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A series of 15 novel opioid derivatives were made where the prototypic phenolic-OH group of traditional opioids was replaced by a carboxamido (CONH(2)) group. For 2,6-methano-3-benzazocines and morphinans similar or, in a few instances, enhanced affinity for mu, delta and kappa opioid receptors was observed when the OH-->CONH(2) switch was applied. For 4,5alpha-epoxymorphinans, binding affinities for the corresponding carboxamide derivatives were much lower than the OH partner consistent with our pharmacophore hypothesis concerning carboxamide bioactive conformation. The active metabolite of tramadol and its carboxamide counterpart had comparable affinities for the three receptors.

We have developed a first generation of hybrid sparsomycin-linezolid compounds into a new family of orally bioavailable biaryloxazolidinones that have activity against both linezolid-susceptible and -resistant gram-positive bacteria as well as the fastidious gram-negative bacteria Haemophilus influenzae and Moraxella catarrahalis. The convergent synthesis of these new compounds is detailed.

Background: Decompressive craniectomy is an important method for managing refractory intracranial hypertension in patients with head injury. We reviewed a large series of patients who underwent this surgical procedure to establish the incidence and type of postoperative complications., Methods: From 1998 to 2005, decompressive craniectomy was performed in 108 patients who suffered from a closed head injury. The incidence rates of complications secondary to decompressive craniectomy and risk factors for developing these complications were analysed. In addition, the relationship between outcome and clinical factors was analysed., Findings: Twenty-five of the 108 patients died within the first month after surgical decompression. A lower GCS at admission seemed to be associated with a poorer outcome. Complications related to surgical decompression occurred in 54 of the 108 (50%) patients; of these, 28 (25.9%) patients developed more than one type of complication. Herniation through the cranial defect was the most frequent complication within 1 week and 1 month, and subdural effusion was another frequent complication during this period. After 1 month, the "syndrome of the trephined" and hydrocephalus were the most frequent complications. Older patients and/or those with more severe head trauma had a higher occurrence rate of complications., Conclusions: The potential benefits of decompressive craniectomy can be adversely affected by the occurrence of complications. Each complication secondary to surgical decompression had its own typical time window for occurrence. In addition, the severity of head injury was related to the development of a complication.

From the X-ray crystal structures of linezolid and the non-selective antibiotic sparsomycin, we have derived a new family of hybrid oxazolidinones. From this initial compound set we have developed a new biaryloxazolidinone scaffold that shows both potent antimicrobial activity as well as selective inhibition of ribosomal translation. The synthesis of these compounds is outlined.

The synthesis and evaluation of a series of aryl-containing N-monosubstituted analogues of the lead compound 8-carboxamidocyclazocine were performed to probe a putative hydrophobic binding pocket of opioid receptors. High binding affinity to mu, kappa, and delta opioid receptors was observed for the 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogue.

Background: Although Shiga toxin (Stx) mediates classical hemolytic uremic syndrome (HUS), it is not fully understood why only some subjects exposed to Stx-expressing Escherichia coli develop HUS. We have previously shown in a baboon model of Stx-mediated HUS that coadministration of lipopolysaccharide (LPS) results in an augmented host response to otherwise subtoxic Stx1 doses. We used this model to test the hypothesis that LPS upregulates renal Stx receptor (Gb(3)) expression., Methods: Juvenile baboons were treated with either Stx1 (100 ng/kg), LPS (1 mg/kg as two divided doses 24 h apart), or a sham injection of saline, and sacrificed and immediately autopsied at 72 h. Renal cortical tissue Gb(3) content was quantitated by lipid extraction and thin-layer chromatography, and Stx1 and Gb(3)/CD77 immunostaining was assessed by quantitative immunofluorescent microscopy., Results: Compared to saline-injected controls, LPS administration resulted in a 2.2-fold increase in renal cortical Gb(3) by chromatography (p < 0.01), a 2.5-fold increase in Stx1 staining (p = 0.003) and a 1.7-fold increase in CD77 immunostaining (p = 0.004). Stx treatment did not significantly alter either Stx or CD77 immunostaining., Conclusion: These observations

8-Position variants of cyclazocine have been made where the phenolic 8-OH was replaced by thioamide, amidine, guanidine, urea and thiourea groups. High affinity for opioid receptors was observed for the 8-CSNH2 and 8-NHCHS analogues indicating that these groups are isosteric with not only the 8-OH but with the previously synthesized 8-CONH2 and 8-NHCHO cyclazocine derivatives.

Very high affinity for opioid receptors (e.g., K(i)=0.052nM for mu) has been observed in the rationally designed naltrexone analogue 5. SAR and physical data supports the hypothesis that the 4-OH group of 5 stabilizes the 3-carboxamido group in the putative bioactive conformation.

Introduction: Spinal cord injuries in newborn infants following a traumatic delivery are well known, but occasionally cord damage is appreciated in children whose birth did not involve any complications; in some of them there has been proof of an ischemic process that originated inside the uterus., Case Report: We describe the case of a newborn female with atrophy of the cervical spinal cord compatible with an intrauterine ischemic infarct. It extended to the C4-C6 territory of the anterior spinal artery, with greater participation on the left side. Clinical symptoms were apparent from the moment of birth and took the form of an asymmetric pseudoarthrogryposis in the upper limbs. The left arm was held in abduction at the height of the shoulder, with complete flexion of the elbow and the hand at the height of the chin was hypotonic, inactive and hypotrophic; the right arm was extended and in adduction. The patient presented episodes of hyperthermia that remitted on cooling the body., Conclusions: When faced with a newborn infant with symptoms that are compatible with chronic cervical spinal cord damage and in the absence of any perinatal traumatic injury, other causes, including prenatal ischemic infarct, must be taken into account.

High affinity binding for mu and kappa opioid receptors has been observed in analogues of cyclazocine, ethylketocyclazocine and naltrexone where the prototypic (of opiates) phenolic OH group was replaced with a formamide (-NHCHO) group. For the 8-formamide analogue of cyclazocine, binding is highly enantiospecific (eudismic ratios approximately 2000 for mu and kappa) with K(i) values

8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [(35)S]GTPgammaS assays.

Objective: To identify the effect of XW630 on the expression of type I collagen in the epiphyseal plates of mice., Methods: The immunohistochemical method was used to measure the change of type I collagen protein after being treated with XW630., Results: With 10(-7) mol/L or 10(-7) mol/L of XW630, the area of positive stain cells in every zone increased significantly compared to the control group. A more significant increase of the area of positive cells in the proliferative zone and hypertrophic zone was observed in the XW630 group than in the estrone group at a concentration of 10(-7) mol/L. When the XW630 was decreased to 10(-9) mol/L, the increase of positive cells was only found in the hypertrophic zone. The area of positive cells increased with the concentration of XW630., Conclusion: The XW630 upregulates the dose-dependent expression of type I collagen protein in the resting zone, proliferative zone, and hypertrophic zone in the epiphyseal plates of mice in vitro.

The gene expression profile of developing human hippocampus is of particular interest and importance to neurobiologists devoted to development of the human brain and related diseases. To gain further molecular insight into the developmental and functional characteristics, we analyzed the expression profile of active genes in developing human hippocampus. Expressed sequence tags (ESTs) were selected by sequencing randomly selected clones from an original 3'-directed cDNA library of 150-day human fetal hippocampus, and a digital expression profile of 946 known genes that could be divided into 16 categories was generated. We also used for comparison 14 other expression profiles of related human neural cells/tissues, including human adult hippocampus. To yield more confidence regarding differential expression, a method was applied to attach normalized expression data to genes with a low false-positive rate (<0.05). Finally, hierarchical cluster analysis was used to exhibit related gene expression patterns. Our results are in accordance with anatomical and physiological observations made during the developmental process of the human hippocampus. Furthermore, some novel findings appeared to be unique to our results. The abundant expression of genes for cell surface components and disease-related genes drew our attention. Twenty-four genes are significantly different from adult, and 13 genes might be developing hippocampus-specific candidate genes, including wnt2b and some Alzheimer's disease-related genes. Our results could provide useful information on the ontogeny, development, and function of cells in the human hippocampus at the molecular level and underscore the utility of large-scale, parallel gene expression analyses in the study of complex biological phenomena., (Copyright 2002 Wiley-Liss, Inc.)

To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the kappa-receptor, and no change in the affinity for the mu-opioid receptor, with both compounds having K(i) values of less than 1 nM, based on radioligand binding assays. In the guanosine 5'-O -(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human kappa- and mu-receptors. When given by i.c.v. injection, the compounds produced less than 60% antinociception in the mouse 55 degrees C warm-water tail-flick test. However, in the mouse writhing test, the compounds had high potency in producing antinociception. Antinociception induced by either 8-carboxamidocyclazocine or cyclazocine was mediated by both kappa- and mu-opioid receptors. Cyclazocine acted as a mu-antagonist in addition to its agonist properties at the mu-receptor, as measured by the inhibition of morphine-induced antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit morphine-induced antinociception, demonstrating that it was not a mu-opioid receptor antagonist in this assay. An i.p. injection of an ED(70) dose of 8-carboxamidocyclazocine produced antinociception that lasted for 15 h in contrast to cyclazocine, which produced antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.

Objective: To investigate the physiological role of fragile X mental retardation protein (FMRP) and screen the proteins interacting with FMRP in human fetal hippocampus cDNA library., Methods: Human fetal hippocampus cDNA library was constructed in yeast two-hybrid DAD vector pGAD10. Quality of the library was measured by picking up random colonies as templates for PCR testing. Proteins interacting with FMRP were screened by yeast two-hybrid system. Furthermore, the interaction site of FMRP was mapped in yeast., Results: The average length of inserts of the two-hybrid library was 1.5 kb, and the ratio of recombinant colonies was about 90%. Human NDK/Nm23-H2 was found interacting with FMRP. NDK/Nm23-H2 interacted with FMRP exon 1-12, as well as FMRP isoforms without exon 12, and exons 14-17. NDK/Nm23-H2 couldn't interact with FMRP exon 1-6 and exon 2-7 fragments., Conclusions: Human NDK/Nm23-H2 can bind FMRP directly. The interaction site of FMRP is located at its exon 1-11. This interaction in vitro might alter the intracellular distribution of NDK/Nm23-H2, and even regulates the transcription and expression of FMRP.

Shiga toxin (Stx) and lipopolysaccharide (LPS) both participate in the pathogenesis of post-diarrheal hemolytic uremic syndrome (HUS), yet little is known about the factors that modulate the host response to these toxins. We have previously shown that the baboon develops HUS if 100 ng/kg of purified Stx-1 is administered rapidly as a single bolus, but not if it is given as four 25-ng/kg doses every 12 h. We therefore used this baboon model to study the response to small intravenous doses of Stx-1, with and without the co-administration of LPS. The co-administration of two 1-mg/kg doses of LPS (given at 0 and 24 h) and four 25-ng/kg doses of Stx-1 (given at 0, 12, 24, and 36 h) resulted in HUS, but the administration of either toxin separately did not. The development of HUS was associated with a rise in urinary, but not plasma concentrations of TNF, and a rise in both urinary and plasma concentrations of IL-6 and IL-8. We speculate that LPS is not required for disease expression in the human, but that it can augment the response to otherwise subtoxic amounts of Stx and this augmentation may be mediated by LPS-induced cytokine release., (Copyright 2001 S. Karger AG, Basel)

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH(2) analogues of morphine and naltrexone. High affinity (K(i)=34 and 1.7nM) for mu opioid receptors was seen, however, the new targets were 39- and 11-fold less potent than morphine and naltrexone, respectively.

Unexpectedly high affinity for opioid receptors has been observed for a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group. For mu and kappa opioid receptors, the primary carboxamido derivative of cyclazocine ((+/-)-15) displayed high affinity (Ki=0.41 and 0.53 nM, respectively) nearly comparable to cyclazocine. A high enantiopreference ((2R,6R,11R)-) for binding was also observed. Compound (+/-)-15 also displayed potent antinociception activity in mice when administered icv.

Objective: To analyze the interactions between domains within the NH2- and COOH-terminal regions of presenilins., Methods: The various constructions corresponding to NH2-terminal fragment (NTF) and COOH-terminal fragment (CTF) derivatives of presenilin 1 (PS1) and presenilin 2 (PS2) were generated by RT-PCR, and their interactions were assayed by yeast two-hybrid system., Results: Domains within the NH- and COOH-terminal fragments of presenilins could directly interact with each other, and therefore form high molecular weight complex. The interaction site between domains within PS1 located at amino acid 361-447 of PS1 CTF, without the involvement of other partners. Similar interaction was not observed between PS11-360 and PS2341-448, PS2(1)-340 and PS1(361)-467., Conclusions: Intramolecular interaction between domains within the NH2- and COOH-terminal regions of presenilins may be critical to the folding and assembly of mature PS molecules.

Objective: To investigate the reconstructional method of posterior wall of vagina after the resection of rectum carcinoma., Methods: From August 1991 to March 1996, 10 patients with rectum carcinoma were adopted in this study, among them, there were 4 cases belong to B stage of Dukas, and 6 cases belong to C stage of Dukes. In operation, rectum carcinoma and posterior wall of vagina were resected, and concurrent reconstruction was finished by using pedicled muscular flap of uterus., Results: The effect of operation were satisfactory except one case who was failed because of insufficient blood supply of the flap. Followed-up for 3-6 months, the posterior wall of vagina healed in 7 cases, the width of vagina was 2-3 fingers and the depth was 5-6 cm., Conclusion: Reconstruction of the posterior wall of vagina with pedicled muscular flap of uterus was available in clinic. For its simplicity and feasibility, it's suitable for the resection of rectum carcinoma in which the posterior wall of vagina was infiltrated.

A method for correcting the beam hardening artefacts in computerised tomography is introduced. After an initial reconstruction of the object the uncorrected image is used to estimate the amount of bone and tissue along each ray. The bone and tissue lengths obtained from the initial reconstruction are used to add a correction term to each original projection. A second reconstruction using the corrected projection data yields the final beam hardening corrected image. The results are presented showing the application of this formalism to a mathematical phantom. The instability of the correction method with respect to various possible sources of error is examined.

From 1983 to 1985, 214 patients with rectal carcinoma were assessed for the conformation rate of the rectal examination to the gross findings of the extent of perirectal infiltration in the resected specimens. It was found that the conventional classification of the extent of rectal infiltration by rectal examination, 1/4, 1/3, 2/4, 3/4 and 4/4 of the circumference, had only a conformation rate of 32.7% to the gross findings. According to the classification of 1/4 or less and more, the conformation rate could reach 93%. It was also found that the extent of perirectal infiltration, being closely related to the regional lymph node metastasis and the depth of invasion, was only demonstrated by this latter classification, which was not shown in the conventional classification. Hence, it is suggested that the rectal examination implying the extent of perirectal infiltration by simply classified into two groups: equal to or less than 1/4 and more than 1/4 of the circumference of the rectal wall.