Global longitudinal strain: an early marker for cardiotoxicity in patients treated for breast cancer.

BACKGROUND: Patients treated with anthracyclines and trastuzumab are at increased risk of developing heart failure. Early diagnosis and treatment may prevent irreversible left ventricular (LV) dysfunction. This study investigates whether subclinical deterioration of global longitudinal strain (GLS) is a more reliable early predictor for LV dysfunction than three-dimensional (3D) LV ejection fraction (LVEF). METHODS: Adult patients receiving anthracyclines and trastuzumab for breast cancer who had serial echocardiographic follow-up were included in this retrospective study. The primary endpoint was the necessity to temporarily pause chemo- or immunotherapy due to declining LVEF (decline in 3D LVEF of > 10 percentage points to < 53%). Linear mixed-effects models were used to assess the longitudinal evolution of 3D LVEF and GLS over time. RESULTS: Fifty-one women were included, mean age 54 (50.5-57.6) years, with a total of 216 follow-up echocardiograms (mean follow-up 1.1 ± 0.45 years). GLS and 3D LVEF were significantly correlated (Spearman's rho: -0.36, p < 0.001). A decrease in GLS significantly predicted a lower LVEF on the subsequent echocardiogram [ß -0.6, 95% confidence interval (CI) (-1.0 to -0.2), p < 0.006]. Conversely, prior LVEF did not significantly predict GLS on the subsequent echocardiogram [ß -0.04, 95% CI -0.1 to -0.01, p = 0.12]. Nine patients reached the primary endpoint. On average, patients who reached the primary endpoint had a relative decrease of 15% GLS at day 205 and an absolute 10% decrease of LVEF to LVEF < 53% at day 235. DISCUSSION: GLS is able to identify subclinical LV dysfunction earlier than 3D LVEF measurement in women undergoing treatment for breast cancer with anthracyclines followed by trastuzumab.

Small dense LDL cholesterol in human subjects with different chronic inflammatory diseases.

BACKGROUND AND AIMS: Chronic inflammatory diseases (CID) are associated with a profound increase in cardiovascular (CV) risk resulting in reduced life expectancy. However, LDL-cholesterol is reported to be low in CID patients which is referred to as the "LDL paradoxon". The aim of the present study was to investigate whether LDL-particles in CID exhibit an increased content of the highly atherogenic small-dense LDL subfraction (sdLDL). METHODS AND RESULTS: In this prospective, single center, observational study we enrolled 141 patients with CID (RA n = 59, inflammatory bowel disease (IBD) n = 35, ankylosing spondylitis (SpA) n = 25, Psoriasis n = 22) in 2011 through 2013 to evaluate sdLDL levels before as well as 6 and 26 weeks after initiation of different anti-cytokine therapies (anti-TNFα, anti-IL-6R antibodies). sdLDL levels were compared to 141 healthy individuals in a case control design. Compared to healthy controls, all CID patients displayed a significantly higher sdLDL content within the LDL cholesterol fraction: RA 35.0 ± 9.2% (p < 0.001), SpA 42.5 ± 10.5% (p < 0.001), IBD 37.5 ± 7.1% (p < 0.001), Psoriasis 33.6 ± 4.6% (p < 0.01). Furthermore, the sdLDL/LDL ratio was significantly higher in male compared to female RA subjects (p < 0.05). Neither anti-TNFα nor anti-IL6R medication altered sdLDL levels despite a significant improvement of disease activity. CONCLUSION: In several different chronic inflammatory disease entities, LDL-cholesterol is shifted toward a pro-atherogenic phenotype due to an increased sdLDL content which might in part explain the LDL paradoxon. Since premature CV disease is a major burden of affected patients, specifically targeting lipid metabolism should be considered routinely in clinical patient care. CLINICAL TRIALS: Registration at German Clinical Trial Register (DRKS): DRKS00005285.

Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: We report the maternal and foetal outcomes at birth and after 6 months in a cohort of pregnant women with hypertrophic cardiomyopathy (HCM). Although most women with HCM tolerate pregnancy well, there is an increased risk of obstetric and cardiovascular complications. METHODS AND RESULTS: All pregnant women with HCM entered into the prospective worldwide Registry of Pregnancy and Cardiac disease (ROPAC) were included in this analysis. The primary endpoint was a major adverse cardiovascular event (MACE), which included death, heart failure (HF), thrombo-embolic event, and arrhythmia. Baseline and outcome data were analysed and compared for patients with MACE vs. without MACE and for patients with obstructive HCM vs. non-obstructive HCM. Sixty pregnant women (mean age 30.4 ± 6.0 years) with HCM (41.7% obstructive) were included. No maternal mortality occurred in this cohort. In 14 (23%) patients at least one MACE occurred: 9 (15.0%) HF and 7 (12%) an arrhythmia (6 ventricular and 1 atrial fibrillation). MACE occurred most commonly during the 3rd trimester and postpartum period. In total, 3 (5.0%) women experienced foetal loss. Women with MACE had a higher rate of emergency Caesarean delivery for cardiac reasons (21.4% vs. 0%, P = 0.01). No significant differences in pregnancy outcome were found between women with obstructive and non-obstructive HCM. NYHA functional class of ≥II and signs of HF before pregnancy, were associated with MACE. CONCLUSION: Although most women with HCM tolerated pregnancy well, cardiovascular complications were not uncommon and predicted by pre-pregnancy status facilitating pre-pregnancy counselling and targeted antenatal care.

Insights into the genetic architecture of morphological traits in two passerine bird species.

Knowledge about the underlying genetic architecture of phenotypic traits is needed to understand and predict evolutionary dynamics. The number of causal loci, magnitude of the effects and location in the genome are, however, still largely unknown. Here, we use genome-wide single-nucleotide polymorphism (SNP) data from two large-scale data sets on house sparrows and collared flycatchers to examine the genetic architecture of different morphological traits (tarsus length, wing length, body mass, bill depth, bill length, total and visible badge size and white wing patches). Genomic heritabilities were estimated using relatedness calculated from SNPs. The proportion of variance captured by the SNPs (SNP-based heritability) was lower in house sparrows compared with collared flycatchers, as expected given marker density (6348 SNPs in house sparrows versus 38 689 SNPs in collared flycatchers). Indeed, after downsampling to similar SNP density and sample size, this estimate was no longer markedly different between species. Chromosome-partitioning analyses demonstrated that the proportion of variance explained by each chromosome was significantly positively related to the chromosome size for some traits and, generally, that larger chromosomes tended to explain proportionally more variation than smaller chromosomes. Finally, we found two genome-wide significant associations with very small-effect sizes. One SNP on chromosome 20 was associated with bill length in house sparrows and explained 1.2% of phenotypic variation (VP), and one SNP on chromosome 4 was associated with tarsus length in collared flycatchers (3% of VP). Although we cannot exclude the possibility of undetected large-effect loci, our results indicate a polygenic basis for morphological traits.

Differences and similarities between mothers and fathers of premature children: a qualitative study of parents' coping experiences in a neonatal intensive care unit.

BACKGROUND: The aim of this study was to explore and describe the coping experiences of parents to children admitted to a neonatal unit. METHODS: A qualitative research approach was chosen, using in-depth interviews with eight fathers and eight mothers. RESULTS: The main findings were that parents with previous complicated births had more difficulties in coping compared to those parents with no experience with complications. Coping seemed easier where parents' opinions were heard regarding their baby's care and when both parents were present in the neonatal intensive care unit (NICU). The main similarities between mothers and fathers were the reluctance to speak their opinions on childcare, and both experienced a sense of alienation and problems in bonding with the baby. They also needed a limitation on the number of visitors in the NICU. Differences between mothers and fathers were that fathers tried hard to be the strong partner in the relationship, and were more concerned with the mother if she was seriously ill postpartum, while mothers were more concerned for their baby. Mothers' postpartum period was felt as more stressful if the father was not present, but mothers were also better at welcoming support from the health personnel. CONCLUSION: This study highlights the parent's coping experiences in NICUs. Coping seemed easier where parents' opinions were heard. Nurses in the NICU should take the former experiences of the parents into consideration when nursing in the NICU and planning for discharge.

The wingless-related integration site-5a/secreted frizzled-related protein-5 system is dysregulated in human sepsis.

Sepsis and type 2 diabetes exhibit insulin resistance as a common phenotype. In type 2 diabetes we and others have recently provided evidence that alterations of the proinflammatory wingless-related integration site (wnt)-5a/anti-inflammatory secreted frizzled-related protein (sFRP)-5 system are involved in the pathogenesis of insulin resistance. The aim of the present study was to investigate whether this novel cytokine system is dysregulated in human sepsis, which may indicate a potential mechanism linking inflammation to metabolism. In this single-centre prospective observational study, critically ill adult septic patients were examined and proinflammatory wnt5a and wnt5a inhibitor sFRP5 were measured in serum samples by enzyme-linked immunosorbent assay (ELISA) at admission to the intensive care unit (ICU) and 5 days later. Sixty sepsis patients were included, and 30 healthy individuals served as controls. Wnt5a levels were found to be increased significantly in septic patients compared to healthy controls (2·21 ± 0·33 versus 0·32 ± 0·03 ng/ml, P < 0·0001). In contrast, sFRP5 was not altered significantly in septic patients (19·72 ± 3·06 versus 17·48 ± 6·38 ng/ml, P = 0·07). On admission to the ICU, wnt5a levels exhibited a significant positive correlation with the leucocyte count (rs = 0·3797, P = 0·004). Interestingly, in patients recovering from sepsis, wnt5a levels declined significantly within 5 days (2·17 ± 0·38-1·03 ± 0·28 ng/ml, P < 0·01). In contrast, if sepsis was worsening, wnt5a levels increased in the same time-period by trend (2·34 ± 0·59-3·25 ± 1·02 ng/ml, P > 0·05). sFRP5 levels did not change significantly throughout the study period. The wnt5a/sFRP5 system is altered in human sepsis and might therefore be of interest for future studies on molecular pathophysiology of this common human disease.

Peripartum cardiomyopathy: Euro Observational Research Program.

Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology remains poorly understood, hence treatment options are limited and possibly harmful to the foetus. Furthermore, geographical incidence varies greatly and little is known about the incidence in Western countries. To gain further understanding of the pathophysiology and incidence of peripartum cardiomyopathy, the European Society of Cardiology initiated a study group to implement a registry. This review provides an overview of current insights into peripartum cardiomyopathy, highlights the need for such a registry and provides information about this Euro Observational Research Program.

Ankle-brachial index predicts stroke in the general population in addition to classical risk factors.

BACKGROUND: Predictors of future stroke events gain importance in vascular medicine. Herein, we investigated the value of the ankle-brachial index (ABI), a simple non-invasive marker of atherosclerosis, as stroke predictor in addition to established risk factors that are part of the Framingham risk score (FRS). METHODS: 4299 subjects from the population-based Heinz Nixdorf Recall study (45-75 years; 47.3% men) without previous stroke, coronary heart disease or myocardial infarcts were followed up for ischemic and hemorrhagic stroke events over 109.0±23.3 months. Cox proportional hazard regressions were used to evaluate ABI as stroke predictor in addition to established vascular risk factors (age, sex, systolic blood pressure, LDL, HDL, diabetes, smoking). RESULTS: 104 incident strokes (93 ischemic) occurred (incidence rate: 2.69/1000 person-years). Subjects suffering stroke had significantly lower ABI values at baseline than the remaining subjects (1.03±0.22 vs. 1.13±0.14, p<0.001). In a multivariable Cox regression, ABI predicted stroke in addition to classical risk factors (hazard ratio=0.77 per 0.1, 95% confidence interval=0.69-0.86). ABI predicted stroke events in subjects above and below 65 years, both in men and women. ABI specifically influenced stroke risk in subjects belonging to the highest (>13%) and intermediate (8-13%) FRS tercile. In these subjects, stroke incidence was 28.13 and 8.13/1000 person-years, respectively, for ABI<0.9, compared with 3.97 and 2.07/1000 person-years for 0.9≤ABI≤1.3. CONCLUSIONS: ABI predicts stroke in the general population, specifically in subjects with classical risk factors, where ABI identifies subjects at particularly high stroke risk.

Effects of ACTH and cAMP on steroidogenic acute regulatory protein and P450 11beta-hydroxylase messenger RNAs in rainbow trout interrenal cells: relationship with in vitro cortisol production.

Steroidogenic acute regulatory protein (StAR) transfers cholesterol over the inner mitochondrial membrane, thereby making the molecule available for cholesterol side-chain cleavage enzyme, which carries out the first conversion in the steroidogenic pathway. In mammals, StAR controls this rate limiting step in steroidogenesis, and both StAR protein and StAR mRNA levels become rapidly elevated in response to tropic hormone stimulation. The relationship between StAR gene expression and steroid production in fish has not yet been well explored. We investigated the relationship between adrenocorticotropic hormone (ACTH)- and cAMP-stimulated cortisol production in vitro and levels of StAR transcripts in interrenal cells of rainbow trout. To assess the effect of ACTH on mRNA levels of a downstream steroidogenic enzyme, we also investigated the effects of ACTH on transcripts encoding 11beta hydroxylase (P450 11beta). In a series of experiments, juvenile rainbow trout head kidney tissue containing interrenal cells was incubated with either ACTH or dibutyryl cyclic AMP (dbcAMP). Cortisol in incubation media were measured by radioimmunoassay and total RNA was isolated from the tissue for Northern analysis or for quantitative real-time PCR. Incubation of tissue with 150 ng/mL ACTH for 1-18 h induced a progressive increase in cortisol accumulation in media, but StAR mRNA levels increased modestly and mostly insignificantly over 18 h, irrespective of treatment. Exposure of tissue for 18 h to 5, 150, 500 or 1,500 ng ACTH/mL resulted in a strong increase in cortisol production, with a peak response (15-fold increase over controls) achieved with 150 ng/mL ACTH. Although there was a trend towards a dose-response effect, mean StAR mRNA levels were only significantly affected by the highest concentration of ACTH used (1,500 ng/mL), which induced a less than 2-fold increase in StAR transcripts. However, there was a significant linear relationship between StAR mRNA levels and ACTH-induced cortisol accumulation in media (p<0.001, r(2)=0.55). Incubation of tissue with 5mM dbcAMP for 6 or 18 h induced large increases in cortisol accumulation in media over controls, but had no significant effect on StAR mRNA levels. By contrast, ACTH induced a clear dose-dependent increase in P450 11beta transcripts, with 150 ng/mL ACTH inducing an 8-fold increase in levels compared to control; nonetheless, only a weak correlation existed between transcript levels and ACTH-induced cortisol secretion (p<0.003, r(2)=0.26). Thus, despite the relatively high degree of conservation of StAR proteins in vertebrates, we have been unable to demonstrate that a rapid, acute increase in transcription of the StAR gene is the dominant mechanism supporting flow of cholesterol to the mitochondria during acute increases in cortisol production in rainbow trout. The strong stimulation of P450 11beta gene transcription by ACTH probably enhances biosynthetic capacity during longer term chronic ACTH stimulation.

High-dose diclofenac for postoperative analgesia after elective caesarean section in regional anaesthesia.

Although the use of non-steroidal anti-inflammatory drugs (NSAIDs) is well established in the postoperative setting, their use after caesarean sections is still controversial. In a randomised, double-blinded, placebo controlled study we have estimated the opioid-sparing effect of diclofenac suppositories after elective caesarean sections in spinal anaesthesia. Eighty-two women ASA class I or II scheduled for caesarean section were randomised to receive either diclofenac suppositories 100 mg or placebo every 12 h after the operation. The diclofenac group (n = 40) consumed significantly less morphine in the postoperative period (14.0 +/- 1.5 mg in 32 h) compared with the placebo group (21.5 +/- 1.6 mg in 32 h, P < 0.05). The average level of postoperative pain as estimated by a visual analogue scale (VAS) and a verbal scale tended to be lower in the diclofenac group, but this was not significant. There were no differences in demographic data, perioperative bleeding, side-effects or discharge time between the groups. Diclofenac suppositories 100 mg given twice daily after caesarean section are opioid sparing.

Bupivacaine 2.5 mg/ml versus bupivacaine 0.625 mg/ml and sufentanil l microg/ml with or without epinephrine 1 microg/ml for epidural analgesia in labour.

We have compared three different methods of epidural analgesia in labour, bupivacaine 2.5 mg/ml (group B), bupivacaine 0.625 mg/ml + sufentanil 1 microg/ml (group BS) and bupivacaine 0.625 mg/ml + sufentanil 1 microg/ml + epinephrine 1 microg/ml (group BSE). One hundred and forty parturients with a singleton fetus with cephalic presentation were randomly allocated to one of the three groups. Group BSE had significantly less pain than groups B and BS. Group B had a significantly higher degree of motor blockade assessed on the Bromage scale. Significantly, more women in group B required urinary bladder catheterization than in the two other groups and they also had significantly less urge to push during active delivery. The incidence of mild pruritus was 18% in group BS and 36% in group BSE. The frequency of instrumental delivery and caesarean section was low (12% and 6.4%, respectively) with no significant differences between the groups. All women were highly satisfied with the method of analgesia and 97% would prefer the same kind of pain alleviation at the next delivery. We conclude that epidural analgesia with low-dose bupivacaine and sufentanil is as good an analgesic method as high-dose bupivacaine. Addition of low-dose epinephrine improves the analgesia.

[Obstetric analgesia in Norwegian hospitals]. / Smertelindring ved fødsler i norske sykehus.

We report the results of a questionnaire sent to anaesthetists and midwives on the use of obstetric analgesia and anaesthesia in Norwegian hospitals in 1996. 95% of the 49 hospitals involved responded to the questionnaire, representing a total of 56,884 births. The use of epidural analgesia in labour varied from 0 to 25% in the different hospitals with a mean value of 15%. Epidural analgesia was much more widely used in university and regional hospitals than in local hospitals (p < 0.001). Five of the local hospitals did not offer epidural analgesia during labour at all. The combination of low-dose local anaesthetic and an opioid (either sufentanil or fentanyl) had not been introduced in nine of the hospitals (20%). The optimal use of epidural analgesia to relieve labour pain was judged to be more frequent by the anaesthetists than by the midwives (19% versus 11%, p < 0.01). In response to what factors limited the frequency of epidural analgesia, the anaesthetists specified factors related to the attitude of the midwife, and the midwives specified factors related to the anaesthetist. Only five of the hospitals provided written information on the various analgesic methods that could be employed during labour. The majority of midwives considered the analgesic methods employed on their maternity ward to be good or excellent. The frequency of Caesarean section was 12%; spinal anaesthesia was used in 55%, epidural anaesthesia in 17%, and general anaesthesia in 28% of the cases.

Comparison of extracellular matrix in human osteosarcomas and melanomas growing as xenografts, multicellular spheroids, and monolayer cultures.

BACKGROUND: The composition of extracellular matrix in human xenografts and spheroids were compared with the monolayer cultures from which they originated. Collagen I, fibronectin, acetylglucosamine, and acetylgalactosamine were quantitated in two osteosarcomas and one melanoma. METHODS: Using fluorescence microscopy, extracellular matrix constituents in the cellular and extracellular compartment were measured, whereas flow cytometry measured the extracellular matrix constituents bound to the cell surface as well as the total cellular amount including intracellular and surface bound constituents. RESULTS: The fluorescence microscopy measurements, demonstrated that the xenografts contained more or equal quantities of the extracellular matrix constituents compared with the spheroids. Flow cytometric measurements of total cellular amounts, showed that cells from xenografts usually contained more or equal amounts as the spheroid cells, which contained less or equal amounts as the monolayer cells. The surface expression of the extracellular matrix constituents increased or there were no significant differences, comparing cells grown as monolayers, spheroids, and xenografts. CONCLUSIONS: The data shows that multicellular spheroids being an in vitro system of intermediate complexity between monolayer cultures and tumours, contain an extracellular matrix corresponding to some degree to this intermediate position.

In-vitro photocytotoxicity of lysosomotropic immunoliposomes containing pheophorbide a with human bladder carcinoma cells.

Pheophorbide a is a photocytotoxic agent. To develop a tissue-specific, intracellularly targeted photoactive system, pheophorbide a was incorporated into immunoliposomes coated with a monoclonal antibody (T-43) directed against the T-24 bladder tumor cell line. The efficacy of this system was studied in vitro using the human bladder tumor cell line MGH-U1. Uptake and localization were determined by the fluorescence of the immunoliposome markers within biochemically resolved subcellular components. The results demonstrate localization of the immunoliposome markers within the lysosomes of the tumor cells. Specific monoclonal antibody enhancement of the immunoliposomes uptake by MGH-U1 cells was demonstrated by the use of soluble T-43 monoclonal antibody as a competitive inhibitor. Pheophorbide-a-loaded immunoliposomes were shown to be photocytotoxic towards MGH-U1 cells at concentrations equivalent to photosensitizer at 500 ng ml-1. Treated cells, when protected from light, showed no cytotoxicity. These results demonstrate that uptake of pheophorbide-a-containing immunoliposomes by target cells and subsequent delivery to the lysosomes cause photoactivated killing of tumor cells. The utilization of immunoliposomes for intracellular lysosomal targeting of photoactive drugs to tumor cells constitutes a potentially valuable approach to photodynamic therapeutics.

Three cases of acute hepatitis E virus infection imported into Norway.

We report 3 cases of acute hepatitis E virus (HEV) infection imported from Asia. All 3 patients had fever and upper abdominal discomfort preceding jaundice which lasted 2-3 weeks with maximum bilirubin levels of 141-254 mmol/l. The ALT values peaked between 1,347 and 3,690 U/l. Both values normalized within 1-2 months. During the acute phase of the disease, all patients had high levels of IgG and IgM antibodies against HEV (anti-HEV) recombinant and synthetic peptides. The duration of the anti-HEV IgM was about 1-2 months.

Metabolically convertible lipophilic derivatives of pH-sensitive amphipathic photosensitizers.

We propose the use of acetoxymethyl esters of pH-sensitive amphipathic photosensitizers (PS) for photodynamic therapy (PDT). These compounds may be applicable for PDT involving endocytosis of lipophilic carriers leading to lysosomal uptake of the esterified PS by target cells. Partial and/or total enzymatic de-esterification may result in the extralysosomal distribution of the photoactive agents, possibly culminating in a multisite photochemical response. We report here the synthesis and properties of chlorin e6 triacetoxymethyl ester (CAME) and pheophorbide a acetoxymethyl ester (PAME). Chlorin e6 and pheophorbide a are photocytotoxic chlorins that possess free carboxylate groups and exhibit optimum wavelengths of excitation substantially red shifted relative to hematoporphyrin derivative. Acetoxymethyl esterification of chlorin e6 and pheophorbide a was accomplished with bromomethyl acetate. High-performance liquid chromatography allowed for the purification of PAME, in 87% purity, and CAME, in 63% yield and 94% purity, as well as the detection of the presumed mono- and diesters of chlorin e6 as transient intermediates in the synthesis of CAME. The ultraviolet-visible absorption, fluorescence excitation and emission, NMR and mass spectra of the chlorin e6 triester are consistent with those expected for CAME. The pH-sensitive amphipathicity of pheophorbide a and chlorin e6 but not CAME was demonstrated using a water/1-octanol partition assay. The production of pheophorbide a from PAME and the sequential formation of the di- and monoesters and free chlorin e6 from CAME, by the action of lysosomal esterases obtained from cancer cells, demonstrate the potential of cellular enzymes to convert the lipophilic esters to pH-sensitive amphipathic PS.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of polycyclic aromatic hydrocarbons in urine from coke-oven workers with a radioimmunoassay.

Considerable amounts of polycyclic aromatic hydrocarbons (PAH) are present in the workplace. In order to obtain a better understanding of the occupational hazards connected with PAH exposure various biomonitoring methods need to be applied. The level of PAH in urine collected from coke-oven workers has been measured by a recently developed radioimmunoassay. A significant correlation between estimated exposure levels for PAH and urinary levels of PAH was observed. During the winter period the control group was found to have an average concentration of 0.44 ng PAH/mmol creatinine, whereas the low, medium and high exposure groups contained 0.44, 0.71 and 0.85 ng PAH/mmol creatinine respectively. The urinary PAH level in the samples collected during the summer period was higher, i.e. 0.81, 0.94 and 1.10 ng PAH/mmol creatinine, for the low, medium and high exposure groups. Furthermore, a correlation was also observed between smoking and levels of urinary PAH. We conclude that this radioimmunoassay may be suitable as a simple and sensitive routine assay for monitoring individuals exposed to PAH.

Absorption of paracetamol from suppositories in geriatric patients with fecal accumulation in the rectum.

The bioavailability of paracetamol from suppositories was studied in 16 geriatric in-patients in stable clinical condition; 9 had significant amounts of feces in the rectum. Rectal accumulation of feces reduced the peak plasma paracetamol concentration by 32% (p = 0.05) and the AUC0-8h by 27% (p = 0.04). The peak concentration, however, appeared earlier among patients with rectal accumulation of feces. Compared to findings in 6 healthy young controls, geriatric patients had higher plasma concentrations of the main paracetamol metabolites.

A monoclonal antibody against PDGF B-chain inhibits PDGF-induced DNA synthesis in C3H fibroblasts and prevents binding of PDGF to its receptor.

A monoclonal antibody (MAb 6D11) against platelet-derived growth factor (PDGF) was studied. We found that the MAb 6D11 in concentrations equimolar to PDGF blocked the [3H]thymidine incorporation in C3H/10T1/2 C18 fibroblasts stimulated by PDGF B-B and PDGF A-B. This inhibition was overcome by high doses of PDGF. The [3H]thymidine incorporation stimulated by other growth factors (aFGF, bFGF and bombesin) was not inhibited by the antibody. The MAb 6D11 blocked receptor binding of PDGF B-B, but not PDGF A-A. These findings suggest that the MAb 6D11 abolishes PDGF-induced DNA synthesis by blocking PDGF receptor binding. In this communication we demonstrate an isoform-specific monoclonal antibody against PDGF.