Meningeal carcinomatosis in lung cancer. Case 2. Carcinomatous meningitis.
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Adenocarcinoma↗
Biomedical subjects
F Brown
Publications and source records attributed to F Brown.
Inactivation of viruses by aziridines.
Ethyleneimine (EI) and N-acetylethyleneimine (AEI) have been shown to inactivate viruses belonging to most of the families described by the International Committee for the Taxonomy of Viruses. The mechanism by which they inactivate the viruses has not been established. In this paper, experiments with foot-and-mouth disease virus (FMDV) and poliovirus are described which indicate that the inactivating lesion is on the RNA.
Animals↗
Delineation of a neutralizing subregion within the immunodominant epitope (GH loop) of foot-and-mouth disease virus VP1 which does not contain the RGD motif.
The major immunogenic site of foot-and-mouth disease virus (FMDV) is contained in a disordered loop comprising residues 134-158 of capsid protein VP1, located on the surface of the viral particle. Peptides corresponding to this sequence generally elicit protective levels of neutralizing antibodies in guinea pigs. In some instances, however, the level of neutralizing antibodies is low although the level of antibodies against the peptide, determined by ELISA, is as high as that in the sera with high neutralizing antibody titres. In an attempt to ascertain the reason for this difference, we have synthesized on a cellulose membrane 10 overlapping decapeptides, offset by one residue, covering the segment 141-159 of VP1 of two viruses belonging to serotypes A12 and O1, and tested them with guinea pig antisera raised against peptide 141-159, VP1 and FMDV particles (SPOTscan method). With type A, some peptides which were strongly positive with highly neutralizing antisera did not include the RGD triplet located at residues 145-147. In contrast, antisera with low neutralization titres reacted only with decapeptides which included the RGD motif. Moreover, peptide 147-156 coupled to keyhole limpet haemocyanin, but not peptide 141-149 coupled to the same carrier, elicited high levels of neutralizing antibodies in guinea pigs. In the case of serotype O, highly neutralizing antisera to virus reacted in ELISA with peptides 141-150 (containing the RGD motif) and 135-144 (located upstream from the RGD motif). The results suggest that the RGD triplet is not an indispensable constituent of peptides able to elicit a neutralizing antibody response against the virus.
Amino Acid Sequence↗
Differentiation of convalescent animals from those vaccinated against foot-and-mouth disease by a peptide ELISA.
We have identified continuous antigenic determinants within the amino acid sequences of the conserved nonstructural region containing proteins 2C and 3ABC of foot-and-mouth disease virus which can distinguish between the sera from vaccinated and infected animals. An ELISA based on a 3B peptide gave a positive reaction with sera from cattle, pigs, sheep and guinea pigs infected with all seven serotypes of the virus, but not with sera from vaccinated animals. In experiments with cattle and pigs to determine the duration of the antibody response, positive reactions were obtained as late as one year after infection. The advantages of using peptides from the nonstructural viral proteins instead of recombinant proteins for differentiating vaccinees from infected animals include their exquisite specificity, nonreactivity with antibodies against host cell-derived proteins (e.g. E. coli and insect cell proteins), and their ease of preparation.
Animals↗
Protection of swine from foot-and-mouth disease with one dose of an all-D retro peptide.
Nine pigs were given a single inoculum of 100 microg of the all-D retro peptide corresponding to the immunodominant GH loop encompassing residues 141-159 of capsid protein VP1 of foot-and-mouth disease virus serotype A, sub-type 12. The peptide was conjugated to activated keyhole limpet haemocyanin and oil-adjuvanted before inoculation. The animals were challenged eleven weeks post-vaccination by exposing them to a pig which had been infected with the virus by inoculation. Two naive animals were included in the challenge study as controls. One of the vaccinated animals was completely unprotected and two developed very small lesions. None of the six remaining animals exhibited any clinical signs but two developed antibodies against nonstructural proteins indicating that replication of the virus had occurred. No evidence of replication could be detected in the remaining four animals, either by rise in neutralizing antibody titre or by production of antibodies against non-structural proteins specific for virus replication.
Animals↗
Disposition and exposure of the fibrinogen receptor antagonist XV459 on alphaIIBbeta3 binding sites in the guinea pig.
The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H-SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 microg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 microg/mL was obtained at the 2.0 microg/kg dose. Pooling individual concentration-time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig at the 0.5 microg/kg dose. The 2.0 microg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non-plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists.
Amino Acids↗
South Turkwel: a new pliocene hominid site in Kenya.
New fossils discovered south of the Turkwel River in northern Kenya include an associated metacarpal, capitate, hamate, lunate, pedal phalanx, mandibular fragment, and teeth. These fossils probably date to around 3.5 m.y.a. Faunal information suggests that the environment at South Turkwel was predominantly bushland. The mandibular and dental remains are fragmentary, but the postcranial fossils are informative. Comparisons with Australopithecus, modern human, chimpanzee and gorilla hand bones suggest that the Turkwel hominid was most like Australopithecus afarensis and A. africanus. Carpometacarpal articulations are intermediate between those of modern humans and African apes, suggesting enhanced gripping capabilities compared with extant apes. The hamulus was strikingly large, similar in proportion only to Neandertals and some gorillas, suggesting the presence of powerful forearms and hands. There are no indicators of adaptations to knuckle-walking or suspensory locomotion in the hand, and the pedal phalanx suggests that this hominid was habitually bipedal.
Animals↗
Foot-and-mouth disease and beyond: vaccine design, past, present and future.
The first experimental vaccines against foot-and-mouth disease were made in 1925 by Vallee, Carre and Rinjard using formaldehyde inactivation of tongue tissue from cattle infected with the virus. This method was essentially unaltered until the late 1940s when the important experiments by Frenkel in Holland showed that the quantities of virus required for vaccine production could be obtained from fragments of tongue epithelium incubated in vitro following infection with the virus. This major step made possible the comprehensive vaccination programmes which followed in Western Europe and which, in turn, resulted in the elimination of the disease from that part of the world by 1989. This spectacular success has led many to question whether other kinds of vaccine are required to control the disease worldwide. Such reservations ignore the danger to the environment associated with the growth of large amounts of virus. This can never be a zero-risk situation. Consequently, a vaccine which is not based on infectious virus as starting material has many attractions from safety considerations alone. In addition, a vaccine based on more fundamental considerations would not only be more aesthetically satisfying but could possibly provide an understanding at the molecular level of antigenic variation, still a problem in the control of the disease. The advances in our knowledge of the structure of the virus and the fragments which elicit a protective immune response now allow us to envisage a vaccine which does not require infectious virus and which protects against the multiple serotypes of the agent. Since antigenic variation is still a major problem in the control of the disease by vaccination, such a product would have important advantages over the current vaccines.
Animals↗
Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry.
1. This study describes the pharmacological comparison of the muscarinic partial agonists sabcomeline, xanomeline and milameline at human cloned muscarinic receptor subtypes (hM1-5). 2. Radioligand binding studies at the hM1-5 muscarinic receptor subtypes were compared with functional studies using microphysiometry using carbachol as the standard full agonist. 3. In binding assays none of the compounds studied displayed preferential affinity for the M1,3,4 or M5 subtypes although carbachol was less potent at hM1 than hM3,4,5. 4. In functional studies, all of the compounds studied displayed similar levels of efficacy across the muscarinic receptors with the exception of M3, where there was a large apparent receptor reserve and the compounds behaved essentially as full agonists. 5. Sabcomeline was the most potent agonist in functional studies but also showed the lowest efficacy. In terms of potency, xanomeline showed some selectivity for M1 over M2 receptors and milameline showed some selectivity for M2 over M1 receptors. 6. These results show the value of microphysiometry in being able to compare receptor pharmacology across subtypes irrespective of the signal transduction pathway. 7. None of the partial agonists showed functional selectivity for M1 receptors, or indeed any muscarinic receptor, in the present study.
Animals↗
Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR.
The cellular mechanisms underlying the physiological effects of the orexins are poorly understood. Therefore, the pharmacology of the recombinant human orexin receptors was studied using FLIPR. Intracellular calcium ([Ca2+]i) was monitored in Chinese hamster ovary (CHO) cells stably expressing orexin-1 (OX1) or orexin-2 (OX2) receptors using Fluo-3AM. Orexin-A and orexin-B increased [Ca2+]i in a concentration dependent manner in CHO-OX1 (pEC50=8.03+/-0.08 and 7. 30+/-0.08 respectively, n=5) and CHO-OX2 (pEC50=8.18+/-0.10 and 8. 43+/-0.09 respectively, n=5) cells. This response was typified as a rapid peak in [Ca2+]i (maximal at 6 - 8 s), followed by a gradually declining secondary phase. Thapsigargin (3 microM) or U73122 (3 microM) abolished the response. In calcium-free conditions the peak response was unaffected but the secondary phase was shortened, returning to basal values within 90 s. Calcium (1.5 mM) replacement restored the secondary phase. In conclusion, orexins cause a phospholipase C-mediated release of calcium from intracellular stores, with subsequent calcium influx.
Aniline Compounds↗
Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts.
Vascular endothelial growth factor (VEGF) is abundant in synovium and synovial fluids, where it probably contributes to vascular permeability and angiogenesis in arthritic joints. To investigate the probable sources of VEGF in synovium, we compared the ability of several cytokines (TGF-beta, platelet-derived growth factor (PDGF), IL-1, tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF) that are associated with arthritis and angiogenesis, to stimulate secretion of VEGF protein by human synovial fibroblasts. TGF-beta was the strongest inducer of VEGF secretion; six times more VEGF was secreted when cells were stimulated by TGF-beta than when stimulated by PDGF or IL-1 for 24 h. TNF-alpha and bFGF did not stimulate any secretion of VEGF. The stimulatory effects of TGF-beta and IL-1 on VEGF secretion were additive. Hypoxic culture alone also stimulated VEGF secretion, but more importantly, hypoxic culture conditions doubled the rate of VEGF secretion stimulated by the cytokines TGF-beta and IL-1. When dermal and synovial fibroblasts were stimulated identically by hypoxia and cytokines (TGF-beta and IL-1), synovial fibroblasts secreted four times more VEGF than did dermal fibroblasts. Thus in rheumatoid arthritis, the capacity of synovial fibroblasts in the hypoxic environment to secrete large amounts of VEGF in response to cytokines such as TGF-beta probably contributes significantly to angiogenesis in the synovium.
Arthritis↗
Adherence to the ten steps of the Baby-Friendly Hospital Initiative in Minnesota hospitals.
BACKGROUND: A worldwide campaign has been initiated to improve the in-hospital care of mothers and babies through increased breastfeeding. The four objectives of the current investigation were to determine the in-hospital breastfeeding rate for Minnesota hospitals, to analyze the relationship between the in-hospital breastfeeding rates and selected hospital demographic characteristics, to determine the rate of adherence to each of the Baby-Friendly Hospital Initiative (BFHI) Ten Steps, and to analyze the relationship between the adherence rates for each of the Ten Steps and selected demographic characteristics. METHODS: A descriptive survey was conducted and analyzed for the year of 1994 from 79 (83%) Minnesota hospitals. Respondents were directors of nursing, nursing managers, or other staff familiar with their hospital's breastfeeding policies and practices. RESULTS: The average breastfeeding initiation rate was 59 percent. Four of the Ten Steps were implemented with a low adherence rate (0-49%), five were implemented with a moderate rate (50-89%), and none was implemented with a high rate (90-100%). Breastfeeding initiation rates and adherence to the Ten Steps varied with the size of the city and the number of births per year. CONCLUSIONS: Improvements in breastfeeding policies, practices, and staff education are needed if Minnesota hospitals are to provide care consistent with the Ten Steps of the BFHI. The results provide baseline information to guide institutional change that could promote successful breastfeeding experiences for postpartum families. This survey instrument could be used easily by researchers in other sites to assess nine of the Ten Steps.
Breast Feeding↗
Evidence for the persistence of foot-and-mouth disease virus in pigs.
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Animals↗
Safety of perioperative subcutaneous heparin for prophylaxis of venous thromboembolism in patients undergoing craniotomy.
OBJECTIVE: To determine whether perioperative subcutaneous heparin is safe to use for patients undergoing craniotomy and to determine the incidence of venous thromboembolism in patients undergoing craniotomy. METHODS: Perioperative prophylaxis with subcutaneous heparin, 5000 U every 12 hours, was begun at induction of anesthesia for craniotomy and continued for 7 days postoperatively or until the patient was ambulating. Entry criteria to the study included patient age over 18 years and no evidence of deep vein thrombosis (DVT) preoperatively as judged by lower limb duplex ultrasound. Patients were excluded if they had duplex evidence of DVT or clinical evidence of pulmonary embolus (PE) preoperatively, had hypersensitivity to heparin or related products, had sustained a penetrating head injury, or refused informed consent. Any patient undergoing craniotomy was eligible, including patients with a ruptured aneurysm or arteriovenous malformation and those with spontaneous intracranial hemorrhage. Patients underwent duplex study 1 week after surgery and 1 month of clinical follow-up. Records were also kept on 68 nonstudy patients who refused consent. All patients were treated with lower limb pneumatic compression devices. RESULTS: One hundred six patients were treated. No differences were noted between study and nonstudy patients in some individual risk factors for DVT or PE, such as obesity, smoking, paralysis, infection, pregnancy or postpartum state, varicose veins, heart failure, or previous DVT or PE. Significantly more (43 of 106) patients in the study group had a history of risk factors for DVT or PE, particularly malignancy, however, compared with nonstudy patients (20 of 68 patients; chi2, P < 0.01). There were no differences between groups in intraoperative blood loss, transfusion requirements, or postoperative platelet counts. Four clinically significant hemorrhages occurred during surgery in patients receiving heparin. Three resulted from intraoperative aneurysm rupture and one from intraventricular bleeding during resection of an arteriovenous malformation. These events were believed to be related to known complications of these operations, not to heparin. Of the study patients, two developed symptomatic DVT and one developed a nonfatal PE during the 1-month postoperative period. One additional study patient developed DVT below the popliteal veins, which was not treated. Four study patients developed DVT 1 to 2 months after surgery. In nonstudy patients, three developed DVT and two developed PE (one fatal, one nonfatal). CONCLUSION: Perioperative heparin may be safe to administer to patients undergoing craniotomy, but a larger study is needed to demonstrate efficacy.
Adult↗
Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers.
OBJECTIVE: Ganciclovir is commonly used in the treatment of cytomegalovirus (CMV) disease in patients who are immunocompromised and for the prevention of CMV disease in solid organ transplant recipients. Owing to limited bioavailability and saturable absorption, the use of oral ganciclovir in CMV retinitis is restricted to maintenance therapy only. As induction therapy must be given intravenously, an oral formulation which could be used for induction would offer significant benefits. A previous study of valganciclovir, a valyl ester prodrug of ganciclovir showed a 10-fold increase in plasma ganciclovir concentrations compared with the oral formulation. However, before studies can be conducted to confirm the utility of oral valganciclovir for the treatment and prevention of CMV disease, a dose must be selected for use in these studies. This study was designed to investigate the pharmacokinetics of ganciclovir and valganciclovir. DESIGN AND PARTICIPANTS: The study was an open-label, randomised, 4-way crossover, dose-ranging pharmacokinetic study, conducted in 39 patients who were HIV- and CMV-seropositive. The participants were randomised to one of 2 groups: fasted (n = 19) and fed (n = 20). In both groups, participants received 450, 875, 1750 and 2625 mg oral valganciclovir once daily for 3 days in a randomised order. RESULTS: In the 32 participants who completed the study, valganciclovir was rapidly absorbed and converted into ganciclovir (maximum ganciclovir concentrations occurred after 1.0 to 1.75 hours in the fasted group and 1.5 to 2.0 hours in the fed group). Systemic exposure to valganciclovir was low [with an area under the concentration-time curve to 24 hours (AUC24) of 1.3 to 2.5% that of ganciclovir]. The mean plasma concentrations of ganciclovir were dose-related. Peak concentrations of ganciclovir were achieved approximately 30 minutes after those for valganciclovir. In the fed state, the AUC24 of ganciclovir increased proportionally with dose. The mean AUC24 values for ganciclovir were slightly higher following food (24 to 56%) than in the fasted state. Based on linear regression of AUC24 values from the fed group, a dose of valganciclovir of 900 mg/day is expected to produce a daily exposure (AUC24) comparable with an intravenous dose of ganciclovir 5 mg/kg/day. CONCLUSIONS: These results show that once daily oral valganciclovir can produce exposures of ganciclovir (AUC24) exceeding those attained using intravenous ganciclovir 10 mg/kg. This suggests that oral valganciclovir may be suitable in many circumstances currently requiring intravenous ganciclovir, allowing for more convenience in the management of patients with CMV retinitis by utilising a 2 or 4 tablet daily regimen to cover all phases of treatment.
Administration, Oral↗
A universal virus inactivant for decontaminating blood and biopharmaceutical products.
Removal of virus infectivity from blood and biopharmaceutical products prepared from blood is an issue of considerable importance. Irrespective of the methods that are chosen it is vital that the biological activity of the product is not impaired. For blood and unfractionated plasma or serum, the problem is even more challenging. Selective inactivation of the genome is the key step in the preparation of killed virus vaccines. Imines have been used for more than 30 years for the preparation of inactivated foot-and-mouth disease virus vaccines without any evidence of survival of virus infectivity. Moreover, the immunogenicity of the virus is unimpaired. Viruses belonging to all the recognised families can be inactivated by imines. The biological properties of several proteins, including the cell growth-promoting factors in calf serum, are not impaired using conditions which ensure the inactivation of > 10(15) infectious units of poliovirus and foot-and-mouth disease virus (FMDV). Moreover, both viruses can be inactivated by imines at 4 degrees C, thus providing a method for removing infectivity from protein preparations which are unstable at higher temperatures. The mechanism by which FMDV is inactivated has been studied. We found that the RNA extracted from the virus after inactivation at 4 degrees C was not degraded and contained no hidden breaks but nevertheless was non-infectious. However, it could be amplified by PCR using primers corresponding to the gene coding for a portion of the viral RNA polymerase, but not from that coding for VP1, one of the structural proteins, showing that alteration of a base or bases had occurred in that region.
Animals↗
Control of foot-and-mouth disease by vaccination.
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Animals↗
Structural and kinetic studies of phosphorylation-dependent regulation in smooth muscle myosin.
In this study, we have examined the mechanism of phosphorylation-dependent regulation in smooth muscle myosin through the use of structural and kinetic methodologies applied to several myosin fragments. Fluorescence anisotropy decay measurements demonstrate that regulatory light chain phosphorylation significantly reduces the rotational correlation time of regulatable myosin preparations, whereas minimally regulated ones show little effect in this assay. Sedimentation equilibrium studies show that the regulatory domain can dimerize with a dissociation constant that is unaffected by regulatory light chain phosphorylation. Finally, kinetic studies on the interactions of myosin-ADP constructs with actin are also consistent with a model in which interactions occur between the two heads, which are lost with regulatory light chain phosphorylation. We propose that in the absence of regulatory light chain phosphorylation, the two heads of myosin interact with each other, due to a weak intrinsic dimerization of the regulatory domains that is significantly stabilized by the proximal rod. Regulatory light chain phosphorylation abolishes the stabilizing effect of the proximal rod, leading to a loss of this interaction.
Actins↗