Improved Accuracy with 3D Planning and Patient-Specific Instruments During Simulated Pelvic Bone Tumor Surgery

In orthopaedic surgery, resection of pelvic bone tumors can be inaccurate due to complex geometry, limited visibility and restricted working space of the pelvis. The present study investigated accuracy of patient-specific instrumentation (PSI) for bone-cutting during simulated tumor surgery within the pelvis. A synthetic pelvic bone model was imaged using a CT-scanner. The set of images was reconstructed in 3D and resection of a simulated periacetabular tumor was defined with four target planes (ischium, pubis, anterior ilium, and posterior ilium) with a 10-mm desired safe margin. Patient-specific instruments for bone-cutting were designed and manufactured using rapid-prototyping technology. Twenty-four surgeons (10 senior and 14 junior) were asked to perform tumor resection. After cutting, ISO1101 location and flatness parameters, achieved surgical margins and the time were measured. With PSI, the location accuracy of the cut planes with respect to the target planes averaged 1 and 1.2 mm in the anterior and posterior ilium, 2 mm in the pubis and 3.7 mm in the ischium (p < 0.0001). Results in terms of the location of the cut planes and the achieved surgical margins did not reveal any significant difference between senior and junior surgeons (p = 0.2214 and 0.8449, respectively). The maximum differences between the achieved margins and the 10-mm desired safe margin were found in the pubis (3.1 and 5.1 mm for senior and junior surgeons respectively). Of the 24 simulated resection, there was no intralesional tumor cutting. This study demonstrates that using PSI technology during simulated bone cuts of the pelvis can provide good cutting accuracy. Compared to a previous report on computer assistance for pelvic bone cutting, PSI technology clearly demonstrates an equivalent value-added for bone cutting accuracy than navigation technology. When in vivo validated, PSI technology may improve pelvic bone tumor surgery by providing clinically acceptable margins.     

Intestinal IFN-γ production is associated with protection from clinical signs,but not with elimination of worms,in Echinostoma caproni infected-mice

In the present paper, we assess the relationship between the expression of IFN-γ and the development of clinical signs in Echinostoma caproni-infected mice. For this purpose, we studied the course of the infection in three mouse strains: ICR (CD-1®) (a host of high compatibility with E. caproni), BALB/c (a prototypical Th2 strain), and BALB/c deficient for IFN-γ mice (IFN-γ^?/?). Infection in ICR mice is characterized by the elevated expression of IFN-γ and iNOS in the intestine concomitantly with the lack of clinical signs. In contrast, the infection was more virulent in BALB/c and IFN-γ-deficient mice that developed a severe form of the disease together with the absence of IFN-γ expression. The disease was more severe in IFNγ^?/? mice in which the disease was lethal during the few first weeks of the infection. The analysis of different parameters of the infection in each host strain showed that most of the features were similar in the three mouse strains, suggesting the IFN-γ plays a central role in that protection against severe disease. Thus, IFN-γ seems to play a dichotomous role in the infection facilitating the parasite establishment, but it may also benefit mice since it protects the mice from morbidity and mortality induced by the parasite.     

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.     

Levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta in intervillous blood plasma samples from women with placental malaria and human immunodeficiency virus infection

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta play an important role in modulating immune responses. To understand their importance in immunity to placental malaria (PM) and in human immunodeficiency virus (HIV)-PM coinfection, we investigated levels of these chemokines in the placental intervillous blood plasma (IVB plasma) and cord blood plasma of HIV-negative PM-negative, HIV-negative PM-positive, HIV-positive PM-negative, and HIV-positive PM-positive women. Compared to HIV-negative PM-negative women, the MIP-1 beta concentration in IVB plasma was significantly elevated in HIV-negative PM-positive women and HIV-positive PM-positive women, but it was unaltered in HIV-positive PM-negative women. Also, PM-infected women, irrespective of their HIV status, had significantly higher levels of MIP-1 beta than HIV-positive PM-negative women. The MIP-1 alpha level was not altered in association with either infection. The IVB plasma levels of MIP-1 alpha and MIP-1 beta positively correlated with the cord blood plasma levels of these chemokines. As with IVB plasma, only cord plasma from PM-infected mothers had significantly elevated levels of MIP-1 beta compared to PM-negative mothers, irrespective of their HIV infection status. MIP-1 beta and MIP-1 alpha levels in PM-positive women were positively associated with parasite density and malaria pigment levels. Regardless of HIV serostatus, the IVB MIP-1 beta level was significantly lower in women with PM-associated anemia. In summary, an elevated level of MIP-1 beta was associated with PM. HIV infection did not significantly alter these two chemokine levels in IVB plasma.     

B cell apoptosis accelerates the onset of murine lupus

To investigate whether the increased rate of lymphocyte apoptosis in systemic lupus erythematosus is involved in the onset of the disease, apoptotic or necrotic T or B lymphocytes from various cell lines were injected intraperitoneally into pre-autoimmune (NZBxNZW)F1 mice (BW) and non-autoimmune BALB/c mice. The intraperitoneal production of cytokines and chemokines, the specific T cell response in the spleen, and the production of anti-histone and anti-dsDNA Ab were investigated. The onset of the disease was characterized by creatinine levels and evaluation of glomerular IgG deposits. In BW, but not in BALB/c mice, injection of apoptotic and not necrotic cells up-regulated IL-6 and IL-10 in resident macrophages. Administration of apoptotic cells augmented the number of Th2 and B lymphocytes recruited in the peritoneal cavity. Only the treatment with apoptotic B cells promoted a systemic Th2 autoimmune response to H2 histones, associated with earlier occurrence of high levels of anti-dsDNA autoantibodies, higher creatinine levels and more numerous glomerular IgG deposits than in BW controls not injected with apoptotic B cells. In genetically susceptible mice exposure to apoptotic of B, but not T, lymphocytes can elicit a Th2 response to H2 histones that helps B cell production of anti-dsDNA Ab and finally triggers the onset of lupus.     

Peripheral Thy1+ lymphocytes rearranging TCR‐γδ genes in LAT‐deficient mice

Linker for activation of T cells (LAT) is an adaptor molecule indispensable for development of αβ and γδ T lymphocytes. Surprisingly, using a new model of LAT‐deficient mice we found that despite arrested thymic development, a discrete population of cells with active Lat promoter, expressing Thy1 molecules, accumulated in peripheral lymphoid organs of homozygous (Lat^Inv/Inv) mutant mice. By measuring frequencies of TCR gene rearrangements in conjunction with a panel of cell surface Ag, we dissected two subsets of these Thy1⁺ cells. Thy1^dull cells expressed markers of NK lymphocytes and contained low frequency of TCR‐γ gene rearrangements without detectable TCR‐δ rearrangements. Thy1^high cells resembled immature CD44⁺CD25⁺ thymocytes and contained high frequency of non‐productive TCR‐γ and TCR‐δ rearrangements, indicating that cells displaying molecular signatures of commitment toward γδ T‐cell lineage can develop and populate lymphoid tissues of LAT‐deficient mice. Phenotypically similar Thy1^high cells were also found in lymph nodes of lymphocyte‐deficient (Rag2^?/?) mice but not in T lymphocyte proficient, heterozygous Lat^+/Inv mice suggesting that Thy1^high cells of LAT‐deficient mice identified in this study accumulate in peripheral lymphoid organs as a result of congenital lymphopenia.