The intervertebral disc's (IVD) annulus fibrosus (AF) retains the hydrostatic pressure of the nucleus pulposus (NP), controls the range of motion, and maintains the integrity of the motion segment. ...The microstructure of the AF is not yet fully understood and quantitative characterization is lacking, leaving a caveat in modern medicine's ability to prevent and treat disc failure (e.g., disc herniation). In this study, we show a reconstruction of the 3D microstructure of the fibers that constitute the AF via MRI diffusion tensor imaging (DTI) followed by fiber tracking. A quantitative analysis presents an anisotropic structure with significant architectural differences among the annuli along the width of the fibrous belt. These findings indicate that the outer annuli's construction reinforces the IVD while providing a sufficient degree of motion. Our findings also suggest an increased role of the outer annuli in IVD nourishment.
The CRC is performed through binary polynomial division between the transmitted message and a polynomial divisor and is usually implemented using a linear feedback shift register (LFSR). An LFSR is a ...shift register where its next state is a linear combination of its previous state and input bits. In our context, the linear operators are Logical XOR and Logical AND.
The aim of this study was to define and compare the infectious and non-infectious complications associated with Hickman catheters and implantable ports in children. The study was conducted over a ...three-year period in the Department of Haematology–Oncology at the Schneider Children's Medical Center of Israel. All patients who required a central venous catheter (CVC) were included in the study. For each episode of catheter-associated bloodstream infection, demographic, clinical and microbiology data were recorded. During the study period, 419 tunnelled CVCs (246 implantable ports and 173 Hickman) were inserted in 281 patients. Compared with implantable ports, Hickman catheters were associated with a significantly higher rate of bloodstream infections (4.656 vs 1.451 episodes per 1000 catheter-days), shorter time to first infection (52.31 vs 108.82 days,
P<0.001), shorter duration of catheterization (140.75 vs 277.28 days,
P<0.001), and higher rate of removal because of mechanical complications (
P<0.005). Gram-positive bacterial infections were more prevalent in the implantable port group (63.6% vs 41.6%), whereas Gram-negative rods, polymicrobial infections and mycobacterial infections were more prevalent in the Hickman group (31.4% vs 50.9%, 17% vs 36% and 0% vs 4.4%, respectively;
P<0.05 for all). Haematopoietic stem cell transplantation was identified as an independent risk factor for infection odds ratio (OR) −1.68,
P=0.005 and for catheter removal due to complications (OR −2.0,
P<0.001). Implantable ports may be considered the preferred device for most paediatric oncology and stem cell transplantation patients.
The long interval between hematopoietic stem cell transplantation (HSCT) and hematopoietic engraftment and immune reconstitution is a dangerous time for patients. Although neutrophil counts usually ...rise within several weeks following stem cell transplantation, recovery of functional T and B cell repertoires can often take months; during this period patients are at risk for severe infections, and graft vs. tumor effects may be attenuated. We have examined the use of a recombinant fusion protein consisting of the N-terminal 9 amino acid segment of the HIV TAT protein transduction domain (PTD) fused to the MYC protein as a means of enhancing stem cell graft performance.
Methods: Coding sequences for the 9-amino acid TAT PTD and the cDNA encoding MYC were ligated in-frame and cloned into the pET101/D-Topo vector for expression in E Coli. The fusion protein, which we designated TBX-4000, was purified to homogeneity, analyzed for contaminants, and prepared to clinical grade for administration in accordance with good manufacturing practices.
Results: Following a 1-hour incubation of TBX-4000 with human cord blood cells, the chimeric protein appeared in the nucleus of target cells within 2 hours, but was rapidly metabolized, vanishing by 72 hours. Whole murine marrow and purified murine LSK+ cells that were incubated with TBX-4000 significantly out-performed control cells in competitive engraftment experiments in immune deficient recipient mice, even at ratios of 1:9 treated to control cells. Significantly higher numbers of T and B cells were recovered from both peripheral blood and splenic tissue of irradiated immune deficient mice transplanted with stem cell grafts that had been cultured for 60 minutes with TBX-4000, relative to control mice. TBX-4000 cultured cells demonstrate resistance to apoptosis induced by Granzyme B, which may account for their hardiness during engraftment in marrow niches recently exposed to the stress of pre-transplant conditioning therapy. Extensive toxicologic studies demonstrated that prolonged exposure to TBX-4000 does not cause malignant transformation of hematopoietic cells in culture, and does not lead to tumor formation in mice repeatedly injected with the recombinant protein. Mice transplanted with stem cells incubated with TBX-4000 did not develop leukemia or solid tumors during 4 months of follow-up, or following three “generations” of successive, serial transplantation. Because TBX-4000 augments immune reconstitution following hematopoietic stem cell transplantation and may stimulate graft vs. host diseases reactions, T and B cell depletion of the graft will be performed in pilot studies in humans to prevent this complication.
Conclusion: Brief exposure to the TAT-MYC recombinant fusion protein enhances the performance of hematopoietic stem cells in a pre-clinical transplantation model. The brief presence of the protein protects engrafting cells from apoptotic stimuli, and does not lead to transformation of the cells following transplantation. The efficacy and safety of TBX-4000 in our pre-clinical studies serve as the basis for currently planned clinical trials of this chimeric protein in patients undergoing stem cell transplantation.
Gregory:Taiga Biotechnologies, Inc.: Employment, Equity Ownership. Turner:Taiga Biotechnologies, Inc.: Employment, Equity Ownership. Refaeli:Taiga Biotechnologies, Inc.: Employment, Equity Ownership.
Current evidence indicates sub-optimal incidence of fertility preservation (FP) in eligible patients. We present herein our designated multidisciplinary program for FP in pediatric and adolescent ...population and present our data on FP in female patients.
Pediatric patients (age 0-18) who were candidate for highly gonadotoxic treatments were referred to FP program for a multidisciplinary discussion and gonadal risk-assessment followed by either oocyte cryopreservation or ovarian cryopreservation (OCP) for female patients, and sperm banking for male patients. The OCP protocol consists of aspiration of oocytes from small antral follicles and in-vitro maturation followed by cryopreservation, as well as ovarian tissue cryopreservation.
The establishment of a designated FP program resulted in a significant increase in referral and subsequent FP procedures of all eligible patients. Sixty-two female patients were referred for FP discussion during a period of 36 months; 41 underwent OCP; 11 underwent oocyte cryopreservation and six were declined due to parental decision. The median age was 13.2y (range 18 months-18y). Thirty-two (51.6 %) were chemotherapy-naïve. Seventeen patients (27 %) had sarcoma, 16 patients (26 %) had acute leukemia. The mean number of mature oocytes that were eventually vitrified was significantly higher in chemotherapy-naïve patients compared with chemotherapy-exposed patients (mean 12 oocytes (1-42) versus 2 (0-7)).
Multidisciplinary programs that encompass experts of all relevant fields, skilled laboratory resources and a facilitated path appear to maximize the yield. We observed a considerable higher referral rates following launching a designated program and earlier OCP in chemo-naïve patients that culminated in a better fertility preservation procedure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mobilized peripheral blood (mPB) is a prevalent source of hematopoietic progenitors for transplantation; however, allogeneic and haploidentical transplants are often accompanied by severe GVHD. ...Following the observation that murine GVHD is ameliorated by pretransplant donor cell exposure to Fas-ligand (FasL) without host-specific sensitization, we assessed the susceptibility of mPB cells to spontaneous and receptor-induced apoptosis as a possible approach to GVHD prophylaxis. Short incubation for 4 h resulted in spontaneous apoptosis of 50% of the T and B lymphocytes and 60% myeloid cells. Although expression of Fas and TNF-R1 was proportionate to fractional apoptosis, cell death was dominated by spontaneous apoptosis. Functional assays revealed that the death receptors modulated mPB graft composition as compared with incubation in medium, without detectable quantitative variations. Removal of dead cells increased the frequency of mPB myeloid progenitors (P<0.001 vs medium), and recipients of mPB exposed to death ligands displayed reduced GVHD (P<0.01 vs medium) and improved survival following lipopolysacharide stimulation. mPB grafts exposed to the apoptotic challenge retained SCID reconstituting potential and graft versus tumor activity. These data emphasize that short-term exposure of mPB grafts to an apoptotic challenge is effective in reduction of GVHD effector activity.
Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis ...factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and C-reactive protein CRP) was developed to assist in differentiation between bacterial and viral disease.
We performed double-blind, multicenter assay evaluation using serum remnants collected at 5 pediatric emergency departments and 2 wards from children ≥3 months to ≤18 years without (
= 68) and with (
= 529) suspicion of acute infection. Infectious cohort inclusion criteria were fever ≥38°C and symptom duration ≤7 days. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results. Assay performers were blinded to the reference standard. Assay cutoffs were predefined.
Of 529 potentially eligible patients with suspected acute infection, 100 did not fulfill infectious inclusion criteria and 68 had insufficient serum. The resulting cohort included 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The assay distinguished between bacterial and viral patients with 93.8% sensitivity (95% confidence interval: 87.8%-99.8%) and 89.8% specificity (85.6%-94.0%); 11.7% had an equivocal assay outcome. The assay outperformed CRP (cutoff 40 mg/L; sensitivity 88.2% 80.4%-96.1%, specificity 73.2% 67.6%-78.9%) and procalcitonin testing (cutoff 0.5 ng/mL; sensitivity 63.1% 51.0%-75.1%, specificity 82.3% 77.1%-87.5%).
Double-blinded evaluation confirmed high assay performance in febrile children. Assay was significantly more accurate than CRP, procalcitonin, and routine laboratory parameters. Additional studies are warranted to support its potential to improve antimicrobial treatment decisions.
Eukaryotic translation initiation factor 2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. Mutations in any of its five subunits ...lead to leucoencephalopathy with vanishing white matter, an inherited chronic-progressive fatal brain disease with unknown aetiology, which is among the most prevalent childhood white matter disorders. We generated the first animal model for the disease by introducing a point mutation into the mouse Eif2b5 gene locus, leading to R132H replacement corresponding to the clinically significant human R136H mutation in the catalytic subunit. In contrast to human patients, mice homozygous for the mutant Eif2b5 allele (Eif2b5R132H/R132H mice) enable multiple analyses under a defined genetic background during the pre-symptomatic stages and during recovery from a defined brain insult. Time-course magnetic resonance imaging revealed for the first time the delayed development of the brain white matter due to the mutation. Electron microscopy demonstrated a higher proportion of small-calibre nerve fibres. Immunohistochemistry detected an abnormal abundance of oligodendrocytes and astrocytes in the brain of younger animals, as well as an abnormal level of major myelin proteins. Most importantly, mutant mice failed to recover from cuprizone-induced demyelination, reflecting an increased sensitivity to brain insults. The anomalous development of white matter in Eif2b5R132H/R132H mice underscores the importance of tight translational control to normal myelin formation and maintenance.
Endocrine dysfunction and parameters of metabolic syndrome were assessed in 91 patients aged 4.3-32.5 years who underwent allogeneic or autologous BMT in childhood. Final short stature, found in five ...of the 35 patients who attained final height, was associated with the underlying disease (specifically, Fanconi anemia) (P=0.0013), previous cranial irradiation (P=0.0007), type of conditioning irradiation (P<0.05) and allogeneic BMT (P=0.05). Growth hormone deficiency (n=10) was associated with previous cranial irradiation (P<0.005) and conditioning total body irradiation (P<0.001). Twelve patients had primary hypothyroidism, one had hyperthyroidism and one papillary thyroid carcinoma. Hypothyroidism was associated with neck/mediastinal (P<0.005) and conditioning irradiation (P<0.05). Primary gonadal failure was found in 24 of the mature patients (62.5% females). Hypogonadism was associated with the underlying disease (especially hematological malignancies) (P<0.05), pretransplant treatment (P<0.05), irradiation conditioning (P<0.001), older age (P<0.005) and advanced pubertal stage at BMT (P<0.05). Obesity (body mass index >2 s.d.) was found in 4.4% and type II diabetes and impaired glucose tolerance in 3.3% each. Dyslipidemia was found in 27.9% of the 43 patients tested. These findings emphasize the need for long-term follow-up of endocrine and metabolic parameters in young patients after BMT in order to offer proper treatment and improve quality of life.
PDF
