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Biomedical subjects

T Littlejohn

Publications and source records attributed to T Littlejohn.

15 recordsLinked to original sources
PubMed2001

Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis.

Porphyromonas gingivalis is a key periodontal pathogen which has been implicated in the etiology of chronic adult periodontitis. Our aim was to develop a protein based vaccine for the prevention and or treatment of this disease. We used a whole genome sequencing approach to identify potential vaccine candidates. From a genomic sequence, we selected 120 genes using a series of bioinformatics methods. The selected genes were cloned for expression in Escherichia coli and screened with P. gingivalis antisera before purification and testing in an animal model. Two of these recombinant proteins (PG32 and PG33) demonstrated significant protection in the animal model, while a number were reactive with various antisera. This process allows the rapid identification of vaccine candidates from genomic data.

Amino Acid Sequence↗
PubMed2000

Induction of indolamine 2,3-dioxygenase in primary human macrophages by human immunodeficiency virus type 1 is strain dependent.

Increased kynurenine pathway metabolism has been implicated in the etiology of AIDS dementia complex (ADC). The rate-limiting enzyme for this pathway is indolamine 2,3-dioxygenase (IDO). We tested the efficacy of different strains of human immunodeficiency virus type 1 (HIV1-BaL, HIV1-JRFL, and HIV1-631) to induce IDO in cultured human monocyte-derived macrophages (MDM). A significant increase in both IDO protein and kynurenine synthesis was observed after 48 h in MDM infected with the brain-derived HIV-1 isolates, laboratory-adapted (LA) HIV1-JRFL, and primary isolate HIV1-631. In contrast, almost no kynurenine production or IDO protein was evident in MDM infected with the highly replicating macrophage-tropic LA strain HIV1-BaL. The induction of IDO and kynurenine synthesis by HIV1-JRFL and HIV1-631 declined to baseline levels by day 8 postinfection. Abundant HIV-1 replication did not reduce the ability of exogenous gamma interferon (IFN-gamma) to induce IDO and kynurenine synthesis in HIV-infected MDM. The addition of anti-IFN-gamma antibody to MDM infected with HIV1-JRFL resulted in an absence of detectable IDO protein after 48 h and a decrease of 64% +/- 1% in supernatant kynurenine concentration. Together, these results indicate that only selected strains of HIV-1 are capable of inducing IDO synthesis and subsequent kynurenine metabolism in MDM. The induction of IDO, while apparently independent of replication capacity, appears to be mediated by a transient production of IFN-gamma in MDM responding to the initial infection with selected strains of HIV-1.

Cells, Cultured↗
PubMed2000

Induction of indoleamine 2,3-dioxygenase in primary human macrophages by HIV-1.

Increased kynurenine pathway metabolism has been implicated in the aetiology of the AIDS dementia complex (ADC). The rate limiting enzyme for this pathway is indoleamine 2,3-dioxygenase (IDO). We tested the efficacy of different strains of HIV-1 (HIV1-BaL, HIV1-JRFL and HIV1-631) to induce IDO in cultured human monocyte-derived macrophages (MDM). A significant increase in both IDO protein and kynurenine synthesis was observed after 48 h in MDM infected with the brain derived HIV-1 isolates, laboratory adapted (LA) HIV1-JRFL, and primary isolate HIV1-631. In contrast, almost no kynurenine production or IDO protein was evident in MDM infected with the high replicating macrophage tropic LA strain, HIV1-BaL. The induction of IDO and kynurenine synthesis by HIV1-JRFL and HIV1-631 declined to baseline levels by day-8 post-infection. Together, these results indicate that only selected strains of HIV-1 are capable of inducing IDO synthesis and subsequent oxidative tryptophan catabolism in MDM.

Brain↗
PubMed2000

A prospective, randomized, open-label trial comparing telmisartan 80 mg with valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring.

OBJECTIVE: To compare the antihypertensive efficacy and tolerability of telmisartan 80 mg with valsartan 80 mg throughout a 24 h dosing interval. DESIGN: A prospective, randomized, open-label, blinded end point, parallel group study. Treatment efficacy was compared using ambulatory blood pressure monitoring (ABPM), cuff sphygmomanometry and calculated responder rates. Tolerability was assessed by physical examination, laboratory parameters, 12-lead electrocardiogram, blood pressure and heart rate monitoring, and evaluation of adverse events. SETTING: Thirty-five centres in the United States. PATIENTS: Four hundred and twenty-six patients with mild to moderate essential hypertension entered the study. Ninety-two per cent (n=393) completed the study. INTERVENTIONS: Patients underwent a four-week, single-blind, placebo run-in period before being randomly assigned to once-daily oral telmisartan 80 mg (n=214) or valsartan 80 mg (n=212) for an eight-week, open-label treatment period. RESULTS: Treatment with telmisartan was associated with a significantly greater mean reduction from baseline in the last 6 h ABPM mean for diastolic blood pressure compared with the valsartan-treated group (-7.5+/-0.6 mmHg versus -5.2+/-0.6 mmHg, respectively, P<0.01). Secondary analyses showed significantly greater efficacy with telmisartan 80 mg than with valsartan 80 mg, including greater mean reductions from baseline of ABPM (systolic blood pressure and diastolic blood pressure) during the daytime (06:00 to 21:59) and morning (06:00 to11:59) hours, and larger decreases in trough cuff blood pressure (P<0.01). Both treatments showed placebo-like tolerability profiles. CONCLUSIONS: Telmisartan 80 mg once daily was superior to valsartan 80 mg once daily in reducing diastolic blood pressure during the last 6 h of the 24 h dosing interval. These results may be due to telmisartan's longer plasma half-life or to a higher potency compared with valsartan, such that a higher dose of valsartan may produce effects similar to those of 80 mg telmisartan. These data confirm the long duration of action of telmisartan with consistent and sustained control of blood pressure over 24 h and during the last 6 h of the dosing interval. Both treatments were well tolerated; the adverse event data confirmed the excellent tolerability profiles of telmisartan and valsartan that have been reported previously.

Administration, Oral↗
PubMed1999

An online locus-specific mutation database for familial hypertrophic cardiomyopathy.

The aim of this locus-specific mutation database was to provide an online resource that contains summarised and updated information on familial hypertrophic cardiomyopathy (FHC)-associated mutations and related data, for researchers and clinicians. It also serves as a means of publishing previously unpublished data, which could be of value in understanding genotype/phenotype correlations. There are 123 FHC-associated mutations catalogued along with ancillary information. By implementing the cgi/http method, remote users can query the database via the HTML interface on the Web browser and obtain data of relevance to them. The online service is available on http://www.angis.org.au/Databases/Heart.

Alternative Splicing↗
PubMed1999

Regulation of indoleamine 2,3-dioxygenase, the first enzyme in UV filter biosynthesis in the human lens. Relevance for senile nuclear cataract.

3-Hydroxykynurenine (3OHKyn), the precursor of UV filters in human lens, is highly autooxidizable, generates H2O2, and binds to lens proteins, yielding a tanned/yellow product resembling senile nuclear cataractous materials. Thus, if 3OHkyn can be shown to be the causative agent in cataract, it may be possible to prevent the disease by lowering the level of 3OHKyn. To this end, indoleamine 2,3-dioxygenase, the first enzyme in UV filter synthesis, was studied using lens epithelial cell lines. The results indicated that the IDO expression is mediated by IFN-gamma. Immuno-suppressants which inhibit production of IFN-gamma may act as anti-cataract agents. Another way to lower the level of 3OHKyn is to use specific inhibitors for IDO. A recombinant human IDO was expressed to develop the inhibitors.

Aged↗
PubMed1999

Cisapride 20 mg b.d. for preventing symptoms of GERD induced by a provocative meal. The CIS-USA-89 Study Group.

BACKGROUND: Cisapride is a substituted piperidinyl benzamide indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastro-oesophageal reflux disease (GERD). The currently recommended dosing regimen for cisapride is 10 mg q.d.s., but the elimination half-life of 8-10 h supports b.d. dosing with 20 mg. METHODS: This multicentre, randomized, double-blind, placebo-controlled trial was undertaken to determine the efficacy and safety of cisapride 20 mg b.d. dosing in reducing or preventing heartburn and other meal-related symptoms after challenge with a provocative fatty meal. In phase 1 of the study, 137 patients with at least a 3-month history of symptoms suggestive of GERD and at least five episodes of GERD on 7-day diary were eligible to receive single-blind treatment with placebo for 7 (range +/- 3) days and then ingested a provocative meal. One hundred and twenty-two patients (45 men and 77 women, 22-65 years of age) who experienced heartburn during the 3 h after ingestion of the meal qualified for the double-blind phase of the study and were randomly assigned to either cisapride 20 mg or matching placebo b.d. for 7 (+/-3) days. At the end of this period, 118 patients again ate a fatty meal and were assessed for symptoms of GERD. RESULTS: Heartburn was prevented in a significantly higher percentage of cisapride-treated patients (40%; 24 out of 60) than placebo-treated patients (21%; 12 out of 58) after the repeat provocative meal at the end of the double-blind phase (P = 0.017). Cisapride was also significantly more effective in reducing the severity of postprandial heartburn, belching, and regurgitation (P < 0.05). Twice-daily dosing with cisapride 20 mg was well tolerated; the number of cisapride- and placebo-treated patients who experienced at least one adverse event was similar (31% and 22%, respectively). The most common adverse events were diarrhoea (cisapride, 18%; placebo, 0%) and rhinitis (cisapride, 2%; placebo, 5%). CONCLUSIONS: These results demonstrate that cisapride 20 mg b.d. is effective in preventing or reducing symptoms of heartburn in patients who developed heartburn after ingesting a provocative fatty meal. Cisapride was also effective in reducing the severity of heartburn-related symptoms such as belching and regurgitation.

Adult↗
PubMed1999

Long-term safety and antihypertensive efficacy of irbesartan: pooled results of five open-label studies.

An analysis of 5 multicenter, open-label studies was conducted to evaluate the long-term safety and efficacy of irbesartan in 1,006 patients with seated diastolic blood pressure (SeDBP) 95-110 mm Hg. Irbesartan monotherapy was started at 75 mg and titrated to 300 mg at 2- to 4-week intervals to achieve normalized blood pressure (SeDBP <90 mm Hg). If normalized BP was not attained with irbesartan 300 mg alone, adjunctive medications could be added. At 12 months of therapy, the mean reduction in seated systolic blood pressure/SeDBP was 21.0/15.8 mm Hg, and 83% (684/821) of patients were normalized. Of those normalized, 64% were receiving irbesartan monotherapy and 86% were receiving irbesartan or irbesartan/hydrochlorothiazide only. No evidence of tachyphylaxis to the antihypertensive effect of irbesartan was noted. Thus, long-term irbesartan therapy, with or without other antihypertensives, achieved and maintained normalized BP in the majority of patients and was well tolerated.

Adolescent↗
PubMed1998

Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators.

The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan (P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 (P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class.

Adolescent↗
PubMed1998

Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes.

OBJECTIVE: To demonstrate the efficacy, tolerability, and safety of acarbose compared with placebo in patients with type 2 diabetes inadequately controlled with diet and metformin (2,000 or 2,500 mg/day in divided doses). RESEARCH DESIGN AND METHODS: This study had a multicenter randomized double-blind placebo-controlled parallel-group comparison design. The trial lasted 31 weeks and consisted of a 1-week screening period, a 6-week placebo pretreatment period, and a 24-week period of acarbose or placebo, with a forced titration from 25-50 mg t.i.d. and a titration of 50-100 mg tid that was based on glucose control. The primary efficacy variable was the mean change from baseline in HbA1c. Secondary efficacy variables included mean changes from baseline in fasting and postprandial plasma glucose, serum insulin, and triglyceride levels. RESULTS: The addition of acarbose to patients on background metformin and diet therapy showed a statistically significant reduction in mean HbA1c of 0.65%. There were statistically significant reductions in fasting and postprandial plasma glucose and serum insulin levels compared with placebo. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. No significant differences in liver transaminase elevations were observed between patients treated with acarbose and those treated with placebo. CONCLUSIONS: The results of this study demonstrate that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with metformin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and fasting and postprandial glucose and insulin levels.

Acarbose↗
PubMed1997

Parental sex effects in bipolar affective disorder pedigrees.

A combined linkage analysis was performed on chromosome 18 data and produced modest evidence in three of four data sets for linkage of a susceptibility locus for bipolar disorder to markers on chromosome 18p. All data sets showed a preponderance of females among affected individuals. When this was taken into account, no convincing evidence was obtained for excess transmission from mothers compared to fathers. In addition, there was no evidence for differences in the proportions of affected offspring from affected fathers and mothers. We conclude that these combined data do not support previous suggestions of a maternal effect on transmission of bipolar affective disorder.

Adolescent↗
PubMed1997

Better cutters for protein mass fingerprinting: preliminary findings.

Peptide-Mass Fingerprinting (PMF) encompasses a number of techniques for protein characterization which have as a first step the cleaving of target proteins by chemical or enzymatic reagents. Software systems exist which perform similar analyses. However, this is the first study which examines theoretically the effectiveness of the particular reagents for PMF. In this study, the task of PMF was to identify every sequence in a non-redundant protein database, via "in silico" digestion with theoretical proteases. From these experiments, some conclusions are drawn about the characteristics of better reagents and the experimental conditions which are more likely to be useful for PMF. The need for strongly non-redundant databases is also highlighted.

Amino Acid Sequence↗
PubMed1996

Brompheniramine, terfenadine, and placebo in allergic rhinitis.

BACKGROUND: Second-generation antihistamines, reported to lack central nervous system depressant activity, may be considered to have a clinical advantage over traditional antihistamines. OBJECTIVE: To compare the effectiveness, at recommended doses, of an extended-release formulation of nonprescription brompheniramine and prescription terfenadine in the treatment of allergic rhinitis. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter, parallel study. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg (n = 96), terfenadine 60 mg (n = 96), or placebo (n = 95) twice daily for 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, the investigator assessed symptom severity (i.e., rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). The investigator and the subject each completed a global efficacy evaluation, and subjects were interviewed regarding the occurrence of adverse experiences. Symptoms were analyzed as summed severity scores for (1) all symptoms and (2) for the symptom cluster of rhinorrhea, sneezing, and nasal blockage. RESULTS: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P < or = .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. Terfenadine was significantly better (P < or = .05) than placebo on the physician's global at day 14. Central nervous system-related complaints were the most frequently reported adverse experiences among all three groups; somnolence was reported most frequently by brompheniramine-treated subjects. CONCLUSION: A nonprescription, extended-release formulation of brompheniramine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitis than terfenadine, 60 mg bid.

Adolescent↗
PubMed1996

An attitudinal survey of euthanasia in Windward Oahu. A cross-sectional pilot study of four age groups.

Exploring the attitudes of 185 respondents toward euthanasia, this 1990 cross-sectional pilot study utilized 12 survey questions addressing participants' demographic profiles and 18 focusing on: abortion; capital punishment; euthanasia; sterilization; and suicide. Cross-tabulation of structural, behavioral and attitudinal variables revealed age and education were the key factors in this study's finding that the greater a person's life experience, the more favorable one's attitude toward euthanasia.

Adolescent↗