Vulval intraepithelial neoplasia with extra mammary Pagets disease: a rare association.
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Aged↗
Biomedical subjects
P Bhatia
Publications and source records attributed to P Bhatia.
Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.
BACKGROUND AND PURPOSE: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. EXPERIMENTAL APPROACH: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. KEY RESULTS: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. CONCLUSIONS AND IMPLICATIONS: The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.
Analgesia↗
Massive haemoptysis: causes and management.
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Hemoptysis↗
Enhanced immunogenicity of a contraceptive vaccine using diverse synthetic carriers with permissible adjuvant.
A vaccine directed against human chorionic gonadotropin (hCG) has previously undergone clinical testing demonstrating the feasibility of the approach in preventing pregnancy in women. Some individuals, however, did not respond adequately despite employing highly immunogenic bacterial toxoids as carriers. We investigated the potential of three promiscuous pathogen-derived Th peptides as carriers, employing alum as the adjuvant. While conjugation with each peptide improved the antibody response against hCG in mice of different haplotypes, immunisation with a combination of these peptide-conjugates generated anti-hCG responses higher than those achieved with the individual peptides or tetanus toxoid (TT). Antibodies were of high affinity and capable of neutralising the bioactivity of hCG but were devoid of anti-peptide reactivity. These results have implication for the design of hCG vaccine with improved immunogenicity for diverse population.
Adjuvants, Immunologic↗
Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis.
Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4, 4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47.Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47.Na inhibited ionophore-stimulated LTB(4) formation with an IC(50) = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC(4) and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC(4) (IC(50) = 0.16 nM) over PGE(2) (IC(50) = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED(50) = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB(4), ED(50) = 2.5 mg/kg; LTE(4), ED(50) = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED(50) = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB(4) and LTC(4) but not PGH(2) biosynthesis. However, 47.Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47.Na acts as a FLAP inhibitor.
Administration, Oral↗
Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors.
A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.
Acrylic Resins↗
Pregnancy and the lungs.
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Bronchial Diseases↗
Common mechanisms of osteosarcoma and Paget's disease.
One of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1% of Paget's patients develop osteosarcoma, an increase in risk that is several thousand-fold higher than the general population. This risk contributes significantly to the mortality and morbidity of Paget's disease patients. We examined several cases of pagetic and sporadic osteosarcoma for tumor-specific loss of constitutional heterozygosity (LoH) on chromosome 18q. Our analysis found that both pagetic and sporadic osteosarcoma tumors showed LoH for all or part of the distal portion of chromosome 18q. The pattern of LoH in both types of tumors identified a region between loci D18S60 and D18S42 that must contain the putative tumor suppressor locus. This region is tightly linked to familial Paget disease and familial expansile osteolysis (FEO). Our hypothesis is that the predisposition locus for Paget's disease and the tumor suppressor locus for osteosarcoma are either the same gene or that osteosarcoma in Paget's disease represents a deletion affecting two adjacent genes. In either model, localization of the osteosarcoma tumor suppressor gene would be of benefit in the eventual isolation of the predisposition locus for Paget's disease. We have begun to isolate and test candidate genes from within the region defined by both the familial Paget's disease families and the minimal region of LoH in osteosarcomas for evidence that one or more of them is responsible for predisposition to Paget's disease and/or osteosarcoma.
Bone Neoplasms↗
Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas.
BACKGROUND: Osteochondroma most frequently arises sporadically and as a solitary lesion, but also may arise as multiple lesions characterizing the autosomal dominant disorder hereditary multiple exostoses (HME) and the contiguous gene syndromes Langer-Giedion and DEFECT-11 syndromes. HME is genetically heterogeneous with association of three loci including 8q24.1 (EXT1), 11p11-12 (EXT2), and 19p (EXT3). Constitutional chromosomal microdeletions of 8q24.1 and 11p11-12 are features of the Langer-Giedion and DEFECT-11 syndromes, respectively. Cytogenetic studies of osteochondroma are rare. METHODS: Cytogenetic analysis was performed on 34 osteochondroma specimens from 22 patients with sporadic lesions and 4 patients with HME utilizing standard methodologies. Fluorescence in situ hybridization with chromosome specific probes was performed on three cases to define structural rearrangements further. RESULTS: Clonal abnormalities were detected in ten cases. Notably, deletion of 11p11-13 was observed in one case (a sporadic tumor) and loss or rearrangement of 8q22-24.1 in eight cases (seven sporadic and one hereditary tumor). CONCLUSIONS: These findings: 1) confirm previous observations of 8q24.1 karyotypic anomalies in sporadic osteochondroma, 2) reveal the presence of somatic chromosomal anomalies in hereditary osteochondromata, 3) suggest that similar to hereditary lesions, sporadic osteochondromas also are genetically heterogeneic (involvement of both 8q24.1 and 11p11-12), and 4) support the hypothesis that loss or mutation of EXT1 and EXT2, two putative tumor suppressor genes, may be important in the pathogenesis of sporadic as well as hereditary osteochondromata.
Adolescent↗
Lymphoepithelioma-like carcinoma of the colon: report of a case with histologic, immunohistochemical, and molecular studies for Epstein-Barr virus.
We report a case of lymphoepithelioma-like carcinoma of the colon in a 62-year-old Hispanic male with multiple other tumors, including thyroid, breast, pharyngeal, and prostate carcinomas; a neurofibrosarcoma; and a meningioma. The association with Epstein-Barr virus infection and colonic lymphoepithelioma-like carcinoma was studied using immunohistochemical and polymerase chain reaction techniques.
Blotting, Southern↗
Vernix caseosa peritonitis as a rare complication of cesarean section. A case report.
BACKGROUND: Vernix caseosa peritonitis is a rare complication of cesarean section with distinctive histopathologic findings. CASE: Vernix caseosa peritonitis occurred in a 28-year-old, pregnant woman following emergency cesarean section. Exploratory laparotomy revealed right subphrenic and perihepatic fluid collections with multiple small abdominal abscesses. Cytopathologic examination of the peritoneal lavage specimen showed a purulent inflammatory exudate admixed with occasional squamous debris, portions of hair shafts, meconium pigment, and foamy and multinucleated giant cells. During hospitalization the patient had developed Clostridium perfringens acute endometritis, presumably due to aggressive treatment with broad-spectrum antibiotics. CONCLUSION: Pathologists are in a unique position to make the correct diagnosis in an otherwise-ambiguous clinical presentation because of the distinctive histopathologic and cytopathologic findings of this entity. Computed tomography-guided fine needle aspiration cytologic evaluation can be diagnostic in such cases.
Adult↗
Characterization of A-93178, an iminoxy-quinoline inhibitor of leukotriene biosynthesis.
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Animals↗
Synthesis of indolylalkoxyiminoalkylcarboxylates as leukotriene biosynthesis inhibitors.
A series of substituted indolylalkoxyiminoalkylcarboxylates were found to be potent leukotriene biosynthesis inhibitors. The structure-activity relationships were investigated. Representative potent inhibitors identified were the quinolyl 3a (A-86885) and pyridyl 3b (A-86886) congeners with in vitro IC50s of 21 and 9 nM and in vivo leukotriene inhibition in the rat with oral ED50s of 0.9 and 1.7 mg/kg, respectively.
5-Lipoxygenase-Activating Proteins↗
Strongyloides stercoralis eosinophilic granulomatous enterocolitis.
Six patients suffering from an unusual form of colitis produced by Strongyloides stercoralis hyperinfection are described. In contrast to the usual Strongyloides hyperinfection syndrome, in which small intestinal and pulmonary manifestations are seen in patients with some forms of immunodeficiency, the patients described here presented with only a characteristic transmural eosinophilic granulomatous inflammation affecting mostly the colonic wall and clinically mimicking ulcerative colitis or Crohn's disease. This Strongyloides eosinophilic granulomatous enterocolitis apparently results from a florid inflammatory response by eosinophils, histiocytes, and giant cells with formation of granulomas that destroy the larvae entering the colon. This morphologic picture differs from that of the well-described hyperinfection syndrome, in which the bulk of the larvae pass through the colonic wall to complete the life cycle, with only a few larvae destroyed in the colon. The probable pathophysiologic mechanism of this unusual manifestation of hyperinfection is discussed based on the anatomic and clinical observations of patients who presented at different stages in the evolution of their condition and whose length of follow-up varied.
Aged↗
(R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl- 2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.
Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N- hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2- thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.
Animals↗
Juvenile chronic myelocytic leukemia--report of 10 cases.
Ten children (five boys and five girls) with juvenile chronic myelocytic leukemia were seen over a period of 12 years (1980-1991) at the All India Institute of Medical Sciences, New Delhi. With the exception of one who was aged 4.5 years, all children were below 4 years of age (mean age 20.4 months). The presenting features included fever, bleeding secondary to thrombocytopenia, marked hepatosplenomegaly, and skin rash. The striking hematological features were anemia, thrombocytopenia, peripheral blood monocytosis, and normoblastemia. There was no significant myeloid proliferation in the bone marrow aspirate (mean M:E = 5:1), while erythroid proliferation was prominent along with monocytosis (mean 11.2%). Fetal hemoglobin was raised in 8 of the 10 patients (mean 14.1%). Long-term survival was poor, with maximum survival being 18 months in one case. New modalities of management of this rare entity are discussed.
Child, Preschool↗
Exacerbation of chronic ulcerative colitis with mesalamine.
Activation of ulcerative colitis with mesalamine has rarely been reported. In case 1, a 34-year-old man was treated with oral mesalamine, resulting in an exacerbation of colitis that rapidly improved with glucocorticoids and mesalamine withdrawal. Oral cromolyn sodium and occasional low-dose prednisone therapy has maintained long-term remission. In case 2, a 28-year-old man receiving prednisone treatment developed chest pain and myalgias 1 week after initiation of mesalamine that resolved on mesalamine withdrawal. A lower dose of mesalamine with continued glucocorticoids resulted in clinical improvement, and both drugs were tapered. Mesalamine sensitivity was documented endoscopically and histologically by evaluating mucosal changes after two mesalamine enemas during a 24-hour period. There was dramatic progression from quiescent disease to active colitis in 24 hours. Mesalamine sensitivity must be included in the differential diagnosis of ulcerative colitis exacerbations. Concurrent steroid therapy can suppress systemic side effects, making the diagnosis even more elusive.
Adult↗
Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28S-ribosomal RNA gene expression as RNA loading controls for northern blot analysis of cell lines of varying malignant potential.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been a gene of choice in Northern blot analyses as an internal RNA loading control. We have investigated the expression of GAPDH and 28S-ribosomal RNA (28S rRNA) genes in mouse 10T1/2 cells and in a variety of tumorigenic and highly malignant metastatic cell lines derived from the 10T1/2 cell line. We observed that GAPDH mRNA levels varied markedly among the tumorigenic and highly malignant cell lines and were elevated in these cell lines when compared to the normal mouse 10T1/2 cells. In contrast, the levels of 28S rRNA did not significantly vary among the tumorigenic and highly malignant cell lines and were approximately at the same level as that found in the normal parental mouse 10T1/2 cell line. These observations indicate that much caution should be taken when using GAPDH gene expression as an RNA loading control for Northern blots. Based upon these observations, we recommend the use of 28S rRNA gene expression as a preferred RNA loading control for Northern blot analysis in which total RNA is used.
Animals↗