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Biomedical subjects

R Sweet

Publications and source records attributed to R Sweet.

At least 19 recordsLinked to original sources
PubMed2003

Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study.

AIMS: To investigate the safety and efficacy of bupropion sustained release (bupropion SR) in promoting abstinence from smoking in subjects with cardiovascular disease (CVD). METHODS: Six hundred twenty-nine subjects with CVD who smoked >/=10 cigarettes/day were randomised in a double-blind, multicentre study to receive bupropion SR (150 mg twice daily) or placebo for 7 weeks, with a follow-up of 52 weeks. Primary efficacy endpoint: continuous abstinence from smoking from weeks 4 to 7. Secondary endpoints: continuous abstinence (weeks 4-12, 4-26 and 4-52) and weekly point prevalence abstinence. All participants received brief motivational support. Safety was evaluated throughout the study. RESULTS: Continuous smoking abstinence rates from weeks 4 to 7 were significantly higher in subjects receiving bupropion SR compared with placebo (43 vs. 19%, odds ratio [OR]=3.27, 95% confidence interval [CI] 2.24-4.84; P<0.001). Continuous abstinence rates from weeks 4 to 26 and 4 to 52 continued to be more than double for bupropion SR compared with placebo (27 vs. 11%; 22 vs. 9%, P<0.001). Weekly point prevalence abstinence was significantly higher for participants who received bupropion SR compared with placebo at weeks 3, 7, 26 and 52 (P<0.001). In both groups, there were no clinically significant changes in blood pressure and heart rate throughout the treatment phase. Overall, 6% of the participants (n=36) discontinued study medication due to an adverse event (bupropion SR, n=17; placebo, n=19). CONCLUSIONS: After 7 weeks of bupropion SR treatment, more than twice as many smokers with CVD had quit smoking at 1 year compared with placebo. The safety profile of bupropion SR was similar to that previously observed in general smoking populations.

Adult↗
PubMed2003

A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation.

BACKGROUND: Bupropion sustained release (bupropion SR) has been shown to increase smoking cessation success rates in the US studies. OBJECTIVE: To determine whether bupropion SR, in combination with counselling, is effective for smoking cessation in a multi-country study. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 707 smokers. A total of 527 received bupropion SR 300 mg daily for 7 weeks and 180 received placebo. A total of 11 clinic visits and 10 telephone contacts were scheduled, during the course of 1 year. Seven-week and 12-month abstinence rates were the study outcomes. RESULTS: Both continuous and weekly point prevalence smoking abstinence rates were significantly higher in the bupropion SR group compared with placebo. The continuous abstinence rate from weeks 4 to 7 was 46% in the bupropion SR group compared with 23% in the placebo group [odds ratio (OR) = 2.82; 95% confidence interval (CI) 1.89-4.28; P < 0.001). At month 12, the continuous abstinence rates were 21% for the bupropion SR group and 11% for the placebo group (OR = 2.19; 95% CI 1.29-3.86, P = 0.002). For most nicotine-withdrawal symptoms small changes were measured. Adverse events were higher for the bupropion SR group compared with placebo (insomnia 24% vs. 15%; dry mouth 13% vs. 5%). CONCLUSION: Bupropion SR in combination with counselling increased the abstinence rate compared with placebo, and was well tolerated.

Adult↗
PubMed2001

Sequential parapharyngeal abscesses.

Deep neck infections are not unusual in either the pediatric or adult populations. Multiple, and recurrent abscesses are found not infrequently, especially in immunocompromised and debilitated persons. It is very rare to find sequential parapharyngeal abscesses without identifiable etiology in an otherwise healthy pediatric patient while receiving appropriate, culture-directed, intravenous antibiotics. This could be due to underestimation of the extent of the infection by CT scanning. The use of intravenous clindamycin as a first-line therapy may not be sufficient if a large phlegmon exists. We describe a case of sequential, bilateral parapharyngeal abscesses in a 3-year-old patient.

Anti-Bacterial Agents↗
PubMed2001

The representation of blood flow in endourologic surgical simulations.

An image-based approach has been developed to represent bleeding in a simulator for transurethral resection of prostate (TURP). While previous attempts have simulated bleeding over tissue surfaces or in blood vessels, our approach focused on the macroscopic visualization of bleeding in a fluid environment. TURP is an ideal procedure for simulation-based training because of the dynamic environment and the variety of flow patterns it presents. The first step in the development of the simulator was the generation of blood flow movies which consisted of capturing videos of bleeding vessels in vitro, processing them to separate the actual blood from the background anatomy and organizing the movies into a parametric database. During the running of the simulation, resection of prostate tissue systematically triggers bleeding events and the playback of a blood flow movie. The blood flow movie is texture mapped onto a virtual surface that is positioned oriented, morphed, composited and looped into the virtual scene.

Blood Loss, Surgical↗
PubMed2000

Molecular function of the CD4 D1 domain in coreceptor-mediated entry by HIV type 1.

The surface molecule CD4 plays a key role in initiating cellular entry by the human immunodeficiency virus type 1 (HIV-1), and it is now recognized as acting synergistically with select chemokine receptors (coreceptors) in the infection process. The present study was undertaken to determine whether the extracellular region of CD4 is sufficient to induce fusion of HIV-1 virions with target cells in the absence of its anchoring function. Using pseudotype reporter viruses to quantitate infection, soluble CD4 (sCD4) was tested for its ability to induce fusion by viruses utilizing CCR5 as their coreceptor. We found that sCD4 was competent to replace membrane-bound CD4 to trigger infection mediated by several HIV-1 envelopes. Furthermore, in a comparison of the envelopes of HIV-1 NL4-3 and a chimera containing the gp120 V3 loop of Ba-L, the V3 region was found to be one factor affecting susceptibility to induction by sCD4. In addition, using truncated and mutant derivatives of sCD4, the amino-terminal D1 domain of CD4 was found to be necessary and sufficient for induction of fusion and to require an intact gp120-binding site for this activity. These results delineate determinants on CD4 and gp120 required for fusion induction in collaboration with a coreceptor, and suggest a mechanism whereby CD4 may contribute to viral infection in trans.

CD4 Antigens↗
PubMed2000

Foreign body aspiration following unconventional use of a metered dose inhaler.

PURPOSE: Aspiration of a foreign body may be life-threatening. This report describes laryngeal obstruction after inhalation of a piece of a Turbuhaler which resulted from a patient tampering with the device. CLINICAL FEATURES: A 27-yr-old man disassembled a Turbuhaler and inadvertently aspirated a plastic dispensing medication disc (22 mm diameter) while attempting to inhale the remnant terbutaline sulfate which accumulated on it. Although the patient was hoarse, he was not in acute respiratory distress. X-ray revealed the disc lodged in the larynx below the vocal cords. The patient was immediately transferred to an operating theatre, and a drying agent (glycopyrrolate), judicious sedation (midazolam and fentanyl) and O2 were administered. The airway was anesthetized with lidocaine 4% delivered using high-flow O2 through an atomizer. Direct laryngoscopy revealed a partially obstructed view of the disc lodged distal to the vocal cords which was inaccessible for retrieval. Loss of consciousness was subsequently induced by spontaneous mask ventilation with sevoflurane (in O2). The airway was visualized using a suspension laryngoscope and the foreign body was removed with grasping forceps. The patient was awakened, transferred to the ICU and given 4 mg decadron i.v. every eight hours (two doses). Laryngoscopy prior to discharge indicated good mobility of the vocal cords and normal glottic structure. CONCLUSION: Aspiration of a foreign body is a potentially life-threatening situation requiring coordination between anesthesiologist, surgeon, and nursing staff. Anesthetic goals include avoidance of upper airway obstruction and maintenance of adequate ventilation while the foreign body is retrieved. Provisions must be made for tracheostomy if these goals cannot be realized.

Adult↗
PubMed2000

Prevention of perinatal group B streptococcal infection: current controversies.

Group B streptococcus (GBS) is the most frequent cause of neonatal sepsis in the United States. The Centers for Disease Control and Prevention (CDC) issued guidelines for its prevention in 1996. This article details areas of controversy with those guidelines and offers recommendations for resolution. We recommend that a prevention policy be adopted by all hospitals. If a screening-based policy is chosen, compliance is essential. Penicillin is the antibiotic of choice for GBS prevention. Increasing resistance to clindamycin and erythromycin might eliminate them as alternative choices in patients allergic to penicillin. Group B streptococcal prophylaxis might not be necessary in women who have repeat elective cesarean delivery. In asymptomatic women, a positive urine culture for GBS should be considered clinically equivalent to a positive vaginal or rectal sample for screening. Neonatal sepsis caused by organisms other than GBS must be monitored carefully by all hospitals providing obstetrics services.

Antibiotic Prophylaxis↗
PubMed2000

Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design.

In this international, multicentre, double-blind, placebo-controlled, single attack study, 'triptan naive' migraine patients were randomized in an 8:8:1 ratio to receive zolmitriptan 5 mg, sumatriptan 100 mg or placebo. The all-treated analysis included 1058 patients who took study medication. The primary endpoint, complete headache response, was reported by 39%, 38% and 32% of patients treated with zolmitriptan, sumatriptan and placebo, respectively, with no significant difference between treatment groups. In patients with moderate headache at baseline, complete response was significantly greater following zolmitriptan than after placebo (48% vs. 27%; P=0.01); there was no significant difference between sumatriptan and placebo groups (40% vs. 27%). In patients with severe baseline headache (where a greater reduction in headache intensity is required for a headache response), there was no significant difference between any groups in complete headache response rates. For secondary endpoints, active treatment groups were significantly superior to placebo for: 1-, 2- and 4-h headache response (e.g. 2-h headache response rates: zolmitriptan 59%; sumatriptan 61%; placebo 44%; P < 0.01 vs. placebo); pain-free response rates at 2 and 4 h; alleviation of nausea and vomiting; use of escape medication and restoration of normal activity. The incidence of adverse events was similar between zolmitriptan and sumatriptan groups but was slightly lower in the placebo group. The lack of difference between active treatments and placebo for complete response probably reflects the high placebo response obtained, which is probably a result of deficiencies in trial design. For example, the randomization ratio may result in high expectation of active treatment. Thus, while ethically patient exposure to placebo should be minimized, this must be balanced against the scientific rationale underpinning study design.

Adolescent↗
PubMed1999

Conformational changes of gp120 in epitopes near the CCR5 binding site are induced by CD4 and a CD4 miniprotein mimetic.

Binding of the T-cell antigen CD4 to human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 has been reported to induce conformational rearrangements in the envelope complex that facilitate recognition of the CCR5 coreceptor and consequent viral entry into cells. To better understand the mechanism of virus docking and cell fusion, we developed a three-component gp120-CD4-17b optical biosensor assay to visualize the CD4-induced conformational change of gp120 as seen through envelope binding to a neutralizing human antibody, 17b, which binds to epitopes overlapping the CCR5 binding site. The 17b Fab fragment was immobilized on a dextran sensor surface, and kinetics of gp120 binding were evaluated by both global and linear transformation analyses. Adding soluble CD4 (sCD4) increased the association rate of full-length JR-FL gp120 by 25-fold. This change is consistent with greater exposure of the 17b binding epitope on gp120 when CD4 is bound and correlates with CD4-induced conformational changes in gp120 leading to higher affinity binding to coreceptor. A smaller enhancement of 17b binding by sCD4 was observed with a mutant of gp120, DeltaJR-FL protein, which lacks V1 and V2 variable loops and N- and C-termini. Biosensor results for JR-FL and DeltaJR-FL argue that CD4-induced conformational changes in the equilibrium state of gp120 lead both to movement of V1/V2 loops and to conformational rearrangement in the gp120 core structure and that both of these lead to greater exposure of the coreceptor-binding epitope in gp120. A 17b binding enhancement effect on JR-FL also was observed with a 32-amino acid charybdotoxin miniprotein construct that contains an epitope predicted to mimic the Phe 43/Arg 59 region of CD4 and that competes with CD4 for gp120 binding. Results with this construct argue that CD4-mimicking molecules with surrogate structural elements for the Phe 43/Arg 59 components of CD4 are sufficient to elicit a similar gp120 conformational isomerization as expressed by CD4 itself.

Amino Acid Sequence↗
PubMed1998

A 9 A resolution X-ray crystallographic map of the large ribosomal subunit.

The 50S subunit of the ribosome catalyzes the peptidyl-transferase reaction of protein synthesis. We have generated X-ray crystallographic electron density maps of the large ribosomal subunit from Haloarcula marismortui at various resolutions up to 9 A using data from crystals that diffract to 3 A. Positioning a 20 A resolution EM image of these particles in the crystal lattice produced phases accurate enough to locate the bound heavy atoms in three derivatives using difference Fourier maps, thus demonstrating the correctness of the EM model and its placement in the unit cell. At 20 A resolution, the X-ray map is similar to the EM map; however, at 9 A it reveals long, continuous, but branched features whose shape, diameter, and right-handed twist are consistent with segments of double-helical RNA that crisscross the subunit.

Crystallography, X-Ray↗
PubMed1998

Morbidity of homebound versus inpatient elderly psychiatric patients.

This study compares the demographic and clinical characteristics of homebound (HB) elders referred for psychiatric services (N = 251) with those of inpatients (IP) admitted to a geriatric psychiatry unit (N = 594). Demographically, HB patients were older (78.8 vs 74.7 years), were more likely to be women (83% vs 68%), were widowed (54% vs. 44%), and had fewer years of education (10.3 vs. 11.1), but were similar in race, income, and proportion living alone. Clinically, HB patients had less functional disability, less severe depression, less cognitive impairment, and fewer medical problems. However, they were similar in the distribution of most psychiatric diagnoses except dementia (higher in the IP group) and dementia with depression (higher in the HB group). Outcome data for the HB group over 15 (range, 1 to 38) months revealed medical hospitalization in 20.7%, psychiatric hospitalization in 16.3%, nursing home placement in 9.2% and mortality in 8.4%. These preliminary data show that the HB group had psychiatric problems that were comparable to those of the IP group but were not as severely impaired.

Age Distribution↗
PubMed1997

A primatized MAb to human CD4 causes receptor modulation, without marked reduction in CD4+ T cells in chimpanzees: in vitro and in vivo characterization of a MAb (IDEC-CE9.1) to human CD4.

A Primatized anti-CD4 monoclonal antibody (MAb), CE9.1, with V-domain from cynomolgus macaque (showing 92% homology with human consensus sequence V-domains), and a human IgG1 constant region, was characterized in vitro and in vivo in chimpanzees. This MAb binds human CD4 with Kd of 1.0 nM and was also able to bind to human IgG Fc receptors (Fc gamma R). However, despite being of the IgG1 subclass, CE9.1 did not bind to complement component C1q, nor did it mediate complement-dependent cytotoxicity. Examination of T cells from a number of species showed restricted reactivity for CE9.1, recognizing only human and chimpanzee CD4. In both human and chimpanzee MLRs, it had an IC50 of about 10.0 ng/mL. Therefore, a chimpanzee in vivo model was used to characterize CE9.1, CE9.1 caused transient decrease in the number of lymphocytes bearing the CD4 receptor starting at doses of 0.3 mg/kg in an in vivo dose ranging study in one chimpanzee. This effect was reversed within approximately 7 days. In a multiple high-dose study in which 10.0 mg/kg of CE9.1 was administered at intervals of 1-3 months, there was a dramatic loss of CD4 marker with a reciprocal increase in the number of CD3+ CD8- CD4- cells. The CD4 receptor was totally undetectable on these lymphocytes for 1-2 weeks, with a gradual, but complete, reversal within 4 weeks. We interpret these observations as receptor modulation because, although there was apparent loss of CD4+ lymphocytes, an equivalent number of CD3+CD8- T lymphocytes were present in circulation in all four chimpanzees treated with 10.0 mg/kg CE9.1. Even at this high dose, only limited reduction of CD4+ T lymphocytes was observed in these animals. These observations are in sharp contrast to what has been reported in rodents or in human clinical studies using other IgG1 mAbs to human CD4. CD8 counts, although variable, remained unaffected by CE9.1 treatment. No adverse events were observed following administration of CE9.1 to chimpanzees, and there was no detectable host immune responses to the Primatized MAb.

Animals↗
PubMed1997

Plasma levels of citalopram enantiomers and metabolites in elderly patients.

Ten patients with dementia and significant behavioral disturbances (mean age of 77.2 +/- 8.2 years) received citalopram, 10 mg/day for 3 days, followed by 20 mg/day for 2 weeks. Six of the 10 patients completing 17 days of treatment had a clinically impressive response, as assessed by significant improvement in six target items on the Neurobehavioral Rating Scale. Eight patients were also analyzed by measuring the racemic and enantiomeric plasma levels of citalopram (CIT) and desmethylcitalopram (DCIT). A sensitive high-performance liquid chromatography (HPLC) assay for citalopram enantiomers and metabolites was developed using ultraviolet detection. The lower limit of detection was 10 ng/ml for each enantiomer. Steady-state plasma level ranges were 11.2 to 92.2 ng/ml for the biologically active S(+) citalopram and 12.8 to 95.7 ng/ml for the inactive R(-) enantiomer. For the S and R enantiomers of desmethylcitalopram, plasma levels ranged from 11.0 to 22.0 ng/ml and 9.2 to 22.0 ng/ml, respectively. The racemic citalopram plasma level to dose ratio of 3.50 was higher than the ratio (1.96) reported by Overo (1982) for 55 younger patients. The stereoselective metabolism of the enantiomers for citalopram and desmethylcitalopram (S(+) and R(-) enantiomers) in these older subjects differed from that reported in younger patients, suggesting possible age-associated changes in CYP2C19 activities. We hypothesize that quantification of S(+) citalopram will permit a more accurate examination of dose/response relationships. This measure seems to be especially important for older subjects, given the wide ranges and higher concentrations evident from our preliminary results.

Aged↗
PubMed1997

An open pilot study of citalopram for behavioral disturbances of dementia. Plasma levels and real-time observations.

Citalopram, in European studies, has shown some early promise for treatment of poststroke depression and behavioral complications of dementia. An open pilot study of citalopram was conducted in 16 patients with dementia and behavioral disturbances. Citalopram was well tolerated by 13 of the patients, and 9 had a clinically impressive response. A significant overall mean reduction in disruptive vocalizations was observed by means of a novel technique of computer-assisted real-time observation. The mean citalopram plasma level-to-dose ratio was found to be twice that previously reported in younger patients. These pilot findings should encourage future placebo concentration-controlled trials.

Aged↗
PubMed1996

Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association.

Through the interaction with its ligands, CD80/B7-1 and CD86/B7-2 or B70, the human CD28 molecule plays a major functional role as a costimulator of T cells along with the CD3-TcR complex. We and others have previously reported that phosphatidylinositol 3-kinase inducibly associates with CD28. This association is mediated by the SH2 domains of the p85 adaptor subunit interacting with a cytoplasmic YMNM consensus motif present in CD28 at position 173-176. Disruption of this binding site by site-directed mutagenesis abolishes CD28-induced activation events in a murine T-cell hybridoma transfected with human CD28 gene. Here we show that the last 10 residues of the intracytoplasmic domain of CD28 (residues 193-202) are required for its costimulatory function. These residues are involved in interleukin-2 secretion, p85 binding, and CD28-associated phosphatidylinositol 3-kinase activity. In contrast, the CD28/CD8O interaction is unaffected by this deletion, as is the induction of other second messengers such as the rise in intracellular calcium and tyrosine phosphorylation of CD28-specific substrates. Furthermore, we also demonstrate that, within these residues, the tyrosine at position 200 is involved in p85 binding, probably together with the short proline-rich motif present between residues 190 and 194 (PYAPP).

Amino Acid Sequence↗
PubMed1996

Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis.

CD28, which is a member of the immunoglobulin superfamily of molecules (IgSF), is a homodimer of two polypeptides containing a single V-like domain with short transmembrane and cytoplasmic regions. It serves as a co-signalling molecule for T cell activation through binding to its cognate counter-receptors CD80 and B70, expressed on antigen presenting cells. In the current study, we investigated the regions of CD28 which are involved in its interactions with CD80 and B70, using site directed mutagenesis, CD28 mAb epitope mapping, receptor based adhesion assays and direct binding of Ig-fusion proteins to cell surface receptors. Truncation or substitution of a stretch of a proline rich "hallmark" sequence, "MYPPPY", abrogates binding to CD80 or B70, while retaining CD28 mAb epitopes and cell surface expression. On an Ig-fold model of the CD28 V-domain, this fully conserved motif localizes to a CDR3-like region. Mutations introduced into other loops, including the CDRI-like and CDR2-like regions, had very little effect on CD80 or B70 binding. Mutations introduced within the predicted beta-strand regions caused loss of receptor expression. Conservative substitution of both the flanking tyrosine residues within the "MYPPPY" motif with phenylalanine, caused loss of binding to B70 but not to CD80. These results show that, although the same overall region on CD28 may be involved in the interactions with CD80 and B70, subtle but important differences distinguish recognition by the two molecules. These finding, along with previous observations on the differential pattern of expression and tissue distribution of CD80 and B70, support the contention that these molecules play distinct roles in the regulation of immune responses in vivo.

Abatacept↗