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Biomedical subjects

Sarah Fowler

Publications and source records attributed to Sarah Fowler.

11 recordsLinked to original sources
PubMed2006

The influence of age on the effects of lifestyle modification and metformin in prevention of diabetes.

BACKGROUND: The incidence of type 2 diabetes increases with age. It is unknown whether interventions to prevent diabetes are as effective in elderly persons as in younger adults. METHODS: The Diabetes Prevention Program (DPP) demonstrated that an intensive lifestyle intervention (ILS) or metformin could prevent or delay diabetes. A predefined secondary outcome of DPP was to determine if treatment effects varied by age. RESULTS: At baseline, participants aged 60-85 years were leaner and had the best insulin sensitivity and lowest insulin secretion compared to younger age groups. Diabetes incidence rates did not differ by age in the placebo group, but ILS was more effective with increasing age (6.3, 4.9, and 3.3 cases per 100 person-years, in the 25-44, 45-59, and 60-85 year age groups, respectively; p(trend) =.007). Participants aged 60-85 years had the most weight loss and metabolic equivalent (MET)-hours of physical activity. The metformin group showed a trend toward higher diabetes incidence among older participants (6.7, 7.7, and 9.3 cases per 100 person-years in the 25-44, 45-59, and 60-85 year age groups, respectively; p(trend) =.07); and diabetes risk increased with age (hazard ratio [age 60-85 vs 25-44] 1.63, p =.02), after adjusting for the greater weight loss in the 60-85 year age group. CONCLUSIONS: Lifestyle modification was exceptionally effective in preventing diabetes in older individuals; this finding was largely explained by greater weight loss and physical activity. The limited effectiveness of metformin in older persons may reflect age-related differences in insulin action and secretion. A lifestyle modification program can be recommended for older individuals at high risk for type 2 diabetes.

Adult↗
PubMed2005

Distinct roles of GIGANTEA in promoting flowering and regulating circadian rhythms in Arabidopsis.

The circadian clock acts as the timekeeping mechanism in photoperiodism. In Arabidopsis thaliana, a circadian clock-controlled flowering pathway comprising the genes GIGANTEA (GI), CONSTANS (CO), and FLOWERING LOCUS T (FT) promotes flowering specifically under long days. Within this pathway, GI regulates circadian rhythms and flowering and acts earlier in the hierarchy than CO and FT, suggesting that GI might regulate flowering indirectly by affecting the control of circadian rhythms. We studied the relationship between the roles of GI in flowering and the circadian clock using late elongated hypocotyl circadian clock associated1 double mutants, which are impaired in circadian clock function, plants overexpressing GI (35S:GI), and gi mutants. These experiments demonstrated that GI acts between the circadian oscillator and CO to promote flowering by increasing CO and FT mRNA abundance. In addition, circadian rhythms in expression of genes that do not control flowering are altered in 35S:GI and gi mutant plants under continuous light and continuous darkness, and the phase of expression of these genes is changed under diurnal cycles. Therefore, GI plays a general role in controlling circadian rhythms, and this is different from its effect on the amplitude of expression of CO and FT. Functional GI:green fluorescent protein is localized to the nucleus in transgenic Arabidopsis plants, supporting the idea that GI regulates flowering in the nucleus. We propose that the effect of GI on flowering is not an indirect effect of its role in circadian clock regulation, but rather that GI also acts in the nucleus to more directly promote the expression of flowering-time genes.

Arabidopsis↗
PubMed2005

The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.

BACKGROUND: The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance. OBJECTIVE: To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution. DESIGN: Randomized, controlled clinical trial. SETTING: Research and community-based centers. PARTICIPANTS: Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level >or=5.3 mmol/L [>or=95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo. INTERVENTIONS: Metformin, 850 mg twice daily, or intensive lifestyle intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week. MEASUREMENTS: The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III. RESULTS: Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group. LIMITATIONS: The study involved a volunteer group with impaired glucose tolerance, which limits generalizability. CONCLUSIONS: The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants.

Adult↗
PubMed2005

Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance.

Increases in subclinical inflammation (C-reactive protein [CRP]) and impaired coagulation have been associated with increased obesity and insulin resistance. Only a few small studies have examined the effect of lifestyle changes, such as weight loss, increased physical activity, and insulin-sensitizing intervention on inflammation and coagulation. The Diabetes Prevention Program (DPP) clinical trial studied the effect of an intensive lifestyle intervention or metformin on progression to diabetes relative to placebo in 3,234 adults with impaired glucose tolerance. The effects of these interventions on CRP and fibrinogen at 12 months are examined in this report. Metformin reduced CRP in women compared with the placebo group. In men, the median changes in CRP from baseline to 1 year were -33% in the lifestyle group, -7% in the metformin group, and +5% in the placebo group. In women, the changes in CRP from baseline to follow-up were -29% in the lifestyle group, -14% in the metformin group, and 0% in the placebo group. In the lifestyle group weight loss rather than increased physical activity seems to account for most of the changes in CRP. Only modest reductions (although significant) were seen in fibrinogen levels in the lifestyle group relative to the metformin and placebo group. Lifestyle intervention reduced levels of nontraditional cardiovascular risk factors relative to both placebo and to a lesser degree to metformin.

Blood Coagulation↗
PubMed2005

Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program.

OBJECTIVE: The Diabetes Prevention Program demonstrated the ability to delay or prevent type 2 diabetes in participants with impaired glucose tolerance (IGT). Participants with IGT are at high risk for cardiovascular disease (CVD), with a marked increase in the number and severity of CVD risk factors. We prospectively assessed the impact of our interventions on hypertension, dyslipidemia, and CVD events. RESEARCH DESIGN AND METHODS: The study group consisted of 3,234 individuals with IGT randomly assigned to receive intensive lifestyle intervention, metformin, or placebo. Annual assessment of blood pressure, lipids, electrocardiogram, and CVD events was undertaken. RESULTS: Hypertension was present in 30% of participants at study entry and then increased in the placebo and metformin groups, although it significantly decreased with intensive lifestyle intervention. Triglyceride levels fell in all treatment groups, but fell significantly more with intensive lifestyle intervention. Total cholesterol and LDL cholesterol levels were similar among treatment groups. Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up, the use for pharmacologic therapy to achieve established goals in the intensive lifestyle group was 27-28% less for hypertension and 25% less for hyperlipidemia compared with placebo and metformin groups. Over an average of 3 years, 89 CVD events from 64 participants were positively adjudicated studywide, with no differences among treatment groups. CONCLUSIONS: Lifestyle intervention improves CVD risk factor status compared with placebo and metformin therapy. Although no differences in CVD events were noted after 3 years, achieved risk factor modifications suggest that longer intervention may reduce CVD event rates.

Cardiovascular Diseases↗
PubMed2004

A prominent role for the CBF cold response pathway in configuring the low-temperature metabolome of Arabidopsis.

The Arabidopsis CBF cold response pathway has a central role in cold acclimation, the process whereby plants increase in freezing tolerance in response to low nonfreezing temperatures. Here we examined the changes that occur in the Arabidopsis metabolome in response to low temperature and assessed the role of the CBF cold response pathway in bringing about these modifications. Of 434 metabolites monitored by GC-time-of-flight MS, 325 (75%) were found to increase in Arabidopsis Wassilewskija-2 (Ws-2) plants in response to low temperature. Of these 325 metabolites, 256 (79%) also increased in nonacclimated Ws-2 plants in response to overexpression of C-repeat/dehydration responsive element-binding factor (CBF)3. Extensive cold-induced changes also occurred in the metabolome of Arabidopsis Cape Verde Islands-1 (Cvi-1) plants, which were found to be less freezing tolerant than Ws-2 plants. However, low-temperature-induced expression of CBF1, CBF2, CBF3, and CBF-targeted genes was much lower in Cvi-1 than in Ws-2 plants, and the low-temperature metabolome of Cvi-1 plants was depleted in metabolites affected by CBF3 overexpression. Taken together, the results indicate that the metabolome of Arabidopsis is extensively reconfigured in response to low temperature, and that the CBF cold response pathway has a prominent role in this process.

Acclimatization↗
PubMed2004

Penile cancer in the UK: clinical presentation and outcome in 1998/99.

OBJECTIVE: To use the British Association of Urological Surgeons (BAUS) Cancer Registry data to audit a cohort of patients with penile cancer, and thus evaluate current management practices in the UK. PATIENTS AND METHODS: In all, 243 patients were registered over an 18-month period shortly before the publication of the UK National Institute of Clinical Excellence cancer guidelines. Clinical data, including preceding skin disorders, the clinical presentation, management, treatment-related complications and the outcome in terms of local, nodal or distant disease recurrence, survival and cause of death, were sought from the originating clinician. RESULTS: Data were obtained on 193 patients (79% of the initial population). One consultant reported five patients and the most from one centre was eight. A painless lump or ulcer was the commonest presentation; 45 patients had pre-existing skin disorders. The median age was 65.5 years and 67 patients were aged < 60 years. Squamous cell carcinoma accounted for 94% of the pathology. There were wide variations in treatment for patients of similar disease stage. Twenty-six patients had palpable regional nodes and 44 had a lymph node dissection; complications were reported in 43, including 18 of 44 having node dissection. The median follow-up was 27.7 months from the date of diagnosis. Death from penile cancer was recorded in one of 22 patients with stage 0 disease and seven of nine with stage IV disease. Positive lymph nodes had a detrimental effect on survival. CONCLUSION: Experience in the management of penile cancer is shared by many urological surgeons in the UK. These data provide a 'baseline' against which to measure the outcome of specialist multidisciplinary team activity.

Adult↗
PubMed2003

Modifications of the catalytic and binding subunits of pertussis toxin by formaldehyde: effects on toxicity and immunogenicity.

A panel of pertussis toxin (PT) preparations with varying levels of residual toxicity was prepared by treatment of native PT with formaldehyde (0-1.00% (w/v)) with the purpose of investigating the effects of residual toxicity on immunogenicity. The catalytically inactive mutant PT (PT-9K/129G) was used for comparison. Results from in vitro ADP-ribosyl transferase and Chinese hamster ovary (CHO)-cell toxicity assays demonstrated a formaldehyde-dependent reduction in PT toxicity, and implied that both A and B domain functions of PT were modified. The in vivo histamine sensitisation and leukocyte proliferation tests suggested that the formaldehyde-treated native PT preparations were subject to reversion to toxicity. Reversion was confirmed by in vitro toxicity assays, which demonstrated recovery of A and B domain functions. The presence of high molecular weight aggregated and cross-linked species of PT in these preparations did not appear to be detrimental to the production of a neutralising antibody response. IgG responses to native and non-catalytic mutant PT suggested that low levels of residual activity in the native PT enhanced the antibody response, while higher levels of activity inhibited the response. Using the non-catalytic mutant PT showed that formaldehyde-induced changes were not detrimental to the magnitude of the PT-specific antibody response but did reduce the PT-specific neutralising activity. In conclusion, the residual toxicity of PT preparations following formaldehyde treatment may play an important role in the immune response to pertussis vaccine, potentially altering the quality, class and magnitude of the antibodies produced to PT.

Animals↗
PubMed2003

Novel configurations of high molecular weight species of the pertussis toxin vaccine component.

Pertussis toxin (PT) is used in its formaldehyde-detoxified form in acellular pertussis vaccines for preventing whooping cough in children. The effects of formaldehyde treatment (up to 0.5% (w/v) formaldehyde) on the size, molecular association, folding and monoclonal antibody (mAb) binding of PT were studied to further define the structural nature of the high molecular weight species as related to their epitope integrity. Analytical ultracentrifugation (AUC) demonstrated that formaldehyde treatment of PT prevented the dissociation of the holotoxin. Together with results from size exclusion chromatography (SEC), SEC/multi-angle laser light scattering (MALLS) and immunoblotting it was demonstrated that PT increased in molecular weight and heterogeneity as a function of formaldehyde concentration, caused at least in part by covalent cross-linking. Five mAbs specific for PT subunits (S1-S5) bound to the cross-linked species, although there was some loss of epitopes in the larger aggregates. Intrinsic fluorescence spectroscopy gave evidence of progressive unfolding and re-association of PT. These findings demonstrate that a favourable balance between protein stabilisation and denaturation may be achieved by the treatment of pertussis toxin with formaldehyde, and provides a basis for determining the significance of high molecular weight cross-linked species of pertussis toxin in protection against whooping cough.

Amino Acid Substitution↗
PubMed2002

Arabidopsis transcriptome profiling indicates that multiple regulatory pathways are activated during cold acclimation in addition to the CBF cold response pathway.

Many plants, including Arabidopsis, increase in freezing tolerance in response to low, nonfreezing temperatures, a phenomenon known as cold acclimation. Previous studies established that cold acclimation involves rapid expression of the CBF transcriptional activators (also known as DREB1 proteins) in response to low temperature followed by induction of the CBF regulon (CBF-targeted genes), which contributes to an increase in freezing tolerance. Here, we present the results of transcriptome-profiling experiments indicating the existence of multiple low-temperature regulatory pathways in addition to the CBF cold response pathway. The transcript levels of approximately 8000 genes were determined at multiple times after plants were transferred from warm to cold temperature and in warm-grown plants that constitutively expressed CBF1, CBF2, or CBF3. A total of 306 genes were identified as being cold responsive, with transcripts for 218 genes increasing and those for 88 genes decreasing threefold or more at one or more time points during the 7-day experiment. These results indicate that extensive downregulation of gene expression occurs during cold acclimation. Of the cold-responsive genes, 48 encode known or putative transcription factors. Two of these, RAP2.1 and RAP2.6, were activated by CBF expression and thus presumably control subregulons of the CBF regulon. Transcriptome comparisons indicated that only 12% of the cold-responsive genes are certain members of the CBF regulon. Moreover, at least 28% of the cold-responsive genes were not regulated by the CBF transcription factors, including 15 encoding known or putative transcription factors, indicating that these cold-responsive genes are members of different low-temperature regulons. Significantly, CBF expression at warm temperatures repressed the expression of eight genes that also were downregulated by low temperature, indicating that in addition to gene induction, gene repression is likely to play an integral role in cold acclimation.

Acclimatization↗