The Bering Strait was flooded 10,000 years before the Last Glacial Maximum.

The cyclic growth and decay of continental ice sheets can be reconstructed from the history of global sea level. Sea level is relatively well constrained for the Last Glacial Maximum (LGM, 26,500 to 19,000 y ago, 26.5 to 19 ka) and the ensuing deglaciation. However, sea-level estimates for the period of ice-sheet growth before the LGM vary by > 60 m, an uncertainty comparable to the sea-level equivalent of the contemporary Antarctic Ice Sheet. Here, we constrain sea level prior to the LGM by reconstructing the flooding history of the shallow Bering Strait since 46 ka. Using a geochemical proxy of Pacific nutrient input to the Arctic Ocean, we find that the Bering Strait was flooded from the beginning of our records at 46 ka until [Formula: see text] ka. To match this flooding history, our sea-level model requires an ice history in which over 50% of the LGM's global peak ice volume grew after 46 ka. This finding implies that global ice volume and climate were not linearly coupled during the last ice age, with implications for the controls on each. Moreover, our results shorten the time window between the opening of the Bering Land Bridge and the arrival of humans in the Americas.

Criteria for placental examination for obstetrical and neonatal providers.

Pathologic examination of the placenta can provide insight into likely (and unlikely) causes of antepartum and intrapartum events, diagnoses with urgent clinical relevance, prognostic information for mother and infant, support for practice evaluation and improvement, and insight into advancing the sciences of obstetrics and neonatology. Although it is true that not all placentas require pathologic examination (although alternative opinions have been expressed), prioritization of placentas for pathologic examination should be based on vetted indications such as maternal comorbidities or pregnancy complications in which placental pathology is thought to be useful for maternal or infant care, understanding pathophysiology, or practice modifications. Herein we provide placental triage criteria for the obstetrical and neonatal provider based on publications and expert opinion of 16 placental pathologists and a pathologists' assistant, formulated using a modified Delphi approach. These criteria include indications in which placental pathology has clinical relevance, such as pregnancy loss, maternal infection, suspected abruption, fetal growth restriction, preterm birth, nonreassuring fetal heart testing requiring urgent delivery, preeclampsia with severe features, or neonates with early evidence of multiorgan system failure including neurologic compromise. We encourage a focused gross examination by the provider or an attendant at delivery for all placentas and provide guidance for this examination. We recommend that any placenta that is abnormal on gross examination undergo a complete pathology examination. In addition, we suggest practice criteria for placental pathology services, including a list of critical values to be used by the relevant provider. We hope that these sets of triage indications, criteria, and practice suggestions will facilitate appropriate submission of placentas for pathologic examination and improve its relevance to clinical care.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Ureaplasma infection-mediated release of matrix metalloproteinase-9 and PGP: a novel mechanism of preterm rupture of membranes and chorioamnionitis.

BACKGROUND: Premature rupture of membranes and preterm delivery are associated with Ureaplasma infection. We hypothesized that Ureaplasma induced extracellular collagen fragmentation results in production of the tripeptide PGP (proline-glycine-proline), a neutrophil chemoattractant. PGP release from collagen requires matrix metalloproteases (MMP-8/MMP-9) along with a serine protease, prolyl endopeptidase (PE). METHODS: Ureaplasma culture negative amniotic fluid (indicated preterm birth, n = 8; spontaneous preterm birth, n = 8) and Ureaplasma positive amniotic fluid (spontaneous preterm birth, n = 8) were analyzed by electro-spray ionization-liquid chromatography tandem mass spectrometry for PGP, and for MMP-9 by zymography. PE was evaluated in lysates of U. parvum serovar 3 (Up3) and U. urealyticum serovar 10 (Uu10) by western blotting and activity assay. RESULTS: PGP and MMP-9 were increased in amniotic fluid from spontaneous preterm birth with positive Ureaplasma cultures, but not with indicated preterm birth or spontaneous preterm birth with negative Ureaplasma cultures. Human neutrophils cocultured with Ureaplasma strains showed increased MMP-9 activity. PE presence and activity were noted with both Ureaplasma strains. CONCLUSION: Ureaplasma spp. carry the protease necessary for PGP release, and PGP and MMP-9 are increased in amniotic fluid during Ureaplasma infection, suggesting Ureaplasma spp. induced collagen fragmentation contributes to preterm rupture of membranes and neutrophil influx causing chorioamnionitis.

Regulation of alveolar septation by microRNA-489.

MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.

Integrated genomic analyses in bronchopulmonary dysplasia.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. STUDY DESIGN: A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. RESULTS: Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. CONCLUSIONS: Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.

Pathology of the stillborn infant for the general pathologist: part 1.

As the information obtained from previable fetal and stillbirth autopsies is used not only to explain the loss to the parents, but for future pregnancy planning, general pathologists need to be comfortable in dealing with these autopsies. The importance of an adequate fetal examination has been emphasized in a recent policy on the subject by the American Board of Pathology http://www.abpath.org/FetalAutopsyPolicy.pdf. This review paper covers the approach to the fetal and stillbirth autopsy. This first article covers the approach to the nonanomalous and anomalous autopsy. Hydrops fetalis will be covered in the second part of this series to be published subsequently.

Pathology of the stillborn infant for the general pathologist: part 2.

As the information obtained from previable fetal and stillbirth autopsies is used not only to explain the loss to the parents, but for future pregnancy planning, general pathologists need to be comfortable in dealing with these autopsies. The importance of an adequate fetal examination has been emphasized in a recent policy on the subject by the American Board of Pathology http://www.abpath.org/FetalAutopsyPoli'cy.pdf. This second review paper covers the approach to hydrops fetalis. The approach to the nonanomalous and anomalous fetus was covered in the first part of this series.

Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants.

OBJECTIVE: To test the hypothesis that increasing severity of the fetal inflammatory response (FIR) would have a dose-dependent relationship with severe neurodevelopmental impairment or death in extremely preterm infants. STUDY DESIGN: We report 347 infants of 23-28 weeks gestational age admitted to a tertiary neonatal intensive care unit between 2006 and 2008. The primary outcome was death or neurodevelopmental impairment at the 18- to 22-month follow-up. Exposure status was defined by increasing stage of funisitis (stage 1, phlebitis; stage 2, arteritis with or without phlebitis; stage 3, subacute necrotizing funisitis) and severity of chorionic plate vasculitis (inflammation with or without thrombosis). RESULTS: A FIR was detected in 110 placentas (32%). The rate of severe neurodevelopmental impairment/death was higher in infants with subacute necrotizing funisitis compared with infants without placental/umbilical cord inflammation (60% vs 35%; P < .05). Among infants with stage 1 or 2 funisitis, the presence of any chorionic vasculitis was associated with a higher rate of severe neurodevelopmental impairment/death (47% vs 23%; P < .05). After adjustment for confounding factors, only subacute necrotizing funisitis (risk ratio, 1.87; 95% CI, 1.04-3.35; P = .04) and chorionic plate vasculitis with thrombosis (risk ratio, 2.21; 95% CI, 1.10-4.46; P = .03) were associated with severe neurodevelopmental impairment/death. CONCLUSION: Severe FIR, characterized by subacute necrotizing funisitis and severe chorionic plate vasculitis with thrombosis, is associated with severe neurodevelopmental impairment/death in preterm infants.

Effect of corticosteroid interval on markers of inflammation in spontaneous preterm birth.

OBJECTIVE: The objective of the study was to evaluate whether the time interval from corticosteroid administration to delivery is associated with variations in inflammatory/infectious markers in women with spontaneous preterm birth (SPTB). STUDY DESIGN: We conducted a secondary analysis of a prospectively collected cohort of women experiencing SPTB from 23(0/7) to 31(6/7) weeks. Patients were categorized by corticosteroid receipt and time interval until delivery. Prevalence of markers of inflammation and colonization/infection (cord blood interleukin [IL]-6 levels; Ureaplasma urealyticum [UU], Mycoplasma hominis [MH], and other anaerobic/aerobic cultures; histology of the placental disc, membranes and cord) were compared between groups using χ(2) and Mantel-Haenszel tests. RESULTS: Two hundred seventy-three patients had SPTB. Prevalence of elevated IL-6 (P = .028) and positive UU/MH cultures (P = .019) were highest in women not receiving corticosteroids and those delivering more than 7 days from receipt. The prevalence of both decreased in groups with delivery delayed at least 12 hours but increased as the interval lengthened to more than 48 hours. Overall positive placental cultures also nadired among those delivering at 12-24 hours after corticosteroids (P = .049). As the interval increased, prevalence of acute inflammation at the rupture site increased (P = .017). There were similar, but nonsignificant, increases in chorionic plate inflammation and funisitis. CONCLUSION: The relationship between time interval from corticosteroids and evidence of inflammation in women experiencing SPTB is U shaped, suggesting earlier stages of inflammation in women with delayed delivery or transient decreases of inflammation in response to corticosteroids. This warrants further investigation to elucidate the natural history of SPTB and its modulation by corticosteroids.

The influence of elastic modulus mismatch between tooth and post and core restorations on root fracture.

AIM: To investigate the influence of elastic modulus mismatch between tooth and post and core restorations on mechanisms of root fracture. METHODOLOGY: Three-dimensional mathematical models of a root filled maxillary premolar tooth with supporting periodontium were constructed. The tooth was restored with a cast Ni-Cr alloy or fibre-reinforced composite post and core that was bonded or nonbonded to dentine. In the nonbonded simulation, a nonlinear contact analysis was executed to simulate a friction and a potential sliding phenomenon in the interface between tooth and post and core. Risks of root fracture and debonding at the bonded interface were estimated based on the principal stress of the root and the shear stress on the interface, respectively. RESULTS: The fracture risk of the bonded cast post and core was lower than that of the composite post and core, although the cast restoration exhibited eight times greater stress than the composite. The risk of root fracture based on the tensile stress of the tooth structures was higher with the bonded composite post and core than that with the cast post and core. These stresses doubled when the restorations were not bonded to the tooth structures. The risk of debonding of the cast post and core based on the shear stress was approximately twice that of the composite post and core. CONCLUSIONS: The elastic modulus mismatch appears to be a factor responsible for the debonding of post and cores from root canals, with the potential to increase the risk of root fracture indirectly.

Response of irrigated tomato (Solanum lycopersicum Mill) to mulch application rates.

Rapid decline in available water for crop production has led to the adoption of irrigation schedules for meeting water supply throughout cropping seasons. Nonetheless, the loss of water from soil often results in spells of water stress between schedules, which adversely affect crop yield. Hence, the use of mulch in conserving soil moisture in irrigated farming is becoming popular among farmers. In this study, a two-year screenhouse pot experiment was conducted to evaluate the effects of Pennisetum purpureum (Pp) mulch on tomato (Roma variety) grown in daily irrigation (IFdaily), irrigation at 3-days interval (IF3), and irrigation at 5-days interval (IF5) conditions. The Pp mulch was chopped to 5 cm and applied on the soil surface of each experimental pot at 1 t ha-1 (Pp1), 2 t ha-1 (Pp2), 3 t ha-1 (Pp3), and 4 t ha-1 (Pp4). These rates were compared against a bare soil as control (Pp0). The treatments were laid in a completely randomised design with four replicates. Tomato yield decreased by 53.6% and 26.6% in IF3, and 86.2% and 65.0% in IF5 compared with IFdaily in years 1 and 2, respectively. Among mulch rates, Pp4 and Pp3 increased tomato yield respectively by 107.5% and 99.9% compared with Pp0, while Pp2 and Pp1 were similar in year 1. In year 2, mulch increased tomato yield by 84.1% (Pp1) - 215.3% (Pp4) and contributed substantially to tomato yield in IFdaily (R2 = 0.99; p < 0.01); IF3 (R2 = 0.93; p < 0.01); and IF5 (R2 = 0.25; p < 0.05). However, withdrawing irrigation at 5 days interval was detrimental to tomato yield production.

RAFTK, a novel member of the focal adhesion kinase family, is phosphorylated and associates with signaling molecules upon activation of mature T lymphocytes.

The related adhesion focal tyrosine kinase (RAFTK), a recently discovered member of the focal adhesion kinase family, has previously been reported to participate in signal transduction in neuronal cells, megakaryocytes, and B lymphocytes. We have found that RAFTK is constitutively expressed in human T cells and is rapidly phosphorylated upon the activation of the T cell receptor (TCR). This activation also results in an increase in the autophosphorylation and kinase activity of RAFTK. After its stimulation, there was an increase in the association of the src cytoplasmic tyrosine kinase Fyn and the adapter protein Grb2. This association was mediated through the SH2 domains of Fyn and Grb2. RAFTK also co-immunoprecipitates with the SH2 domain of Lck and with the cytoskeletal protein paxillin through its COOH-terminal proline-rich domain. The tyrosine phosphorylation of RAFTK after T cell receptor-mediated stimulation was reduced by the pretreatment of cells with cytochalasin D, suggesting the role of the cytoskeleton in this process. These observations indicate that RAFTK participates in T cell receptor signaling and may act to link signals from the cell surface to the cytoskeleton and thereby affect the host immune response.

[Integral control of cardiovascular risk factors in type 2 diabetes in the Pallars Jussà and Sobirà regions (area of influence of the regional hospital of Pallars-Lleida)]. / Control integral de los factores de riesgo cardiovascular en diabetes tipo 2 en dos comarcas rurales.

UNLABELLED: FUNDAMENTALS AND OBJECTIVES: Control of cardiovascular risk factors is especially important in type 2 diabetes (DM2). The degree of control has not been studied specifically in rural population and how it affects quality of life. We have assessed the degree of accomplishment of the main control objectives in the area assigned to a regional hospital and evaluated their quality of life. MATERIAL AND METHODS: Cross-sectional study, in DM2 patients seen in Primary Care Centers on the Pallars Jussà y Sobirà (Lleida) regions. Smoking, body mass index (BMI), blood pressure (BP), HbA1c, total cholesterol, LDLc, HDL-c and triglycerides were evaluated. Quality of life was assessed with a health questionnaire (EQ-5D). RESULTS: 109 subjects (55% male) were recruited, with a medium age (standard deviation) of 70 (7.7) years old. 25% of cases had BMI <27kg/m(2) and 92% were non-current smokers. Systolic and diastolic BP were under control on the 36% and 53%, and HbA1c, on the 41%. Total Cholesterol was found optimal on the 54%, LDL-c on the 30%, HDL-c on the 64% and triglycerides on the 75%. 1.8% of patients achieved all the goals. The medium global subjective assessment of health status was 69 points. CONCLUSIONS: A very small percentage of patients with DM2 are in the recommended target. The most difficult to achieve were BMI and BP and the highest achievement were triglycerides and smoking abstinence. Subjective perception of health status was not associated with degree of objectives' control.

Acute promyelocytic leukemia during pregnancy: A case report and 10-year institutional review of hematologic malignancies during pregnancy.

Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.

Molecular identification of two genotypes of mumps virus causing two regional outbreaks in Asturias, Spain.

BACKGROUND: In spite of universal vaccination, several sporadic cases of mumps infection, which could produce outbreaks, are detected every year in different countries. OBJECTIVE: Mumps virus strains causing two regional outbreaks in Asturias (Spain) were phylogenetically characterized. STUDY DESIGN: Mumps virus strains, which were detected in samples from patients belonging to two regional outbreaks in Asturias, were characterized by sequencing of the SH gene and further alignment to homologous sequences of representative strains of the different mumps genotypes. RESULTS: Two different strains (Ast/SP02 and Ast/SP07) were isolated. Sequence analysis revealed that while Ast/SP02 belonged to genotype H, Ast/SP07 was phylogenetically close to UK02-19, a reference strain for a new genotype. Both strains belonged to different genotypes from those used in the vaccination (Jeryl-Lynn strain is genotype A). CONCLUSION: Mumps virus strains different from those used in vaccination program can cause mumps outbreaks even in vaccinated patients.

Nonlinear finite element analyses: advances and challenges in dental applications.

OBJECTIVES: To discuss the development and current status of application of nonlinear finite element method (FEM) in dentistry. DATA AND SOURCES: The literature was searched for original research articles with keywords such as nonlinear, finite element analysis, and tooth/dental/implant. References were selected manually or searched from the PUBMED and MEDLINE databases through November 2007. STUDY SELECTION: The nonlinear problems analyzed in FEM studies were reviewed and categorized into: (A) nonlinear simulations of the periodontal ligament (PDL), (B) plastic and viscoelastic behaviors of dental materials, (C) contact phenomena in tooth-to-tooth contact, (D) contact phenomena within prosthodontic structures, and (E) interfacial mechanics between the tooth and the restoration. CONCLUSIONS: The FEM in dentistry recently focused on simulation of realistic intra-oral conditions such as the nonlinear stress-strain relationship in the periodontal tissues and the contact phenomena in teeth, which could hardly be solved by the linear static model. The definition of contact area critically affects the reliability of the contact analyses, especially for implant-abutment complexes. To predict the failure risk of a bonded tooth-restoration interface, it is essential to assess the normal and shear stresses relative to the interface. The inclusion of viscoelasticity and plastic deformation to the program to account for the time-dependent, thermal sensitive, and largely deformable nature of dental materials would enhance its application. Further improvement of the nonlinear FEM solutions should be encouraged to widen the range of applications in dental and oral health science.

Cytokine signaling through the novel tyrosine kinase RAFTK in Kaposi's sarcoma cells.

A number of cytokines, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), oncostatin M (OSM), IL-6, and tumor necrosis factor alpha (TNF-alpha), have been postulated to have a role in the pathogenesis of Kaposi's sarcoma (KS). The proliferative effects of bFGF and OSM may be via their reported activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway in KS cells. We now report that KS cells express a recently identified focal adhesion kinase termed RAFTK which appears in other cell systems to coordinate surface signals between cytokine and integrin receptors and the cytoskeleton as well as act downstream to modulate JNK activation. We also report that the tyrosine kinase receptor FLT-4, present on normal lymphatic endothelium, is robustly expressed in KS cells. Treatment of KS cells with VEGF-related protein (VRP), the ligand for the FLT-4 receptor, as well as with the cytokines bFGF, OSM, IL-6, VEGF, or TNF-alpha resulted in phosphorylation and activation of RAFTK. Following its activation, there was an enhanced association of RAFTK with the cytoskeletal protein paxillin. This association was mediated by the hydrophobic COOH-terminal domain of the kinase. Furthermore, JNK activity was increased in KS cells after VEGF or VRP stimulation. We postulate that in these tumor cells RAFTK may be activated by a diverse group of stimulatory cytokines and facilitate signal transduction to the cytoskeleton and downstream to the growth promoting JNK pathway.