bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Plasminogen Activator Inhibitor 2 in the Adult and Embryonic Mouse Tissues
Authors: Kawata Yoichi , Mimuro Jun , Kaneko Munekiyo , Shimada Kazuyuki , Sakata Yoichi
Published: July 2018

We have studied the expression of plasminogen activator inhibitor 2 (PAI-2) in the adult mouse and during embryonic development using immunohistochemistry and the polymerase-chain reaction. Mouse PAI-2 mRNA was mainly expressed in the skin, bone-marrow, spleen, lung, thymus, and urinary bladder. Immunohistochemical studies suggested that PAI-2 was synthesized in macrophages and epithelial cells such as skin epithelial cells, transitional cells of the urinary bladder, and mesothelial cell of peritoneum and pleura. PAI-2 mRNA and antigen expression was observed only in the skin of 15 day-old mouse embryos. These data suggest that PAI-2 may play a role in protecting the mouse embryo from the protease attack in the amniotic fluid and also in maintaining and/or protecting the structure of various surfaces in the mouse.
HLA Class II Profile: A Weak Determinant of Factor VIII Inhibitor Development in Severe Haemophilia A
Authors: Hay C R M , Oilier W , Pepper L , Cumming A , Keeney S , Goodeve A C , Colvin B T , Hill F G H , Preston F E , Peake I R ,   UKHCDO Inhibitor Working Party
Published: July 2018

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (>10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion.

HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies from 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA- DRB*1501, DQB 1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7,1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB 1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB 1*01, DQB 1 *0501, DQA 1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.
A Novel Missense Mutation in the Endoglin Gene in Hereditary Hemorrhagic Telangiectasia
Authors: Yamaguchi Hiroshi , Azuma Hiroyuki , Shigekiyo Toshio , Inoue Hideo , Saito Shiro
Published: July 2018

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystem vascular dysplasia and recurrent hemorrhage. Recent investigation has mapped one of the responsible genes for HHT to chromosome 9q33-q34; subsequently, nine different mutations have been identified in the endoglin gene, which encodes a transforming growth factor β(TGF-β) binding protein, in nine unrelated families with HHT. We examined the endoglin gene in a Japanese patient with HHT and her family members. Using PCR-SSCP. analysis followed by sequencing, we identified a C to A missense mutation in exon 4 which changed an Ala160 codon(GCT) to an Asp160 codon (GAT). Since this mutation destroys one of three Fnu4H I sites in exon 4, the Fnu4H I digestion patterns of the PCR-amplified exon 4 fragments from each family member were analyzed. In affected members, the restriction patterns were all consistent with a phenotype of HHT. PCR-amplified exon 4 fragments from 150 normal individuals were also analyzed by allele-specific oligonucleotide hybridization analysis. As a result, the mutation was not found in any of them. We conclude that the C to A mutation in exon 4 of the endoglin gene in this proband is responsible for the occurrence of HHT in this family.
Molecular Characterization of a Type I Quantitative Factor V Deficiency in a Thrombosis Patient that Is “Pseudo Homozygous” for Activated Protein C Resistance
Authors: Guasch Joan F , Lensen Ruud P M , Bertina Rogier M
Published: July 2018

Resistance to activated protein C (APC), which is associated with the FV Leiden mutation in the large majority of the cases, is the most common genetic risk factor for thrombosis. Several laboratory tests have been developed to detect the APC-resistance phenotype. The result of the APC-resistance test (APC-sensitivity ratio, APC-SR) usually correlates well with the FV Leiden genotype, but recently some discrepancies have been reported. Some thrombosis patients that are heterozygous for FV Leiden show an APC-SR usually found only in homozygotes for the defect. Some of those patients proved to be compound heterozygotes for the FV Leiden mutation and for a type I quantitative factor V deficiency. We have investigated a thrombosis patient characterized by an APC-SR that would predict homozygosity for FV Leiden. DNA analysis showed that he was heterozygous for the mutation. Sequencing analysis of genomic DNA revealed that the patient also is heterozygous for a G5509→A substitution in exon 16 of the factor V gene. This mutation interferes with the correct splicing of intron 16 and leads to the presence of a null allele, which corresponds to the “non-FV Leiden” allele. The conjunction of these two defects in the patient apparently leads to the same phenotype as observed in homozygotes for the FV Leiden mutation.
Factor V Leiden Is Not Common in Children with Portal Vein Thrombosis
Authors: Seixas C A , Hessel G , Ribeiro C C , Arruda V R , Annichino-Bizzacchi J M
Published: July 2018

Portal vein thrombosis (PVT) is a rare condition affecting both children and adults, and occurs in association with a wide variety of clinical situations. On the other hand, the development of PVT in patients under these situations indicates that other contributing factors could be envolved. Recently a missense mutation in the factor V gene (1691G→A), known as factor V Leiden, has been identified and results in abnormal factor V product, resistant to proteolytic inactivation by activated protein C and thus predisposes to thrombosis. This study was carried out to verify if children with PVT have an increase in frequency of factor V Leiden. Allele-specific restriction analysis and single strand conformational polymorphism (SSCP) were used to test for factor V Leiden in 20 children with PVT and 64 normal children. None of the PVT children were heterozygous or homozygous for the factor V Leiden, and one control child was heterozygous. This study demonstrates that factor V Leiden is not common in children with PVT, and is not a prerequisite for this thrombotic event.
Reliability of Five Rapid D-Dimer Assays Compared to ELISA in the Exclusion of Deep Venous Thrombosis
Authors: Janssen M C H , Heebels A E , de Metz M , Verbruggen H , Wollersheim H , Janssen S , Schuurmans M M J , Nováková I R O
Published: July 2018

Studies measuring the fibrin degradation product D-Dimer (DD) using enzyme-linked immunosorbent assays (ELISA) in patients with venographically proven deep venous thrombosis (DVT) suggest that it is possible to exclude DVT when DD level is below a certain cut-off level. However, ELISA methods are time-consuming and not available in all laboratories. Different rapid latex-agglutination assays have been investigated, but their sensitivity is considerably lower.

In the present study we compared the value of four novel latex DD tests (Tinaquant®, Minutex®, Ortho® and SimpliRed®) and one rapid ELISA (VIDAS®) to a classical ELISA DD assay (Organon Mab Y18®) in 132 patients suspected of DVT.

The VIDAS®, a new quantitative automated ELISA, had a sensitivity of 100% and a negative predictive value of 100% for both proximal and distal DVT at a cut-off level of 500 ng/ml. The Tinaquant® assay, a new quantitative latex method, had a sensitivity of 99% and a negative predictive value of 93% for both proximal and distal DVT at a cut-off level of 500 ng/ml. For proximal DVT only, both assays had a sensitivity and negative predictive value of 100%. VIDAS® and Tinaquant® correlated well with ELISA (correlation of r = 0.96 and r = 0.98 respectively). Sensitivities of the semi-quantitative latex assays Minutex®, Ortho® and SimpliRed® were considerably lower (77%, 51 % and 61 % respectively).

These results suggest that VIDAS® and Tinaquant® may be used instead of ELISA DD in the exclusion of DVT. Tinaquant® can be performed within 20 min and VIDAS® within 35 min. Both assays might be used as a routine screening test and should be evaluated in large clinical management studies.
Massive Fibrin Formation with Consecutive Impairment of Fibrinolysis in Patients with Out-of-Hospital Cardiac Arrest
Authors: Gando Satoshi , Kameue Takashi , Nanzaki Satoshi , Nakanishi Yoshimi
Published: July 2018

Hypoxia and ischaemia influence blood coagulation and fibrinolysis. This study has been made to determine whether human cardiopulmonary arrest causes fibrin formation and reduction of fibrinolysis. Serial levels of fibrinopeptide A (FPA), fibrinopeptide Bβ15-42 (FPBβ15-42), D-dimer, tissue plasminogen activator antigen concentration (t-PA antigen), t-PA activity, plasminogen activator inhibitor-1 antigen concentration (PAI-1 antigen), and PAI-1 activity were determined in 63 patients with out-of-hospital cardiopulmonary arrest. In the resuscitated patients, the markedly elevated FPA (194.8 ± 54.2 ng/ml) at the beginning of cardiopulmonary resuscitation (CPR) significantly decreased to 32.4 ± 9.1 ng/ml at 24 h after admission (p <0.01), however, this was still about 20 times that of the normal controls. FPBβ15-42 and D-dimer increased from the start of CPR to 60 min (189.3 ± 97.4 ng/ml; p <0.01 and 7726 ± 3556 ng/ml; p <0.001, respectively), and then decreased at 24 h after arrival at the Emergency Department (40.4 ±11.1 ng/ml and 5434 ± 1049 ng/ml, respectively). At 30 min after arrival, FPA and FPBβ15-42 significantly differed between the resuscitated patients and the patients who died (p <0.001 and P <0.05, respectively). Although t-PA antigen and t-PA activity was elevated at the time of arrival, 24 h thereafter, no t-PA activity was detected. At 24 h after admission, PAI-1 antigen and PAI-1 activity were significantly increased (472.2 ± 145.5 ng/ml; p <0.001 and 103.6 ± 36.1 IU/ml; p <0.001, respectively). In conclusion, during and after CPR in patients with out-of-hospital cardiac arrest, massive fibrin generation with consecutive impairment of fibrinolysis were observed. These fibrin-mediated events may have some role in the derangement of vital organ function after cardiac arrest.
Recombinant, B-domain Deleted Factor VIII (r-VIII SQ): Pharmacokinetics and Initial Safety Aspects in Hemophilia A Patients
Authors: Fijnvandraat K , Berntorp E , ten Cate J W , Johnsson H , Peters M , Savidge G , Tengborn L , Spira J , Stahl C
Published: July 2018

The pharmacokinetics of a second-generation recombinant B-domain deleted factor VIII (FVIII) preparation (r-VIII SQ) were studied in 36 patients with severe hemophilia A. In contrast to full-length recombinant FVIII, no albumin needs to be added to stabilize the final formulation of this B-domain deleted FVIII preparation.

The in vivo recovery and half-life of r-VIII SQ were similar to those of plasma-derived (pd) FVIII (mean half-life of r-VIII SQ, 11.7 h). The volume of distribution and clearance were slightly, but significantly, higher for r-VIII SQ than for pdFVIII (p<0.05). Peak plasma levels of FVIII were consistently related to the administered dose of r-VIII SQ (r = 0.94, p<0.0001). The pharmacokinetic profile of r-VIII SQ remained essentially unchanged in a dose range of 25-100 IU/kg body weight and could be reproduced after repeated doses. r-VIII SQ was well tolerated.

In conclusion, deletion of the B-domain of FVIII does not influence its in vivo pharmacokinetics.
Production Method Affects the Pharmacokinetic and Ex Vivo Biological Properties of Low Molecular Weight Heparins
Authors: Brieger David , Dawes Joan
Published: July 2018

Low molecular weight (LMW) heparins have prolonged circulating half-lives relative to unfractionated heparin, but the rates of plasma clearance differ between different LMW preparations. To determine the impact of method of production on their pharmacokinetic and ex vivo biological properties, two LMW heparins of similar molecular weight distribution, Logiparin and Fragmin, were radiolabelled with 125I, administered intravenously with 4 mg/kg of carrier drug into rabbits, and the circulating radiolabelled material and anti-Xa activity were analysed by size exclusion chromatography and affinity for antithrom#bin and Polybrene. Following administration of Logiparin, the anti-Xa amidolytic activity was eliminated with the same half-life as the anti#thrombin-binding radiolabel and was not neutralised by antibody against tissue factor pathway inhibitor (TFPI). Larger molecules were cleared preferentially and were no longer detectable 8 h post injection. These findings resemble those we have previously described for Enoxaparin. After Fragmin administration the antithrombin binding radiolabel was cleared more rapidly than the anti-Xa activity, and at late times after injection a significant amount of this activity was neutralised by antibody against TFPI. Sulphated radiolabel was eliminated with a similar half-life to the anti-Xa activity and sulphated molecules >6000 Da remained in the circulation 8 h after administra#tion. Fragmin, unlike Logiparin and Enoxaparin, has no negatively charged sulphamino group at the reducing end of the molecule. We sug#gest that this minimises cellular interaction and protects the larger molecules from elimination. They remain in the circulation, contributing to anti-Xa activity by binding TFPI. Thus the method of production of LMW heparins may significantly influence their pharmacokinetic properties and circulating anticoagulant activities.
Commercial Antithrombin Concentrate Contains Inactive L-forms of Antithrombin
Authors: Chang Wun-Shaing W , Harper Paul L
Published: July 2018

The preparation of antithrombin concentrate for clinical use requires a viral inactivation step. In most commercial preparations this is achieved by heat pasteurisation. This process would be expected to alter the conformation of antithrombin from the active native species to an inactive latent (L-form) state (1, 2). To determine if this occurs during commercial preparation and to identify the proportion of the product in the inactive state, we examined the various antithrombin conformations within a therapeutic concentrate. The antithrombin concentrate was separated into five fractions by heparin-Sepharose chromatography. The fraction with the highest heparin affinity retained full activity, whereas the four fractions with reduced heparin affinity (~40% of the total antithrombin) had lost their inhibitory function. These inactive antithrombins were intact, monomeric, thermostable and resistant to unfolding in 8 M urea. Moreover, the protein patterns on isoelectric focusing and non-denaturing-PAGE showed that there were at least two different L-forms with isoelectric points separate from the native active species. Our findings demonstrate that approximately 40% of the antithrombin preparation examined exists as inactive l-forms. The clinical significance of administering this altered material is uncertain.
Prevalence of Factor V Leiden Mutation in Non-European Populations
Authors: Pepe Guglielmina , Rickards Olga , Vanegas Olga Camacho , Brunelli Tamara , Gori Anna Maria , Giusti Betti , Attanasio Monica , Prisco Domenico , Gensini Gian Franco , Abbate Rosanna
Published: July 2018

A difference in the prevalence of venous thromboembolism (TE) in major human groups has been described and an uneven distribution of FV Leiden mutation over the world has recently been reported.

We investigated FV Leiden mutation in 584 apparently healthy sub#jects mostly from populations different from those previously investi#gated: 170 Europeans (Spanish, Italians), 101 sub-saharan Africans (Fon, Bariba, Berba, Dendi), 115 Asians (Indonesians, Chinese, Tharus), 57 Amerindians (Cayapa), 84 Afroamericans (Rio Cayapa, Viche), and 57 Ethiopians (Amhara, Oromo).

The mutation was detected in only 1/115 Asian (Tharu) and in 5/170 Europeans (4 Italians, 1 Spanish).

These data confirm that in non-Europeans the prevalence of FV mutation is at least 7 times lower than in Europeans and provide indirect evidence of a low prevalence not only of the FV Leiden gene but also of other genes leading to more severe thrombophilia. Finally, findings from the literature together with those pertaining to this study clearly show a marked heterogeneity among Europeans.
Evaluation of Original and Modified APC-Resistance Tests in Unselected Outpatients with Clinically Suspected Thrombosis and in Healthy Controls
Authors: Svensson Peter J , Zöller Bengt , Dahlbäck Björn
Published: July 2018

APC-resistance is the most common hereditary condition associated with venous thrombosis. It is in a majority of cases due to a single point mutation in the factor V gene (FVR506Q). Currently used functional APC-resistance tests have 85-90% sensitivity and specificity for the FVR506Q mutation. A modified test which includes predilution of patient plasma in factor V depleted plasma has increased the sensitivity and specificity for the factor V mutation. However, neither the original nor the modified APC-resistance test have been evaluated in patients with acute thrombotic events. We have therefore used the original and the modified APC-resistance tests in 220 patients with clinically suspected acute deep venous thrombosis and in 278 healthy controls. The FVR506Q mutation was determined in all patients. The patients were classified as either DVT (deep venous thrombosis)-negative or DVT-positive depending on the outcome of contrast phlebography. In individuals with normal factor V genotype, the original APC-resistance test gave significantly lower APC-ratio values both in DVT-positive and DVT-negative patients than in healthy controls. The specificity of the original APC-resistance test for the FVR506Q mutation in controls and in DVT-negative and DVT-positive patients were 85%, 54% and 28%, respectively, when a cut off APC-ratio of 3.2 which insured 100% sensitivity was used. Using the modified APC-resistance test, essentially no difference in APC-ratios between patients with normal factor V genotype and healthy controls with normal factor V genotype was observed. The modified APC-resistance test had a specificity for the FVR506Q mutation of 98.8% at an APC-ratio cut off of 2.1 which ensured 100% sensitivity. The original APC-resistance test gave lower APC-ratios in women than in men and in patients with acute thrombosis as compared to controls. In conclusion, the modified APC-resistance test is highly sensitive and specific for the FVR506Q mutation. This test can be used in clinical practice as an easy to perform screening test for the FVR506Q allele. Moreover, the test performs equally well in patients with acute suspected venous thrombosis as in healthy controls.
Simultaneous Occurrence of Human Antibodies Directed against Fibrinogen, Thrombin, and Factor V Following Exposure to Bovine Thrombin: Effects on Blood Coagulation, Protein C Activation and Platelet Function
Authors: Chouhan Vibhuti D , De La Cadena Raul A , Nagaswami Chandrasekaran , Weisel John W , Kajani Mehdi , Rao A Koneti
Published: July 2018

We describe a patient with severe epistaxis, prolonged coagulation tests and decreased plasma factor V following exposure to bovine topical thrombin. Patient IgG, but not normal IgG, showed binding to immobilized thrombin (bovine > human) and fibrinogen, and to factor V by Western blotting; the binding to thrombin was inhibited by hirudin fragment 54-65. Electron microscopy of rotary shadowed preparations showed complexes with IgG molecules attached near the ends of trinodular fibrinogen molecules. Patient IgG inhibited procoagulant, anticoagulant and cell-stimulating functions of thrombin demonstrated by inhibition of fibrinogen clotting, protein C activation and platelet aggregation; thrombin hydrolysis of S-2238 was not inhibited. The results suggest that the antibody is targeted against anion-binding exosite and not catalytic site of thrombin. Antifibrinogen antibodies have not been reported in patients exposed to bovine thrombin. There is a pressing need to re-evaluate the role of bovine thrombin as a therapeutic agent.
Enhanced Increases in Cytosolic Ca2+ in ADP-Stimulated Platelets from Patients with Delta-Storage Pool Deficiency – A Possible Indicator of Interactions between Granule-Bound ADP and the Membrane ADP Receptor
Authors: Lages Bruce , Weiss Harvey J
Published: July 2018

The possible involvement of secreted platelet substances in agonist- induced [Ca2+]i increases was investigated by comparing these increases in aspirin-treated, fura-2-loaded normal platelets and platelets from patients with storage pool deficiencies (SPD). In the presence and absence of extracellular calcium, the [Ca2+]i response induced by 10 µM ADP, but not those induced by 0.1 unit/ml thrombin, 3.3 µM U46619, or 20 µM serotonin, was significantly greater in SPD platelets than in normal platelets, and was increased to the greatest extent in SPD patients with Hermansky-Pudlak syndrome (HPS), in whom the dense granule deficiencies are the most severe. Pre-incubation of SPD-HPS and normal platelets with 0.005-5 µM ADP produced a dose-dependent inhibition of the [Ca2+]i response induced by 10 µ
M
ADP, but did not alter the [Ca2+]i increases induced by thrombin or U46619. Within a limited range of ADP concentrations, the dose-inhibition curve of the [Ca2+]i response to 10 µM ADP was significantly shifted to the right in SPD-HPS platelets, indicating that pre-incubation with greater amounts of ADP were required to achieve the same extent of inhibition as in normal platelets. These results are consistent with a hypothesis that the smaller ADP-induced [Ca2+]i increases seen in normal platelets may result from prior interactions of dense granule ADP, released via leakage or low levels of activation, with membrane ADP receptors, causing receptor desensitization. Addition of apyrase to platelet-rich plasma prior to fura-2 loading increased the ADP-induced [Ca2+]i response in both normal and SPD-HPS platelets, suggesting that some release of ADP derived from both dense granule and non-granular sources occurs during in vitro fura-2 loading and platelet washing procedures. However, this [Ca2+]i response was also greater in SPD-HPS platelets when blood was collected with minimal manipulation directly into anticoagulant containing apyrase, raising the possibility that release of dense granule ADP resulting in receptor desensitization may also occur in vivo. Thus, in addition to enhancing platelet activation, dense granule ADP could also act to limit the ADP-mediated reactivity of platelets exposed in vivo to low levels of stimulation.
Searching for a Cell-Based Therapeutic Tool for Haemophilia A within the Embryonic/Foetal Liver and the Aorta-Gonads-Mesonephros Region
Authors: Serrano Luis , Cañete Ana , Garcia-Leal Tamara , Tomás-Gallardo Laura , Flores Ana , de la Torre Paz , Liras Antonio , Sánchez María
Published: July 2018

The development of new strategies based on cell therapy approaches to correct haemophilia A (HA) requires further insights into new cell populations capable of producing coagulation factor VIII (FVIII) and presenting stable engraftment potential. The major producers of FVIII in the adult are liver sinusoidal endothelial cells (LSECs) and in a lesser degree bone marrow-derived cells, both of which have been shown to ameliorate the bleeding phenotype in adult HA mice after transplantation. We have previously shown that cells from the foetal liver (FL) and the aorta-gonads-mesonephros (AGM) haematopoietic locations possess higher LSEC engraftment potential in newborn mice compared with adult-derived LSECs, constituting likely therapeutic targets for the treatment of HA in neonates. However, less is known about the production of FVIII in embryonic locations. Quantitative polymerase chain reaction and Western blot analysis were performed to assess the relative level of FVIII production in different embryonic tissues and at various developmental stages, identifying the FL and AGM region from day 12 (E12) as prominent sources of FVIII. Furthermore, FL-derived VE-cad+CD45-Lyve1+/− endothelial/endothelial progenitor cells, presenting vascular engraftment potential, produced high levels of F8 ribonucleic acid compared with CD45+ blood progenitors or Dlk1+ hepatoblasts. In addition, we show that the E11 AGM explant cultures expanded cells with LSEC repopulation activity, instrumental to further understand signals for in vitro generation of LSECs. Taking into account the capacity for FVIII expression, culture expansion and newborn engraftment potential, these results support the use of cells with foetal characteristics for correction of FVIII deficiency in young individuals.
The Contribution of Untreated and Treated Anxiety and Depression to Prenatal, Intrapartum, and Neonatal Outcomes
Authors: Ogunyemi Dotun , Jovanovski Andrew , Liu James , Friedman Perry , Sugiyama Nathaniel , Creps James , Madan Ichchha
Published: July 2018

Objective To determine independent perinatal associations of anxiety and depression in women who were and were not treated with psychotropic drugs in comparison to unaffected pregnancies.

Study Design From 2013 to 2014, 978 (6.3%) cases of anxiety/depression, of which 35% used psychotropic drugs, were compared with 14,514 (93.7%) unaffected pregnancies using logistic regression.

Results Subjects were more likely to be Non-Hispanic Whites, use tobacco and illegal substances, be unmarried, use public insurance, and have medical complications of pregnancy. For independent maternal outcomes, untreated anxiety/depression was associated with labor induction (adjusted odds ratio [aOR] = 2.02), cesarean deliveries (aOR = 1.69), longer length of stay (aOR = 1.96), readmission (aOR = 2.40), fever (aOR = 2.03), magnesium exposure (aOR = 1.82), and postpartum hemorrhage (aOR = 2.57), whereas treated cases were associated with increased blood transfusion (aOR = 4.81), severe perineal lacerations (aOR = 2.93), and postpartum hemorrhage (aOR = 3.85), but decreased risk of cesarean deliveries (aOR = 0.59). Independent neonatal outcomes included small for gestational age (aOR = 3.04), meconium-stained fluid (aOR = 1.85; 2.61), respiratory failure (aOR = 5.84), neonatal adaptation syndrome (aOR = 11; 10.2), and neonatal seizures (aOR = 12.3) in treated cases, whereas untreated cases were associated with hypoxia (aOR = 2.83), low Apgar score (aOR = 3.82), and encephalopathy (aOR = 18.3). Exposure to multiple psychotropic medications independently increased the risk of neonatal adaptation syndrome, neonatal length of stay, and hypoglycemia.

Conclusion Untreated cases were associated with increased maternal adverse outcomes, whereas treated cases were associated with more adverse neonatal outcomes when compared with unaffected pregnancies.
Isolated Tibial Component Failure in Total Knee Arthroplasty: A Case Series Evaluating Inflammatory Response versus Mechanical Failure
Authors: Yokhana Sanar S. , Bergum Christopher , Ren Weiping , Markel David C.
Published: July 2018

Total knee prostheses are routinely redesigned to improve performance, longevity, and to closer mimic the native kinematics of the knee. Despite continued improvements, all knee implants, even those with proven design features, have failures. We identified a cohort of patients with isolated tibial component failures that occurred in a popular and successful knee system. Our purpose was to (1) characterize the observed radiographic failure pattern; (2) investigate the biologic response that may have contributed to the failure; and (3) to determine if the failure mechanism was of a biological or a mechanical nature. Twenty-one knees from 19 patients met the inclusion criteria of isolated tibial component failure in a single knee implant system. Radiographs from the primary and revision knee surgery were analyzed for implant positioning and the failure pattern. Inflammatory biomarkers interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were available in 16/21 knees and peripheral CD14+/16+ monocytes were measured in 14 of the aforementioned 16 knee revisions. Serum CD3, CD4, and CD19 were measured in 10 of the aforementioned 14 knees. Additionally, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were measured to rule out infection as a cause of the cytokine upregulation. Radiographic findings demonstrated that all of the 21 tibial components were implanted in either neutral or 2 to 3 degrees varus in the coronal plane, and none of the revisions was implanted in valgus. All tibias showed obvious radiographic loosening and the implant failed into varus. The inflammatory biomarkers IL-1β, IL-6, and TNF-α were negative. WBC, ESR, and CRP were normal. Serum CD3, CD4, and CD19 flow cytometry analyses were found to be in the normal range. Peripheral CD14+/16+ and total CD16+ monocytes measurements were consistent with previous findings of patients with osteoarthritis, rather than particulate-induced inflammatory loosening. The findings support the implant failure observed in our study occurred by a different mechanism than the wear debris–induced aseptic loosening. We believe that a mechanical failure can occur based on our findings. The loosening, collapse, and debonding from the cement may have been related to the implantation technique, stresses due to favorable rotational freedoms of the implant, or patient characteristics/behavior. Continued exploration into implant failure mechanisms and particularly into the biologic response associated with failure is ongoing.
Inflammasome, T Lymphocytes and Innate-Adaptive Immunity Crosstalk: Role in Cardiovascular Disease and Therapeutic Perspectives
Authors: Pedicino Daniela , Giglio Ada , Ruggio Aureliano , Massaro Gianluca , D'Aiello Alessia , Trotta Francesco , Lucci Claudia , Graziani Francesca , Biasucci Luigi , Crea Filippo , Liuzzo Giovanna
Published: July 2018

Over the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque.
The Role of Surgical Closure Position in Total Knee Arthroplasty: Flexion versus Extension—A Randomized Prospective Study
Authors: Pepe Murad , Calisal Emre , Kocadal Onur , Bicer Eren , Taskin Suhan , Aktekin Cem Nuri
Published: July 2018

We aimed to investigate the effect of the knee position during the surgical closure on isokinetic muscle strength, clinical score, and range of motion in total knee arthroplasty. Seventy-five eligible patients were enrolled in the study and randomly divided into two groups; wound closure was performed with the knee flexed at 90° in group 1 and knee extended in group 2. All the surgeries were performed by the same surgeon and by the same prosthesis type. All the patients received the same rehabilitation program postoperatively. The primary outcomes were the knee flexion degrees and the American Knee Society Score values at preoperative and postoperative 6 weeks, 3, and 6 months. The secondary outcome was the isokinetic muscle strength measurements of both knees before the surgery and after 6 months. There were no significant differences in the American Knee Society Scores and knee flexion degrees between the flexion and extension groups. However, a significant decrease was found in the extensor muscle strength in the extension group after 6 months of the surgery. The findings of our study are that the closing of the knee in flexion or extension does not affect the postoperative knee flexion degrees and scores in total knee arthroplasty. However, quadriceps strength recovers early if the knee closure is performed in flexion position.
The Pellegrini–Stieda Lesion of the Knee: An Anatomical and Radiological Review
Authors: Somford M. P. , Janssen R. P. A. , Meijer D. , Roeling T. A. P. , Brown C. , Eygendaal D.
Published: July 2018

The Pellegrini–Stieda lesion is a calcification on the medial side of the knee. The origin of this tissue is controversial. The purpose of our study is to investigate the origin of the Pellegrini–Stieda lesion using conventional radiography as to recreate the circumstances in which Pellegrini and Stieda had to study this pathology. Six nonpaired fresh-frozen cadaveric knees were used. A surgical approach to the medial side of the knee was performed using the layered approach. The origin of the gastrocnemius muscle (GM) (n = 3) or the superficial medial collateral ligament (sMCL) (n = 3) were marked with a radio-opaque fluid. X-ray analysis was performed by measuring the distance from the proximal part of the marking to the medial tibial plateau, multilayer views, and comparison to the original X-rays by Pellegrini–Stieda. Two out of three markings in both the GM and sMCL group were matched with the correct structure. The images were digitally processed so that the osseous structures became partly transparent. After overlaying the images, we found a random distribution of the markings. The Stieda/GM group had no overlap of the markings at all. Compared with the original images from the publications by Pellegrini and Stieda, no comparable position could be found between the original lesions and the markings in our specimens. Conventional X-ray of the knee could not reproduce a distinction between the sMCL and GM as origins for the Pellegrini–Stieda lesion as suggested by Pellegrini and Stieda.
Robustness of the analysis of Doppler-shift attenuation lifetime measurements according to the coincidence differential decay curve method with respect to class of uncertainties in the stopping powers
Authors: Petkov P.
Published: July 2018

It is shown that the Differential decay curve method applied to analyze coincidence Doppler-shift attenuation lifetime measurements with a gate on the shifted component of a directly feeding feeding transition is characterized by stable results within scaling variations of the stopping powers of up to 15% at least. This is due to cancellation in the formula used for the lifetime determination while when using the traditional data analysis methods the imprecision in the stopping powers cannot be surrounded.
Theory of curvature-dependent kinetics of diffusion-limited reactions and its application to ligand binding to a sphere with multiple receptors
Authors: Eun Changsun
Published: July 2018

We present a simple theory that explains how surface curvature affects the reaction kinetics of diffusion-limited reactions on spherically curved surfaces. In this theory, we derive a quadratic equation under the conditions that the rate constant satisfies the Hill and Smoluchowski rate constants at the lowest and highest curvatures, respectively, and that at a certain intermediate curvature, there should be a maximum value of the rate constant, which was recently found in our previous work. We find that the result obtained from our theory is in good agreement with the corresponding one obtained from numerical calculation. In addition, we show that our theory can be directly applied to the Šolc-Stockmayer model of axially symmetric reactants, which can be considered as a spherical reactant with a single reaction site. Furthermore, we discuss using our theory to improve the formula for the rate constant in the Berg-Purcell ligand-binding model of a cell membrane covered by multiple receptors. Our simple theory yields insight into the effect of curvature on diffusion-influenced reactions and provides a useful formula for easily and quantitatively evaluating the curvature effect.
A new representation model of standard and available active materials for electrochemical batteries
Authors: García-Plaza M. , Eloy-García Carrasco J. , Alonso-Martínez J. , Peña-Asensio A.
Published: July 2018

The main goal of this paper is the introduction of a predictive model to calculate the remaining run-time of a battery. It is not meant to increase precision or compete with other methods but to be a reliable model by using a new formulation, more representative of the active material used zones. This paper defines two different states of charge (SOC) based on the concepts of standard and available capacities, named SOCs and SOCav, respectively. Concepts such as uncharged and undischarged capacities and loss charge efficiency are included as well. With these new definitions, an estimation algorithm is proposed. It is implemented as a runtime SOC estimation model based on an ampère-hour counting electrical model. The characterization of SOC model parameters of an 11 Ah Ni-Cd battery is also presented. These tests combine non-standard charge or discharge processes with end-of-charge/discharge detection methods that avoid overcharge or over discharge. Four case studies are carried out: two on a single battery cell and the other two on a 210 battery stack. The results show a good performance, with an approximate improvement of the estimation of 5%. They also show the importance of differentiating standard and available SOC in order to calculate the available capacity.
Tri-stage quasimonoenergetic proton acceleration from a multi-species thick target
Authors: Wan Y. , Pai C.-H. , Hua J. F. , Wu Y. P. , Lu W. , Li F. , Zhang C. J. , Xu X. L. , Joshi C. , Mori W. B.
Published: July 2018

We show that quasimonoenergetic proton beams can be generated through a multi-ion thick target irradiated by a circularly polarized laser pulse. After disrupted by the transverse instabilities in the laser pressure acceleration process, heavy ions as majority species can still provide a co-moving electric field. Different from the dynamics using ultrathin foil, protons with small doped rates can experience a full tri-stage quasimonoenergetic acceleration (hole boring, sheath boosting, and free expansion stages) in this scenario. A theoretical model is developed to explain the proton energy evolution in detail and verified by two-dimensional particle-in-cell simulations. The scaling of proton energy with laser intensity indicates that the 200 MeV proton beam with narrow energy spread (3%–10%) and sufficiently large charges (1010–1011) required for medical applications can be obtained using 100s TW class laser systems in near future.
Maximum spreading of a ferrofluid droplet under the effect of magnetic field
Authors: Ahmed Abrar , Fleck Brian A. , Waghmare Prashant R.
Published: July 2018

This study presents a theoretical and an experimental study of the effects of an applied external magnetic field on the maximum spreading of a ferrofluid droplet impacting on a solid substrate. Although many studies have explored the theoretical modeling of the droplet impact scenario, a theoretical model representing the impact of ferrofluid droplets of different magnetic characteristics, strongly affected by the magnetic field, is yet to be addressed. In this study, we developed a theoretical model based on the principle of the conservation of energy to predict the maximal deformation of both diamagnetic and paramagnetic ferrofluid droplets upon impact under the influence of the magnetic field. The physics behind the variation of maximum drop spread, as a function of Weber number (We), Reynolds number (Re), and magnetic Bond number (Bom) for 5–45, 150–400, and 150–3000, respectively, was studied. By validating the theoretical model with the experimental observations, we demonstrated that the proposed theoretical model could successfully predict experimental observations. Through theoretical analysis and extensive experimental investigations, a rational understanding was formulated which allowed us to comment on the effect of all the governing dimensionless numbers (We, Re, and Bom) on the maximum spreading of a ferrofluid droplet upon impact.
Biological characterization of the modified poly(dimethylsiloxane) surfaces based on cell attachment and toxicity assays
Authors: Jastrzebska Elzbieta , Zuchowska Agnieszka , Flis Sylwia , Sokolowska Patrycja , Bulka Magdalena , Dybko Artur , Brzozka Zbigniew
Published: July 2018

Poly(dimethylsiloxane) (PDMS) is a material applicable for tissue and biomedical engineering, especially based on microfluidic devices. PDMS is a material used in studies aimed at understanding cell behavior and analyzing the cell adhesion mechanism. In this work, biological characterization of the modified PDMS surfaces based on cell attachment and toxicity assays was performed. We studied Balb 3T3/c, HMEC-1, and HT-29 cell adhesion on poly(dimethylsiloxane) surfaces modified by different proteins, with and without pre-activation with plasma oxygen and UV irradiation. Additionally, we studied how changing of a base and a curing agent ratios influence cell proliferation. We observed that cell type has a high impact on cell adhesion, proliferation, as well as viability after drug exposure. It was tested that the carcinoma cells do not require a highly specific microenvironment for their proliferation. Cytotoxicity assays with celecoxib and oxaliplatin on the modified PDMS surfaces showed that normal cells, cultured on the modified PDMS, are more sensitive to drugs than cancer cells. Cell adhesion was also tested in the microfluidic systems made of the modified PDMS layers. Thanks to that, we studied how the surface area to volume ratio influences cell behavior. The results presented in this manuscript could be helpful for creation of proper culture conditions during in vitro tests as well as to understand cell response in different states of disease depending on drug exposure.
Effect of fluid shear stress on in vitro cultured ureteric bud cells
Authors: Kimura Hiroshi , Nishikawa Masaki , Yanagawa Naomi , Nakamura Hiroko , Miyamoto Shunsuke , Hamon Morgan , Hauser Peter , Zhao Lifu , Jo Oak D. , Komeya Mitsuru , Ogawa Takehiko , Yanagawa Norimoto
Published: July 2018

Most kidney cells are continuously exposed to fluid shear stress (FSS) from either blood flow or urine flow. Recent studies suggest that changes in FSS could contribute to the function and injury of these kidney cells. However, it is unclear whether FSS influences kidney development when urinary flow starts in the embryonic kidneys. In this study, we evaluated the influence of FSS on in vitro cultured ureteric bud (UB) cells by using a pumpless microfluidic device, which offers the convenience of conducting parallel cell culture experiments while also eliminating the need for cumbersome electronic driven equipment and intricate techniques. We first validated the function of the device by both mathematical model and experimental measurements. UB cells dissected from E15.5 mouse embryonic kidneys were cultured in the pumpless microfluidic device and subjected to FSS in the range of 0.4–0.6 dyn mm−2 for 48 h (dynamic). Control UB cells were similarly cultured in the device and maintained under a no-flow condition (static). We found from our present study that the exposure to FSS for up to 48 h led to an increase in mRNA expression levels of UB tip cell marker genes (Wnt11, Ret, Etv4) with a decrease in stalk cell marker genes (Wnt7b, Tacstd2). In further support of the enrichment of UB tip cell population in response to FSS, we also found that exposure to FSS led to a remarkable reduction in the binding of lectin Dolichos Biflorus Agglutinin. In conclusion, results of our present study show that exposure to FSS led to an enrichment in UB tip cell populations, which could contribute to the development and function of the embryonic kidney when urine flow starts at around embryonic age E15.5 in mouse. Since UB tip cells are known to be the proliferative progenitor cells that contribute to the branching morphogenesis of the collecting system in the kidney, our finding could imply an important link between the FSS from the initiation of urine flow and the development and function of the kidney.
Perspective: Basic understanding of condensed phases of matter via packing models
Authors: Torquato S.
Published: July 2018

Packing problems have been a source of fascination for millennia and their study has produced a rich literature that spans numerous disciplines. Investigations of hard-particle packing models have provided basic insights into the structure and bulk properties of condensed phases of matter, including low-temperature states (e.g., molecular and colloidal liquids, crystals, and glasses), multiphase heterogeneous media, granular media, and biological systems. The densest packings are of great interest in pure mathematics, including discrete geometry and number theory. This perspective reviews pertinent theoretical and computational literature concerning the equilibrium, metastable, and nonequilibrium packings of hard-particle packings in various Euclidean space dimensions. In the case of jammed packings, emphasis will be placed on the “geometric-structure” approach, which provides a powerful and unified means to quantitatively characterize individual packings via jamming categories and “order” maps. It incorporates extremal jammed states, including the densest packings, maximally random jammed states, and lowest-density jammed structures. Packings of identical spheres, spheres with a size distribution, and nonspherical particles are also surveyed. We close this review by identifying challenges and open questions for future research.
Anomalous multipole expansion: Charge regulation of patchy inhomogeneously charged spherical particles
Authors: Lošdorfer Božič Anže , Podgornik Rudolf
Published: July 2018

Charge regulation is an important aspect of electrostatics in biological and colloidal systems, where the charges are generally not fixed but depend on the environmental variables. Here, we analyze the charge regulation mechanism in patchy inhomogeneously charged spherical particles, such as globular proteins, colloids, or viruses. Together with the multipole expansion of inhomogeneously charged spherical surfaces, the charge regulation mechanism on the level of linear approximation is shown to lead to a mixing between different multipole moments depending on their capacitance—the response function of the charge distribution with respect to the electrostatic potential. This presents an additional anomalous feature of molecular electrostatics in the presence of ionic screening. We demonstrate the influence of charge regulation on several examples of inhomogeneously charged spherical particles, showing that it leads to significant changes in their multipole moments.