Increased micronucleus frequency after oral administration of cadmium in dogs

Cadmium (Cd) is a toxic heavy metal that has been classified as a human carcinogen by the International Agency for Research on Cancer. The genotoxic effects of cadmium oxide (CdO) were investigated in cultured dog lymphocytes after a short-term oral CdO administration by the micronucleus (MN) test. The dogs were given 10 mg CdO/kg body weight per day for 3 and 28 d, respectively group I (n=7) and group II (n=6). Blood samples were collected at the beginning of feeding and at 4 and 29 d after Cd administration and cultured for 72 h. Whereas no significant increase in the MN frequency in group I was observed (p=0.398), a significant MN induction with CdO was found in group II (p=0.028) when compared with initial MN frequencies of dogs in both groups. Our results suggest that CdO might be directly and/or indirectly genotoxic after a monthly oral administration of CdO in dogs.     

The Effects of Leptin on Rat Brain Development; An Experimental Study

International Journal of Peptide Research and Therapeutics -     

The stiffness characteristics of hybrid Ilizarov fixators

The use of hybrid Ilizarov models around femoral area is gaining clinical popularity lately. Hybrid systems show different mechanical properties. The purpose of this report is to examine the stiffness characteristics of the C-arch and half-pins on the hybrid Ilizarov fixators. Eight models that included standard Ilizarov and hybrid models were applied to six femoral sawbones. The distal part of fixation was composed of a two-ring frame applied identically to all bones. The difference of the configuration was at the proximal part, where half-pins with or without C-arches were either added to the proximal two-ring frame or replaced the proximal one- or two-ring frame. Osteotomy was performed in the femoral diaphysis and the bone was distracted 2cm. The stability of the system was tested with the axial compression testing machine. Displacements between the adjacent fracture sides were measured with the video extensometer in three dimensions. We found that proximal half-pin applications alone had less stiffness, but half-pins with C-arch had more stiffness than the model including only half-pins. Additional half-pins onto one- or two-ring frames had more longitudinal stiffness, but this system showed weak resistance against transverse displacement.     

IFN-gamma and Fas ligand are required for graft-versus-tumor activity against renal cell carcinoma in the absence of lethal graft-versus-host disease

To determine the mechanisms of graft-versus-tumor (GVT) activity in the absence of graft-versus-host disease (GVHD) against a solid tumor, we established two allogeneic bone marrow transplantation models with a murine renal cell carcinoma (RENCA). The addition of 0.3 x 10(6) donor CD8(+) T cells to the allograft increased the survival of tumor-bearing mice without causing GVHD. The analysis of CD8(+) T cells deficient in cytotoxic molecules demonstrated that anti-RENCA activity is dependent on IFN-gamma and Fas ligand (FasL), but does not require soluble or membrane-bound TNF-alpha, perforin, or TRAIL. Recipients of IFN-gamma(-/-) CD8(+) T cells are unable to reject RENCA compared with recipients of wild-type CD8(+) T cells and, importantly, neither group develops severe GVHD. IFN-gamma(-/-) CD8(+) T cells derived from transplanted mice are less able to kill RENCA cells in vitro, while pretreatment of RENCA cells with IFN-gamma enhances class I and FasL expression and rescues the lytic capacity of IFN-gamma(-/-) CD8(+) T cells. These results demonstrate that the addition of low numbers of selected donor CD8(+) T cells to the allograft can mediate GVT activity without lethal GVHD against murine renal cell carcinoma, and this GVT activity is dependent on IFN-gamma and FasL.     

Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation

Delayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.     

Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality

Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8⁺ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.     

Comparative phylogeography of two African carnivorans presumably introduced into Europe: disentangling natural versus human‐mediated dispersal across the Strait of Gibraltar

Aim Natural processes of colonization and human‐mediated introductions have shaped current patterns of biodiversity in the Mediterranean Basin. We use a comparative phylogeographic approach to investigate the genetic structure of Herpestes ichneumon and Genetta genetta (Carnivora) across the Strait of Gibraltar, and test for their supposedly contemporaneous introduction into Iberia. Location Mediterranean Basin and Africa. Methods We sequenced two mitochondrial fragments (cytochrome b and control region) of 91 (H. ichneumon) and 185 (G. genetta) individuals, including the sole archaeological record of G. genetta in Iberia, dating from the Muslim occupation. We used phylogenetic and tokogenetic methods, summary statistics, neutrality tests, geographic–genetic pairwise comparisons and coalescent estimates to explore the history of the two species in the Mediterranean Basin. Results In North Africa, an autochthonous (Clade I) and a western African mtDNA clade, coalescing in the Middle to Late Pleistocene, co‐occurred in both species. Only Clade I was present in Europe. In H. ichneumon, the European pool showed deep coalescence (median = 335 kyr) and high genetic differentiation and diversity compared with its North African counterpart, suggesting long‐term stability of female effective population size. In sharp contrast, G. genetta in Europe exhibited lower genetic diversity, weak differentiation with North Africa and recent demographic expansion; however, Andalusia and Catalonia (Spain) showed distinctly higher genetic diversity, and the archaeological specimen had the predominant European haplotype. Main conclusions The co‐occurrence of autochthonous and sub‐Saharan lineages in North Africa (1) supports a new, emerging biogeographic scenario in North Africa, and (2) suggests a connection through the Sahara, possibly from the Middle Pleistocene onwards. Our results refute the idea that H. ichneumon was introduced into Europe contemporaneously with G. genetta. Instead, they support a scenario of sweepstake dispersal during Late Pleistocene sea‐level fluctuations, followed by long‐term in situ evolution throughout the last glaciation cycles. Genetta genetta appears to have undergone a recent spread from at least two independent introduction ‘hotspots’ in Catalonia and Andalusia, possibly following antique trade routes and/or Muslim invasions. Despite their contrasting histories, the European gene pools of both species represent unusual cases leading to the preservation of autochthonous, North African lineages.     

Thiamine-responsive megaloblastic anemia syndrome: a novel mutation

The thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural hearing loss due to mutations in SLC 19A2 that encodes a thiamine transporter protein. The disease can manifest at any time between infancy and adolescence, and not all cardinal findings are present initially. The anemia typically improves significantly with pharmacological doses of thiamine. Variable improvement in diabetes is also noted. However, the hearing loss is apparently irreversible, although a delay in the onset of deafness may be possible. We present a 2-year old girl with non-autoimmune diabetes mellitus and anemia in whom we found a novelc.95T>A (leu32X) mutation in the SLC19A2 gene in this study.Our patient with this new mutation did not suffer from hearing loss.