Messinian age and savannah environment of the possible hominin Graecopithecus from Europe.

Dating fossil hominids and reconstructing their environments is critically important for understanding human evolution. Here we date the potentially oldest hominin, Graecopithecus freybergi from Europe and constrain the environmental conditions under which it thrived. For the Graecopithecus-bearing Pikermi Formation of Attica/Greece, a saline aeolian dust deposit of North African (Sahara) provenance, we obtain an age of 7.37-7.11 Ma, which is coeval with a dramatic cooling in the Mediterranean region at the Tortonian-Messinian transition. Palaeobotanic proxies demonstrate C4-grass dominated wooded grassland-to-woodland habitats of a savannah biome for the Pikermi Formation. Faunal turnover at the Tortonian-Messinian transition led to the spread of new mammalian taxa along with Graecopithecus into Europe. The type mandible of G. freybergi from Pyrgos (7.175 Ma) and the single tooth (7.24 Ma) from Azmaka (Bulgaria) represent the first hominids of Messinian age from continental Europe. Our results suggest that major splits in the hominid family occurred outside Africa.

Odontogenic differentiation and biomineralization potential of dental pulp stem cells inside Mg-based bioceramic scaffolds under low-level laser treatment.

This study aimed to investigate the potential of low-level laser irradiation (LLLI) to promote odontogenic differentiation and biomineralization by dental pulp stem cells (DPSCs) seeded inside bioceramic scaffolds. Mg-based, Zn-doped bioceramic scaffolds, synthesized by the sol-gel technique, were spotted with DPSCs and exposed to LLLI at 660 nm with maximum output power of 140 mw at fluencies (a) 2 and 4 J/cm2 to evaluate cell viability/proliferation by the MTT assay and (b) 4 J/cm2 to evaluate cell differentiation, using real-time PCR (expression of odontogenic markers) and a p-nitrophenylphosphate (pNPP)-based assay for alkaline phosphatase (ALP) activity measurement. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis were used for structural/chemical characterization of the regenerated tissues. Exposure of the DPSCs/scaffold complexes to the proposed LLLI scheme was associated with statistically significant increase of odontogenesis-related markers (bone morphogenetic protein 2 (BMP-2): 22.4-fold, dentin sialophosphoprotein (DSPP): 28.4-fold, Osterix: 18.5-fold, and Runt-related transcription factor 2 (Runx2): 3.4-fold). ALP activity was significantly increased at 3 and 7 days inside the irradiated compared to that in the non-irradiated SC/DPSC complexes, but gradually decreased until 14 days. Newly formed Ca-P tissue was formed on the SC/DPSC complexes after 28 days of culture that attained the characteristics of bioapatite. Overall, LLLI treatment proved to be beneficial for odontogenic differentiation and biomineralization of DPSCs inside the bioceramic scaffolds, making this therapeutic modality promising for targeted dentin engineering.

Severe impairment of regulatory T-cells and Th1-lymphocyte polarization in patients with Gaucher disease.

We investigated peripheral blood T-lymphocyte subpopulations and intracellular expression of IFN-γ, IL-4, IL-10, and IL-13, by whole blood flow cytometry, in 22 type I Gaucher disease (GD) patients. Results were compared with those of 19 sex- and age-matched controls. Patients with GD exhibited decreased frequencies and absolute numbers of CD3+/CD4+ helper T lymphocytes (40.8 ± 9.8% vs. 49.4 ± 5.7%, p = 0.002, and 0.77 ± 0.33 vs. 1.04 ± 0.28 × 10(9)/µL, p = 0.011), as well as increased frequencies of CD3+CD8+ suppressor T lymphocytes (23.8 ± 8.0% vs. 18.4 ± 3.8%, p = 0.010), resulting in a significantly decreased CD4/CD8 cell ratio (p < 0.001). Moreover, they had significantly increased percentages of IFNγ-producing both CD4+ and CD8+ T cells (p = 0.0003 and p = 0.023, respectively), implying a TH-1 polarization pattern. Finally, patients with GD had decreased percentages and absolute numbers of CD4+CD25(dim) T lymphocytes (p = 0.033 and p = 0.007, respectively), of CD4+CD25(high) T lymphocytes (p = 0.039 and p = 0.016, respectively), and of CD4+CD25(high)FOXP3+ regulatory T cells (p = 0.036 and p = 0.019, respectively). Our results demonstrate that patients with GD have a significant numerical impairment of T-helper lymphocytes and a constitutive TH1 direction pattern of activation of both CD4+ and CD8+ cells, associated with a significant decrease of T-regs. Ineffective T-cell control may explain the chronic inflammatory reaction and the increased incidence of lymphoid malignancies, which have been repeatedly reported among patients with GD.

Alterations in T-lymphocyte subpopulations in patients with complicated liver cirrhosis.

AIM: To investigate possible alterations of T-lymphocyte subpopulations in patients with cirrhosis complicated with infection and variceal bleeding, and to evaluate the relationship between T-lymphocyte subpopulations and outcome. PATIENTS AND METHODS: This was a prospective study on 99 patients with liver cirrhosis, who were admitted to a university hospital over a period of 18 months. Twenty-six patients (37.6%, group A) were admitted for reasons other than infection or bleeding, 24 (34.7%, group B) presented with sepsis, and 19 (27.5%, group C) were admitted with variceal bleeding. A group of 30 healthy individuals admitted to the hospital without cirrhosis and served as the control group. We evaluated T-cell subsets CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils by using flow cytometry. Measurements for group A were taken only on admission, while for patients of group B and C measurements were repeated on the third and the last hospital day. RESULTS: T-cell subsets (CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils) were reduced in septic cirrhotics, but this reduction was not statistically significant compared to the other groups. A significant decrease was observed in T helper cells between cirrhotic patients with and without variceal bleeding (day 3: CD4: 293 ± 214 versus 442 ± 277 [P < 0.049]; discharge day: CD4:178 ± 113 versus 442 ± 277 [P < 0.003]). Concerning phagocytic potential as detected by CD14 and/or CD64 expression on monocytes and neutrophils, a significant decrease was noted in septic versus nonseptic cirrhotics (day 1: 61.66 ± 40.16 versus 252 ± 73 [P < 0.039]; day 3: 66.99 ± 34.64 versus 252 ± 73 [P < 0.042]). CONCLUSIONS: Our study showed that the T helper cells and phagocytic potential of monocytes and neutrophils are decreased in patients with liver cirrhosis complicated by sepsis and variceal bleeding. Particularly, these abnormalities seem to be more pronounced in cirrhosis with variceal bleeding. To our knowledge, this is the first study to show these T-cell abnormalities in patients with cirrhosis. Further studies are needed to confirm these findings.

A case of severe ADAMTS13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy.

INTRODUCTION: Thrombotic thrombocytopenic purpura is a rare life-threatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. CASE REPORT: We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency < 5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5 x volume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. DISCUSSION: Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. CONCLUSION: Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

T-lymphocyte subsets in peripheral blood and liver tissue of patients with chronic hepatitis B and C.

AIM: To evaluate the immune response in peripheral blood and liver tissue, through the measurement of T-cell subsets, in patients with chronic hepatitis B (CHB) and C (CHC). PATIENTS AND METHODS: Thirty-four patients with CHB (21 with active HBV infection and 13 inactive HBV carriers) and 20 patients with CHC were included in the study. We also evaluated 21 biopsies from patients with active CHB infection and 20 patients with CHC. We measured CD3, CD4, CD8 and CD4/CD8 ratio in peripheral blood and liver tissue. RESULTS: We found no differences in the numbers of all T-lymphocyte subpopulations between patients with active HBV infection and inactive carriers. We found a significant increase in the absolute numbers of CD3(+), CD4(+) and CD8(+) T-lymphocytes in CHC compared to CHB patients (p=0.005, p=0.034 and p<0.0001 respectively). There was a significant increase in the number of CD3(+) and CD8(+) T-lymphocytes in the area of portal tracts (p=0.012 and p=0.009 respectively) and lobules (p=0.011 and p=0.01 respectively) in patients with CHC compared to those with CHB. In both groups there was a direct correlation between CD3(+) cells in portal tracts and HAI score (r=0.783, p=0.008), while we noted a correlation between CD8(+) cells in portal tracts and HAI score only in patients with CHC. Interface hepatitis correlated to CD3(+) cells in lobules of patients with CHC and CHB but a direct relationship between CD8(+) cells and HAI score was found only in those with CHC. CONCLUSION: Insufficient cellular immune response is critical for the ineffective virus clearance and liver damage in chronic hepatitis B, while in chronic hepatitis C, immune response, as represented by CD8(+) T-cells, is present in the peripheral blood and the liver. However, there is an immunological escape of HCV, which seems to survive in the presence of an adequate immune response. The significant correlation between portal and periportal CD8(+) T-lymphocyte expression and interface hepatitis may be considered evidence of the occurrence of cytotoxic immune-mediated toxicity.

Arabidopsis FHY3 specifically gates phytochrome signaling to the circadian clock.

Circadian gating of light signaling limits the timing of maximum responsiveness to light to specific times of day. The fhy3 (for far-red elongated hypocotyl3) mutant of Arabidopsis thaliana is involved in independently gating signaling from a group of photoreceptors to an individual response. fhy3 shows an enhanced response to red light during seedling deetiolation. Analysis of two independent fhy3 alleles links enhanced inhibition of hypocotyl elongation in response to red light with an arrhythmic pattern of hypocotyl elongation. Both alleles also show disrupted rhythmicity of central-clock and clock-output gene expression in constant red light. fhy3 exhibits aberrant phase advances under red light pulses during the subjective day. Release-from-light experiments demonstrate clock disruption in fhy3 during the early part of the subjective day in constant red light, suggesting that FHY3 is important in gating red light signaling for clock resetting. The FHY3 gating function appears crucial in the early part of the day for the maintenance of rhythmicity under these conditions. However, unlike previously described Arabidopsis gating mutants that gate all light signaling, gating of direct red light-induced gene expression in fhy3 is unaffected. FHY3 appears to be a novel gating factor, specifically in gating red light signaling to the clock during daytime.