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1.
Biol Psychiatry ; 45(11): 1403-11, 1999 Jun 01.
Article in English | MEDLINE | ID: mdl-10356621

ABSTRACT

BACKGROUND: Past 1H magnetic resonance spectroscopy (MRS) studies of the temporal lobe in schizophrenic patients have shown decreased levels of N-acetylaspartate (NAA) suggesting reduced neuronal density in this region. However, the measured volumes have been large and included contributions from mostly white matter. METHODS: Short echo 1H MRS was used to measure levels of NAA and other metabolites (i.e., glutamate and glutamine) from a 6 cm3 volume in the left mesial-temporal lobe of 11 first-episode schizophrenic patients and 11 healthy control subjects of comparable age, gender, handedness, education, and parental education levels. Spectra were quantified without operator interaction using automated software developed in our laboratory. Metabolite levels were normalized to the internal water concentration of each volume studied. Images were also obtained to determine temporal lobe gray and white matter volumes. RESULTS: No significant differences were found between levels of NAA or other metabolites, or gray and white matter volumes, in first-episode schizophrenic patients and comparison subjects. CONCLUSIONS: Since the volume studied was small compared to previous studies and contained mostly gray matter, this result suggests consequential NAA decreases may be restricted to regions of white matter.


Subject(s)
Schizophrenia , Temporal Lobe/metabolism , Adolescent , Adult , Analysis of Variance , Aspartic Acid/analogs & derivatives , Aspartic Acid/analysis , Case-Control Studies , Female , Fourier Analysis , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Spectroscopy , Male , Neural Pathways/chemistry , Neural Pathways/pathology , Protons , Schizophrenia/pathology , Schizophrenia/physiopathology , Temporal Lobe/pathology
2.
Bioorg Med Chem ; 7(4): 581-8, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10353637

ABSTRACT

Cathepsin K (EC 3.4.22.38) is a cysteine protease of the papain superfamily which is selectively expressed within the osteoclast. Several lines of evidence have pointed to the fact that this protease may play an important role in the degradation of the bone matrix. Potent and selective inhibitors of cathepsin K could be important therapeutic agents for the control of excessive bone resorption. Recently a series of peptide aldehydes have been shown to be potent inhibitors of cathepsin K. In an effort to design more selective and metabolically stable inhibitors of cathepsin K, a series of electronically attenuated alkoxymethylketones and thiomethylketones inhibitors have been synthesized. The X-ray co-crystal structure of one of these analogues in complex with cathepsin K shows the inhibitor binding in the primed side of the enzyme active site with a covalent interaction between the active site cysteine 25 and the carbonyl carbon of the inhibitor.


Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Endopeptidases , Ketones/chemistry , Cathepsin B/antagonists & inhibitors , Cathepsin K , Cathepsin L , Cysteine Endopeptidases , Kinetics , Models, Chemical , Models, Molecular
3.
J Med Chem ; 41(23): 4567-76, 1998 Nov 05.
Article in English | MEDLINE | ID: mdl-9804696

ABSTRACT

Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes.


Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Dipeptides/chemistry , Leupeptins/chemistry , Models, Molecular , Papain/chemistry , Binding Sites , Cathepsin K , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/metabolism , Dipeptides/metabolism , Drug Design , Leupeptins/metabolism , Papain/metabolism , Protein Structure, Tertiary
4.
Am J Psychiatry ; 155(11): 1584-91, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9812122

ABSTRACT

OBJECTIVE: It is likely that the corpus striatum is involved in obsessive-compulsive disorder (OCD). Prior studies have inconsistently found alterations in caudate volumes in patients with OCD. This study was undertaken in the hope that N-acetylaspartate and volumetric measures together would elucidate the presence and nature of corpus striatum volumetric abnormalities in OCD. METHOD: Thirteen patients meeting the DSM-IV criteria for OCD, who had been medication free for a minimum of 6 weeks, and 13 psychiatrically normal matched comparison subjects participated in the study. Short echo 1H magnetic resonance spectroscopy (1H-MRS) was used to measure levels of N-acetylaspartate and several other cerebral metabolites from a 4.5-cm3 volume in the left corpus striatum of all 26 subjects. Metabolite levels were estimated by fitting the time domain spectroscopy data with a noninteractive computer program. Volumes of the left and right head of the caudate nucleus in each subject were determined by semiautomatic segmentation of the volumetric images. RESULTS: N-Acetylaspartate levels from the left corpus striatum were significantly lower in the patients with OCD than in the comparison subjects. There were no differences in either left or right caudate volume between the two groups. CONCLUSIONS: Despite the lack of differences in caudate volumes between the OCD patients and the comparison subjects, the lower level of N-acetylaspartate in the left corpus striatum of the patients suggests reduced neuronal density in this region. Inconsistent volumetric findings among prior studies may reflect a poorer sensitivity of magnetic resonance imaging morphometry for detecting neuronal loss compared with 1H-MRS measurement of N-acetylaspartate.


Subject(s)
Corpus Striatum/anatomy & histology , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Obsessive-Compulsive Disorder/diagnosis , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Cell Count , Corpus Striatum/metabolism , Corpus Striatum/pathology , Female , Functional Laterality , Humans , Hydrogen , Image Processing, Computer-Assisted , Male , Neurons/cytology , Obsessive-Compulsive Disorder/metabolism , Obsessive-Compulsive Disorder/pathology
5.
Arch Gen Psychiatry ; 54(10): 959-65, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9337777

ABSTRACT

BACKGROUND: Positron emission tomographic and postmortem studies comparing schizophrenic patients with healthy control subjects have found medial prefrontal cortical and anterior cingulate abnormalities that suggest dysfunction in glutamatergic neurons. The glutamate used for nerve signal transduction is predominantly derived from glutamine. After signal transduction, glutamate released into the synapse is converted to glutamine in glial cells, transported back to the presynaptic neuron, and reconverted to glutamate for reuse. In this study, levels of glutamate and glutamine were examined by means of in vivo proton (1H) magnetic resonance spectroscopy. METHODS: Localized in vivo 1H spectra were acquired from a 4.5-cm3 volume in the left medial prefrontal cortex encompassing portions of Brodmann areas 24, 32, and 9 in 10 never-treated schizophrenic subjects and 10 healthy controls of comparable age, sex, handedness, education, and parental education. From each spectrum, metabolite levels were estimated for glutamate and glutamine, as well as 10 other metabolites and 3 macromolecules, by means of a noninteractive computer program that combined modeled in vitro spectra of every metabolite to reconstruct each in vivo spectrum. RESULTS: A significant increase in glutamine level was found in the medial prefrontal cortex of the schizophrenic patients compared with controls. N-acetylaspartate and other measured metabolites and macromolecules were not significantly changed in schizophrenics. CONCLUSION: Increased glutamine levels in the medial prefrontal region most likely reflect decreased glutamatergic activity in this region in never-treated schizophrenic patients compared with healthy controls.


Subject(s)
Glutamic Acid/analysis , Glutamine/analysis , Magnetic Resonance Spectroscopy , Prefrontal Cortex/chemistry , Schizophrenia/metabolism , Adolescent , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/analysis , Educational Status , Female , Functional Laterality , Humans , Male , Protons , Schizophrenia/diagnosis , Sex Factors , Tomography, Emission-Computed
6.
J Psychiatry Neurosci ; 22(2): 111-7, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9074305

ABSTRACT

The purpose of this study was to examine the relationship between phosphorus magnetic resonance spectroscopy (31P MRS) parameters and left prefrontal volumes in both patients with schizophrenia and healthy subjects. 31P MRS parameters and magnetic resonance imaging (MRI) volumetric data were collected in the left prefrontal region in 10 patients with schizophrenia and 10 healthy subjects of comparable age, handedness, sex, educational level, and parental educational level. No correlations were found between any MRS parameter and grey matter volumes in the combined subjects. Phosphomonoester (PME) and grey matter volumes, however, were both correlated negatively with age. PMEs were found to be decreased, and calculated intracellular magnesium ([Mg2+]intra) was found to be increased in the patients with schizophrenia compared with healthy subjects after adjusting for left prefrontal grey and white matter, total brain volume, and age. These findings suggest that cortical grey and white manner volumes are not directly related to PME and [Mg2+]intra abnormalities in schizophrenia patients.


Subject(s)
Brain/pathology , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy/methods , Neurocognitive Disorders/diagnosis , Phosphorus/metabolism , Schizophrenia/diagnosis , Schizophrenic Psychology , Adult , Brain/physiopathology , Brain Mapping , Female , Humans , Image Processing, Computer-Assisted , Male , Membrane Lipids/metabolism , Middle Aged , Neurocognitive Disorders/physiopathology , Neurocognitive Disorders/psychology , Phospholipids/metabolism , Prefrontal Cortex/pathology , Prefrontal Cortex/physiopathology , Schizophrenia/physiopathology
7.
Blood ; 87(2): 706-11, 1996 Jan 15.
Article in English | MEDLINE | ID: mdl-8555494

ABSTRACT

Posttransplantation lymphoproliferative disease (PTLD) is virtually always associated with Epstein-Barr virus (EBV) infection. BCL-2 and other proteins that confer resistance to apoptosis have been implicated in the pathogenesis of a variety of malignancies including lymphomas. One EBV protein, BHRF1, is a homologue of BCL-2, whereas another, the latency membrane protein 1 (LMP-1), upregulates BCL-2 expression in vitro. In the present study, we used immunohistochemistry to study the expression of these viral and cellular proteins as well as a variety of other EBV-encoded proteins in PTLD. BHRF1 was not detected in any PTLD specimen, whereas BCL-2 was shown in 12 of 17 lesions examined. With one exception, all LMP1-positive cases also expressed BCL-2 and the absence of LMP1 was always associated with a lack of BCL-2 expression. The results do not support a role for the EBV homologue of BCL-2 in PTLD, but they do support a role for viral induction of BCL-2 expression.


Subject(s)
Gene Expression Regulation, Neoplastic , Gene Expression Regulation, Viral , Herpesviridae Infections/genetics , Herpesvirus 4, Human/pathogenicity , Lymphoma, Non-Hodgkin/genetics , Postoperative Complications/virology , Proto-Oncogene Proteins/biosynthesis , Tumor Virus Infections/genetics , Viral Matrix Proteins/physiology , Viral Proteins/biosynthesis , Amino Acid Sequence , Antigens, Viral/biosynthesis , Antigens, Viral/genetics , Apoptosis , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Epstein-Barr Virus Nuclear Antigens , Gene Rearrangement, B-Lymphocyte , Herpesviridae Infections/virology , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Humans , In Situ Hybridization , Lymphoma, Non-Hodgkin/virology , Molecular Sequence Data , Postoperative Complications/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2 , Transplantation , Tumor Virus Infections/virology , Viral Matrix Proteins/biosynthesis , Viral Matrix Proteins/genetics , Viral Proteins/genetics , Virus Activation
8.
Schizophr Bull ; 22(4): 597-609, 1996.
Article in English | MEDLINE | ID: mdl-8938914

ABSTRACT

The level of the 1H metabolites in the left dorsolateral prefrontal region of schizophrenia patients at different stages of illness were measured in vivo using a short echo time spectroscopy technique. During both the early onset and chronic stages, normal N-acetylaspartate levels were observed, which suggests that these patients had no significant neuronal cell damage and/or loss. The in vivo measurements of glutamate in the first-episode, drugnaive patients failed to provide convincing evidence for the involvement of the glutamatergic system in the dorsolateral prefrontal region. Significant differences in the glutamine levels were observed in the acutely medicated and chronic patients; however, the interpretation of these differences requires further study.


Subject(s)
Aspartic Acid/analogs & derivatives , Glutamic Acid/metabolism , Glutamine/metabolism , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Prefrontal Cortex/physiopathology , Schizophrenia/physiopathology , Adolescent , Adult , Antipsychotic Agents/therapeutic use , Aspartic Acid/metabolism , Chronic Disease , Female , Humans , Male , Middle Aged , Psychiatric Status Rating Scales , Schizophrenia/diagnosis , Schizophrenia/drug therapy , Schizophrenic Psychology
9.
Blood ; 86(9): 3333-40, 1995 Nov 01.
Article in English | MEDLINE | ID: mdl-7579436

ABSTRACT

Posttransplant lymphoproliferative disorder (PTLD) is a frequently fatal complication of organ transplantation, occurring in 2% to 6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality on the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly caused by the concomitant use of immunosuppressives. Nineteen consecutive cardiac recipients with PTLD were studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented less than 6 months after transplantation (median 6 weeks). Only 1 of 4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or = 6 months after transplantation. In 8 of 12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved complete remission (CR) and 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2 of 8 (25%) died during treatment, 6 of 8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 38 months. Neutropenic sepsis and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is both feasible and effective in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Heart Transplantation , Immunosuppression Therapy/adverse effects , Lymphoproliferative Disorders/drug therapy , Postoperative Complications/drug therapy , Adult , Aged , Bleomycin/administration & dosage , Cyclophosphamide/administration & dosage , Cytarabine/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Humans , Immunocompromised Host , Life Tables , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/mortality , Male , Mechlorethamine/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Multiple Organ Failure/etiology , Multiple Organ Failure/mortality , Postoperative Complications/etiology , Postoperative Complications/mortality , Prednisone/administration & dosage , Procarbazine/administration & dosage , Retrospective Studies , Survival Analysis , Treatment Outcome , Vincristine/administration & dosage
10.
Arch Gen Psychiatry ; 52(5): 399-406, 1995 May.
Article in English | MEDLINE | ID: mdl-7726721

ABSTRACT

BACKGROUND: In this study, phospholipid metabolism of cell membranes, high-energy phosphate metabolism, and intracellular free magnesium concentration in the prefrontal cortex of first-episode drug-naive schizophrenic patients and medicated schizophrenic patients at different stages of illness were compared with those of controls. METHODS: Localized in vivo phosphorus 31 magnetic resonance spectra of the left dorsolateral prefrontal cortex of 11 drug-native, eight newly diagnosed medicated, and 10 chronic medicated patients with schizophrenia were compared with controls of similar gender, education, parental education, and handedness. RESULTS: Significantly decreased levels of phosphomonoesters in drug-native, newly diagnosed medicated, and chronic medicated patients and significantly increased levels of phosphodiesters in drug-native patients were observed when compared with controls. There were no significant differences in the levels of high-energy phosphate metabolites between the groups except for a significant decrease in the inorganic orthophosphate levels of newly diagnosed medicated patients. A significant increase in the intracellular free magnesium concentration was observed in drug-naive, newly diagnosed medicated, and chronic medicated patients compared with controls. There were no correlations between the patients' negative and positive symptoms and the observed phosphorus-containing metabolites. CONCLUSIONS: A reduction in precursors of membrane phospholipid are observed during the early and chronic stages of the schizophrenia illness, and breakdown products of membrane phospholipids are increased at the early stage of illness before medication treatment.


Subject(s)
Magnetic Resonance Spectroscopy , Phospholipids/metabolism , Prefrontal Cortex/metabolism , Schizophrenia/metabolism , Adolescent , Adult , Cell Membrane/metabolism , Educational Status , Female , Functional Laterality , Humans , Magnesium/metabolism , Male , Parents , Phosphorus Isotopes , Schizophrenia/diagnosis , Schizophrenia/drug therapy , Schizophrenic Psychology
11.
Schizophr Res ; 13(3): 209-15, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7841133

ABSTRACT

Membrane phospholipid metabolism was studied with 31P magnetic resonance spectroscopy in the left dorsal prefrontal cortex of 19 male, medicated, schizophrenic patients and compared to 18 normal male controls matched in age, education and parental education level. The schizophrenic patients had significantly decreased phosphomonoester levels (PMEs, metabolites predominantly involved in the synthesis of membrane phospholipids). Phosphodiester levels (PDEs, breakdown products of membrane phospholipids) were not statistically different in schizophrenic patients compared to controls. However, a significant increase in the PDE levels was observed in the newly diagnosed patient subgroup. This observed pattern of the PMEs and PDEs would be consistent with the presence of an abnormal neurodevelopment early in the illness of schizophrenia.


Subject(s)
Magnetic Resonance Spectroscopy , Membrane Lipids/metabolism , Phospholipids/metabolism , Schizophrenia/physiopathology , Schizophrenic Psychology , Adolescent , Adult , Brain Mapping , Humans , Male , Middle Aged , Prefrontal Cortex/physiopathology , Psychiatric Status Rating Scales , Reference Values , Schizophrenia/diagnosis , Synaptic Membranes/physiology , Synaptic Transmission/physiology
12.
Biochemistry ; 33(39): 11671-7, 1994 Oct 04.
Article in English | MEDLINE | ID: mdl-7918383

ABSTRACT

(2R,4S,5S,1'S)-2-Phenylmethyl-4-hydroxy-5-(tert-butoxycarbonyl) amino-6-phenylhexanoyl-N-(1'-imidazo-2-yl)-2'-methylpropanamide (compound 2) is a tripeptide analogue inhibitor of HIV-1 protease in which a C-terminal imidazole substituent constitutes an isoelectronic, structural mimic of a carboxamide group. Compound 2 is a potent inhibitor of the protease (K(i) = 18 nM) and inhibits HIV-1 acute infectivity of CD4+ T-lymphocytes (IC50 = 570 nM). Crystallographic analysis of an HIV-1 protease-compound 2 complex demonstrates that the nitrogen atoms of the imidazole ring assume the same hydrogen-bonding interactions with the protease as amide linkages in other peptide analogue inhibitors. The sole substitution of the C-terminal carboxamide of a hydroxyethylene-containing tripeptide analogue with an imidazole group imparts greatly improved pharmacokinetic and oral bioavailability properties on the compound compared to its carboxamide-containing homologue (compound 1). While the oral bioavailability of compound 1 in rats was negligible, compound 2 displayed oral bioavailabilities of 30% and 14%, respectively, in rats and monkeys.


Subject(s)
HIV Protease/drug effects , HIV-1/enzymology , Imidazoles/chemistry , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Evaluation Studies as Topic , HIV Protease/chemistry , Half-Life , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Macaca fascicularis , Metabolic Clearance Rate , Molecular Conformation , Molecular Mimicry , Rats , Rats, Sprague-Dawley
13.
Biochemistry ; 31(29): 6646-59, 1992 Jul 28.
Article in English | MEDLINE | ID: mdl-1637805

ABSTRACT

Analogues of peptides ranging in size from three to six amino acids and containing the hydroxyethylene dipeptide isosteres Phe psi Gly, Phe psi Ala, Phe psi NorVal, Phe psi Leu, and Phe psi Phe, where psi denotes replacement of CONH by (S)-CH(OH)CH2, were synthesized and studied as HIV-1 protease inhibitors. Inhibition constants (Ki) with purified HIV-1 protease depend strongly on the isostere in the order Phe psi Gly greater than Phe psi Ala greater than Phe psi NorVal greater than Phe psi Leu greater than Phe psi Phe and decrease with increasing length of the peptide analogue, converging to a value of 0.4 nM. Ki values are progressively less dependent on inhibitor length as the size of the P1' side chain within the isostere increases. The structures of HIV-1 protease complexed with the inhibitors Ala-Ala-X-Val-Val-OMe, where X is Phe psi Gly, Phe psi Ala, Phe psi NorVal, and Phe psi Phe, have been determined by X-ray crystallography (resolution 2.3-3.2 A). The crystals exhibit symmetry consistent with space group P6(1) with strong noncrystallographic 2-fold symmetry, and the inhibitors all exhibit 2-fold disorder. The inhibitors bind in similar conformations, forming conserved hydrogen bonds with the enzyme. The Phe psi Gly inhibitor adopts an altered conformation that places its P3' valine side chain partially in the hydrophobic S1' pocket, thus suggesting an explanation for the greater dependence of the Ki value on inhibitor length in the Phe psi Gly series. From the kinetic and crystallographic data, a minimal inhibitor model for tight-binding inhibition is derived in which the enzyme subsites S2-S2' are optimally occupied. The Ki values for several compounds are compared with their potencies as inhibitors of proteolytic processing in T-cell cultures chronically infected with HIV-1 (MIC values) and as inhibitors of acute infectivity (IC50 values). There is a rank-order correspondence, but a 20-1000-fold difference, between the values of Ki and those of MIC or IC50. IC50 values can approach those of Ki but are highly dependent on the conditions of the acute infectivity assay and are influenced by physiochemical properties of the inhibitors such as solubility.


Subject(s)
Antiviral Agents/chemical synthesis , HIV Protease Inhibitors , HIV-1/physiology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Protease Inhibitors/chemical synthesis , Virus Replication/drug effects , Amino Acid Sequence , Blotting, Western , Cell Line , Ethylenes/chemistry , Ethylenes/pharmacology , HIV Protease/chemistry , HIV Protease/isolation & purification , HIV-1/drug effects , HIV-1/enzymology , Humans , Indicators and Reagents , Kinetics , Models, Molecular , Molecular Sequence Data , Oligopeptides/chemical synthesis , Protein Binding , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Structure-Activity Relationship , Substrate Specificity , T-Lymphocytes , X-Ray Diffraction
14.
Chest ; 101(2): 371-4, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1735257

ABSTRACT

Magnetic resonance imaging of the thorax was performed on ten occasions in eight HIV-positive patients with a clinical picture suggestive of Pneumocystis carinii pneumonia. The diagnosis of PCP was subsequently confirmed on six occasions. Patients without PCP had low MRI profusion scores, while four of six patients with PCP had MRI profusion scores greater than 6/21. Neither the chest roentgenogram appearance nor computer-generated T1 and T2 relaxation times could reliably distinguish between these two groups. Magnetic resonance imaging may be useful in the early and noninvasive diagnosis of PCP in HIV-positive patients.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , HIV-1 , Magnetic Resonance Imaging , Pneumonia, Pneumocystis/diagnosis , Humans , Lung/pathology , Pneumonia, Pneumocystis/complications
15.
Nature ; 343(6253): 90-2, 1990 Jan 04.
Article in English | MEDLINE | ID: mdl-1688646

ABSTRACT

The gag and pol genes of the human immunodeficiency virus type 1 (HIV-1) (ref. 1) are translated as two polyproteins, Pr55gag and Pr160gag-pol (refs 2-6), which are subsequently cleaved by the action of a virus-encoded protease into the four structural gag proteins of the virion core (p17, p24, p7 and p6) and the pol-encoded enzymes essential for retrovirus replication (protease, reverse transcriptase, ribonuclease H, and endonuclease). Mutational inactivation of the proteases of HIV-1 and other retroviruses results in immature, non-infectious virions, indicating that exogenous inhibition of the protease may represent an attractive approach to anti-AIDS therapy. Here we demonstrate that synthetic peptide analogues, which are potent inhibitors of purified HIV-1 protease, inhibit the processing of the viral polyproteins in cultures of HIV-1-infected T lymphocytes and attenuate viral infectivity.


Subject(s)
Endopeptidases/metabolism , HIV-1/enzymology , Oligopeptides/pharmacology , Amino Acid Sequence , Cell Line , Fusion Proteins, gag-pol/metabolism , Gene Products, gag/metabolism , HIV Protease , Humans , Molecular Sequence Data , Molecular Weight , Protease Inhibitors/pharmacology , Protein Processing, Post-Translational , RNA-Directed DNA Polymerase/metabolism , T-Lymphocytes/enzymology , T-Lymphocytes/microbiology , Virus Replication/drug effects
16.
Proc Natl Acad Sci U S A ; 86(24): 9752-6, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2690072

ABSTRACT

Inhibitors of the protease from human immunodeficiency virus 1 (HIV-1) were designed, synthesized, and kinetically characterized. Analogues of a heptapeptide substrate of HIV-1 protease with sequence similar to the p17-p24 cleavage site in the natural substrate, Pr55gag, were synthesized in which the scissile dipeptide bond was replaced with bonds from six categories of stable mimics of an aspartic proteolysis transition state or intermediate. These mimics included an analogue of statine, hydroxyethylene isosteres, two categories of phosphinic acids, a reduced amide isostere, and an alpha,alpha-difluoroketone. The resulting peptide analogues were linear competitive inhibitors of purified recombinant HIV-1 protease with inhibition constants ranging from 18 nM to 40 microM depending on the type of inhibitor. A truncated inhibitor, an analogue of a hexapeptide, retained full inhibitory potency. The most potent inhibitors, containing the hydroxyethylene isostere, effectively blocked the proteolytic processing of a recombinant form of Pr55gag by HIV-1 protease in a cell-free assay.


Subject(s)
HIV-1/enzymology , Oligopeptides/pharmacology , Protease Inhibitors/pharmacology , Amino Acid Sequence , Drug Design , Escherichia coli/genetics , HIV-1/genetics , Kinetics , Molecular Sequence Data , Molecular Structure , Oligopeptides/chemical synthesis , Peptide Hydrolases/genetics , Protease Inhibitors/chemical synthesis , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship , Substrate Specificity
17.
Chest ; 92(1): 31-9, 1987 Jul.
Article in English | MEDLINE | ID: mdl-3036427

ABSTRACT

Patients with active interstitial lung disease (ILD) are often treated with high-dose corticosteroids, although such therapy is not universally effective and has significant risks. Clinicians have utilized various ancillary diagnostic techniques to help with difficult treatment decisions. Since magnetic resonance imaging (MRI) has the theoretic and experimental potential of differentiating various stages of ILD, we prospectively studied 34 adult patients in a 0.15 Tesla resistive magnet body imager. The most severely affected patients, who were thought to warrant a steroid trial, had the greatest MRI image intensity, and dramatic improvement was seen following successful treatment. Qualitative MRI data were as useful as any other ancillary diagnostic technique (radiographic, physiologic, scintigraphic) in predicting clinical course. Computer-generated relaxation times were not sufficiently precise to differentiate active from inactive disease. Although limited by availability and cost, MRI appears to be a useful ancillary diagnostic technique in ILD patients facing immunomodulating therapy.


Subject(s)
Lung Diseases/diagnosis , Magnetic Resonance Spectroscopy , Pulmonary Fibrosis/diagnosis , Adjuvants, Immunologic/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Evaluation Studies as Topic , Female , Humans , Lung Diseases/diagnostic imaging , Lung Diseases/drug therapy , Male , Middle Aged , Peptidyl-Dipeptidase A/blood , Prospective Studies , Radiography , Respiratory Function Tests
18.
Chest ; 91(4): 500-2, 1987 Apr.
Article in English | MEDLINE | ID: mdl-3829741

ABSTRACT

Confirmation of the diagnosis of intralobar pulmonary sequestration has usually required angiographic demonstration of the systemic arterial supply. We report a young man who presented with non-resolving pneumonia where magnetic resonance imaging (MRI) suggested the correct diagnosis by demonstrating two arteries arising from the aorta supplying the sequestrum. MRI appears to offer a safe, noninvasive alternative for the diagnosis of sequestration.


Subject(s)
Bronchopulmonary Sequestration/diagnosis , Magnetic Resonance Spectroscopy , Adult , Arteries , Humans , Lung/blood supply , Lung/diagnostic imaging , Male , Tomography, X-Ray Computed
19.
J Otolaryngol ; 15(5): 273-8, 1986 Oct.
Article in English | MEDLINE | ID: mdl-3773042

ABSTRACT

Magnetic Resonance imaging (MRi) is a new imaging technique. The authors review the basic principles and present several cases comparing MRi with CT scanning and surgical findings. The major advantages of MRi include lack of ionizing radiation, non-invasiveness and absence of interpetrous artifact when visualizing the posterior fossa. Magnetic Resonance imaging of the posterior fossa, especially of the brain stem and cranial junction, has significant advantages over imaging by CT scanning.


Subject(s)
Head and Neck Neoplasms/diagnosis , Magnetic Resonance Spectroscopy , Adolescent , Adult , Aged , Arnold-Chiari Malformation/diagnosis , Brain Neoplasms/diagnosis , Carcinoma, Squamous Cell/diagnosis , Cysts/diagnosis , Female , Glioma/diagnosis , Humans , Magnetic Resonance Spectroscopy/methods , Male , Middle Aged , Mouth Neoplasms/diagnosis , Nasopharyngeal Neoplasms/diagnosis , Neuroma, Acoustic/diagnosis
20.
CMAJ ; 135(6): 639-43, 1986 Sep 15.
Article in English | MEDLINE | ID: mdl-3756694

ABSTRACT

Eighty-two patients with known or suspected multiple sclerosis (MS) were examined by means of magnetic resonance imaging (MRI) with a 0.15-T resistive scanner. The diagnosis could be made by MRI in 34 (97%) of the 35 patients with chronic, well-documented, stable MS and by high-volume delayed x-ray computed tomography (HVD CT) in only 6 (54%) of 11 patients in this group. The stage of the disease as judged from the MRI scans correlated poorly with the clinical status of the patient and with the known duration of the disease. MRI identified 28 (88%) of the 32 patients in whom MS was subsequently diagnosed by a neurologist, whereas regular contrast or HVD CT identified only 11 (52%) of 21 such patients. MRI is the most sensitive imaging modality for MS but is of little value in assessing the severity of the disease: many of the lesions seen on MRI scans are clinically "silent", and MRI does not usually detect small lesions in the brainstem, cerebellum or spinal cord that may be clinically significant.


Subject(s)
Magnetic Resonance Spectroscopy , Multiple Sclerosis/diagnosis , Brain/pathology , Humans , Neurologic Examination , Tomography, X-Ray Computed
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