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R Jordan

Publications and source records attributed to R Jordan.

At least 55 records · Page 3Linked to original sources
PubMed1997

Toxoplasmic myocarditis and polymyositis in patients with acute acquired toxoplasmosis diagnosed during life.

The presence of both toxoplasmic myocarditis and myositis in the same individual has been reported only at autopsy. We report the first case of biopsy-proven toxoplasmic myocarditis and polymyositis simultaneously occurring in the same individual that was diagnosed during life. Results of her toxoplasmic serology were consistent with acute toxoplasmosis. She subsequently developed visual symptoms consistent with toxoplasmic chorioretinitis. She had a positive clinical response to therapeutic agents specific against Toxoplasma gondii. Her toxoplasmic serological profile established the diagnosis of acute toxoplasmosis. A toxoplasmic serological profile should be obtained for patients with myocarditis and/or polymyositis of unclear etiology. Endomyocardial or skeletal muscle tissue biopsies may establish the definitive diagnosis of toxoplasmic myocarditis or polymyositis, respectively. Examination of blood by polymerase chain reaction analysis before antitoxoplasmic treatment and early in the course of primary infection with T. gondii may prove useful.

Acute Disease↗
PubMed1997

The relationship between E-cadherin expression, clinical stage and tumour differentiation in oral squamous cell carcinoma.

OBJECTIVES: To evaluate the expression of E-cadherin, a calcium-dependent cell adhesion molecule, in a retrospective analysis of paraffin embedded tissue specimens of oral squamous cell carcinoma and relationship with the clinical TNM stage and histochemical differentiation. DESIGN: Paraffin embedded tissue sections of normal oral mucosa (n = 6), oral squamous cell carcinoma (SCC, n = 18) and metastatic lymph nodes (n = 2) were immunostained by a three-stage streptoavidin-biotin immunoperoxidase method using monoclonal antibody. The TNM staging and histochemical grading were done according to the standard criteria. RESULTS: Normal oral epithelium showed a strongly positive pericellular distribution of E-cadherin in basal, parabasal and spinous layers and no staining was observed in the parakeratinized and cornified layers. In well differentiated SCCs, the centrally located cells in tumour islands showed no staining, but peripheral basally located tumour cells showed positive staining. Poorly differentiated SCCs were devoid of staining. In moderately differentiated SCCs, the staining pattern was found to be one of the following three types: (1) a pattern similar to that of well differentiated SCC; (2) central cells of tumour aggregates were reactive but peripheral cells showed weak to negative reaction; and (3) all cells showed a negative reaction, resembling the poorly differentiated SCC. Fischer exact test showed a statistically significant correlation with loss of E-cadherin and grades of tumour differentiation as well as an advancing T and N stage. CONCLUSION: The loss of E-cadherin may correlate with advancing T and N stages of the tumour and a poor tumour cell differentiation in oral squamous cell carcinomas.

Cadherins↗
PubMed1997

Activation of gene expression by herpes simplex virus type 1 ICP0 occurs at the level of mRNA synthesis.

ICP0 is a nuclear phosphoprotein involved in the activation of herpes simplex virus type 1 (HSV-1) gene expression during lytic infection and reactivation from viral latency. Although available evidence suggests that ICP0 acts at the level of transcription, definitive studies specifically addressing this issue have not been reported. In the present study we measured the ability of ICP0 to activate gene expression (i) from promoters representing the major kinetic classes of viral genes in transient expression assays and (ii) from the same promoters during viral infection at multiplicities of infection ranging from 0.1 to 5.0 PFU/cell. The levels of synthesis and steady-state accumulation of mRNA, mRNA stability, and levels of protein synthesis were compared in cells transfected with a reporter plasmid in the presence and absence of ICP0 and in cells infected with wild-type HSV-1 or an ICP0 null mutant, n212. In transient expression assays and during viral infection at all multiplicities tested, the levels of steady-state mRNA and protein were significantly lower in the absence of ICP0, indicating that ICP0 activates gene expression at the level of mRNA accumulation. In transient expression assays and during infection at low multiplicities (< 1 PFU/cell) in the presence or absence of ICP0, marked increases in the levels of viral mRNAs accompanied by proportional increases in the levels of protein synthesis were observed with increasing multiplicity. At a high multiplicity (5 PFU/cell) in the presence or absence of ICP0, mRNA levels did not increase as a function of multiplicity and changes in the levels of protein were no longer related to changes in the levels of mRNA. Collectively, these tests indicate that transcription of viral genes is rate limiting at low multiplicities and that translation is rate limiting at high multiplicities, independent of ICP0. Consistent with the lower levels of mRNA detected in the absence of ICP0, the rates of transcription initiation measured by nuclear run-on assays were uniformly lower in cells infected with the ICP0 null mutant at all multiplicities tested, implying that ICP0 enhances transcription at or before initiation or both. No evidence was found of posttranscriptional effects of ICP0 (i.e., effects on the stability of mRNA, nuclear-cytoplasmic distribution, polyribosomal mRNA distribution, or rates of protein synthesis). Taken together, these results suggest that ICP0 activates gene expression prior to or at the level of initiation of mRNA synthesis in transient expression assays and during viral infection. Based on these findings; we hypothesize that the exaggerated multiplicity-dependent growth phenotype characteristic of ICP0 null mutants reflects the requirement for ICP0 under conditions where the steady-state level of mRNA is rate limiting, such as during low-multiplicity infection and reactivation from latency.

Animals↗
PubMed1997

An appraisal of the efficacy and cost effectiveness of antenatal screening for hepatitis B.

In this review published data are used to determine the benefits and costs of antenatal screening for hepatitis B carriers to prevent the later occurrence of hepatoma and chronic liver disease in their offspring. In Britain, babies born to carrier mothers have a 25% risk of perinatal infection and of becoming carriers themselves (the risk is 82% if their mothers are positive for the e antigen and 10% if negative). The carrier state increases the risk of hepatoma an estimated 86 times and the risk of chronic liver disease 20 times. Life table analysis showed that there is an 11% lifetime risk in carriers in Britain of dying from hepatoma (which results in seven years of life lost on average) and a 7% risk of chronic liver disease (14 years of life lost). Neonatal vaccination reduces the risk of the infant becoming a carrier by about 90%. Perinatal transmission occurs in 38 of every 100,000 neonates in Britain. Antenatal screening of all women and vaccinating babies of carrier mothers would prevent perinatal transmission in 34 of the 38 children (90%), or 255 per year in Britain. Of these 34, 8.4 children would be Chinese in ethnic origin, 4.2 African, 11.5 South Asian (from the Indian subcontinent), 2.0 Caribbean, and 7.3 would be white. Six deaths in the 34 from hepatoma or chronic liver disease caused by hepatitis B would then be prevented. The direct cost in Britain of screening all women, irrespective of ethnicity, at their first pregnancy only, would be 1300 pounds for each year of life saved (undiscounted) or 2500 pounds if screening at every pregnancy. Screening just Chinese, Africans, and South Asians, at first pregnancy only, would cost 330 pounds for each year of life saved but would prevent only 64% of these deaths. Vaccinating the infants of carrier mothers is likely also to prevent horizontal transmission of hepatitis B in early childhood and prevent the carrier state developing in an estimated three extra children for each child protected from vertical transmission. When this is taken into account the number of deaths prevented increases fourfold, reducing the cost for each year of life saved by 75%. Screening all women at first pregnancy only is an acceptably cost effective policy in Britain (1300 pounds for each year of life saved), actually preventing 45 deaths a year from hepatoma and chronic liver disease (or about 180 deaths if those horizontally infected are included), at a total cost of 540,000 pounds a year. It has the advantage of being comprehensive, equitable, and easier to implement than a policy based on screening of high risk ethnic groups.

Adolescent↗
PubMed1996

Site-directed mutations affecting the spectroscopic characteristics and midpoint potential of the primary donor in photosystem I.

Photosystem I is a member of the iron-sulfur center or type I reaction centers. The primary electron donor in photosystem I is a chlorophyll a dimer termed P700. The biophysical properties of P700 are well understood, but the protein environment that gives it such unique properties is unknown. We have characterized site-directed mutants of the photosystem I reaction center protein PsaB and identified an amino acid, His-656, that interacts closely with one of the P700 chlorophylls. Mutation of His-656 to Asn or Ser increases the oxidation midpoint potential of P700/P700+. by 40 mV. The P700/P700+. optical difference spectra show the appearance of a new bleaching band at 667 nm. Electron nuclear double resonance spectroscopy indicates a significant increase in the hyperfine coupling corresponding to methyl protons at position 12 of the spin carrying chlorophyll a of P700+. The implication of these results to current structural models of the photosystem I reaction center is discussed.

Amino Acid Sequence↗
PubMed1996

The myocardial lesions produced by the potassium channel opener aprikalim in monkeys and rats are prevented by blockade of cardiac beta-adrenoceptors.

Aprikalim is a potent, specific, and selective opener of ATP-sensitive K+ (KATP) channels. By virtue of this pharmacological property, aprikalim affords cardioprotection in experimental models of ischemia/reperfusion injury, and, at higher doses, also causes peripheral or coronary vasodilatation. Direct-acting peripheral vasodilators can cause myocardial lesions, particularly in rats and dogs. However, unexpectedly, aprikalim produced this effect also in monkeys. Thus, the primary aim of this investigation was to assess whether in monkeys these myocardial lesions were the direct or indirect consequence of the vascular effects of aprikalim. Cynomologus monkeys were given the beta-adrenoceptor antagonist nadolol (2 mg/kg p.o., twice daily) for 4 consecutive days. On the third and fourth day of the experiment, they received aprikalim (1 mg/kg p.o.). In another series, two monkeys carrying telemetry transmitters for blood pressure and heart rate measurements were also given aprikalim or its vehicle. Finally, aprikalim (1 mg/kg p.o. for 2 days) or its vehicle was administered to rats which were concurrently treated with the beta-adrenoceptor antagonist atenolol (5 mg/kg s.c.) or its vehicle. In cynomologus monkeys, aprikalim produced focal and multifocal myocardial necrosis of minimal to moderate intensity in or near the papillary muscles of the left ventricle. These effects were abrogated by nadolol. Similarly, necrotic lesions were caused by aprikalim only in those rats which had not been pretreated with atenolol. In monkeys, aprikalim produced a marked and long-lasting decrease in aortic blood pressure, accompanied by an even more prolonged tachycardia. These results demonstrate that aprikalim can produce myocardial necrosis not only in rats but also in monkeys. To our knowledge, this is the first time that such adverse effects are reported for a vasodilator in monkeys. More importantly, these effects were prevented by blocking cardiac beta-adrenoceptors. Thus, the myocardial lesions produced by aprikalim may be attributed to its profound and prolonged hemodynamic effects.

Adrenergic beta-Antagonists↗
PubMed1995

Modulation of the ATPase activity of the molecular chaperone DnaK by peptides and the DnaJ and GrpE heat shock proteins.

Previous studies have demonstrated that the Escherichia coli DnaK, DnaJ, and GrpE heat shock proteins participate in the initiation of bacteriophage lambda DNA replication by mediating the required disassembly of a preinitiation nucleoprotein structure that is formed at the phage replication origin. To gain some understanding in a simpler system of how the DnaJ and GrpE cochaperonins influence the activity of DnaK, we have examined the effect of the cochaperonins on the weak intrinsic ATPase activity of the molecular chaperone DnaK in the presence and absence of peptide effectors. We have found that random sequence peptide chains of 8 or 9 amino acid residues in length yield optimal (10-fold) activation of the DnaK ATPase, whereas peptides with 5 or fewer residues fail to stimulate the ATPase of this bacterial hsp70 homologue. Furthermore, we have discovered that those peptides that interact best with DnaK, as judged by their KA as activators of ATP hydrolysis by DnaK, also act as strong inhibitors of lambda DNA replication in vitro. The inhibitory effect of peptides on lambda DNA replication was overcome by increasing the concentration of DnaK in the replication system. Diminished inhibition was also found when the replication system was supplemented with GrpE cochaperonin, a protein known to increase the effectiveness of DnaK action in lambda DNA replication. These and other results suggest that the peptide-binding site of DnaK is required for its function in lambda DNA replication. Apparently, peptides sequester free DnaK protein and block lambda DNA replication by reducing the amount of DnaK that is free to mediate disassembly of nucleoprotein preinitiation structures. In related studies, we have found that DnaJ, like short peptides, activates the intrinsic ATPase activity of DnaK. DnaJ, however, is substantially more potent in this regard, since it activates DnaK at concentrations 1000-fold below those required for a peptide of random sequence. By itself, the GrpE cochaperonin has no effect on the peptide-independent ATPase activity of DnaK, but GrpE does vigorously stimulate the peptide-dependent ATPase of the DnaK chaperone. Under steady-state conditions, the Vmax of ATP hydrolysis by DnaK was elevated approximately 40-fold by the presence of GrpE and saturating levels of peptides.

Adenosine Triphosphatases↗
PubMed1995

Comparative real-time effects on platelet adhesion and aggregation under flowing conditions of in vivo aspirin, heparin, and monoclonal antibody fragment against glycoprotein IIb-IIIa.

BACKGROUND: A real-time in vitro system of human platelet thrombosis under arterylike flowing conditions similar to those produced in vivo by angioplasty would be useful for the evaluation of potential antiarterial thrombotic agents in association with in vivo trials. Aspirin, heparin, and the chimeric monoclonal antibody antigen-binding fragment 7E3 (c7E3 Fab) directed against platelet glycoprotein (GP) IIb-IIIa have been used in attempts to delay or prevent thrombotic reocclusion of coronary arteries after angioplasty. We compared the effects of these agents administered in vivo on GPIb-mediated platelet adhesion to von Willebrand factor (vWF)/collagen type I (as in atherosclerotic subendothelium) and on subsequent GPIIb-IIIa-fibrinogen/vWF-mediated platelet aggregation under flowing conditions analogous to those in constricted coronary arteries. METHODS AND RESULTS: Citrated whole blood containing mepacrine-labeled platelets from patients and healthy donors was perfused for 1 minute at an abnormally elevated shear rate of 1500 seconds-1 (arterial wall shear stress of 50 to 60 dynes/cm2) at 37 degrees C over collagen I/vWF. The number of adherent fluorescent platelets was quantified every 15 seconds with a low-light-level video camera and epifluorescent microscopy. After 5 healthy donors had ingested 975 mg aspirin, platelet adhesion was unaffected in the aspirin-treated blood compared with the control blood in all experiments (10 of 10), and subsequent aggregation was unchanged in most runs (8 of 10). The blood of 3 aspirin-treated patients undergoing angioplasty was analyzed before and after a 12,000-U heparin injection and 2 minutes, 2 hours, and 24 hours after infusion of 0.25 mg/kg of c7E3 Fab. In these patients, the bolus of heparin did not inhibit either platelet adhesion to collagen I/vWF or subsequent aggregation. In contrast, there was > 50% inhibition of platelet aggregation 2 minutes after the infusion of c7E3 Fab in all 3 patients, and inhibition persisted in 2 of the 3 patients at 2 hours and 24 hours after c7E3 Fab. CONCLUSIONS: In contrast to aspirin or heparin, the in vivo injection of c7E3 Fab considerably reduces platelet aggregate formation mediated by the binding of fibrinogen, vWF, or some other ligand to platelet GPIIb-IIIa under conditions of abnormally increased shear stress analogous to those in narrowed coronary arteries. Platelet adherence to collagen I/vWF is not affected. This study describes an in vitro model of arterial injury (similar to angioplasty) that uses human blood to compare directly, in real time, the precise relative effects of aspirin, heparin, and c7E3 Fab on platelet adhesion and subsequent aggregation.

Abciximab↗
PubMed1995

Shear-induced platelet aggregation is inhibited by in vivo infusion of an anti-glycoprotein IIb/IIIa antibody fragment, c7E3 Fab, in patients undergoing coronary angioplasty.

BACKGROUND: Elevated levels of shear stress such as those that occur in stenotic arterial vessels can directly activate and aggregate platelets and thus contribute to the pathogenesis of acute arterial thrombosis. This shear-induced platelet aggregation (SIPA) is mediated by von Willebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa. The chimeric Fab fragment of the monoclonal antibody 7E3 (c7E3 Fab) that binds selectively to GPIIb/IIIa is under clinical evaluation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA. METHODS AND RESULTS: Six patients received aspirin (325 mg) and boluses of heparin (12,00o U) followed by c7E3 Fab 0.25 mg/kg. Blood collected from each patient before and after heparin treatment and at various time points after c7E3 Fab administration was subjected to laminar shear stress in a cone-and-plate viscometer. Flow cytometry was used to quantify the extents of platelet aggregation and of antibody binding to GPIIb/IIIa. Results indicate that c7E3 Fab injection resulted in a rapid, extensive blockade of GPIIb/IIIa receptors (98.6 +/- 0.2%) and a 50% inhibition of ex vivo platelet aggregation induced by shear stress. c7E3 Fab also completely abolished the formation of large platelet aggregates ("large" refers to particles > 10 microns in equivalent sphere diameter), which are presumably the aggregates of greatest clinical significance. Partial reversibility of the inhibition was noted within 2 days after drug administration, but even after 1 week, platelet function had not been fully restored. CONCLUSIONS: This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mechanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronary artery disease after angioplasty.

Abciximab↗
PubMed1995

Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): potent dose-dependent inhibition of platelet function.

The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPII/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20-0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25-0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (+/- SE) GPIIb/IIIa receptor blockade was 81 +/- 3%, ex vivo platelet aggregation in response to 20 microM ADP was 14 +/- 6% of baseline, and the median bleeding time was > 20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.

Adult↗
PubMed1995

The immunogenicity of the 7E3 murine monoclonal Fab antibody fragment variable region is dramatically reduced in humans by substitution of human for murine constant regions.

A murine monoclonal antibody (7E3) directed against the platelet glycoprotein IIb/IIIa was engineered to reduce immunogenicity by substituting human for murine constant regions. The chimeric antibody is functionally identical to the murine antibody in vitro. Results from clinical trials with 7E3 Fab antibody fragments, however, show that the 7E3 variable region, which elicits the vast majority of the immune response to murine 7E3 Fab, is rendered dramatically less immunogenic (incidence reduced from 17% to 1%) when the identical variable region is linked to human rather than murine constant regions. Neither murine nor human constant regions were highly immunogenic themselves. We conclude that the constant regions of the Fab fragments are critical in modulating the immune response elicited by the linked 7E3 variable region. Because naturally occurring anti-human Fab fragment antibodies are prevalent both in the normal human population and in the patient population studied here, murine 7E3 Fab and chimeric 7E3 Fab may be fundamentally different in their interactions with the human immune system. This difference may be related to the dramatic difference in immunogenicity observed between murine 7E3 Fab and chimeric 7E3 Fab.

Animals↗
PubMed1995

Differential inhibition of platelet aggregation induced by adenosine diphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors.

OBJECTIVES: This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) in patients undergoing elective coronary angioplasty. BACKGROUND: Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes. METHODS: Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/liter TRAP were assessed. RESULTS: Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h. Platelet aggregation in response to 20 mumol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/liter TRAP-induced aggregation. CONCLUSIONS: After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.

Abciximab↗
PubMed1995

Immunoglobulin gene rearrangements in lymphoplasmacytic infiltrates of labial salivary glands in Sjögren's syndrome. A possible predictor of lymphoma development.

OBJECTIVES: Sjögren's syndrome is an autoimmune disorder in which patients have a well-recognized risk of developing malignant lymphoma. Although some clinical parameters may herald the onset of lymphoma, few reliable histologic or molecular markers are available that predict progression to a malignant lymphoproliferative disorder. The purpose of this study was to identify the prevalence of immunoglobulin heavy chain monoclonality in labial gland biopsies of patients with Sjögren's syndrome and to compare this to clinical outcome. STUDY DESIGN: The polymerase chain reaction was applied to 76 sequential labial salivary gland biopsies from patients under investigation for Sjögren's syndrome. A seminested polymerase chain reaction technique was used on DNA extracted from formalin-fixed, paraffin-embedded tissue to amplify the V-D-J region of the immunoglobulin heavy chain gene. Thirty-four randomly selected labial salivary glands that showed nonspecific sialadenitis from patients without Sjögren's syndrome were used as controls. RESULTS: Monoclonality, as defined by a single band on polyacrylamide gel electrophoresis was detected in 11 cases (14.5%). Of cases that showed monoclonality, four patients were subsequently diagnosed with extrasalivary lymphoma. In each case the rearranged bands in the lip biopsy and the lymphoma were the same size. In one patient who later developed lymphoma, a monoclonal rearranged immunoglobulin band was not identified. In addition, no cases of the translocation t(14;18) were identified by polymerase chain reaction in any of the lip biopsies showing heavy chain monoclonality or in any of the extrasalivary gland lymphomas. CONCLUSIONS: These results suggest that monoclonal immunoglobulin heavy chain gene rearrangements are a relatively common finding in patients with Sjögren's syndrome and may prove to be a useful marker for predicting the progression to, and early detection of malignant lymphoma.

Adolescent↗
PubMed1995

Different sensitivity to cell killing and chromosome mutation induction by gamma rays in two human lymphoblastoid cell lines derived from a single donor: possible role of apoptosis.

The gamma-ray sensitivity of two human lymphoblastoid cell lines, TK6 and WI-L2-NS, was studied; both cell lines are derived from the same parent, WI-L2. TK6 was more sensitive to the cytotoxic effects of gamma rays, but showed fewer induced chromosome aberrations. There was no difference between the two cell lines in their capacity to rejoin DNA double-strand breaks or in the kinetics of the rejoining process. The kinetics of cell cycle progression following radiation exposure was also similar in TK6 and WI-L2-NS. However, while TK6 cells were very sensitive to apoptosis induction, showing high levels of apoptotic cells within 24 h of exposure, no evidence for any significant levels of apoptosis was found for WI-L2-NS within 30 h of irradiation, when chromosome aberration frequency was determined. Evidence of apotosis were seen at later times in WI-L2-NS cells, but the levels were significantly lower than comparably treated TK6 cells. The results support a hypothesis that the lower survival and induced aberration frequencies in TK6 cells are due to selective removal of damaged cells by apoptotic processes prior to analysis of chromosome aberration frequencies in mitosis.

Apoptosis↗
PubMed1994

Early detection of lymphomas in Sjögren's syndrome by in situ hybridisation for kappa and lambda light chain mRNA in labial salivary glands.

Sjögren's syndrome (SS) is an autoimmune disease characterised by a generalised lymphoproliferation. Patients have an increased risk of developing lymphomas which are usually of the type associated with mucosa-associated lymphoid tissue (MALT). Histological examination of the minor salivary glands of the lower lip is a common and useful diagnostic test for SS but has not been able to provide information with regard to potential malignant change. In this study, a sensitive in situ hybridisation technique for the detection of kappa and lambda immunoglobulin light-chain mRNA was applied to labial salivary glands of 14 patients with SS. 7 cases showed light chain restriction, in 5 cases this was kappa(kappa:lambda ratio > 8.0) and in 2 it was lambda(kappa:lambda ratio < 0.6). Of these 7, 5 developed lymphomas--4 were low grade lymphomas of MALT type and the fifth patient died of disseminated lymphoma. The finding of light chain restriction in lip minor salivary glands is strong evidence of a monoclonal population of B-cells at this site. It is concluded that in patients with SS who develop lymphomas, dissemination of malignant cells may result in detectable disease in the minor salivary glands. Determination of kappa:lambda ratios in labial minor salivary glands may thus provide important prognostic information.

Autoimmune Diseases↗
PubMed1994

Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor.

1. We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram. 2. RP 73401 (0.4-400 micrograms kg-1, intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guinea-pigs (ID50: 7 +/- 1 micrograms kg-1) and in anaesthetized rats (ID50: 100 +/- 25 micrograms kg-1). Rolipram inhibited the antigen-induced bronchospasm in guinea-pigs with an ID50 of 5 +/- 1 micrograms kg-1. In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 +/- 0.8 micrograms kg-1 and 3.2 +/- 0.7 micrograms kg-1, respectively). In the rat, inflammatory cell numbers are less affected. Only the highest dose of RP 73401 (400 micrograms kg-1) significantly inhibited eosinophil influx (41 +/- 16% inhibition). 3. RP 73401 (0.02-100 micrograms kg-1, i.v.) inhibited PAF-induced bronchial hyperreactivity to bombesin in the anaesthetized guinea-pig (ID50: 0.09 +/- 0.03 micrograms kg-1) and inhibited (0.4-40 micrograms kg-1, i.t.) histamine-induced airway microvascular leakage in the anaesthetized guinea-pig by approximately 60% at all doses. 4. RP 73401 relaxed guinea-pig isolated trachea under basal tone (EC50: 9 nM) and when precontracted with histamine (IC50: 2 nM), methacholine (IC50: 29 nM) or leukotriene D4 (LTD4, IC50: 4 nM). 5. RP 73401 (0.4-100 microg kg-1, i.t.) inhibited bronchospasm induced by histamine (ID.%: 34 +/- 6 microg kg-1), methacholine (ID50: 66 +/- 12 pg kg-1) and LTD4 (ID50: <4 microg kg-1) in the anaesthetized guinea pig.Against these same bronchoconstrictors, rolipram (i.t.) had ID5o values of 44 +/- 4, 72 +/- 18 and<4 pg kg- respectively. RP 73401 (4 and 40 pg kg-, i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea-pig. At doses producing significant bronchodilatation, RP 73401 was without effect on heart rate or blood pressure in the anaesthetized guinea-pig. RP 73401 (0.01 -0.25 mg kg-1, i.v.) did not affect heart rate and produced only a small fall in blood pressure in the anaesthetized rat.6. These data demonstrate that RP 73401 and rolipram inhibit antigen- and mediator-induced bronchospasmin guinea-pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against allergic airway inflammation. These results indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity. At doses suppressing the inflammatory response in the lung, RP 73401 had little effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti-inflammatory agent in the treatment of asthma.

Albuterol↗
PubMed1994

Demonstration of c-erbB-2 oncogene overexpression in salivary gland neoplasms by in situ hybridization.

The level of c-erbB-2 cellular mRNA in 18 salivary gland tumours and in 7 normal salivary glands was determined by in situ hybridization using [35S] labelled RNA probes. Computer assisted quantitation of the autoradiographic signal indicated a significantly higher c-erbB-2 expression in the tumour group (22.64 grains per cell +/- 3.79; 95% CI) as compared to the non-neoplastic salivary gland tissue (4.11 +/- 0.90; 95% CI). The c-erbB-2 expression as measured by grain counts per cell for the pleomorphic adenomas (16.29 +/- 1.87; 95% CI), mucoepidermoid carcinomas (31.52 +/- 0.08; 95% CI) and the acinic cell carcinomas (44.24 +/- 17.11; 95% CI) were significantly greater than the expression for the normal group. The acinic cell carcinomas exhibited the greatest level of expression. As observed at the individual cell level, the autoradiographic signal was distributed uniformly in the neoplastic tissues, regardless of the cell type. This study confirms the hypothesis that the c-erbB-2 oncogene is overexpressed at the mRNA level in salivary gland tumours.

Adenoma, Pleomorphic↗