Effect of calcium-channel blockers on calcium-phosphate metabolism in patients with end-stage renal disease

After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect.

Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans

Garlic extracts have been shown to decrease drug exposure for saquinavir, a P-glycoprotein and cytochrome P450 3A4 substrate. In order to explore the underlying mechanisms and to study the effects of garlic on pre-systemic drug elimination, healthy volunteers were administered garlic extract for 21 days. Prior to and at the end of this period, expression of duodenal P-glycoprotein and cytochrome P450 3A4 protein were assayed and normalized to villin, while hepatic cytochrome P450 3A4 function and simvastatin, pravastatin and saquinavir pharmacokinetics were also evaluated. Ingestion of garlic extract increased expression of duodenal P-glycoprotein to 131% (95% CI, 105-163%), without increasing the expression of cytochrome P450 3A4 which amounted to 87% (95% CI, 67-112%), relative to baseline in both cases. For the erythromycin breath test performed, the average result was 96% (95% CI, 83-112%). Ingestion of garlic extract had no effect on drug and metabolite AUCs following a single dose of simvastatin or pravastatin, although the average area under the plasma concentration curve (AUC) of saquinavir decreased to 85% (95% CI, 66-109%), and changes in intestinal P-glycoprotein expression negatively correlated with this change. In conclusion, garlic extract induces intestinal expression of P-glycoprotein independent of cytochrome P450 3A4 in human intestine and liver.

End-tidal CO(2). An important parameter for a correct interpretation in functional brain studies using speech tasks

The aim was to investigate the effect of different speech tasks, i.e. recitation of prose (PR), alliteration (AR) and hexameter (HR) verses and a control task (mental arithmetic (MA) with voicing of the result on end-tidal CO2 (PETCO2), cerebral hemodynamics and oxygenation. CO2 levels in the blood are known to strongly affect cerebral blood flow. Speech changes breathing pattern and may affect CO2 levels. Measurements were performed on 24 healthy adult volunteers during the performance of the 4 tasks. Tissue oxygen saturation (StO2) and absolute concentrations of oxyhemoglobin ([O2Hb]), deoxyhemoglobin ([HHb]) and total hemoglobin ([tHb]) were measured by functional near-infrared spectroscopy (fNIRS) and PETCO2 by a gas analyzer. Statistical analysis was applied to the difference between baseline before the task, 2 recitation and 5 baseline periods after the task. The 2 brain hemispheres and 4 tasks were tested separately. A significant decrease in PETCO2 was found during all 4 tasks with the smallest decrease during the MA task. During the recitation tasks (PR, AR and HR) a statistically significant (p < 0.05) decrease occurred for StO2 during PR and AR in the right prefrontal cortex (PFC) and during AR and HR in the left PFC. [O2Hb] decreased significantly during PR, AR and HR in both hemispheres. [HHb] increased significantly during the AR task in the right PFC. [tHb] decreased significantly during HR in the right PFC and during PR, AR and HR in the left PFC. During the MA task, StO2 increased and [HHb] decreased significantly during the MA task. We conclude that changes in breathing (hyperventilation) during the tasks led to lower CO2 pressure in the blood (hypocapnia), predominantly responsible for the measured changes in cerebral hemodynamics and oxygenation. In conclusion, our findings demonstrate that PETCO2 should be monitored during functional brain studies investigating speech using neuroimaging modalities, such as fNIRS, fMRI to ensure a correct interpretation of changes in hemodynamics and oxygenation.

The Validation of a New Visual Anaemia Evaluation Tool HemoHue HH1 in Patients with End-Stage Renal Disease

In chronic haemodialysis patients, anaemia is a frequent finding associated with high therapeutic costs and further expenses resulting from serial laboratory measurements. HemoHue HH1, HemoHue Ltd, is a novel tool consisting of a visual scale for the noninvasive assessment of anaemia by matching the coloration of the conjunctiva with a calibrated hue scale. The aim of the study was to investigate the usefulness of HemoHue in estimating individual haemoglobin concentrations and binary treatment outcomes in haemodialysis patients. A prospective blinded study with 80 hemodialysis patients comparing the visual haemoglobin assessment with the standard laboratory measurement was performed. Each patient's haemoglobin concentration was estimated by seven different medical and nonmedical observers with variable degrees of clinical experience on two different occasions. The estimated population mean was close to the measured one (11.06 ± 1.67 versus 11.32 ± 1.23 g/dL, P < 0.0005). A learning effect could be detected. Relative errors in individual estimates reached, however, up to 50%. Insufficient performance in predicting binary outcomes (ROC AUC: 0.72 to 0.78) and poor interrater reliability (Kappa < 0.6) further characterised this method.

Effect of a lung recruitment maneuver by high-frequency oscillatory ventilation in experimental acute lung injury on organ blood flow in pigs

INTRODUCTION: The objective was to study the effects of a lung recruitment procedure by stepwise increases of mean airway pressure upon organ blood flow and hemodynamics during high-frequency oscillatory ventilation (HFOV) versus pressure-controlled ventilation (PCV) in experimental lung injury. METHODS: Lung damage was induced by repeated lung lavages in seven anesthetized pigs (23-26 kg). In randomized order, HFOV and PCV were performed with a fixed sequence of mean airway pressure increases (20, 25, and 30 mbar every 30 minutes). The transpulmonary pressure, systemic hemodynamics, intracranial pressure, cerebral perfusion pressure, organ blood flow (fluorescent microspheres), arterial and mixed venous blood gases, and calculated pulmonary shunt were determined at each mean airway pressure setting. RESULTS: The transpulmonary pressure increased during lung recruitment (HFOV, from 15 +/- 3 mbar to 22 +/- 2 mbar, P < 0.05; PCV, from 15 +/- 3 mbar to 23 +/- 2 mbar, P < 0.05), and high airway pressures resulted in elevated left ventricular end-diastolic pressure (HFOV, from 3 +/- 1 mmHg to 6 +/- 3 mmHg, P < 0.05; PCV, from 2 +/- 1 mmHg to 7 +/- 3 mmHg, P < 0.05), pulmonary artery occlusion pressure (HFOV, from 12 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 13 +/- 2 mmHg to 15 +/- 2 mmHg, P < 0.05), and intracranial pressure (HFOV, from 14 +/- 2 mmHg to 16 +/- 2 mmHg, P < 0.05; PCV, from 15 +/- 3 mmHg to 17 +/- 2 mmHg, P < 0.05). Simultaneously, the mean arterial pressure (HFOV, from 89 +/- 7 mmHg to 79 +/- 9 mmHg, P < 0.05; PCV, from 91 +/- 8 mmHg to 81 +/- 8 mmHg, P < 0.05), cardiac output (HFOV, from 3.9 +/- 0.4 l/minute to 3.5 +/- 0.3 l/minute, P < 0.05; PCV, from 3.8 +/- 0.6 l/minute to 3.4 +/- 0.3 l/minute, P < 0.05), and stroke volume (HFOV, from 32 +/- 7 ml to 28 +/- 5 ml, P < 0.05; PCV, from 31 +/- 2 ml to 26 +/- 4 ml, P < 0.05) decreased. Blood flows to the heart, brain, kidneys and jejunum were maintained. Oxygenation improved and the pulmonary shunt fraction decreased below 10% (HFOV, P < 0.05; PCV, P < 0.05). We detected no differences between HFOV and PCV at comparable transpulmonary pressures. CONCLUSION: A typical recruitment procedure at the initiation of HFOV improved oxygenation but also decreased systemic hemodynamics at high transpulmonary pressures when no changes of vasoactive drugs and fluid management were performed. Blood flow to the organs was not affected during lung recruitment. These effects were independent of the ventilator mode applied.

Effect on infection resistance of a local antiseptic and antibiotic coating on osteosynthesis implants: an in vitro and in vivo study

The purpose of this study was to acquire information about the effect of an antibacterial and biodegradable poly-L-lactide (PLLA) coated titanium plate osteosynthesis on local infection resistance. For our in vitro and in vivo experiments, we used six-hole AO DC minifragment titanium plates. The implants were coated with biodegradable, semiamorphous PLLA (coating about 30 microm thick). This acted as a carrier substance to which either antibiotics or antiseptics were added. The antibiotic we applied was a combination of Rifampicin and fusidic acid; the antiseptic was a combination of Octenidin and Irgasan. This produced the following groups: Group I: six-hole AO DC minifragment titanium plate without PLLA; Group II: six-hole AO DC minifragment titanium plate with PLLA without antibiotics/antiseptics; Group III: six-hole AO DC minifragment titanium plate with PLLA + 3% Rifampicin and 7% fusidic acid; Group IV: six-hole AO DC minifragment titanium plate with PLLA + 2% Octenidin and 8% Irgasan. In vitro, we investigated the degradation and the release of the PLLA coating over a period of 6 weeks, the bactericidal efficacy of antibiotics/antiseptics after their release from the coating and the bacterial adhesion of Staphylococcus aureus to the implants. In vivo, we compared the infection rates in white New Zealand rabbits after titanium plate osteosynthesis of the tibia with or without antibacterial coating after local percutaneous bacterial inoculations at different concentrations (2 x 10(5)-2 x 10(8)): The plate, the contaminated soft tissues and the underlying bone were removed under sterile conditions after 28 days and quantitatively evaluated for bacterial growth. A stepwise experimental design with an "up-and-down" dosage technique was used to adjust the bacterial challenge in the area of the ID50 (50% infection dose). Statistical evaluation of the differences between the infection rates of both groups was performed using the two-sided Fisher exact test (p < 0.05). Over a period of 6 weeks, a continuous degradation of the PLLA coating of 13%, on average, was seen in vitro in 0.9% NaCl solution. The elution tests on titanium implants with antibiotic or antiseptic coatings produced average release values of 60% of the incorporated antibiotic or 62% of the incorporated antiseptic within the first 60 min. This was followed by a much slower, but nevertheless continuous, release of the incorporated antibiotic and antiseptic over days and weeks. At the end of the test period of 42 days, 20% of the incorporated antibiotic and 15% of the incorporated antiseptic had not yet been released from the coating. The antibacterial effect of the antibiotic/antiseptic is not lost by integrating it into the PLLA coating. The overall infection rate in the in vivo investigation was 50%. For Groups I and II the infection rate was both 83% (10 of 12 animals). In Groups III and IV with antibacterial coating, the infection rate was both 17% (2 of 12 animals). The ID50 in the antibacterial coated Groups III and IV was recorded as 1 x 10(8) CFU, whereas the ID50 values in the Groups I and II without antibacterial coating were a hundred times lower at 1 x 10(6) CFU, respectively. The difference between the groups with and without antibacterial coating was statistically significant (p = 0.033). Using an antibacterial biodegradable PLLA coating on titanium plates, a significant reduction of infection rate in an in vitro and in vivo investigation could be demonstrated. For the first time, to our knowledge, we were able to show, under standardized and reproducible conditions, that an antiseptic coating leads to the same reduction in infection rate as an antibiotic coating. Taking the problem of antibiotic-induced bacterial resistance into consideration, we thus regard the antiseptic coating, which shows the same level of effectiveness, as advantageous.

Effect of mechanical and antiseptic therapy on peri-implant mucositis: an experimental study in monkeys

OBJECTIVES: This experiment was performed to evaluate clinically and histologically the effect of mechanical therapy with or without antiseptic therapy on peri-implant mucositis lesions in nine cynomolgus monkeys. MATERIAL AND METHODS: Two ITI titanium implants were inserted into each side of the mandibles. After 90 days of plaque control and soft tissue healing, a baseline clinical examination was completed. Peri-implant lesions were induced by placing silk ligatures and allowing plaque to accumulate for 6 weeks. The clinical examination was then repeated, and the monkeys were randomly assigned to three treatment groups: group A, mechanical cleansing only; group B, mechanical cleansing and local irrigation with 0.12% chlorhexidine (CHX) and application of 0.2% CHX gel; and group C, control, no treatment. The implants in treatment groups A and B were treated and maintained according to the assigned treatment for two additional months. At the end of the maintenance period, a final clinical examination was performed and the animals were sacrificed for biopsies. RESULTS: The mean probing depths (PD) values at mucositis were: 3.5, 3.7, and 3.4 mm, and clinical attachment level (CAL) = 3.8, 4.1, and 3.9 mm for treatment groups A, B and C, respectively. The corresponding values after treatment were: PD = 1.7, 2.1, and 2.5 mm, and CAL=2.6, 2.6, and 3.1 mm. ANOVA of mean changes (Delta) in PD and CAL after treatment showed no statistical difference between the treatment groups. Comparison of the mean changes in PD and CAL after treatment yielded statistical differences between the control and treatment groups P < 0.01. According to the t-test, no statistical difference was found between treatment groups A and B for the PD reduction but there was a significant difference for the CAL change, P < 0.03. Group A had significantly more recession and less CAL gain than group B. Non-parametric tests yielded no significant differences in modified plaque index (mPlI) and gingival index (GI) after treatment between both treatment groups. Frequencies and percent distributions of the mPlI and GI scores changed considerably for both treatment groups when compared with the changes in the control group after treatment. With regard to the histological evaluation, no statistical differences existed between the treatments for any linear measurement. The proportion of inflammation found in the mucosal tissues of the control implants was greater than the one found for both treatment groups, P < 0.01. More importantly, both treatment groups showed a similar low proportion of inflammation after 2 months of treatment. CONCLUSIONS: Within the limitations of this experiment, and considering the supportive plaque control rendered, it can be concluded that for pockets of 3-4 mm: (1) mechanical therapy alone or combined with CHX results in the clinical resolution of peri-implant mucositis lesions, (2) histologically, both treatments result in minimal inflammation compatible with health, and (3) the mechanical effect alone is sufficient to achieve clinical and histologic resolution of mucositis lesions.

The effect of a myocardial infarction on the normalized time-varying elastance curve

It has been suggested that the shape of the normalized time-varying elastance curve [E(n)(t(n))] is conserved in different cardiac pathologies. We hypothesize, however, that the E(n)(t(n)) differs quantitatively after myocardial infarction (MI). Sprague-Dawley rats (n = 9) were anesthetized, and the left anterior descending coronary artery was ligated to provoke the MI. A sham-operated control group (CTRL) (n = 10) was treated without the MI. Two months later, a conductance catheter was inserted into the left ventricle (LV). The LV pressure and volume were measured and the E(n)(t(n)) derived. Slopes of E(n)(t(n)) during the preejection period (alpha(PEP)), ejection period (alpha(EP)), and their ratio (beta = alpha(EP)/alpha(PEP)) were calculated, together with the characteristic decay time during isovolumic relaxation (tau) and the normalized elastance at end diastole (E(min)(n)). MI provoked significant LV chamber dilatation, thus a loss in cardiac output (-33%), ejection fraction (-40%), and stroke volume (-30%) (P < 0.05). Also, it caused significant calcium increase (17-fold), fibrosis (2-fold), and LV hypertrophy. End-systolic elastance dropped from 0.66 +/- 0.31 mmHg/microl (CTRL) to 0.34 +/- 0.11 mmHg/microl (MI) (P < 0.05). Normalized elastance was significantly reduced in the MI group during the preejection, ejection, and diastolic periods (P < 0.05). The slope of E(n)(t(n)) during the alpha(PEP) and beta were significantly altered after MI (P < 0.05). Furthermore, tau and end-diastolic E(min)(n) were both significantly augmented in the MI group. We conclude that the E(n)(t(n)) differs quantitatively in all phases of the heart cycle, between normal and hearts post-MI. This should be considered when utilizing the single-beat concept.

Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study

BACKGROUND AND OBJECTIVES: Data suggest that atorvastatin may be nephroprotective. This subanalysis of the Treating to New Targets study investigated how intensive lipid lowering with 80 mg of atorvastatin affects renal function when compared with 10 mg in patients with coronary heart disease. DESIGN, SETTING, PARTICIPANTS, ; MEASUREMENTS: A total of 10,001 patients with coronary heart disease and LDL cholesterol levels of <130 mg/dl were randomly assigned to double-blind therapy with 10 or 80 mg/d atorvastatin. Estimated GFR using the Modification of Diet in Renal Disease equation was compared at baseline and at the end of follow-up in 9656 participants with complete renal data. RESULTS: Mean estimated GFR at baseline was 65.6 +/- 11.4 ml/min per 1.73 m2 in the 10-mg group and 65.0 +/- 11.2 ml/min per 1.73 m2 in the 80-mg group. At the end of follow-up (median time to final creatinine measurement 59.5 months), mean change in estimated GFR showed an increase of 3.5 +/- 0.14 ml/min per 1.73 m2 with 10 mg and 5.2 +/- 0.14 ml/min per 1.73 m2 with 80 mg (P < 0.0001 for treatment difference). In the 80-mg arm, estimated GFR improved to > or = 60 ml/min per 1.73 m2 in significantly more patients and declined to < 60 ml/min per 1.73 m2 in significantly fewer patients than in the 10-mg arm. CONCLUSIONS: The expected 5-yr decline in renal function was not observed. Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related.

Effect of risk factors on complicated and uncomplicated ulcers in the TARGET lumiracoxib outcomes study

BACKGROUND ; AIMS: Selective cyclooxygenase-2 inhibitors were developed to reduce the gastrointestinal risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The Therapeutic Arthritis Research and Gastrointestinal Event Trial was the largest study to evaluate primarily the gastrointestinal safety outcomes of selective cyclooxygenase-2 inhibitors. Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial were used to identify risk factors and investigate the safety of lumiracoxib in subgroups. METHODS: Patients with osteoarthritis (age, >or=50 y) were randomized to receive lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg 3 times daily for 12 months. Events were categorized by a blinded adjudication committee. The primary end point was all definite or probable ulcer complications. RESULTS: For patients taking NSAIDs, factors associated with an increased risk of ulcer complications were age 65 years or older (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.48-3.59), previous history of gastrointestinal bleed or ulcer (HR, 3.61; 95% CI, 1.86-7.00), non-Caucasian racial origin (HR, 2.10; 95% CI, 1.35-3.27), and male sex (HR, 1.70; 95% CI, 1.08-2.68). With lumiracoxib, significant risk factors were age 65 years or older (HR, 3.18; 95% CI, 1.40-7.20), male sex (HR, 2.60; 95% CI, 1.25-5.40), non-Caucasian racial origin (HR, 2.16; 95% CI, 1.02-4.59), and concomitant aspirin use (HR, 2.89; 95% CI, 1.40-5.97). Increased risks in patients age 65 years and older were increased further if other risk factors were present. Lumiracoxib maintained an advantage over NSAIDs across all subgroups except aspirin use. CONCLUSIONS: Lumiracoxib was associated with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users.

The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up

BACKGROUND: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. PATIENTS AND METHODS: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. RESULTS: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). CONCLUSIONS: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.

Aperistaltic effect of hyoscine N-butylbromide versus glucagon on the small bowel assessed by magnetic resonance imaging

The aim of this prospective study was to compare the intraindividual aperistaltic effect of 40 mg hyoscine N-butylbromide (HBB/Buscopan) with that of 1 mg glucagon on small bowel motility by using magnetic resonance imaging (MRI). Ten healthy volunteers underwent two separate 1.5-T MRI studies (HBB/glucagon) after a standardized oral preparation with an aqueous solution of Gd-DOTA and ispaghula (Metamucil). A 2D T1-w GRE sequence was acquired (TR 2.7 ms/TE 1.3 ms, temporal resolution 0.25 s) before and after intravenous (i.v.) drug administration and motility was followed over 1 h. On the resulting images the cross-sectional luminal diameters were assessed and plotted over time. Baseline motility frequency, onset of aperistalsis, duration of arrest, reappearance of motility and return to normal motility were analysed. Significant differences regarding reliability and duration of aperistalsis were observed. In the HBB group aperistalsis lasted a mean of 6.8 +/- 5.3 min compared with 18.3 +/- 7 min after glucagon (p < 0.0001). In 50% of cases HBB did not accomplish aperistalsis, whereas glucagon always succeeded (p = 0.05). There were no significant differences in terms of baseline and end frequencies for the onset of aperistalsis (22.2 +/- 37.5 s HBB/13.4 +/- 9.2 s glucagon, p = 0.1), nor for the return to normal motility. Arrest of small bowel motion is achieved more reliably and lasts significantly longer after i.v. administration of 1 mg glucagon compared with 40 mg HBB.

The Effect of Open-Irrigated Radiofrequency Catheter Ablation of Atrial Fibrillation on Left Atrial Pressure and B-Type Natriuretic Peptide

Background Open-irrigated radiofrequency catheter ablation (oiRFA) of atrial fibrillation (AF) imposes a volume load and risk of pulmonary edema. We sought to assess the effect of volume administration during ablation on left atrial (LA) pressure and B-type natriuretic peptide (BNP). Methods LA pressure was measured via transseptal sheath at the beginning and end of 44 LA ablation procedures in 42 patients. BNP plasma levels were measured before and after 10 procedures. Results A median of 3,255 (interquartile range [IQR], 2,014)-mL saline was administered during the procedure. During LA ablation, the median fluid balance was +1,438 (IQR, 1,109) mL and LA pressure increased by median 3.7 (IQR, 5.9) mm Hg (P < 0.001). LA pressure did not change in the 19 procedures with furosemide administration (median ΔP = −0.3 [IQR, 7.1] mm Hg, P = 0.334). The correlation of LA pressure and fluid balance was weak (rs = 0.383, P = 0.021). BNP decreased in all four procedures starting in AF or atrial tachycardia and then converting to sinus rhythm (P = 0.068), and increased in all six procedures starting and finishing in sinus rhythm (P = 0.028). After ablation, symptomatic volume overload responding to diuresis occurred in three patients. Conclusions A substantial intravascular volume load during oiRFA can be absorbed with little change in LA pressure, such that LA pressure is not a reliable indicator of the fluid balance. Subsequent redistribution of the volume load imposes a risk after the procedure. Conversion to sinus rhythm may improve ability to acutely accommodate the volume load.