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Biomedical subjects

C Sweet

Publications and source records attributed to C Sweet.

At least 19 recordsLinked to original sources
PubMed2005

Low grade multiple myeloma that presented as a labial swelling -- a case report.

Myeloma is a disease of the bone marrow in which there is malignant proliferation of plasma cells. Myeloma is usually associated with the accumulation of a monoclonal immunoglobulin or light chains in plasma and subsequently an increase in light chains in the urine (Bence-Jones proteins). Renal failure can occur and bone destruction in the axial skeleton may ensue with pain and fractures. Amyloidosis associated with multiple myeloma is a relatively common finding. The most frequently reported oral sign of amyloidosis is macroglossia. There are numerous cases in the literature of amyloid deposition in tongues related to multiple myeloma. However, none of these cases describe amyloid deposition surrounding arteries in the oral cavity. We therefore report a case of an innocuous lower labial swelling, which subsequently led to the diagnosis of amyloid deposition surrounding an artery, the cause of which was later shown to be multiple myeloma.

Aged↗
PubMed2002

Correlation between levels of apoptosis, levels of infection and haemagglutinin receptor binding interaction of various subtypes of influenza virus: does the viral neuraminidase have a role in these associations.

Previously, we have shown that an H3N2 influenza virus (clone 7a) induced more apoptosis in MDCK cells than an H1N1 (A/Fiji) influenza virus and that the virion neuraminidase (NA) played a role in the induction of apoptosis. In this study we have examined a further 6 N2 (H3/H2) and 3 N1 (Hsw/H1) viruses and confirmed that the N2 viruses induce more apoptosis in MDCK cells than the N1 viruses. Furthermore, the level of apoptosis, the level of cell infection and the NA activity of the virus preparations paralleled each other for all the viruses. The levels of infection depended upon the degree of interaction of the viral haemagglutinin (HA) with its receptors: while all the viruses utilised NeuAc alpha-2,6 Gal containing receptors, the H3/H2 viruses showed a greater interaction than the Hsw/H1 viruses. Removal of sialic acid from virions by treatment with bacterial NA enhanced infection and apoptosis but the effect was much greater for the A/Fiji virus than for the clone 7a virus. Thus, while the relative interaction of the HAs for their receptors is the major factor influencing infectivity and apoptosis, the viral NA possibly plays an indirect role by removing sialic acid from the HA, thereby increasing its receptor binding.

Animals↗
PubMed2002

Exploitation of the Herpes simplex virus translocating protein VP22 to carry influenza virus proteins into cells for studies of apoptosis: direct confirmation that neuraminidase induces apoptosis and indications that other proteins may have a role.

Previously, we have shown that apoptosis induced by influenza virus was inhibited by an anti-neuraminidase compound [4-guanidino-2, 3-dehydro-N-acetylneuraminic acid (GG167; Relenza; Zanamivir)], which does not enter cells, and acts at the attachment/entry phase of virus replication. Furthermore, a virulent virus, clone 7a, induced greater levels of apoptosis than the attenuated A/Fiji and had greater neuraminidase (NA) activity. To confirm more directly that NA induces apoptosis, the NA of clone 7a and A/Fiji was expressed fused to the Herpes simplex virus tegument coat protein VP22, transfected into HeLa cells and the level of apoptosis determined. VP22 translocates between cells via the medium thus allowing expressed proteins to transfer to a larger number of cells than those originally transfected. Clone 7a NA fused to VP22 induced a significant level of apoptosis whereas A/Fiji NA/VP22 did not, confirming that NA activity is an important determinant of apoptosis acting during fusion protein translocation between cells. Furthermore, the induction of apoptosis was abrogated by antibody to transforming growth factor-beta, which is activated by NA. This approach also showed that VP22/NS1 proteins of both clone 7a and A/Fiji induced apoptosis when expressed alone but inhibited double stranded RNA-induced apoptosis suggesting that this protein may have a dual mode of action. Also, the M1 and M2 proteins of both viruses induced apoptosis but their NP proteins did not.

Apoptosis↗
PubMed2001

Cloning, sequencing, and functional characterization of the vitamin D receptor in vitamin D-resistant New World primates.

New World primates (NWPs) have high circulating 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels. Comparable levels would be harmful to Old World primates (OWPs) and humans. Thus, NWPs must have developed mechanisms of 1,25-(OH)2D resistance to survive. In humans, patients with hypocalcemic vitamin D-resistant rickets type II have high circulating vitamin D levels and vitamin D resistance due to expression of a dysfunctional vitamin D receptor (VDR). To examine if this could wholly or in part explain vitamin D resistance in NWPs, VDR from Saguinus oedipus (cotton top tamarin) NWP B95-8 cells was cloned by reverse-transcription polymerase chain reaction (RT-PCR). The NWP VDR cDNA sequence showed 96% homology at the DNA level and 98% homology at the amino acid level compared to human VDR. To assay for function, NWP VDR cDNA was transiently transfected into CV-1 cells with a vitamin D response element reporter plasmid. No difference between OWP and NWP VDR-directed transactivation was observed. These results indicate that the mechanism of vitamin D resistance in NWPs is not due to a dysfunctional VDR, and is consistent with our hypothesis that vitamin D resistance in NWPs is mediated by overexpression of a VDR-independent vitamin D response element binding protein.

Amino Acid Sequence↗
PubMed2000

Replication-defective mutants of mouse cytomegalovirus protect against wild-type virus challenge.

Five temperature-sensitive mutants (tsm9, tsm13, tsm20, tsm22, tsm30) of murine cytomegalovirus have been shown previously not to produce infectious virus in mice. In the present study, the stage at which these mutants are blocked in their replication in vitro was examined by transcriptional analysis of 4 temporally regulated marker genes (IE-1, E-1, gB and gH) using a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) coupled with an electron microscopic analysis of infected cells incubated at permissive (33 degrees C) and non-permissive (39 and/or 40 degrees C) temperatures. Replication of tsm13 appeared to be blocked at a late phase of replication after capsid formation while the block appeared to be as early as the immediate-early phase in tsm22- infected cells. In contrast, mutants tsm9, tsm20 and tsm30 were blocked at a maturation step, probably of capsid formation, as gene transcription of all 4 marker genes occurred, albeit at reduced level, at 39 and 40 degrees C but no capsids or virions were produced at 40 degrees C. Replication and transcription of mutants tsm13, tsm20 and tsm30 were also examined in infected mice. Mutant tsm13 showed no gene expression or infectious virus while mutants tsm20 and tsm30 produced no infectious virus from days 3-60 post infection, except unusually for a low titre of tsm30 (2.3 x 10(3) pfu/ml) in salivary glands 21 days post infection. Gene transcription of all 4 marker genes was observed in one or more tissues (salivary glands, spleen, kidneys, liver, thymus, heart, lungs) at one or more time points (3, 7, 10, 14, 21 days post-infection) with both mutants. Mice became infected latently with tsm20 but not tsm30, and mice previously infected with tsm20 or tsm30 were protected against a sub-lethal challenge with virulent parental virus; tsm30 also protected against a lethal challenge. This suggests that these two mutants may be good model vaccines for further studies on the mechanism of protection induced and for identification of the ts genes.

Animals↗
PubMed2000

Pilot study of combined blockade of the renin-angiotensin system in essential hypertensive patients.

BACKGROUND: Additive hemodynamic effects of combined blockade of the renin-angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure. OBJECTIVE: To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach. DESIGN: Multicenter, randomized, double-blind, parallel-group, pilot study. PATIENTS: 177 patients with mild-to-moderate hypertension [diastolic blood pressure (DBP): 95-115 mmHg after a 4-week placebo run-in period] were included in the study. INTERVENTION: Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks. The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily. MAIN OUTCOME MEASURES: 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment. RESULTS: 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more. The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [confidence interval (95%, CI) 0.7-5.7 mmHg, P = 0.012], and more effective than enalapril by 4.0 mmHg (95% CI, 1.5-6.4 mmHg, P = 0.002). In a subgroup of 28 patients, higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed. This finding confirmed that the combination of the two agents inhibited the renin-angiotensin system to a greater extent than did either agent alone. CONCLUSION: A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary, although modest, fall in clinic DBP in patients with mild-to-moderate essential hypertension.

Adolescent↗
PubMed1999

Correlates of fitness for duty in hazardous materials firefighters.

BACKGROUND AND METHODS: From a statewide medical examination program, we identified firefighters who were deemed unfit for duty by attending physicians (ATTENDING FAIL, n=9) and those who would have been disqualified by the application of selected numerical criteria from the 1997 National Fire Protection Association (NFPA) guidelines (NFPA FAIL, n=27) and criteria from a Medical Workshop (WORK FAIL, n=16). The subjects who were unfit for duty or failed numerical criteria were compared with those who were fit for duty and passed all objective criteria (FIT group, n=302). All subjects were given an overall morbidity rating by a board certified internist. Comparisons on two surrogate measures of fitness, VO(2) max predicted and predicted coronary heart disease (CHD) risk, were also performed. RESULTS: We found a significant tendency towards worse results (e.g. higher blood pressure or lower spirometric function) among the three FAIL groups compared with the FIT group. The FAIL groups shared only a small overlap, however, with the firefighters with the highest morbidity ratings, lowest predicted VO(2) max, and highest CHD risks. Increasing morbidity was associated with higher age, lower spirometric function, lower predicted VO(2) max, increasing cholesterol, greater BMI, and higher predicted 10 year CHD risk. CONCLUSIONS: Although the presence of a single serious or poorly controlled condition may render an individual unfit for safe performance as a firefighter, examination of our cohort suggests that multiple risk factor models or overall clinical assessments are superior means of identifying firefighters with poor health status and increased CHD risk.

Adult↗
PubMed1999

Effects of humanization by variable domain resurfacing on the antiviral activity of a single-chain antibody against respiratory syncytial virus.

HNK20 is a mouse monoclonal IgA that binds to the F glycoprotein of respiratory syncytial virus (RSV) and neutralizes the virus, both in vitro and in vivo. The single-chain antibody fragment (scFv) derived from HNK20 is equally active and has allowed us to assess rapidly the effect of mutations on affinity and antiviral activity. Humanization by variable domain resurfacing requires that surface residues not normally found in a human Fv be mutated to the expected human amino acid, thereby eliminating potentially immunogenic sites. We describe the construction and characterization of two humanized scFvs, hu7 and hu10, bearing 7 and 10 mutations, respectively. Both molecules show unaltered binding affinities to the RSV antigen (purified F protein) as determined by ELISA and surface plasmon resonance measurements of binding kinetics (Ka approximately 1x10(9) M-1). A competition ELISA using captured whole virus confirmed that the binding affinities of the parental scFv and also of hu7 and hu10 scFvs were identical. However, when compared with the original scFv, hu10 scFv was shown to have significantly decreased antiviral activity both in vitro and in a mouse model. Our observations suggest that binding of the scFv to the viral antigen is not sufficient for neutralization. We speculate that neutralization may involve the inhibition or induction of conformational changes in the bound antigen, thereby interfering with the F protein-mediated fusion of virus and cell membranes in the initial steps of infection.

Algorithms↗
PubMed1999

Role of neuraminidase in influenza virus-induced apoptosis.

The virulent influenza virus clone 7a produced a greater level of apoptosis in MDCK cells compared with the attenuated strain A/Fiji. In both cases, apoptosis could be partially blocked by treatment with three anti-neuraminidase compounds [4-amino-(GR121158A) and 4-guanidino- (GG167; Zanamivir) 2,3-dehydro-N-acetylneuraminic acid and 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA)] when they were given to cells during the virus attachment/entry phase, but not subsequent to this phase. In contrast, GG167, which does not enter cells, did not affect the numbers of infected cells and, in addition, acted late in the infection cycle to inhibit virus yields. Clone 7a neuraminidase was more active than A/Fiji neuraminidase when fetuin was used as the substrate. Similar differences in activity between the two viruses were seen when alpha-2,6 sialyl lactose was used as a substrate, but not with alpha-2,3 sialyl lactose. No sequence differences in the enzyme active site of the two neuraminidases were observed, indicating that differences in neuraminidase specificity and activity may be dictated by other residues. These results suggest that neuraminidase plays some role in the induction of apoptosis and that it acts prior to or during virus entry. However, apoptosis was considerably reduced when UV-irradiated virus, which retains >75% of its neuraminidase activity, was used. In addition, ammonium chloride, used to prevent virus entry, reduced virus-induced apoptosis. Amantadine, which inhibits virus uncoating, also inhibited apoptosis induced by the amantadine-sensitive strain A/Udorn/307/72 (H3N2), but not the amantadine-resistant clone 7a. Hence, one or more intracellular processes are also involved in influenza virus-induced apoptosis.

Amantadine↗
PubMed1999

The pathogenicity of cytomegalovirus.

Human cytomegalovirus is ubiquitous, yet causes little illness in immunocompetent individuals. Disease is evident in immunodeficient groups such as neonates, transplant recipients and AIDS patients either following a primary infection or reactivation of a latent infection. Little is known of the mechanisms underlying the pathogenicity of the virus. The recent determination of the nucleotide sequence of both human cytomegalovirus (strain AD169) and murine cytomegalovirus (murine cytomegalovirus strain Smith) has allowed an analysis of the biological importance of several virus genes. Studies with human cytomegalovirus have indicated that many viral genes are non-essential for replication in vitro which are thus assumed to be important in the pathogenesis of the virus. This is being examined in the murine model where the role of the gene and its product in disease can be directly examined in vivo using viral mutants in which the relevant gene has been interrupted or deleted. Current information on the role of cytomegalovirus genes in tissue tropism, immune evasion, latency, reactivation from latency and damage is described.

Animals↗
PubMed1998

Fitness for duty evaluations in hazardous materials firefighters.

We analyzed results from the medical examinations of 340 hazardous materials firefighters and applied various objective standards in simulated fitness for duty determinations. Ten percent had elevated blood pressures, 13% had far visual acuity worse than 20/30 in one or both eyes, and 38% had abnormal audiometry. The strictest standards for resting blood pressure and corrected visual acuity would have failed 2% and 1% of the cohort, respectively. For audiometry, 0%-5% of the cohort would have failed, depending on the hearing requirements set. The strictest hearing standard did not allow for corrective devices so that few failures would be reversible. Visual and audiometric testing and measurement of resting blood pressure all have significant clinical yields. Studies of simulated firefighting are needed to establish minimum hearing requirements and determine whether corrective devices can be worn safely during duty.

Adult↗
PubMed1998

Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection.

We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.

Acetamides↗
PubMed1998

Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071.

GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (Cmaxs; Cmax <0.06 microg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high Cmaxs of GS 4071 (Cmax = 0.47 microg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Acetamides↗
PubMed1997

Differential induction of cytotoxicity and apoptosis by influenza virus strains of differing virulence.

Two influenza viruses of differing virulence, clone 7a (virulent for humans and ferrets) and A/Fiji (attenuated for both species), induced differential levels of cytotoxicity (as measured by release of lactate dehydrogenase from cells) and apoptosis (as determined by altered nuclear morphology or flow cytometry) in MDCK and U-937 cells. Clone 7a induced more apoptosis and cytotoxicity than A/Fiji, despite the fact that its infectious virus yields were similar to or less than those for A/Fiji. This indicates a greater capacity of clone 7a to induce the two phenomena. Nevertheless the replication process was clearly essential, since UV-irradiated virus induced little or no apoptosis, and apoptosis occurred as a late event post-infection. The possible relevance of these findings to destruction of host cells by influenza virus in vivo is discussed.

Animals↗
PubMed1997

Primary intraosseous hemangioma of the orbit: CT and MR appearance.

An 8-year-old girl had acute onset of blurred vision, proptosis, and lateral and vertical gaze palsies on the right. CT and MR examinations showed an expansile mass involving the greater wing of the right sphenoid bone. Pathologic analysis of the surgical specimen revealed a capillary hemangioma. The lesion was inhomogeneous but predominantly isointense with gray matter on T1-weighted images. On T2-weighted images the lesion was inhomogeneous with areas of both high and low signal intensity. The rim enhanced uniformly, and there was inhomogeneous enhancement of the bulk of the lesion.

Child↗
PubMed1997

Are known pyrogenic cytokines responsible for fever in influenza?

The levels of interleukin (IL)-1 beta, IL-6, tumour necrosis factor (TNF)-alpha, and macrophage inflammatory protein (MIP)-1 alpha released from human peripheral blood leucocytes (PBL) following interaction with influenza virus clone 7a (virulent, produces high fever in ferrets) and A/Fiji (attenuated, produces relatively low fever in ferrets) were low and similar for the two viruses. Neither strain induced interferon (IFN)-gamma and release of IL-8 (which occurs on incubation of PBLs alone) was reduced after interaction with the two viruses. The levels of IL-1 and IL-6 detected in the plasma of infected ferrets were low and did not correlate with the onset, duration or magnitude of the fevers produced by clone 7a and A/Fiji. Relatively large amounts (100,000 pg/kg) of IL-1 and TNF-alpha were needed to produce appreciable fever in rabbits, and such quantities of IL-6 were not pyrogenic. Hence, as for previous observations, no evidence could be obtained that induction of known pyrogenic cytokines is responsible for the febrile response in influenza. The possibility that some other mediator(s) may be involved cannot be ruled out.

Animals↗