Search

Despite many statistical applications brush the question of data quality aside, it is a fundamental concern inherent to external data collection. In this paper, data quality relates to the confidence one can have about the covariate values in a regression framework. More precisely, we study how to integrate the information of data quality given by a (n × p) -matrix, with n the number of individuals and p the number of explanatory variables. In this view, we suggest a latent variable model that drives the generation of the covariate values, and introduce a new algorithm that takes all these information into account for prediction. Our approach provides unbiased estimators of the regression coefficients, and allows to make predictions adapted to some given quality pattern. The usefulness of our procedure is illustrated through simulations and real-life applications. Kindly check and confirm whether the corresponding author is correctly identified.Yes [ABSTRACT FROM AUTHOR]

Objectives: Operators performing fetal growth scans are usually aware of the gestational age of the pregnancy, which may lead to expected-value bias when performing biometric measurements. We aimed to evaluate the incidence of expected-value bias in routine fetal growth scans and assess its impact on standard biometric measurements.Methods: We collected prospectively full-length video recordings of routine ultrasound growth scans coupled with operator eye tracking. Expected value was defined as the gestational age at the time of the scan, based on the estimated due date that was established at the dating scan. Expected-value bias was defined as occurring when the operator looked at the measurement box on the screen during the process of caliper adjustment before saving a measurement. We studied the three standard biometric planes on which measurements of head circumference (HC), abdominal circumference (AC) and femur length (FL) are obtained. We evaluated the incidence of expected-value bias and quantified the impact of biased measurements.Results: We analyzed 272 third-trimester growth scans, performed by 16 operators, during which a total of 1409 measurements (354 HC, 703 AC and 352 FL; including repeat measurements) were obtained. Expected-value bias occurred in 91.4% of the saved standard biometric plane measurements (85.0% for HC, 92.9% for AC and 94.9% for FL). The operators were more likely to adjust the measurements towards the expected value than away from it (47.7% vs 19.7% of measurements; P < 0.001). On average, measurements were corrected by 2.3 ± 5.6, 2.4 ± 10.4 and 3.2 ± 10.4 days of gestation towards the expected gestational age for the HC, AC, and FL measurements, respectively. Additionally, we noted a statistically significant reduction in measurement variance once the operator was biased (P = 0.026). Comparing the lowest and highest possible estimated fetal weight (using the smallest and largest biased HC, AC and FL measurements), we noted that the discordance, in percentage terms, was 10.1% ± 6.5%, and that in 17% (95% CI, 12-21%) of the scans, the fetus could be considered as small-for-gestational age or appropriate-for-gestational age if using the smallest or largest possible measurements, respectively. Similarly, in 13% (95% CI, 9-16%) of scans, the fetus could be considered as large-for-gestational age or appropriate-for-gestational age if using the largest or smallest possible measurements, respectively.Conclusions: During routine third-trimester growth scans, expected-value bias frequently occurs and significantly changes standard biometric measurements obtained. © 2019 the Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This paper presents an in-depth study, using wall-resolved Large-Eddy Simulation (wrLES), of a high Reynolds number airfoil in a near-stall condition. The flow around the NACA4412 airfoil, a widely used test case for turbulence modeling validation, is computed at Reynolds number Re = 1.64 × 106 and angle of attack α = 12∘. In the first part of the paper, the results are compared to previous experimental and numerical results, showing close agreement with both. In order to aid wall-model development, the second part of the paper characterizes the effect of the adverse pressure-gradient (APG) on the turbulent boundary layer development, and evaluates different wall-models in an a priori manner. It appears that the simple models, which assume an equilibrium flow, provide a better match to the mean flow velocity than allegedly more advanced models. The study reveals also that the often used simplification of the “Two-Layer Model”(TLM) that takes the pressure-gradient into account but neglects the convective terms, is not adequate. This simplification applied to the TLM indeed leads to a higher error than the simple equilibrium models. Therefore, it is argued that if the convective terms are neglected, the pressure-gradient term needs to be neglected as well. [ABSTRACT FROM AUTHOR]

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose. [ABSTRACT FROM AUTHOR]

Growth disorders resulting in short stature are caused by a wide range of underlying pathophysiological processes. To improve height many of these conditions are treated with recombinant human growth hormone (rhGH). However, substantial inter-individual variability in growth response both in the short and long-term is recognised. Over the last decade, disease-specific growth prediction models have been developed that the clinician can use to define a child's potential response to rhGH and to optimise starting and maintenance doses of rhGH. These models, however, are not able to predict all the variations in treatment response. There has, therefore, been recent interest in using genetic information to contribute to the evaluation of responses to rhGH, including high-throughput technologies for assessing DNA markers (genome) and mRNA transcripts (transcriptome) as pharmacogenomic tools. This review will focus on how these pharmacogenomic approaches are being applied to growth disorders. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Individual sensitivity to recombinant human GH (r-hGH) is variable. Identification of genetic factors contributing to this variability has potential use for individualization of treatment. The objective of this study was to identify genetic markers and gene expression profiles associated with growth response on r-hGH therapy in treatment-naïve, prepubertal children with GH deficiency (GHD) or Turner syndrome (TS). Design: A prospective, multicenter, international, open-label pharmacogenomic study. Methods: The associations of genotypes in 103 growth- and metabolism-related genes and baseline gene expression profiles with growth response to r-hGH (cm/year) over the first year were evaluated. Genotype associations were assessed with growth response as a continuous variable and as a categorical variable divided into quartiles. Results: Eleven genes in GHD and ten in TS, with two overlapping between conditions, were significantly associated with growth response either as a continuous variable (seven in GHD, two in TS) or as a categorical variable (four more in GHD, eight more in TS). For example, in GHD, GRB10 was associated with high response (≥Q3; P=0.0012), while SOS2 was associated with low response (≤Q1; P=0.006), while in TS, LHX4 was associated with high response (P=0.0003) and PTPN1 with low response (P=0.0037). Differences in expression were identified for one of the growth responseassociated genes in GHD (AKT1) and for two in TS (KRAS and MYOD1). Conclusions: Carriage of specific growth-related genetic markers is associated with growth response in GHD and TS. These findings indicate that pharmacogenomics could have a role in individualized management of childhood growth disorders. [ABSTRACT FROM AUTHOR]

Background: Optimal dosage for growth hormone (GH) therapy in short, prepubertal children born small for gestational age (SGA) is controversial. Methods: SGA OPTIMIS (NCT00249821) is a multicenter, open-label, parallel-group, pilot study of short children born SGA who had received recombinant human GH (r-hGH) (57 μg/kg/day) for 3 years. Children were randomized 1:1 to receive either 57 or 35 μg/kg/day r-hGH during year 4. The primary endpoint was height gain during year 4. Results: 22 children were randomized (57 μg/kg/day, n = 10; 35 μg/kg/day, n = 12) and 21 completed the fourth year of therapy; 22 were included in efficacy analyses. During year 4, mean [standard deviation (SD)] height velocity was 6.4 (1.4) and 4.4 (1.2) cm/year (p = 0.001) and height velocity SD score (SDS) was 0.3 (0.3) and -0.1 (0.2) (p = 0.002) in the 57 and 35 μg/kg/day groups, respectively. The 57 μg/kg/day group continued with catch-up growth, had a significantly higher mean weight gain (p = 0.015) and significantly higher insulin-like growth factor-I levels at 12 months (p = 0.038). Five treatment-emergent adverse events were reported; none was serious or caused study withdrawal. Conclusions: Children who continued receiving 57 μg/kg/day r-hGH in year 4 had significantly greater height gain than those receiving 35 μg/kg/day r-hGH. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Children born small for gestational age may demonstrate continued growth retardation, resulting in persistent short stature. In the majority of the cases, this is linked with abnormal growth hormone secretion and also abnormal insulin-like growth factor levels. This review discusses the treatment of such children with recombinant human growth hormone. It illustrates the importance of starting therapy early, the dose-dependent response, and the advantages of continuous therapy and describes safety considerations. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and purpose:The H1 receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood-brain barrier in any delay in brain H1RO.Experimental approach:Concentration-time profiles in plasma and brain were obtained after 0.1 and 1 mg kg−1 oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]-mepyramine and, in the periphery, by measuring the degree of inhibition of histamine-induced contractions of isolated guinea pig ileum.Key results:The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, Kp=0.06-0.08), higher tmax (2-4 h vs 1-1.5 h) and longer terminal half-life (4-5.6 h vs 2.1-2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg−1 were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations.Conclusions and Implications:This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.British Journal of Pharmacology (2007) 151, 1129–1136; doi:10.1038/sj.bjp.0707318; published online 11 June 2007 [ABSTRACT FROM AUTHOR]

We characterized the histamine H1 receptor agonism of various histaprodifen derivatives in guinea pig isolated ileum and trachea in comparison with histamine. Based on their affinity (calculated pKA values for ileum and trachea, respectively), the compounds were ranked as follows: suprahistaprodifen (8.31/8.08) > Nα-(4-phenylbutyl)histaprodifen (7.22/5.93) ≥ histamine (5.79/5.19) &thkap; methylhistaprodifen (5.57/6.07). Based on their efficacy (calculated τ values for ileum and trachea, respectively), the compounds were ranked as follows: methylhistaprodifen (37.67/2.50) > histamine (5.64/1.80) > suprahistaprodifen (1.63/1.42) ≥ Nα-(4-phenylbutyl)histaprodifen (0.083/1.54). In the ileum, histamine and methylhistaprodifen showed a high histamine H1 receptor reserve while suprahistaprodifen and Nα-(4-phen-ylbutyl)histaprodifen are devoid of any histamine H1 receptor reserve. On the trachea, no histamine H1 receptor reserve was demonstrable with the four tested agonists. The kinetic of contraction/relaxation of the ileum was faster with histamine and methylhistaprodifen than with suprahistaprodifen and Nα-(4-phenylbutyl)histaprodifen. Histamine contracted the trachea faster than histaprodifen derivatives. Levocetirizine antagonized contractions induced by histamine and histaprodifen derivatives in both tissues. The differences observed in the calculated pA2 (7.60–8.29) and/or pD′2 values (6.28–7.90) depending on the tissue and/or the agonist are discussed. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary objective GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI ). The short-term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short-term administration of two ‘physiological’ (‘lowest’ dose: 0·0017 mg/kg/day; ‘low’ dose: 0·0033 mg/kg/day) with two ‘supraphy-siological’ (‘high’ dose: 0·010 mg/kg/day; ‘highest’ dose: 0·025 mg/kg/day) GH doses on S I , β-cell function, IGF-1 and IGFBPs -1 and -3 in a group of GHD adults. patients and methods Thirteen GHD adults were recruited (seven men, aged 23–63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7-day treatment phase. Fasting blood samples were collected daily (days 1–8), and SI and β-cell function were calculated using the homeostasis model assessment (HOMA). results All four GH doses increased IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio, and decreased IGFBP-1 from day 3 onwards (P < 0·05). The highest dose increased fasting glucose ( P < 0·001), insulin ( P < 0·001) and β-cell function ( P < 0·001), but decreased S I ( P < 0·001). The high and low doses did not modify fasting glucose and insulin, S I or β-cell function, whereas the lowest dose enhanced β-cell function ( P < 0·05). The overall increase in the GH dose increased IGF-1, IGFBP-3, fasting glucose and insulin ( P < 0·001), demonstrated a positive correlation with the final change in fasting glucose ( r = 0·5, P < 0·05) and insulin ( r = 0·8, P < 0·001) and a negative correlation with final S... [ABSTRACT FROM AUTHOR]

A method for detecting full layout facsimile duplicates based on radial pixel densities is proposed. It caters for facsimiles, including text and/or graphics. Pages may be positioned upright or inverted on the scanner bed. The method is not dependent on the computation of text skew or text orientation. Using a database of original documents, 92% of non-duplicates and upright duplicates as well as 89% of inverted duplicates could be correctly identified. The method is vulnerable to double scanning. This occurs when documents are copied using a photocopier and the copies are subsequently transmitted using a facsimile machine. [ABSTRACT FROM AUTHOR]

Acromicric dysplasia is a rare bone dysplasia characterised by short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and characteristic x ray abnormalities of the hands. Only a very small number of children with this condition have been reported so far. Here we report on a series of 22 patients including 10 boys and 12 girls with acromicric dysplasia. Length was normal at birth and height fell progressively off the centiles postnatally. The mean adult height was 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs were short and OFC was normal. Intelligence was normal and mild dysmorphic features were noted. Other occasional features included well developed muscles, a hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complication, and spine abnormalities. Long term follow up showed that facial dysmorphism was less obvious in adults and that carpal tunnel syndrome was frequent in older patients. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x ray abnormalities. No major complications, such as cardiac disease or major orthopaedic problems, occurred in the course of the disease. The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance. [ABSTRACT FROM AUTHOR]

The aim of this six-centre, split-sample study was to compare ThinPrep fluid-based cytology to the conventional Papanicolaou smear. Six cytopathology laboratories and 35 gynaecologists participated. 5428 patients met the inclusion criteria (age > 18 years old, intact cervix, informed consent). Each cervical sample was used first to prepare a conventional Pap smear, then the sampling device was rinsed into a PreservCyt vial, and a ThinPrep slide was made. Screening of slide pairs was blinded (n = 5428). All non-negative concordant cases (n = 101), all non-concordant cases (n = 206), and a 5% random sample of concordant negative cases (n = 272) underwent review by one independent pathologist then by the panel of 6 investigators. Initial (blinded) screening results for ThinPrep and conventional smears were correlated. Initial diagnoses were correlated with consensus cytological diagnoses. Differences in disease detection were evaluated using McNemar's test. On initial screening, 29% more ASCUS cases and 39% more low-grade squamous intraepithelial lesions (LSIL) and more severe lesions (LSIL+) were detected on the ThinPrep slides than on the conventional smears (P = 0.001), including 50% more LSIL and 18% more high-grade SIL (HSIL). The ASCUS:SIL ratio was lower for the ThinPrep method (115:132 = 0.87:1) than for the conventional smear method (89:94 = 0.95:1). The same trend was observed for the ASCUS/AGUS:LSIL ratio. Independent and consensus review confirmed 145 LSIL+ diagnoses; of these, 18% more had been detected initially on the ThinPrep slides than on the conventional smears (P = 0.041). The ThinPrep Pap Test is more accurate than the conventional Pap test and has the potential to optimize the effectiveness of primary cervical cancer screening. [ABSTRACT FROM AUTHOR]

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10–15 % lower at 9 months ( p = 0.003) and 12 months ( p < 0.05) in the linomide group. The insulin dose was 32–40 % smaller in the linomide group at 3 ( p < 0.03), 6 ( p < 0.02), 9 ( p < 0.001) and 12 months ( p = 0.01). Insulin doses correlated negatively with C peptide values ( p = 0.001–0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45–59 % higher C peptide value at 6 months ( p < 0.05), 9 months ( p < 0.05) and 12 months ( p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10 % in the linomide and placebo groups), thrombocytopenia (24 vs 10 %), and mild joint discomfort (45 vs 5 %) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established. [Diabetologia (1998) 41: 1040–1046] [ABSTRACT FROM AUTHOR]

The prevalence of glutamic acid decarboxylase autoantibodies was determined with an immunotrapping enzyme activity assay in newly-diagnosed Type 1 (insulin-dependent) diabetic patients as well as in first-degree relatives using rat brain homogenate as a source of glutamate decarboxylase. Twenty-six out of 86 islet-cell cytoplasmic autoantibody positive and one out of 24 islet cell autoantibody negative patients of recent onset, had autoantibodies to glutamate decarboxylase above the upper 99% confidence limit obtained from 89 control sera. Among 27 islet cell autoantibody positive relatives including 19 siblings and 8 parents, antibodies to glutamate decarboxylase were found in 8 of 9 (89%) relatives and 7 of 8 (87.5%) siblings with islet cell autoantibody titres above 20 JDF units, in 1 of 19 (5.2%) relatives with islet cell autoantibody titres between 2 and 5 JDF units, in 2 of 263 (0.7%) siblings and 1 of 139 parents without islet cell autoantibodies. In first-degree relatives, high titre islet cell autoantibodies and autoantibodies to glutamate decarboxylase were tightly associated (X=182, p=0.0001). None of the relatives with low genetic risk ( n=64), i.e. HLA-different to the diabetic proband, was found to be antibody positive. Antibodies to glutamate decarboxylase were present only in those relatives sharing at least one haplotype with the diabetic proband, including two islet cell autoantibody negative but HLA-identical siblings. Autoantibodies to glutamate decarboxylase were present in 7 of 9 (77%) relatives who developed the disease, including one islet cell autoantibody negative sibling. Altogether, the simultaneous presence of autoantibodies to glutamate decarboxylase and high titre islet cell autoantibody increases the positive predictive value for the disease from 66% to 75%. This study indicates therefore that autoantibodies to glutamate decarboxylase detected by an immunotrapping enzyme activity assay are additional predictive markers for future development of Type 1 diabetes and should be now prospectively studied in high risk individuals as well as other autoantibodies to Beta-cell autoantigens. [ABSTRACT FROM AUTHOR]

Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage. [ABSTRACT FROM AUTHOR]

Genetic determination as well as prospective analysis of islet cell autoantibodies and autoantibodies to insulin were conducted in a population of 479 first degree relatives of 174 Type 1 (insulin-dependent) diabetic patients. Analysis of HLA haplotypes within families illustrated the high frequency of DR3 and DR4 alleles with preferential transmission from parent to both affected and unaffected offspring. DR4 was preferentially associated with DQw3.2 (TA10) in 60/73 (82.2%) patients and 101/127 (79.5%) relatives. Relatives have been followed for a period of 800 subject-years. Twenty-two out of 430 relatives (5.1%) were found islet cell antibodies (ICA-IgG) positive. Seven sera with low titres became negative 6 months later at two different determinations. Fifteen sera ICA-IgG and ICA-protein A positive with high titres remained positive thereafter. Half of the ICA positive relatives were also found insulin autoantibodies (IAA) positive. All but 3 ICA negative relatives did not have IAA in their sera. Analysis of IAA specificity with competition experiments indicated that most antibodies recognised epitopes shared between human and pork insulins while four were specific for human insulin determinants. Analysis of class I and class II HLA antigen distribution indicated no particular allelic restriction in antibody positive individuals. Metabolic status of antibody positive relatives was determined with oral and intravenous charge of glucose. Two haplo-identical DR3-DQw2 brothers became diabetic during the study. One child and one mother both with DR4-DQw3.2 became intolerant to glucose. Each of these relatives had high titre ICA prior to metabolic deterioration. Taken together, these data indicated that ICA and IAA may be present in first degree relatives of diabetic patients. Individualisation of markers of the ongoing autoimmune process and accurate evaluation of the residual B-cell mass are necessary steps before further immune interventions in the early phases of the disease. [ABSTRACT FROM AUTHOR]

Extracellular matrices (ECM) have been reported to enhance epithelial cell attachment and proliferation as well as to induce differentiation in vitro. Since ECM components are physiological constituents of the dermoepidermal basement membrane, we studied the growth and differentiation of human keratinocytes on ECM in order to determine the benefits of culturing epidermal epithelial cells (keratinocytes) on reconstituted basement membranes. Dissaggregated epidermal cells were grown in primary and subcultures in liquid medium; the attachment of the cells was greatly enhanced by ECM and noted within the first few hours after seeding; cells formed small islets that reached confluence within 2-12 days depending upon the plating density and the type of culture (primary or passages). Histological and ultrastructural crosssections of the cultures clearly indicated that a multilayered epithelium can be obtained including a basal cell layer, several intermediate cell layers with cytoplasmic organelles, intermediate size filaments, desmosomes, and keratohyaline granules, and an upper layer of anucleated cells. Using immunofluorescence, both pemphigus and pemphigoid (basal membrane zone) antigens were expressed. The keratin pattern noted indicated that these epithelia differentiate and keratinize but do not express a complete program of keratinization, a finding usually noted when cells are grown submersed. These data show that ECM favor epidermal cell proliferation and differentiation and suggest that they may be used to obtain large amounts of epidermal equivalent suitable for grafting and/or in vitro studies. [ABSTRACT FROM AUTHOR]

A videodensitometric method for quantification of aortic regurgitation which requires neither measurement of cardiac output nor determination of enddiastolic and endsystolic left ventricular volumes has been developed. The injection of 20 ml of contrast medium into the left ventricle is digitally recorded at 25 images s−1 during 20 s using an equipment for digital subtraction angiography (Digitron 2, Siemens). The Digitron computes 2 ‘time dilution curves’ (TDC) from the unsubtracted image sequence, for 2 regions of interest drawn around the angiographic enddiastolic and endsystolic left ventricular silhouettes. Enddiastolic and endsystolic points of the TDC are then entered into a VAX-750 computer, which calculates the ejection fraction (EF), the forward ejection fraction (FEF) and the regurgitant fraction (RGF). This is performed by a complex fitting algorithm based on a physical model of the washout process of contrast medium, which reconstructs the two best enddiastolic and endsystolic baselines in the washout parts of the two TDC. The EF, FEF and RGF obtained in 9 regurgitant and 11 nonregurgitant patients have been compared with the corresponding values EFv, FEFv and RGFv obtained by a conventional technique (Cardiogreen and biplane LV area-length volumetry). Regression analysis yielded: EF = 0.88 × EFv (regression line forced through the origin), r = 0.77, FEF = 0.76 × FEFv + 3, r = 0.96, RGF = 0.94 × RGFv + 5, r = 0.98 (v stands for volumetry). [ABSTRACT FROM PUBLISHER]

We investigated the pharmacological properties of SR 33557, a novel compound with calcium-antagonist properties, in both functional tests in vitro and radioligand binding studies. SR 33557 potently antagonized calcium-induced contraction of potassium-depolarized rat aorta in vitro with an IC value of 5.6 ± 0.9 nM, but was a much weaker inhibitor of noradrenaline-induced contraction of the same tissue (IC = 96 ± 22 nM). SR 33557 totally inhibited [H]-(±)-nitrendipine binding to rat brain membranes with a K value of 0.19 ± 0.03 nM. Diltiazem, which used alone increases [H]-(±)-nitrendipine binding, reversed this inhibition indicating that SR 33557 allosterically regulates [H]-(±)-nitrendipine binding. SR 33557 also fully inhibited [H]-(−)-desmethoxyverapamil binding to cerebral membranes, but inhibition curves were biphasic. IC value calculated for that part of the curve which reflects the high affinity binding site of SR 33557 (IC = 0.20 ± 0.02 nM) was very similar to the K value determined for inhibition of [H]-(±)-nitrendipine binding. Kinetic evidences indicate that SR 33557 binds to a site which is distinct from the 1,4-dihydropyridine or the phenylalkylamine binding sites associated with the calcium channel. To test the pharmacological specificity of these interactions, the ability of SR 33557 to interact with eight other receptors in cerebral or heart membranes was assessed by binding assays. No high-affinity interaction was observed between SR 33557 and any of the receptors investigated. We conclude that SR 33557 binds specifically and with a high affinity to a site closely associated with the voltage-operated calcium channel in cerebral membranes. [ABSTRACT FROM AUTHOR]

Ninety five normal Caucasian subjects (51F, 44M) aged from 2 to 25 y were measured at the hand and wrist level with a small DXA system (pDEXA) in order to obtain the normal values of the bone mineral content (BMC), density (BMD) and projected area (A) of carpal (c) and metacarpal (m) bones. BMDc ranged from 0.065 +/- 0.007 g/cm2 to 0.365 +/- 0.035 g/cm2 in females and 0.425 +/- 0.040 g/cm2 in males. It presented a sharp change of increase rate at 15.5 and 17 y of age in girls and boys, respectively. Ac presented the same kind of evolution as BMDc, but had a larger value dispersion. The second metacarpal bone had the highest BMCm value in 85% of females and 90% of males. The sum of BMCmi or Ami values (i = 1-5) and the projected mean density of the 5 metacarpal bones was well correlated with BMCc, Ac and BMDc, respectively (r > 0.90). A volumetric mineral density, dmi, calculated for each of these bones, approximated to a cylinder, was correlated with age (r > 0.85). [ABSTRACT FROM AUTHOR]

The effect of SR 33805, a novel calcium entry blocker, on calcium overload was studied in six vascular beds in rat. Fantofarone, a parent compound, and verapamil were used as reference calcium entry blockers. Calcium overload induced with a single dose (300 000 IU, i.m. of vitamin D3) was measured by means of atomic absorption and histological techniques. From the time-course of calcium overload, a treatment period of 3 days was selected to determine the effects of drug treatment. The compounds were given orally twice a day in the following dose ranges: SR 33805 2–100 mg/kg, fantofarone 10–300 mg/kg, verapamil 100 mg/kg. SR 33805 significantly decreased the calcium content beginning at the dose of 2 mg/kg in the thoracic aorta, 5 mg/kg in the mesenteric artery and 30 mg/kg in the heart. Fantofarone and verapamil had the same effect at the dose of 100 mg/kg. Histological assessment of the heart revealed that lesions appearing in the tissue adjacent to the arteries were significantly diminished by treatment with SR 33805 at a dose which produced a significant decrease in the arterial calcium content. Thus, SR 33805 can inhibit both calcium overload and its deleterious consequences and its actions are evident at doses as low as 2 mg/kg. [ABSTRACT FROM PUBLISHER]