, each within a domain of bilobal proteins. Presence of carbonate is an important feature of Fe(III)-binding to transferrin. The binding site has been postulated as one involving Tyr 185 and Tyr 188 and suggests that two of the three histidines His 119, His 207 and His 249 also serve as ligands. Arginine 145 is a likely anchor for the carbonate anion. Superoxide dismutase is an enzyme found in erythrocytes which catalyzes the dismutation of superoxide radical. The protein is a dimer made up of two equivalent subunits. The subunits are held together by noncovalent interactions. For optimal enzymatic activity, at least two of the protein's four metal ions must be cupric. The results of the X-ray crystal structural analysis for Cu(II) and Zn(II) containing protein have been reported. In the metal-binding region of one subunit, Cu(II) and Zn(II) are separated by approximately 6A. The Cu(II) is bound to imidazole side chains of histidines 44, 46, 61 and 118 in a distorted square planar arrangement. The imidazole ring of histidine 61 is believed to be deprotonated and to serve as a bridge between Cu(II) and Zn(II).(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1996

Synaptic organization of amphibian sympathetic ganglia.

The synaptic organization of the amphibian sympathetic ganglia was studied, especially in the last two abdominal paravertebral ganglia of the frog. These ganglia appear to form a monosynaptic relay, not containing interneurons. They consist of two systems working in parallel: the principal neurons, by far the most numerous, and a small number of chromaffin (i.e., SIF) cells, usually arranged in clusters. Each principal neuron is innervated by a preganglionic branch forming a set of cholinergic synapses which exhibit classical ultrastructure. The only peculiarity is the presence of a subsynaptic apparatus in a variable percentage of synaptic complexes. Electrophysiological studies have demonstrated that synaptic transmission is due to ACh release and involves several postsynaptic potentials. Moreover, the principal neurons are of two types, B and C, whose preganglionic axons and their own axons have different conduction velocities. C neurons tend to be small in diameter, and B neurons are larger, but the size distribution of the two populations overlaps. More recently, it was demonstrated that these two neuronal systems have different immunocytochemical features. The C preganglionic fibers contain an LHRH-like peptide, which is responsible for late synaptic events. The B preganglionic fibers contain CGRP, whose role has not yet been established. The principal neurons all contain adrenaline, but neuropeptide Y is also present in C neurons and could be a second transmitter at peripheral junctions. SP-containing fibers also pass through the ganglia, but give rise to intraganglionic synapses only rarely, except in the celiac plexus. Galanin can coexist with neuropeptide Y in certain C neurons. Numerous principal neurons are immunoreactive for VIP. Chromaffin cells contain noradrenaline and metenkephalin, and some contain SP or LHRH; they are endocrine cells controlled by preganglionic fibers and can have a modulatory effect on principal neurons endowed with appropriate receptors. The accessibility of frog abdominal ganglia and the anatomical separation of B and C preganglionic fiber pathways provide interesting systems in which to carry out experimentation on the stability and specificity of synaptic contacts. After postganglionic axotomy, the majority of synapses disappear by disruption of synaptic contacts. There is a certain discrepancy between the recovery of synaptic transmission and the reappearance of morphologically identifiable synapses, suggesting that a certain amount of transmission is possible at contacts devoid of synaptic complexes. The selective deafferentation of B or C neurons showed that the subsynaptic apparati are mainly found at B neuron synapses. The course of reinnervation following selective deafferentation reveals the existence of different specificities at B and C synapses: C neurons are easily reinnervated by B preganglionic fibers, whereas C fibers appear fairly ineffective at reinnervating B neurons, even after a long interval. Attempts were made to reinnervate ganglionic neurons with somatic motor nerve fibers. Reinnervation was achieved only rarely, and it is concluded that the ganglionic synapses in the frog have a higher specificity and lower plasticity than in mammals.

Animals↗

PubMed1984

Events governing organization of postmigratory neurons: studies on brain development in normal and reeler mice.

The purpose of the present work is to examine some of the mechanisms responsible for the early architectonic differentiation of the central nervous system, as well as for the abnormal development which occurs in certain hereditary malformations. In order to approach these questions, the embryonic development of the cerebral cortex, the cerebellum, the inferior olivary complex and the facial nerve nucleus has been studied in normal and reeler mutant mice, using morphological methods. The adult reeler phenotype is characterized not only by extreme laminar abnormalities of cell positioning in the telencephalic and cerebellar cortices, but also by relatively less extreme, though distinct abnormal architectonics in non-cortical structures such as the inferior olive and the facial nerve nucleus. Study of the embryonic development of these structures reveals that neurons are generated at the normal time and migrate along normal pathways. Moreover, the processes of directional axonal growth, differentiation of class specific features of neurons and glia, and synaptogenesis appear similar in both genotypes and are probably not directly affected by the reeler mutation. However, in all instances, the early architectonic organization achieved by reeler cortical, Purkinje, olivary or facial neurons at the end of their migration is consistently less regular than in normal embryos. In addition, these anomalies become amplified during the later developmental period. This evidence for the early appearance of abnormalities in reeler embryos indicates that the disposition of neurons at maturity cannot be exclusively regarded as secondary to the maturation of cells, neurites and connections, but is contingent upon a specific mechanism. One may infer that the presence of a normal allele at the reeler locus is necessary for the normal completion of this histogenetic step, which consequently is submitted to genetic control. Although the factor(s) responsible for the stable configuration of the early architectonics is unknown, various hypotheses are considered. Several lines of evidence are presented which argue against a major role being played by diffusible factors, mesodermal components and afferent fiber systems. Two mechanisms are considered particularly worth evaluating: (1) a diminution of relative adhesivity between neurons and radial glial fibers at the end of migration, and (2) a stabilization of neuronal configuration by selective recognition-adhesion among postmigratory neurons. The reeler gene could, directly or indirectly, affect these cell-cell interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

[Human thrombin: enzymatic properties, stability and standardization of preparation].

The work deals with estimation of thrombin preparation having such features as: sedimentation activity 3000-3200 NIH un. per 1 mg of protein and 97% of active centres. The enzyme isolated has been estimated according to the amidolytic activity on synthetic substrates S-2160 and BAPNA being equal 5200 and 185 milli un/mg of protein, respectively. According to the electrophoresis in PAAG in the presence of Ds-Na the preparation is homogenous, its molecular mass is 36000. The fibrinogen sedimentation time dependence on the isolated thrombin concentration has been estimated as well as the comparative analysis with the thrombin of the firm "Sigma" with the previously calibrated activity using the international standartion (coded P4) has been conducted. The absence of proportionality between the substrate sedimentation time and the preparation concentration has been determined. It has been revealed, that if the experimental findings are presented in the units 1/t against the thrombin units NIH the right lines are received within the limits used. The defreezing and secondary freezing of the preparation preserved under -20 degrees C have been showed as rendering an essential effect on thrombin activity. In order of the enzyme stabilizing at preserving the thrombin isolated has been concentrated applying the amycon membranes (MWCo: 30,000). While applying the thrombin water-saline solution in the conditions selected the preparation has showed itself practically stable during a year without utilizing any admixtures. The essential effect on thrombin has been found from the side of 1% glycin, 0.5% PEG, 1% saccharose and so on. The thrombin isolated high functional homogeneity, its stability permit to recommend the preparation as an operative standard.

Binding Sites↗

PubMed2000

Cis-acting influences on Alu RNA levels.

The human short interspersed repeated element (SINE), Alu, amplifies through a poorly understood RNA-mediated mechanism, termed retroposition. There are over one million copies of Alu per haploid human genome. The copies show some internal variations in sequence and are very heterogeneous in chromosomal environment. However, very few Alu elements actively amplify. The amplification rate has decreased greatly in the last 40 million years. Factors influencing Alu transcription would directly affect an element's retroposition capability. Therefore, we evaluated several features that might influence expression from individual Alu elements. The influence of various internal sequence variations and 3' unique flanks on full-length Alu RNA steady-state levels was determined. Alu subfamily diagnostic mutations do not significantly alter the amount of Alu RNA observed. However, sequences containing random mutations throughout the right half of selected genomic Alu elements altered Alu RNA steady-state levels in cultured cells. In addition, sequence variations at the 3' unique end of the transcript also significantly altered the Alu RNA levels. In general, sequence mutations and 3' end sequences contribute to Alu RNA levels, suggesting that the master Alu element(s) have a multitude of individual differences that collectively gives them a selective advantage over other Alu elements.

3T3 Cells↗

PubMed2005

Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy.

A new strategy currently under evaluation in patients with peritoneal carcinomatosis from gastrointestinal and gynecologic cancers is perioperative intraperitoneal chemotherapy. Although results to date show benefit to carefully selected groups of patients, continued local-regional failure is seen in many treated patients. Continued clinical and laboratory research efforts to improve local-regional effects are desired. The chemotherapeutic agents that have been used in the past or are currently being tested were reviewed. Their pharmacologic properties and clinical features were collected from the medical literature and are reviewed in the text. An organized presentation of available data concerning the drugs available for perioperative intraperitoneal chemotherapy for peritoneal surface malignancy was made. From this review, new possibilities for improved doses, schedules, and drug combinations for perioperative intraperitoneal chemotherapy may become important in future clinical studies. Continued optimal utilization of intraperitoneal chemotherapy treatments in the operating room with hyperthermia or normothermic treatment in the early postoperative period is desirable. Innovative treatment strategies can improve the outcome of patients with peritoneal surface malignancy.

Antineoplastic Agents↗

PubMed1998

Elucidation of the mode of interaction of thermolysin with a proteinaceous metalloproteinase inhibitor, SMPI, based on a model complex structure and a structural dynamics analysis.

SMPI is a proteinaceous microbial metalloproteinase inhibitor that was isolated from Streptomyces nigrescens TK-23 in 1979. SMPI is known to selectively inhibit the metalloproteinases in the gluzincin family, according to the Rawling and Barrett classification. There has been no report on the interaction of a metalloproteinase in the family of gluzincins with its specific proteinaceous inhibitor. We have solved the solution structure of SMPI by NMR. Here, we report the binding mode of SMPI to thermolysin, based on the model complex structure generated using our high-resolution NMR structure of SMPI and the crystal structure of thermolysin. The obtained complex model shows that the extruded loop of SMPI, with the scissile bond Cys64-Val65, is complementary in shape to the active cleft of thermolysin. In the complex, the Cys64 (P1) carbonyl oxygen atom can form a tetrahedral coordination to the active zinc in thermolysin, and simultaneously, the methyl groups of Val65 (P1') are closely located in the hydrophobic S1' pocket in thermolysin. From the electrostatic potential surface calculation, the active loop of SMPI and the active cleft in thermolysin have been shown to be complementary in the surface charge distribution, resulting in the stabilization of the complex. The apparently large active loop is less flexible, but maintains a conformation in the nano- to picosecond time-scale, as elucidated from the 15N spin relaxation analysis. This is a quite different structural feature of SMPI from the flexible binding loop generally found in the serine proteinase inhibitors, such as SSI and eglin c, and can be related to the narrow specificity of SMPI. The present study provides the first insight into the interaction between a proteinaceous inhibitor and a gluzincin metalloproteinase.

Bacterial Proteins↗

PubMed2006

Electronic modulation of hyperpolarizable (porphinato)zinc(II) chromophores featuring ethynylphenyl-, ethynylthiophenyl-, ethynylthiazolyl-, and ethynylbenzothiazolyl-based electron-donating and -accepting moieties.

A series of conjugated (porphinato)zinc(II)-based chromophores structurally related to [5-(4-dimethylaminophenylethynyl)-15-(5-nitrothienyl-2-ethynyl)-10,20-bis(3,5-bis(3,3-dimethyl-1-butyloxy)phenyl)]zinc(II) were synthesized using metal-catalyzed cross-coupling reactions involving [5-bromo-15-triisopropylsilylethynyl-10,20-diarylporphinato]zinc(II), [5-bromo-15-(4-dimethylaminophenylethynyl)-10,20-diarylporphinato]zinc(II), [5-(4-dimethylaminophenylethynyl)-15-ethynyl-10,20-diarylporphinato]zinc(II), and [5-(4-nitrophenylethynyl)-15-ethynyl-10,20-diarylporphinato]zinc(II), along with appropriately functionalized aryl, thienyl (or thiophenyl), thiazolyl, benzothiazolyl, and carbazolyl precursors. The linear and nonlinear optical properties of these asymmetrically 5,15-substitued-(10,20-diarylporphinato)zinc(II) chromophores that bear either 2-(9H-carbazol-9-yl)-thiophen-5-yl-ethynyl, 4-dimethylaminophenylethynyl, or 2-(N,N-diphenylamino)thiophen-5-yl-ethynyl electron-releasing groups and an electron-withdrawing group selected from 2-formyl-thiophen-5-yl-ethynyl, 2-(2,2-dicyanovinyl)-thiophen-5-yl-ethynyl, 4-nitrophenylethynyl, 6-nitrobenzothiazol-2-yl-ethynyl, or 5-nitrothiazol-2-yl-ethynyl are reported. The dynamic hyperpolarizabilities of these compounds were determined from hyper-Rayleigh light scattering measurements carried out at a fundamental incident irradiation wavelength (lambda(inc)) of 1300 nm; these measured beta1300 values ranged from 690 --> 1400 x 10(-30) esu. These data (i) show that these neutral dipolar molecules express substantial beta1300 values, (ii) highlight that reductions in the magnitude of the aromatic stabilization energy of (porphinato)metal-pendant arylethynyl groups have a significant impact upon the magnitude of the molecular hyperpolarizability, and (iii) provide insights into advantageous design modifications for closely related structures having potential utility in long-wavelength electrooptic applications.

Journal Article↗

PubMed1995

Zinc-directed inhibitors for zinc proteinases.

Zinc proteinases have been recognized as a distinct class of proteolytic enzymes in which at least one ion of zinc is involved directly in catalysis. This family includes a growing number of biologically important enzymes which are attractive targets for rational drug design. In this paper we examine the special features of the zinc binding environment of these enzymes in order to gain information which could be useful in the preparation of 'zinc-directed' selective inhibitors. Carboxypeptidase A (CPA) is presented as a model for one class of zinc proteinases, and the active-site zinc and its interactions are examined with the primary focus on geometrical considerations. The three-dimensional structure of the native and apoenzyme are discussed, together with the high-resolution structure of several enzyme-inhibitor complexes. This paper will first present a structural analysis of CPA derivatives and then discuss a series of zinc model compounds which have been prepared and characterized in order to examine the ligand and geometrical preferences of the zinc in an unstrained system. X-ray crystallography (macromolecular and small molecule) is the main experimental method used for the structural analyses, while complementary computational methods have been used for the examination of electrostatic potentials. The results from the various experimental efforts are assembled in order to draw general conclusions on the potential use of the zinc ion as the primary target for inhibitor binding. The results of these studies suggest that the zinc ion is important for both the binding and the catalytic activation of the substrate as well as for stabilization of the tetrahedral reaction intermediate.

Journal Article↗

PubMed1991

[3H]SCH39166, a D1 dopamine receptor antagonist: binding characteristics and localization.

Schering-Plough Research has developed a new, more specific analogue of SCH23390. This compound, SCH39166, has been shown to be a potent, specific, D1 receptor antagonist with several features which are advantageous over its predecessor. In this report, the binding characteristics of [3H]SCH39166 are described by in vitro analysis in rat brain tissues. The binding was shown to be of high affinity (Kd in the low nM range), saturable, and specific (readily displaceable with SCH23390, but not with the D2 receptor antagonists sulpiride or haloperidol). The binding of SCH39166 is more selective for binding to D1 receptors than SCH23390 with regard to overlap of the latter compound onto 5HT2 and 5HT1C receptors. Autoradiographic localization of D1 receptor sites labeled with [3H]SCH39166 showed a very specific distribution in areas known to contain high quantities of D1 receptors. These regions included the deepest layer of the cerebral cortex, the caudate-putamen, nucleus accumbens, olfactory tubercle, entopeduncular nucleus, and substantia nigra-pars reticulata, as well as less dense binding in a few other areas. At the concentration of ligand used (1 nM), there was a noticeable paucity of labeling in lamina IV of the cerebral cortex and in the choroid plexus, regions of high 5HT2 and 5HT1C receptor binding, respectively. Thus, SCH39166 represents a new D1 receptor antagonist which shows a greater specificity for the D1 receptor than its predecessor SCH23390. As previously shown, another distinct advantage of this compound is its stability in primates which should allow the determination of the effects and utility of D1 receptor antagonism in vivo.

Animals↗

PubMed1997

Quantitative structure-activity (QSAR) relationships of mutagenic aromatic and heterocyclic amines.

We extended our previous studies of mutagenic/carcinogenic heterocyclic aromatic amines formed during the cooking of foods to 66 aromatic and 99 heterocyclic amines for which mutagenic potency data are available. The amines require activation by enzymes to form metabolites reactive with DNA and exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. To ascertain factors that might influence potency, structural features and quantum mechanical parameters calculated by the Hückel method (and, for a subset of 20 amines, by semi-empirical AM1, and ab initio methods) were analyzed by multiple linear regression. The major findings were: (1) earlier findings on cooked food mutagens and their synthetic congeners can be extended to other amines; (2) mutagenic potency is directly related to the number of fused aromatic rings (size of the aromatic system), the number of ring nitrogen atoms (participation of lone electron pairs in the pi-cloud), and presence of a methyl substituent on a ring nitrogen; (3) potency is inversely related to the energy of the lowest unoccupied molecular orbital (LUMO) of the parent amine. Ford and Griffin (1992) and Sabbioni and Wild (1992) showed that the LUMO energy of the derived nitrenium ion is closely related to its stability (calculated with reference to aniline). Increased stability has been hypothesized to enhance the probability of adduct formation with DNA by avoiding detoxifying side reactions and increasing the lifetime of the ion. In the large heterogeneous series of amines in our present study the Hückel method energy of the highest occupied molecular orbital (HOMO), rather than the LUMO energy, of the nitrenium ion was marginally related to the potency of the parent amine. However, in the selected subset of 20 amines with ab initio calculation, the LUMO energy of the ion confirmed the previous reports. The contribution of quantum chemical factors to mechanistic insight on the mutagenicity and carcinogenicity of aromatic and heterocyclic amines is still under development.

Amines↗

PubMed2005

Predictors of gangrenous necrotizing enterocolitis and extent of disease. Early laparotomy versus peritoneal drainage.

OBJECTIVE: Evaluation of known predictors of gangrene in neonates with necrotizing enterocolitis (NEC) and identification of those suggestive of severe disease, requiring expeditious laparotomy rather than primary peritoneal drainage as a definitive treatment. METHODS: This is a retrospective review of data collected from the medical records of newborns with confirmed NEC, treated at the Maternity and Children's Hospital, Dammam, Kingdom of Saudi Arabia, from May 1993 to May 2004. Fifty-five cases were selected for the study, 23 had successful medical management and 32 underwent laparotomy. Of this group, 15 had peritoneal drainage prior to laparotomy. Nine known clinical, radiological and laboratory features suspicious of bowel perforation or gangrene were evaluated. The operated group was classified according to the extent of disease into isolated, multifocal or pan intestinal and the distribution of these 9 criteria was calculated for each of the 3 groups. Comparison was then carried out between the group with isolated NEC and those with extensive disease. RESULTS: Isolated NEC was present in 8 (25%), multifocal NEC in 19 (59%) and pan intestinal NEC in 5 (16%) of the operated cases. Pneumoperitoneum and palpable abdominal mass were the most specific and predictive signs of perforated or gangrenous bowel in NEC. Severe pneumatosis intestinalis and gasless abdomen were also highly specific and predictive of the same but had a low prevalence. Abdominal wall erythema, persistent metabolic acidosis, portal vein air, gasless abdomen and severe pneumatosis intestinalis were found to be associated with severe or extensive gangrene. Palpable abdominal mass and fixed dilated loops were increased in cases of isolated NEC. Portal vein air was associated with the highest mortality. CONCLUSION: Pneumoperitoneum, though the only absolute evidence of bowel perforation, cannot predict the extent of disease. Peritoneal drainage is a useful stabilizing procedure but the presence of any of the above mentioned criteria which are associated with severe disease necessitate a quick decision in favor of laparotomy. The absence of these signs, however, cannot rule out extensive or progressive NEC and failure to improve after peritoneal drainage also requires an emergency laparotomy, regardless of birth weight or gestational age.

Abdomen↗

PubMed2000

[Classification and treatment of symbrachydactyly. A series of 117 cases].

In the present study, a modification has been proposed of the Blauth and Gekeler classification, aimed at a more accurate definition of appropriate surgical treatment. An analysis was made of a series of 120 cases of symbrachydactyly (117 patients); however, surgery was only performed in 86 cases (51 toe transfers in 49 patients; mean age at surgery 12 months). Type I included the separation of short and sometimes stiff fingers; type II, the 'pseudo-cleft', could be subdivided into three groups. Type IIA included those hands with more than two long and frequently hypoplastic digits, regarding which a decision had to be made between removal of rudimentary fingers or their stabilization. In type IIB, hand function was good and surgery was rarely needed. Type III (monodactylous) could also be subdivided into two categories, i.e., normal thumb in type IIIA and hypoplasia in IIIB. Finally, in type IVA, toe transfer surgery was performed on condition that wrist mobility was sufficient to compensate for the insufficient mobility of the artificial thumb on the anterior aspect of the radius. In all cases, a weak but useful pincer movement was obtained, with poor cosmetic results. In the case of toe transfers, surgery was advocated before the age of one year; and although mobility was disappointing (35 degrees active motion), good growth and excellent discrimination (5 mm on average) was observed. Symbrachydactyly is a fairly frequent congenital malformation; its diverse clinical features require a precise classification to better determine adequate treatment management.

Adolescent↗

PubMed2004

The association of donor center characteristics with attrition from the national marrow donor registry.

BACKGROUND: The National Marrow Donor Program (NMDP) has approximately 5 million registered potential donors and continues to add more than 30,000 new recruits to the registry monthly. However, more than 30% of potential donors are not available or decline to donate at key decision points in the donation process. Although previous researchers have examined the association of individual donor characteristics with attrition from the registry, no published studies have investigated the role of donor center characteristics or features of the donor centers' environment on attrition rates. METHODS: Donor center coordinators from 72 NMDP centers completed questionnaires that included items regarding donor center location and organization, recruitment strategies, and registry management. Center-specific registry composition data and attrition rates were gathered from the NMDP database. RESULTS: Analyses indicated that higher attrition was found at larger centers that needed more center staff and volunteers to deal with larger workloads and more DR-typing requests. Attrition was also higher among centers located in highly populated, urban environments, with larger minority and less stable populations. CONCLUSIONS: The results indicate that the NMDP may need to tailor donor center retention expectations to account for certain unchangeable characteristics (e.g., center size and population stability) and to develop internal strategies to address the unique characteristics of each donor center (e.g., current performance level or improvement needs).

Databases, Factual↗

PubMed1996

Hox homeodomain proteins exhibit selective complex stabilities with Pbx and DNA.

Eight of the nine homeobox genes of the Hoxb locus encode proteins which contain a conserved hexapeptide motif upstream from the homeodomain. All eight proteins (Hoxb-1-Hoxb-8) bind to a target oligonucleotide in the presence of Pbx1a under conditions where minimal or no binding is detected for the Hox or Pbx1a proteins alone. The stabilities of the Hox-Pbx1a-DNA complexes vary >100-fold, with the proteins from the middle of the locus (Hoxb-5 and Hoxb-6) forming very stable complexes, while Hoxb-4, Hoxb-7 and Hoxb-8 form complexes of intermediate stability and proteins at the 3'-side of the locus (Hoxb-1-Hoxb-3) form complexes which are very unstable. Although Hox-b proteins containing longer linker sequences between the hexapeptide and homeodomains formed unstable complexes, shortening the linker did not confer complex stability. Homeodomain swapping experiments revealed that this motif does not independently determine complex stability. Naturally occurring variations within the hexapeptides of specific Hox proteins also do not explain complex stability differences. However, two core amino acids (tryptophan and methionine) which are absolutely conserved within the hexapeptide domains appear to be required for complex formation. Removal of N- and C-terminal flanking regions did not influence complex stability and the members of paralog group 4 (Hoxa-4, b-4, c-4 and d-4), which share highly conserved hexapeptides, linkers and homeodomains but different flanking regions, form complexes of similar stability. These data suggest that the structural features of Hox proteins which determine Hox-Pbx1a-DNA complex stability reside within the precise structural relationships between the homeodomain, hexapeptide and linker regions.

Amino Acid Sequence↗