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Biomedical subjects

J Mann

Publications and source records attributed to J Mann.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

ADP-ribosyl Cyclase 1↗
PubMed2006

Left ventricular growth response to exercise and cigarette smoking: data from LARGE Heart.

BACKGROUND: Increasing left ventricular mass is a risk factor for cardiovascular morbidity and mortality. OBJECTIVE: To examine the possible association of smoking with the left ventricular growth response in men. METHODS: Left ventricular mass was measured in 309 army recruits before and after an identical 12-week physical training programme. Left ventricular mass was determined using cardiovascular magnetic resonance. RESULTS: Left ventricular mass increased with training (mean (standard deviation (SD)) 3.83 (10.81) g, p<0.001). By univariate analysis, exercise-induced change in left ventricular mass was positively associated with cigarette smoking (mean (SD) 1.69 (11.10) g v 4.76 (10.23) g for non-smokers v ex- and current smokers, respectively; p = 0.026), whereas age, height, diastolic and systolic blood pressure (SBP), alcohol consumption or indices of physical activity were not significantly associated with change in left ventricular mass. Multivariate analysis showed body weight, smoking status and SBP to be independent predictors of left ventricular mass (incremental R(2) = 3.4%, p = 0.004; R(2) = 4.9%, p = 0.024; and R(2) = 1.7%, p = 0.041, respectively). CONCLUSIONS: Cigarette smoking and SBP are associated with exercise-induced left ventricular growth in young men. The positive association of smoking with changes in left ventricular mass is surprising, given the limited exposure of these subjects to smoking, and although these data do not prove causation, they are of great interest to those trying to uncover the drivers of left ventricular hypertrophy, as well as to those examining the possible ill-effects of smoking in the young.

Analysis of Variance↗
PubMed2006

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis.

Myofibroblasts are critical cellular elements of wound healing generated at sites of injury by transdifferentiation of resident cells. A paradigm for this process is conversion of hepatic stellate cells (HSC) into hepatic myofibroblasts. Treatment of HSC with DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) blocked transdifferentiation. 5-azadC also prevented loss of IkappaBalpha and PPARgamma expression that occurs during transdifferentiation to allow acquisition of proinflammatory and profibrogenic characteristics. ChIP analysis revealed IkappaBalpha promoter is associated with transcriptionally repressed chromatin that converts to an active state with 5-azadC treatment. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated IkappaBalpha promoter activity, mRNA and protein expression in myofibroblasts. MeCP2 interacts with IkappaBalpha promoter via a methyl-CpG-dependent mechanism and recruitment into a CBF1 corepression complex. We conclude that MeCP2 and DNA methylation exert epigenetic control over hepatic wound healing and fibrogenesis.

Animals↗
PubMed2006

[End stage renal disease after ingestion of mushrooms].

This case report describes a 56 year old patient with acute renal failure caused by a mushroom poisoning. Unspecific symptoms like a gastroenteritis followed by kidney insuffiency lead to the diagnosis of an orellanus syndrome. The toxin can be proved by thin layer chromatography in renal biopsy. Fast processing of hemoperfusion may avoid lasting kidney damage and dialysis.

Humans↗
PubMed2006

[Drug-related disorders of water and electrolyte metabolism].

Pharmacologic treatment may lead to diverse disturbances of water and electrolyte metabolism as adverse drug events. Diuretics are particularly likely to cause these complications typically including volume depletion, metabolic alkalosis, hyponatremia, and hypokalemia. Salt and water retention with edema formation is most frequently elicited by antihypertensives, steroid hormones, and nonsteroidal anti-inflammatory drugs. Drug-induced disorders of Na+ concentration may usually be attributed to altered antidiuretic hormone (ADH) effects, either as diabetes insipidus or as the syndrome of inappropriate ADH secretion. With hyper- and hypokalemia, redistribution between intra- and extracellular fluid as well as renal excretion play a role. Strategies to prevent these adverse drug reactions include careful consideration of risk factors and clinical and laboratory controls in the course of treatment.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Pharmacokinetic interaction between ketoconazole and SPP301 in healthy volunteers.

BACKGROUND: SPP301 is a potent and highly selective ETA receptor blocker. The primary aim of the present study was to investigate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of SPP301. METHODS: In a randomized, open-label 2-period oral crossover study, 12 healthy male subjects received treatments A and B. Treatment A consisted of 200 mg ketoconazole once daily on Days 1 - 4 and concomitantly 5 mg SPP301 on Day 3. Treatment B consisted of 5 mg SPP301 administered alone. Plasma concentrations of SPP301 and its hydroxymethyl metabolite were measured by LC-MS/MS. RESULTS: Ketoconazole coadministration increased the systemic availability of SPP301 and its hydroxymethyl metabolite 3-fold and prolonged their half-lives by a factor of 2. The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of ketoconazole for SPP301 and its metabolite were C(max) (maximum plasma concentration) 1.22 (1.13, 1.32) and 1.2 (1.05, 1.37), AUC(0-infinity) (area under the plasma concentration-time curve from time zero to infinity) 3.16 (2.84, 3.51) and 3.14 (2.49, 3.70) and t1/2 (apparent terminal half-life) 2.21 (1.55, 2.87) and 2.00 (1.17, 2.84), i.e. an increase of systemic exposure by a factor of 3.2, with individual exposures increasing up to 5.9-fold. Single oral doses of SPP301 were well tolerated when administered alone or together with multiple doses of ketoconazole. CONCLUSION: In the presence of potent CYP3A4 inhibitors exposure of SPP301 may be increased up to 6-fold.

Adult↗
PubMed2006

Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers.

BACKGROUND: Avosentan (SPP301) is a potent and highly selective ETA receptor blocker and is clinically investigated in diabetic nephropathy. This study was designed to evaluate whether avosentan influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 16 healthy females received an oral contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg for the first 21 days of a minimum of one menstrual cycle. In a subsequent double-blind, randomized two menstrual cycle crossover treatment phase, subjects received either avosentan 25 mg or placebo once daily concomitantly with the oral contraceptive. Serum ethinylestradiol and plasma levonorgestrel concentrations were measured on Days 14 and 15 of the two treatment periods for the evaluation of the 24-hour kinetic parameters, and an additional sample was collected on Day 21 to determine their trough concentrations. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels as well as plasma avosentan and Ro 68-5925 levels were determined on Days 13, 14, 15 and 21 of each cycle of the treatment phase. RESULTS: Avosentan had a statistically significant lowering effect of 9 - 15% on the ethinylestradiol serum concentration levels. The 90% confidence intervals of the pharmacokinetic parameters did not include 1 or exceeded the 0.8 - 1.25 acceptance range for lack of interaction. The plasma concentration-time curves and pharmacokinetic parameters of levonor-gestrel were not statistically different during concomitant treatment with either avosentan or placebo. Compared to placebo, avosentan lowered the serum concentrations of progesterone statistically significantly by about 8% and increased slightly the LH and FSH serum concentrations. Safety and tolerability patterns were comparable during avosentan and placebo administration. CONCLUSION: Because of the effect of avosentan on the concentration levels of ethinylestradiol and progesterone, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during avosentan treatment.

Adult↗
PubMed2005

Cholesterol lowering effects of nuts compared with a Canola oil enriched cereal of similar fat composition.

BACKGROUND AND AIM: Small quantities of nuts protect against subsequent cardiovascular risk. There is speculation that the cholesterol lowering effect associated with nut consumption arises primarily from the fatty acid composition of nuts but may be caused by some other component. To evaluate this possibility we compared the effect of various nuts, against a Canola oil based cereal with a comparable fatty acid profile, on lipids, lipoproteins and fatty acids to determine whether the fatty acid profile of nuts explains their cholesterol lowering effects. METHODS AND RESULTS: Twenty-eight men and women with mean (s.d.) levels of total and low density lipoprotein cholesterol of 6.0 (1.1) mmol/L, and 4.1 (1.0) mmol/L, respectively and a mean body mass index (BMI) of 26.9 (3.2) kg/m2 took part in a randomised cross over trial. For two periods of six weeks, separated by a four-week washout, participants were asked to consume a low saturated fat diet, which included either 30 g/d nuts (nut diet) or one serving of a cereal containing Canola oil (cereal diet). There were no significant differences in the lipids, lipoproteins, plasma fatty acids or other variables between the two diets at the end of the study. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) were lower on both experimental diets than at baseline, 0.51 mmol/L and 0.40 mmol/L (p<0.001, p<0.01), respectively on the nut diet and 0.42 mmol/L and 0.37 mmol/L (p<0.001, p<0.01), respectively on the cereal diet. CONCLUSION: A 30 g serving of nuts, or a serving of a Canola oil enriched cereal with a similar fatty acid composition reduced total and LDL cholesterol to a similar extent when consumed as part of a lipid lowering diet. Results suggest that foods with a similar fatty acid composition to nuts can produce comparable decreases in lipoprotein mediated cardiovascular risk.

Cholesterol↗
PubMed2005

Anatomical success rate of macular hole surgery with autologous platelet without internal-limiting membrane peeling.

AIM: To describe our experience and success rate of macular hole surgery with pars plana vitrectomy with autologous platelet and without internal limiting membrane peel. METHODS: Retrospective review of 56 consecutive patients who underwent macular hole surgery. RESULTS: Anatomical success was achieved in 55 out of 56 patients (98.2%). Functional success was achieved in 37 out of 56 patients (66.1%). A total of 21 patients (37.5%) achieved postoperative visual acuity of 6/12 or better. No intraoperative complications were encountered. Postoperative complications included cataract progression in eight eyes and raised intraocular pressure in 20 eyes. CONCLUSIONS: Our success rate was comparable to that reported in macular hole surgery incorporating internal limiting membrane (ILM) peel or with autologous platelet without ILM peel.

Aged↗
PubMed2005

Multiple-dose pharmacokinetics, pharmacodynamics and tolerability of the oral ET(A) endothelin-receptor antagonist SPP301 in man.

BACKGROUND: SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ET(A) receptor. The multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of SPP301 were investigated in healthy male subjects. METHODS: In an ascending-dose, double-blind, placebo-controlled trial doses of 5, 20, 40 and 60 mg SPP301 were given orally on Day 1 and, after a wash-out period of 48 hours, once daily for seven days. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1, and of SPP301 and its hydroxymethyl metabolite as well as urinary excretion of the parent drug and its metabolite were determined. RESULTS: SPP301 was generally well-tolerated. With the higher doses asymptomatic and transient increases in liver transaminases were observed. No other clinically relevant effects of SPP301 on hematology, biochemistry or urinalysis parameters were observed. Vital signs, ECG parameters and physical examinations showed no time or treatment effect. The pharmacokinetics of SPP301 and its hydroxymethyl metabolite (Ro 68-5925) were linear up to 40 mg SPP301. Steady state was reached after 3-4 days. The apparent terminal half-life of SPP301 and the metabolite was in the range of 7-10 hours after single and repeated doses. At the 60 mg dose level plasma concentrations of SPP301 decreased from the first to the last day of oral treatment. The average decreases in Cmax and AUC were 33% and 37%, respectively. Cmax and AUC of the metabolite amounted to about 4-6% of the values for SPP301 under single and repeated-dose conditions. Urinary excretion of SPP301 and of its metabolite were below 0.1% and 5%, respectively. CONCLUSION: SPP301 is quite well-tolerated, pharmacokinetics are linear and time-independent up to 40 mg multiple doses. Steady state is reached after 3-4 days. Urinary excretion of the unchanged drug plays a minor role in the elimination process of SPP301. ET-1 plasma concentrations increased about 1.5-fold at 20 mg and all further doses.

Administration, Oral↗
PubMed2005

Pharmacokinetic interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol, celecoxib and cimetidine.

OBJECTIVE: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study investigated the interaction profile of aliskiren, which is of clinical importance because hypertensive patients often require concomitant drug therapy for associated comorbidities. METHODS: Four separate studies investigated the pharmacokinetic interaction between single oral doses of aliskiren and lovastatin, atenolol, celecoxib or cimetidine, respectively. All studies involved healthy male volunteers aged 18-45 years. In 3 studies, subjects (n = 15 in each study) received single doses of aliskiren 150 mg alone, the test drug alone (lovastatin 40 mg, atenolol 100 mg or celecoxib 200 mg), or both drugs in combination, according to a 3-period crossover design. In the cimetidine study (n = 12), aliskiren 150 mg was administered alone or concomitantly with cimetidine 800 mg according to a two-period crossover design. Plasma concentrations of aliskiren and test drugs were determined by liquid chromatography and mass spectrometry methods. Pharmacokinetic parameters were derived from these data. RESULTS: Mean AUC and t1/2 for aliskiren were not significantly changed by lovastatin, atenolol or celecoxib (< 10% difference between treatments). Aliskiren mean Cmax was not affected by either lovastatin or atenolol, although a non-significant 36% increase was observed with celecoxib. Modest, non-significant increases in aliskiren systemic availability followed coadministration with cimetidine (aliskiren mean AUC, Cmax and t1/2 increased by 17%, 19% and 15%, respectively). Aliskiren coadministration had no significant effect on the disposition of lovastatin, atenolol or celecoxib. CONCLUSIONS: Overall, single doses of aliskiren showed no evidence of clinically important pharmacokinetic interactions with lovastatin, atenolol, celecoxib or cimetidine.

Adolescent↗
PubMed2004

In vivo mammary tumourigenesis in the Sprague-Dawley rat and microdosimetric correlates.

Standard methods for risk assessments resulting from human exposures to mixed radiation fields in Space consisting of different particle types and energies rely upon quality factors. These are generally defined as a function of linear energy transfer (LET) and are assumed to be proportional to the risk. In this approach, it is further assumed that the risks for single exposures from each of the radiation types add linearly. Although risks of cancer from acute exposures to photon radiations have been measured in humans, quality factors for protons and ions of heavier atomic mass are generally inferred from animal and/or cellular data. Because only a small amount of data exists for such particles, this group has been examining tumourigenesis initiated by energetic protons and iron ions. In this study, 741 female Sprague-Dawley rats were irradiated or sham irradiated at approximately 60 days of age with 250 MeV protons, 1 GeV/nucleon iron ions or both protons and iron ions. The results suggest that the risk of mammary tumours in the rats sequentially irradiated with 1 GeV/nucleon 56Fe ions and 250 MeV protons is less than additive. These data in conjunction with earlier results further suggest that risk assessments in terms of only mean LETs of the primary cosmic rays may be insufficient to accurately evaluate the relative risks of each type of particle in a radiation field of mixed radiation qualities.

Animals↗
PubMed2004

Replacing cows' with sheep's dairy fat lowers plasma cholesterol concentration in participants consuming dairy fat-rich diets.

OBJECTIVE: To determine the effects on plasma cholesterol concentration of replacing cows' dairy fat with sheep's dairy fat. DESIGN: Randomised crossover dietary intervention. SETTING: General community, Dunedin, New Zealand. SUBJECTS: Volunteer sample of 41 healthy adults with initial plasma cholesterol concentration between 4.8 and 7.8 mmol/l. INTERVENTIONS: Participants were asked to follow a self-selected low-fat background diet throughout the study to which, during each of the 2, 3-week dairy diets, they were asked to add sheep's or cows' dairy products. MAIN OUTCOME MEASURES: Energy and nutrient intakes, plasma triacylglycerol fatty acids, and plasma cholesterol. RESULTS: Energy and nutrient intakes on the sheep-dairy and cow-dairy diets were very similar, with total, saturated, monounsaturated and polyunsaturated fat contributing 34, 18-19, 9, and 3% of total energy intake, respectively. Participants consumed approximately 50 g/day of dairy fat on each diet. Replacing cows' with sheep's dairy fat led to a 0.33 (0.11-0.56, 95% CI) mmol/l decrease (6%) in plasma total cholesterol concentration, from 5.53 (0.90, s.d.) to 5.20 (0.90) mmol/l. Plasma low-density lipoprotein (LDL) cholesterol was 0.18 (0.02-0.33) mmol/l lower on the sheep-dairy diet as was the concentration of plasma high-density lipoprotein (HDL) cholesterol, 0.11 (0.02-0.20) mmol/l. The LDL to HDL cholesterol ratio at the end of the sheep-dairy diet, 2.91 (1.10), was not significantly different (P>0.05) from the cow-dairy diet, 2.73 (0.83). CONCLUSIONS: Within the context of a diet high in dairy fat (50 g/day), replacing cows' milk fat with sheep's milk fat leads to a small reduction in plasma cholesterol concentration, but no change in the ratio of LDL to HDL cholesterol.

Adult↗
PubMed2004

Diet, nutrition and the prevention of type 2 diabetes.

OBJECTIVES: The overall objective of this study was to evaluate and provide evidence and recommendations on current published literature about diet and lifestyle in the prevention of type 2 diabetes. DESIGN: Epidemiological and experimental studies, focusing on nutritional intervention in the prevention of type 2 diabetes are used to make disease-specific recommendations. Long-term cohort studies are given the most weight as to strength of evidence available. SETTING AND SUBJECTS: Numerous clinical trials and cohort studies in low, middle and high income countries are evaluated regarding recommendations for dietary prevention of type 2 diabetes. These include, among others, the Finnish Diabetes Prevention Study, US Diabetes Prevention Program, Da Qing Study; Pima Indian Study; Iowa Women's Health Study; and the study of the US Male Physicians. RESULTS: There is convincing evidence for a decreased risk of diabetes in adults who are physically active and maintain a normal body mass index (BMI) throughout adulthood, and in overweight adults with impaired glucose tolerance who lose weight voluntarily. An increased risk for developing type 2 diabetes is associated with overweight and obesity; abdominal obesity; physical inactivity; and maternal diabetes. It is probable that a high intake of saturated fats and intrauterine growth retardation also contribute to an increased risk, while non-starch polysaccharides are likely to be associated with a decreased risk. From existing evidence it is also possible that omega-3 fatty acids, low glycaemic index foods and exclusive breastfeeding may play a protective role, and that total fat intake and trans fatty acids may contribute to the risk. However, insufficient evidence is currently available to provide convincing proof. CONCLUSIONS: Based on the strength of available evidence regarding diet and lifestyle in the prevention of type 2 diabetes, it is recommended that a normal weight status in the lower BMI range (BMI 21-23) and regular physical activity be maintained throughout adulthood; abdominal obesity be prevented; and saturated fat intake be less than 7% of the total energy intake.

Clinical Trials as Topic↗
PubMed2004

A review of satisfaction with dental service at a Jerusalem community clinic serving elderly patients.

AIM: The audit of dental satisfaction and its association with the reported outcome of a dental health care programme for elderly patients. DESIGN: A telephone survey of 162 patients in a Jerusalem municipal dental clinic for geriatric patients, who had completed a treatment course in oral rehabilitation. RESULTS: The average age of the respondents was 73.2 +/- 8.45 years, over 80% of who were very satisfied or satisfied with the treatment given by the dental clinic staff. Only 1.8% were not satisfied (the remaining 17.9% were unable to answer the question). Among those who responded, 91.6% were currently using their full dentures, 80.4% reported an improvement in chewing ability, and 82.3% an improvement in appearance. Respondents who reported daily use of dentures and improved chewing and appearance, also reported higher levels of satisfaction with the clinic. CONCLUSIONS: These results indicate a potentially important role of satisfaction with dental staff in optimal compliance and success of a geriatric oral health care programme.

Aged↗
PubMed2004

[A new gel for topical use in treating severe periodontal disease--clinical observations].

Within the framework of the efforts to find non-invasive treatment methods for severe periodontitis, a topical gel was developed by an Israeli research group. The aim of the current study is to present clinical observations and X-ray measurements of alveolar bone changes following an 8 week, self-care periodontal treatment in two groups of patients with severe periodontitis. All 31 patients who participated in the study showed an improvement of the periodontal condition as expressed in all the indexes examined. The observation findings testify to the fact that through self-care using a topical gel, significant results were achieved: decrease in probing depth, decrease in bleeding, significant improvement in teeth mobility and in level of the alveolar bone height and its density. These clinical findings raise interesting research questions and hint at the potential for regeneration of supportive periodontal tissues in cases of severe periodontitis, currently achieved only through surgical means. In order to obtain more accurate data regarding the treatment potential of this gel, it is important to conduct additional controlled clinical trials on different populations and also to try and determine how it works.

Adult↗