Polydimethylsiloxane (PDMS) modulates CD38 expression, absorbs retinoic acid and may perturb retinoid signalling

Polydimethylsiloxane (PDMS) is the most commonly used material in the manufacture of customized cell culture devices. While there is concern that uncured PDMS oligomers may leach into culture medium and/or hydrophobic molecules may be absorbed into PDMS structures, there is no consensus on how or if PDMS influences cell behaviour. We observed that human umbilical cord blood (CB)-derived CD34+ cells expanded in standard culture medium on PDMS exhibit reduced CD38 surface expression, relative to cells cultured on tissue culture polystyrene (TCP). All-trans retinoic acid (ATRA) induces CD38 expression, and we reasoned that this hydrophobic molecule might be absorbed by PDMS. Through a series of experiments we demonstrated that ATRA-mediated CD38 expression was attenuated when cultures were maintained on PDMS. Medium pre-incubated on PDMS for extended durations resulted in a time-dependant reduction of ATRA in the medium and increasingly attenuated CD38 expression. This indicated a time-dependent absorption of ATRA into the PDMS. To better understand how PDMS might generally influence cell behaviour, Ingenuity Pathway Analysis (IPA) was used to identify potential upstream regulators. This analysis was performed for differentially expressed genes in primary cells including CD34+ haematopoietic progenitor cells, mesenchymal stromal cells (MSC), and keratinocytes, and cell lines including prostate cancer epithelial cells (LNCaP), breast cancer epithelial cells (MCF-7), and myeloid leukaemia cells (KG1a). IPA predicted that the most likely common upstream regulator of perturbed pathways was ATRA. We demonstrate here that ATRA is absorbed by PDMS in a time-dependent manner and results in the concomitant reduced expression of CD38 on the cell surface of CB-derived CD34+ cells.

Preterm Birth and Surgical Treatment of the Uterine Cervix

Cervical cancer is the second most common cancer among women globally. Most, probably all cases, arise through a precursor, cervical intraepithelial neoplasia (CIN). Effective cytological screening programmes and surgical treatments of precancerous lesions have dramatically reduced its prevalence and related mortality. Although these treatments are effective, they may have adverse effects on future fertility and pregnancy outcomes. The aim of this study was to evaluate the effects of surgical treatment of the uterine cervix on pregnancy and fertility outcomes, with the focus particularly on preterm birth. The general preterm birth rates and risk factors during 1987–2005 were studied. Long-term mortality rates of the treated women were studied. In this study, information from The Medical Birth Register (MBR), The Hospital Discharge Register (HDR), The Cause-of-Death Register (CDR), and hospital records were used. Treatments were performed during 1987–2003 and subsequent deliveries, IVF treatments and deaths were analyzed. The general preterm birth rate in Finland was relatively stable, varying from 5.1% to 5.4% during the study period (1987 to 2005), although the proportion of extremely preterm births had decreased substantially by 12%.The main risk factor as regards preterm birth was multiplicity, followed by elective delivery (induction of delivery or elective cesarean section), primiparity, in vitro fertilization treatment, maternal smoking and advanced maternal age. The risk of preterm birth and low birth weight was increased after any cervical surgical treatment; after conization the risk of preterm birth was almost two-fold (RR 1.99, 95% CI 1.81– 2.20). In the conization group the risk was the highest for very preterm birth (28–31 gestational weeks) and it was also high for extremely preterm birth (less than 28 weeks). In this group the perinatal mortality was also increased. In subgroup analysis, laser ablation was not associated with preterm birth. When comparing deliveries before and after Loop conization, we found that the risk of preterm birth was increased 1.94-fold (95% CI 1.10–3.40). Adjusting for age, parity, or both did not affect our results. Large or repeat cones increased the risk of preterm birth when compared with smaller cones, suggesting that the size of the removed cone plays a role. This was corroborated by the finding that repeat treatment increased the risk as much as five-fold when compared with the background preterm birth rate. We found that the proportion of IVF deliveries (1.6% vs. 1.5%) was not increased after treatment for CIN when adjusted for year of delivery, maternal age, or parity. Those women who received both treatment for CIN and IVF treatment were older and more often primiparous, which explained the increased risk of preterm birth. We also found that mortality rates were 17% higher among women previously treated for CIN. This excess mortality was particularly seen as regards increased general disease mortality and alcohol poisoning (by 13%), suicide (by 67%) and injury death (by 31%). The risk of cervical cancer was high, as expected (SMR 7.69, 95% CI 4.23–11.15). Women treated for CIN and having a subsequent delivery had decreased general mortality rate (by -22%), and decreased disease mortality (by -37%). However, those with preterm birth had increased general mortality (SMR 2.51, 95% CI 1.24–3.78), as a result of cardiovascular diseases, alcohol-related causes, and injuries. In conclusion, the general preterm birth rate has not increased in Finland, as in many other developed countries. The rate of extremely preterm births has even decreased. While other risk factors of preterm birth, such as multiplicity and smoking during pregnancy have decreased, surgical treatments of the uterine cervix have become more important risk factors as regards preterm birth. Cervical conization is a predisposing factor as regards preterm birth, low birth weight and even perinatal mortality. The most frequently used treatment modality, Loop conization, is also associated with the increased risk of preterm birth. Treatments should be tailored individually; low-grade lesions should not be treated at all among young women. The first treatment should be curative, because repeat treatments are especially harmful. The proportion of IVF deliveries was not increased after treatment for CIN, suggesting that current treatment modalities do not strongly impair fertility. The long-term risk of cervical cancer remains high even after many years post-treatment; therefore careful surveillance is necessary. In addition, accidental deaths and deaths from injury were common among treated women, suggesting risk-taking behavior of these women. Preterm birth seems be associated with extremely high mortality rates, due to cardiovascular, alcohol-related and injury deaths. These women could benefit from health counseling, for example encouragement in quitting smoking.

Cardiac function before and after treatment for various types of loading conditions and in myocardial restriction : A prospective study on pediatric patients with two- and three-dimensional echocardiography and measurement of serum natriuretic peptides

Background: The incidence of all forms of congenital heart defects is 0.75%. For patients with congenital heart defects, life-expectancy has improved with new treatment modalities. Structural heart defects may require surgical or catheter treatment which may be corrective or palliative. Even those with corrective therapy need regular follow-up due to residual lesions, late sequelae, and possible complications after interventions. Aims: The aim of this thesis was to evaluate cardiac function before and after treatment for volume overload of the right ventricle (RV) caused by atrial septal defect (ASD), volume overload of the left ventricle (LV) caused by patent ductus arteriosus (PDA), and pressure overload of the LV caused by coarctation of the aorta (CoA), and to evaluate cardiac function in patients with Mulibrey nanism. Methods: In Study I, of the 24 children with ASD, 7 underwent surgical correction and 17 percutaneous occlusion of ASD. Study II had 33 patients with PDA undergoing percutaneous occlusion. In Study III, 28 patients with CoA underwent either surgical correction or percutaneous balloon dilatation of CoA. Study IV comprised 26 children with Mulibrey nanism. A total of 76 healthy voluntary children were examined as a control group. In each study, controls were matched to patients. All patients and controls underwent clinical cardiovascular examinations, two-dimensional (2D) and three-dimensional (3D) echocardiographic examinations, and blood sampling for measurement of natriuretic peptides prior to the intervention and twice or three times thereafter. Control children were examined once by 2D and 3D echocardiography. M-mode echocardiography was performed from the parasternal long axis view directed by 2D echocardiography. The left atrium-to-aorta (LA/Ao) ratio was calculated as an index of LA size. The end-diastolic and end-systolic dimensions of LV as well as the end-diastolic thicknesses of the interventricular septum and LV posterior wall were measured. LV volumes, and the fractional shortening (FS) and ejection fraction (EF) as indices of contractility were then calculated, and the z scores of LV dimensions determined. Diastolic function of LV was estimated from the mitral inflow signal obtained by Doppler echocardiography. In three-dimensional echocardiography, time-volume curves were used to determine end-diastolic and end-systolic volumes, stroke volume, and EF. Diastolic and systolic function of LV was estimated from the calculated first derivatives of these curves. Results: (I): In all children with ASD, during the one-year follow-up, the z score of the RV end-diastolic diameter decreased and that of LV increased. However, dilatation of RV did not resolve entirely during the follow-up in either treatment group. In addition, the size of LV increased more slowly in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides in patients treated percutaneously increased during the first month after ASD closure and normalized thereafter, but in patients treated surgically, they remained higher than in controls. (II): In the PDA group, at baseline, the end-diastolic diameter of LV measured over 2SD in 5 of 33 patients. The median N-terminal pro-brain natriuretic peptide (proBNP) concentration before closure measured 72 ng/l in the control group and 141 ng/l in the PDA group (P = 0.001) and 6 months after closure measured 78.5 ng/l (P = NS). Patients differed from control subjects in indices of LV diastolic and systolic function at baseline, but by the end of follow-up, all these differences had disappeared. Even in the subgroup of patients with normal-sized LV at baseline, the LV end-diastolic volume decreased significantly during follow-up. (III): Before repair, the size and wall thickness of LV were higher in patients with CoA than in controls. Systolic blood pressure measured a median 123 mm Hg in patients before repair (P < 0.001) and 103 mm Hg one year thereafter, and 101 mm Hg in controls. The diameter of the coarctation segment measured a median 3.0 mm at baseline, and 7.9 at the 12-month (P = 0.006) follow-up. Thicknesses of the interventricular septum and posterior wall of the LV decreased after repair but increased to the initial level one year thereafter. The velocity time integrals of mitral inflow increased, but no changes were evident in LV dimensions or contractility. During follow-up, serum levels of natriuretic peptides decreased correlating with diastolic and systolic indices of LV function in 2D and 3D echocardiography. (IV): In 2D echocardiography, the interventricular septum and LV posterior wall were thicker, and velocity time integrals of mitral inflow shorter in patients with Mulibrey nanism than in controls. In 3D echocardiography, LV end-diastolic volume measured a median 51.9 (range 33.3 to 73.4) ml/m² in patients and 59.7 (range 37.6 to 87.6) ml/m² in controls (P = 0.040), and serum levels of ANPN and proBNP a median 0.54 (range 0.04 to 4.7) nmol/l and 289 (range 18 to 9170) ng/l, in patients and 0.28 (range 0.09 to 0.72) nmol/l (P < 0.001) and 54 (range 26 to 139) ng/l (P < 0.001) in controls. They correlated with several indices of diastolic LV function. Conclusions (I): During the one-year follow-up after the ASD closure, RV size decreased but did not normalize in all patients. The size of the LV normalized after ASD closure but the increase in LV size was slower in patients treated surgically than in those treated with the percutaneous technique. Serum levels of ANPN and proBNP were elevated prior to ASD closure but decreased thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically. (II): Changes in LV volume and function caused by PDA disappeared by 6 months after percutaneous closure. Even the children with normal-sized LV benefited from the procedure. (III): After repair of CoA, the RV size and the velocity time integrals of mitral inflow increased, and serum levels of natriuretic peptides decreased. Patients need close follow-up, despite cessation of LV pressure overload, since LV hypertrophy persisted even in normotensive patients with normal growth of the coarctation segment. (IV): In children with Mulibrey nanism, the LV wall was hypertrophied, with myocardial restriction and impairment of LV function. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, indicating that measurement of serum levels of natriuretic peptides can be used in the clinical follow-up of this patient group despite its dependence on loading conditions.

Molecular basis for the development of diagnostic methods and specific treatment modalities for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with unknown aetiology and poor prognosis. IPF is characterized by alveolar epithelial damage that leads tissue remodelling and ultimately to the loss of normal lung architecture and function. Treatment has been focused on anti-inflammatory therapies, but due to their poor efficacy new therapeutic modalities are being sought. There is a need for early diagnosis and also for differential diagnostic markers for IPF and other interstitial lung diseases. The study utilized patient material obtained from bronchoalveolar lavage (BAL), diagnostic biopsies or lung transplantation. Human pulmonary fibroblast cell cultures were propagated and asbestos-induced pulmonary fibrosis in mice was used as an experimental animal model of IPF. The possible markers for IPF were scanned by immunohistochemistry, RT-PCR, ELISA and western blot. Matrix metalloproteinases (MMPs) are proteolytic enzymes that participate in tissue remodelling. Microarray studies have introduced potential markers that could serve as additional tools for the assessment of IPF and one of the most promising was MMP 7. MMP-7 protein levels were measured in the BAL fluid of patients with idiopathic interstitial lung diseases or idiopathic cough. MMP-7 was however similarly elevated in the BAL fluid of all these disorders and thus cannot be used as a differential diagnostic marker for IPF. Activation of transforming growth factor (TGF)-ß is considered to be a key element in the progression of IPF. Bone morphogenetic proteins (BMP) are negative regulators of intracellular TGF-ß signalling and BMP-4 signalling is in turn negatively regulated by gremlin. Gremlin was found to be highly upregulated in the IPF lungs and IPF fibroblasts. Gremlin was detected in the thickened IPF parenchyma and endothelium of small capillaries, whereas in non-specific interstitial pneumonia it localized predominantly in the alveolar epithelium. Parenchymal gremlin immunoreactivity might indicate IPF-type interstitial pneumonia. Gremlin mRNA levels were higher in patients with end-stage fibrosis suggesting that gremlin might be a marker for more advanced disease. Characterization of the fibroblastic foci in the IPF lungs showed that immunoreactivity to platelet-derived growth factor (PDGF) receptor-α and PDGF receptor-β was elevated in IPF parenchyma, but the fibroblastic foci showed only minor immunoreactivity to the PDGF receptors or the antioxidant peroxiredoxin II. Ki67 positive cells were also observed predominantly outside the fibroblastic foci, suggesting that the fibroblastic foci may not be composed of actively proliferating cells. When inhibition of profibrotic PDGF-signalling by imatinib mesylate was assessed, imatinib mesylate reduced asbestos-induced pulmonary fibrosis in mice as well as human pulmonary fibroblast migration in vitro but it had no effect on the lung inflammation.

Uplink Power Control and Base Station Association in Multichannel Cellular Networks

A combined base station association and power control problem is studied for the uplink of multichannel multicell cellular networks, in which each channel is used by exactly one cell (i.e., base station). A distributed association and power update algorithm is proposed and shown to converge to a Nash equilibrium of a noncooperative game. We consider network models with discrete mobiles (yielding an atomic congestion game), as well as a continuum of mobiles (yielding a population game). We find that the equilibria need not be Pareto efficient, nor need they be system optimal. To address the lack of system optimality, we propose pricing mechanisms. It is shown that these mechanisms can be implemented in a distributed fashion.

12-weeks supervised exercise training is a feasible and efficacious treatment for reducing depression in youth with major depressive disorder

Introduction: Major Depressive Disorder (MDD) has high prevalence among adolescents and young adults. Evidence of any effective treatments is limited. Exercise as an effective treatment for adults has some support but studies in younger populations are lacking. Therefore the aim of this study was to investigate the feasibility and preliminary efficacy of brief motivational interviewing (MI) plus 12-weeks exercise training as a treatment for MDD in youth...

Raman spectra of single crystals of dicarboxylic acids - Part I. β-malonic acid and β-succinic acid

Raman spectra of single crystals of β-malonic acid and β-succinic acid have been photographed using λ 2536·5 radiation. 32 Raman lines have been recorded in the case of β-malonic acid. Of these 21 lines have been recorded for the first time. The three intense lattice lines at 52, 90 and 144 cm.-1 have been attributed to rotational lattice oscillations. 29 Raman lines in the case of β-succinic acid have been recorded. The entire lattice spectrum and many internal frequencies have been recorded for the first time. The three intense lattice lines at 80, 135 and 160 cm.-1 have been assigned to the rotational oscillations of the two molecules of the succinic acid in the unit cell.