A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: results of a multicentre analysis.

New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines

The origin of the Palaeoproterozoic AMCG complexes in the Ukrainian shield: New U-Pb ages and Hf isotopes in zircon

© 2017 Elsevier B.V.The Ukrainian shield hosts two Palaeoproterozoic anorthosite-mangerite-charnockite-granite (AMCG) complexes (the Korosten and Korsun-Novomyrhorod complexes) that intruded Palaeoproterozoic continental crust in north-western and central parts of the shield, respectively. We report results of U-Pb zircon and baddeleyite dating of 16 samples from the Korosten plutonic complex (KPC), and 6 samples from the Korsun-Novomyrhorod plutonic complex (KNPC). Fifteen zircon samples from both complexes were also analysed for Hf isotopes. These new, together with previously published data indicate that the formation of the KPC started at c. 1815 Ma and continued until 1743 Ma with two main phases of magma emplacement at 1800–1780 and 1770–1758 Ma. Each of the main phases of magmatic activity included both basic and silicic members. The emplacement history of the KNPC is different from that of the KPC. The vast majority of the KNPC basic and silicic rocks were emplaced between c. 1757 and 1750 Ma; the youngest stages of the complex are represented by monzonites and syenites that were formed between 1748 and 1744 Ma. Both Ukrainian AMCG complexes are closely associated in space and time with mantle-derived mafic and ultramafic dykes. The Hf isotope ratios in the zircons indicate a predominantly crustal source for the initial melts with some input of juvenile Hf from mantle-derived tholeiite melts. The preferred model for the formation of the Ukrainian AMCG complexes involves the emplacement of large volumes of hot mantle-derived tholeiitic magma into the lower crust. This resulted in partial melting of mafic lower-crustal material, mixing of lower crustal and tholeiitic melts, and formation of ferromonzodioritic magmas. Further fractional crystallization of the ferromonzodioritic melts produced the spectrum of basic rocks in the AMCG complexes. Emplacement of the ferromonzodioritic and tholeiitic melts into the middle crust and their partial crystallization caused abundant melting of the ambient crust and formation of the large volumes of granitic rocks present in the complexes

The origin of the Palaeoproterozoic AMCG complexes in the Ukrainian shield: New U-Pb ages and Hf isotopes in zircon

© 2017 Elsevier B.V.The Ukrainian shield hosts two Palaeoproterozoic anorthosite-mangerite-charnockite-granite (AMCG) complexes (the Korosten and Korsun-Novomyrhorod complexes) that intruded Palaeoproterozoic continental crust in north-western and central parts of the shield, respectively. We report results of U-Pb zircon and baddeleyite dating of 16 samples from the Korosten plutonic complex (KPC), and 6 samples from the Korsun-Novomyrhorod plutonic complex (KNPC). Fifteen zircon samples from both complexes were also analysed for Hf isotopes. These new, together with previously published data indicate that the formation of the KPC started at c. 1815 Ma and continued until 1743 Ma with two main phases of magma emplacement at 1800–1780 and 1770–1758 Ma. Each of the main phases of magmatic activity included both basic and silicic members. The emplacement history of the KNPC is different from that of the KPC. The vast majority of the KNPC basic and silicic rocks were emplaced between c. 1757 and 1750 Ma; the youngest stages of the complex are represented by monzonites and syenites that were formed between 1748 and 1744 Ma. Both Ukrainian AMCG complexes are closely associated in space and time with mantle-derived mafic and ultramafic dykes. The Hf isotope ratios in the zircons indicate a predominantly crustal source for the initial melts with some input of juvenile Hf from mantle-derived tholeiite melts. The preferred model for the formation of the Ukrainian AMCG complexes involves the emplacement of large volumes of hot mantle-derived tholeiitic magma into the lower crust. This resulted in partial melting of mafic lower-crustal material, mixing of lower crustal and tholeiitic melts, and formation of ferromonzodioritic magmas. Further fractional crystallization of the ferromonzodioritic melts produced the spectrum of basic rocks in the AMCG complexes. Emplacement of the ferromonzodioritic and tholeiitic melts into the middle crust and their partial crystallization caused abundant melting of the ambient crust and formation of the large volumes of granitic rocks present in the complexes

ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura

The activity of ADAMTS13, the von Willebrand factor cleaving protease, is deficient in patients with thrombotic thrombocytopenic purpura (TTP). In the present study, the phenotype of ADAMTS13 in TTP and in normal plasma was demonstrated by immunoblotting. Normal plasma (n = 20) revealed a single band at 190 kD under reducing conditions using a polyclonal antibody, and a single band at 150 kD under non-reducing conditions using a monoclonal antibody. ADAMTS13 was not detected in the plasma from patients with congenital TTP (n = 5) by either antibody, whereas patients with acquired TTP (n = 2) presented the normal phenotype. Following immunoadsorption of immunoglobulins, the ADAMTS13 band was removed from the plasma of the patients with acquired TTP, but not from that of normal individuals. This indicates that ADAMTS13 is complexed with immunoglobulin in these patients. The lack of ADAMTS13 expression in the plasma from patients with hereditary TTP may indicate defective synthesis, impaired cellular secretion, or enhanced degradation in the circulation. This study differentiated between normal and TTP plasma, as well as between congenital and acquired TTP. This method may, therefore, be used as a complement in the diagnosis of TTP

The Lovisa stratiform Zn-Pb deposit, Bergslagen, Sweden : Structure, stratigraphy, and ore genesis

Medium- to high-grade metamorphosed, 1.9 Ga, stratiform, syngenetic Zn-Pb±Ag sulfide deposits comprise an economically important type of ore deposit in the Bergslagen lithotectonic unit of the Fennoscandian shield. The Lovisa Zn-Pb deposit occurs in a metamorphosed succession of rhyolitic ash-siltstone, rhyolitic mass flow deposits, limestone and iron formation, deposited at a stage of waning volcanism in Bergslagen. Accessory graphite, absence of Ce anomalies in shale-normalized rare-earth element (REE) data, and absence of hematite in Mn-rich iron formations stratigraphically below the Lovisa Zn-Pb deposit indicate a suboxic-anoxic depositional environment. The uppermost Mn-rich iron formation contains disseminated, inferred syngenetic Pb-Ag mineralization with mainly negative δ34S values in sphalerite and galena (-6.1 to -1.9‰). Deposition of this iron formation terminated during a pulse of explosive felsic volcanism. The Lovisa Zn-Pb deposit is interpreted to have formed in an alkali-rich brine pool developed immediately after this volcanic event, based on lithogeochemical and stratigraphic evidence. The first stage of mineralization deposited stratiform sphalerite mineralization with mainly positive δ34S values (-0.9 to +4.7‰). This was succeeded by deposition of more sphalerite-galena stratiform mineralization with δ34S values close to 0‰ (-2.1 to +1.5‰). The more galena-rich mineralization partitioned strain and was partly remobilized during later ductile deformation. The stratigraphic context, sulfide mineralogy, sulfur isotopes and alteration geochemistry suggest that the metalliferous fluids and the depositional environment were H2S-deficient (S-poor or SO42--dominant). The source of sulfur is interpreted to have been a mixture of H2S derived from bacterial and thermochemical seawater sulfate reduction, and sulfur derived from leaching of volcanic rocks, with the latter becoming more important over time. Lovisa formed in a setting where basin subsidence was periodically punctuated by the deposition of thick, syn-eruptive felsic volcaniclastic massflow deposits. Coeval volcanism was likely important for driving hydrothermal activity and supplying a reservoir of metals and sulfur. However, the high rate of deposition of volcaniclastic sediment in Bergslagen also precluded the establishment of long-lived, deep and anoxic environments favorable for accumulation of organic matter and H2S. This stratigraphic pattern is common in Bergslagen and may explain why large stratiform Zn-Pb deposits are uncommon in the region and restricted to the uppermost part of the metavolcanic succession, directly stratigraphically beneath post-volcanic pelitic rocks.Validerad;2018;Nivå 2;2018-05-04 (andbra)Conceptual modelling and exploration criteria for stratiform Zn-Pb-Ag-(Cu) Deposits in Bergslagen, Swede

The prognostic impact of karyotypic subgroups in myelodysplastic syndromes is strongly modified by sex

The prognostic impact of karyotypic patterns in a consecutive series of 389 adult myelodysplastic syndromes (MDS) was investigated. Time period did not significantly influence the survival times. In the analyses, the MDS cases were subdivided into the cytogenetic subgroups used in the International Prognostic Scoring System, i.e. favourable [-Y, del(5q) or del(20q) as single aberrations or normal karyotype, n = 241], poor [-7, del(7q), der(1;7) or complex karyotypes, i.e. > or = three abnormalities, n = 89] and intermediate (other aberrations, n = 59). The survival times correlated well with the prognostic subgroups, confirming that the cytogenetic classification was valid. Expressed as hazard ratios (HRs), with the favourable subgroup as the reference, the intermediate and poor subgroup HRs increased to 1.5 (95% confidence interval, 1.1-2.1) and 3.2 (2.4-4.1) respectively. Sex, age, morphological subtype and smoking habits significantly modified this prognostic impact. Shorter survival was detected for men in the favourable and the intermediate subgroups, but not in the poor prognosis subgroup. Using women in the favourable subgroup as the reference and adjusting for age, the HR for men was 1.6 (1.2-2.1) in the favourable subgroup. Adjusting for smoking habits as well decreased the HR to 1.4 (1.1-2.0) and, when also excluding cases with del(5q) as the sole anomaly, no significant difference could be discerned [HR 1.2 (0.9-1.6], suggesting that the better outcome for women in the favourable subgroup was mainly as a result of the '5q-syndrome' and to smoking habits. In the intermediate subgroup, the corresponding HRs were 3.0 (1.5-6.0) when adjusted for age and 2.7 (1.3-5.5) when also adjusted for smoking habits. Different survival times between men and women have never previously been reported for this MDS group. Although it remains to be elucidated whether environmental and/or constitutional factors cause the observed sex-related difference, these observations have obvious clinical ramifications, not least in designing and evaluating therapy protocols

Acute myeloid leukemia with inv(16)(p13q22): Involvement of cervical lymph nodes and tonsils is common and may be a negative prognostic sign.

Acute myeloid leukemia (AML) with inv(16)(p13q22) or the variant t(16;16)(p13;q22), is strongly associated with the FAB subtype M4Eo. A high incidence of CNS involvement was reported in the 1980s, but otherwise little is known about the pattern of extamedullary leukemia (EML) manifestations in this AML type. We have compiled clinical and cytogenetic data on 27 consecutive AML cases with inv(16)/t(16;16) from southern Sweden. In general, these AMLs displayed the clinical features that have previously been described as characteristic for this disease entity: low median age, hyperleukocytosis, M4Eo morphology, and a favorable prognosis. However, CNS leukemia was only seen in relapse in one patient diagnosed in 1980, whereas the most common EML manifestation in our series was lymphadenopathy (5/27, 19%), most often cervical with or without gross tonsillar enlargement. A review of previously published, clinically informative cases corroborates that lymphadenopathy, with preference for the cervical region, is the most common EML at diagnosis in inv(16)-positive AML (58/175, 33%). CNS leukemia, on the other hand, has been reported in only 17% of the cases, mostly in the relapse setting, with a diminishing frequency over time, possibly due to protective effects of high-dose cytarabine. Other reported EML sites include the scalp, ovaries, and the intestine. Cervicotonsillar EML was in our series associated with a shorter duration of first remission, (P < 0.05), and may hence prove to be an important clinical parameter when deciding treatment strategies in AML with inv(16)/t(16;16). Am. J. Hematol. 71:15-19, 2002

The Lovisa Stratiform Zn-Pb Deposit, Bergslagen, Sweden: Structure, Stratigraphy, and Ore Genesis

Medium- to high-grade metamorphosed, 1.9 Ga, stratiform, syngenetic Zn-Pb ± Ag sulfide deposits constitute an economically important type of ore deposit in the Bergslagen lithotectonic unit of the Fennoscandian Shield. The Lovisa Zn-Pb deposit occurs in a metamorphosed succession of rhyolitic ash-siltstone, rhyolitic mass flow deposits, limestone, and Fe formation, deposited at a stage of waning volcanism in Bergslagen. Accessory graphite, absence of Ce anomalies in shale-normalized rare earth element (REE) data, and absence of hematite in Mn-rich Fe formations stratigraphically below the Lovisa Zn-Pb deposit indicate a suboxic-anoxic depositional environment. The uppermost Mn-rich Fe formation contains disseminated, inferred syngenetic Pb-Ag mineralization with mainly negative δ34S values in sphalerite and galena (–6.1 to –1.9‰). Deposition of this Fe formation terminated during a pulse of explosive felsic volcanism. The Lovisa Zn-Pb deposit is interpreted to have formed in an alkali-rich brine pool developed immediately after this volcanic event, based on lithogeochemical and stratigraphic evidence. The first stage of mineralization deposited stratiform sphalerite mineralization with mainly positive δ34S values (–0.9 to 4.7‰). This was succeeded by deposition of more sphalerite-galena stratiform mineralization with δ34S values close to 0‰ (–2.1 to 1.5‰). The more galena-rich mineralization partitioned strain and was partly remobilized during later ductile deformation. The stratigraphic context, sulfide mineralogy, S isotopes, and alteration geochemistry suggest that the metalliferous fluids and the depositional environment were H2S deficient (S poor or SO4 2– dominant). The source of S is interpreted to have been a mixture of H2S derived from bacterial and thermochemical seawater sulfate reduction and S derived from leaching of volcanic rocks, with the latter becoming more important over time. Lovisa formed in a setting where basin subsidence was periodically punctuated by the deposition of thick, syneruptive felsic volcaniclastic mass flow deposits. Coeval volcanism was likely important for driving hydrothermal activity and supplying a reservoir of metals and S. However, the high rate of deposition of volcaniclastic sediment in Bergslagen also precluded the establishment of long-lived, deep, and anoxic environments favorable for accumulation of organic matter and H2S. This stratigraphic pattern is common in Bergslagen and may explain why large stratiform Zn-Pb deposits are uncommon in the region and restricted to the uppermost part of the metavolcanic succession, directly stratigraphically beneath postvolcanic pelitic rocks.This article is published as Jansson, N. F., Stefan Sädbom, R. L. Allen, Kjell Billström, and Paul G. Spry. "The Lovisa stratiform Zn-Pb deposit, Bergslagen, Sweden: structure, stratigraphy, and ore genesis." Economic Geology 113, no. 3 (2018): 699-739. doi:10.5382/econgeo.2018.4567.</p