Total knee arthroplasty using computer-assisted navigation in patients with deformities of the femur and tibia: A report of 5 cases

Anatomic aberrations of the femur and tibia secondary to trauma, congenital defects, and prior surgery present challenges for the reconstructive knee surgeon because of an altered mechanical axis and distorted anatomic landmarks. Five patients with arthritis of the knee and extra-articular femoral and/or tibial deformity, retained hardware, or intramedullary (IM) implants underwent total knee arthroplasty using a computer navigation system. The navigation system obviated the need for an IM guide, and the normal mechanical axis of the patients was restored. Extensive dissection for hardware removal or osteotomy was not necessary in these patients. In these 5 cases, a navigation system proved to be an effective tool for restoration of limb alignment in the presence of significant extra-articular deformities and/or IM hardware. Thus, it provides an alternative approach to the traditional IM instrumentation for treating these patients in an effective manner

Impacts of extreme 2013–2014 winter conditions on Lake Michigan's fall heat content, surface temperature, and evaporation

Since the late 1990s, the Laurentian Great Lakes have experienced persistent low water levels and above average over‐lake evaporation rates. During the winter of 2013–2014, the lakes endured the most persistent, lowest temperatures and highest ice cover in recent history, fostering speculation that over‐lake evaporation rates might decrease and that water levels might rise. To address this speculation, we examined interseasonal relationships in Lake Michigan's thermal regime. We find pronounced relationships between winter conditions and subsequent fall heat content, modest relationships with fall surface temperature, but essentially no correlation with fall evaporation rates. Our findings suggest that the extreme winter conditions of 2013–2014 may have induced a shift in Lake Michigan's thermal regime and that this shift coincides with a recent (and ongoing) rise in Great Lakes water levels. If the shift persists, it could (assuming precipitation rates remain relatively constant) represent a return to thermal and hydrologic conditions not observed on Lake Michigan in over 15 years.Key PointsLake Michigan has been in an altered thermal regime since the late 1990sThe 2013–2014 winter may return Lake Michigan to pre‐1998 thermal conditionsHydrological impacts of the 2013–2014 cold winter remain unclearPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112001/1/grl52850.pd

Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell

Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells

Giant rafted pumice blocks from the most recent eruption of Taupo volcano, New Zealand: Insights from palaeomagnetic and textural data

Giant blocks of pumice lie strewn along a former shoreline of intracaldera Lake Taupo, New Zealand, and are the sole subaerial evidence of the most recent volcanism at the Taupo supervolcano. Geochemically they are identical to material erupted during the complex and multiphase 1.8 ka Taupo eruption, which they post-date by one to two decades. The blocks, some of which are >10 m long, show complex jointing patterns indicative of both surface chilling and continued interior expansion, as well as heterogeneous vesicularity, with dense rims (mean density 917 kg/m3) grading via an intervening transition zone (mean density 844 kg/m3) into a more highly vesicular interior (mean density 815 kg/m3). Analysis of thermal demagnetisation data indicates significant reorientation of the blocks as they cooled through a series of blocking temperatures. Some parts of block rims cooled to below 580 °C well before emplacement on the shore, whereas other parts in the interior and transition zones, which cooled more slowly, acquired different orientations before stranding. Some block interiors cooled after blocks were finally deposited, and record the direction of the 1.8 ka field. The blocks are believed to be derived from one or both of a pair of rhyolitic lava domes that developed on the bed of Lake Taupo several decades after the climactic Taupo eruption over the inferred vent area.These, and similar giant rafted pumice blocks in other marine and lacustrine settings raise a number of questions about how volatile-rich felsic magma can be erupted underwater with only limited thermal fragmentation. Furthermore, the prolonged flotation of out-sized fragments of vesiculated magma formed during subaqueous dome-growth contrasts with the rapid sinking of smaller pieces of hot plinian pumice under laboratory conditions. The genesis of pumice forming the blocks is not entirely clear. Most simply the blocks may represent part of a vesiculated carapace of a growing lava dome, broken loose as the dome grew and deformed then rising buoyantly to the surface. Parts of the carapace could also be released by local magma-water explosions. Some textures of the pumice, however, suggest fresher magma released from beneath the carapace. This may suggest that silicic dikes and pillows/pods intruded into a growing mound of silicic hyaloclastite, itself formed by quench fragmentation and thermal granulation of the dike margins. This fragmental cover would have inhibited cooling of a still-hot and actively vesiculating interior, which was then released to float to the surface by gravitational destabilisation and collapse of the growing pile. Following their formation, the large fragments of pumice floated to the lake's surface, where they were blown ashore to become embedded in accumulating transgressive shoreface sediments and continue cooling

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival