Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune ...deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5′ region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor‐associated family member, plays an important role in T cell signaling and in RANKL‐dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.
Left picture‐increased radio density of the long bones of the leg and a pathological fracture suggesting osteopetrosis. Right picture‐ after about 45 days, note exuberant femoral callus, metaphyseal widening of the distal femur and proximal tibia, with splaying and fraying.
The influence of TNF-α and Fas-ligand (FasL) on viability and function was evaluated in fresh- and expanded-umbilical cord blood (UCB) cells. CD34(+) progenitors and T cells display outstanding ...survival, whereas ~30% and >50% B lymphocytes and myeloid cells undergo spontaneous apoptosis within 24 and 48 h, respectively. Although the impact of exposure to toxic doses of FasL and TNF-α was undetectable in measurements of apoptosis; removal of dead cells after 2 days of incubation with the ligands revealed a twofold increase in frequency of colony-forming cells (CFU). The sensitivity of progenitors to apoptosis was also unaffected by Fas cross-linking following TNF-induced upregulation of the receptor, increasing CFU frequency without impairing SCID repopulating cell (SRC) activity. Most significant enrichment in CD34(+) progenitors and corresponding increase in CFU frequency were observed when FasL was applied during the final week of ex vivo expansion under the influence of nicotinamide, without impairing SRC activity. These data emphasize differential sensitivities of UCB progenitors and lineage-positive cells to apoptotic signaling mediated by the Fas and TNF receptors, which might be useful in improving the efficiency of ex vivo expansion and improving UCB cell engraftment.
We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin-) have the capacity to differentiate and ...contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hematopoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFPbrightCD45+ progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin- cells incorporate in the islets, convert to GFPdimCD45-PDX-1+ phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin- cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two synergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells.
The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although ...technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI.
Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus).
We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transplant-related mortality and morbidity (both short and long term) have limited the effectiveness of SCT in children with both malignant and nonmalignant diseases. Reduced-intensity preparative ...regimens permit engraftment of allogeneic cells without many of the toxicities associated with standard TBI- and non-TBI-based conditioning. We review the concepts that underlie reduced-intensity transplantation (RIT) and highlight the experience of the technique in children. Although acute organ damage may be reduced after these transplants, the overall incidence of severe infections and of GvHD may be similar to that seen after standard-intensity transplantation. The relatively small numbers of children who have received RIT and the newness of the technique preclude long-term follow-up with which to monitor the incidence of associated long-term side effects and disease-free survival. Future refinements in RIT and appropriate patient selection for these procedures will hopefully extend its utility in the future.
Background
Posterior reversible encephalopathy syndrome (PRES) is a distinct clinico‐radiologic entity that can occur following allogeneic hematopoietic stem cell transplantation, often in the ...context of treatment with calcineurin inhibitors (CNIs).
Procedure
We describe the results of CNI‐free management of 14 children with PRES and review the clinical and radiologic manifestations of their presentation.
Results
Discontinuation of CNIs usually resulted in remission of PRES, but patients with established graft versus host disease (GVHD) at the time when treatment was changed often experienced progressive GVHD despite administration of immune suppressive and modulating treatments. All but three patients experienced full neurologic recovery. Nine children died as a result of either GVHD, disease relapse, or severe infection.
Conclusions
Discontinuation of CNIs results in neurologic improvement in most cases, but superior alternative immune modulatory treatment is needed to prevent progression of established GVHD.
Regulatory T cells (Treg) play a significant role in immune homeostasis and self-tolerance. Excessive sensitivity of isolated Treg to apoptosis has been demonstrated in NOD mice and humans suffering ...of type 1 diabetes, suggesting a possible role in the immune dysfunction that underlies autoimmune insulitis. In this study the sensitivity to apoptosis was measured in T cells from new onset diabetic NOD females, comparing purified subsets to mixed cultures.
Apoptotic cells are short lived in vivo and death occurs primarily during isolation, manipulation and culture. Excessive susceptibility of CD25(+) T cells to spontaneous apoptosis is characteristic of isolated subsets, however disappears when death is measured in mixed splenocyte cultures. In variance, CD25(-) T cells display balanced sensitivity to apoptosis under both conditions. The isolation procedure removes soluble factors, IL-2 playing a significant role in sustaining Treg viability. In addition, pro- and anti-apoptotic signals are transduced by cell-to-cell interactions: CD3 and CD28 protect CD25(+) T cells from apoptosis, and in parallel sensitize naïve effector cells to apoptosis. Treg viability is modulated both by other T cells and other subsets within mixed splenocyte cultures. Variations in sensitivity to apoptosis are often hindered by fast proliferation of viable cells, therefore cycling rates are mandatory to adequate interpretation of cell death assays.
The sensitivity of purified Treg to apoptosis is dominated by cytokine deprivation and absence of cell-to-cell interactions, and deviate significantly from measurements in mixed populations. Balanced sensitivity of naïve/effector and regulatory T cells to apoptosis in NOD mice argues against the concept that differential susceptibility affects disease evolution and progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The management of first-time patellar dislocation remains variable, with limited evidence to support or compare different operative and nonoperative modalities. The primary aim was to establish ...consensus-based guidelines for different components of nonoperative treatment following a first-time patellar dislocation. The secondary aim was to develop guidelines related to management after failed nonoperative treatment. The tertiary aim was to establish consensus-based guidelines for the management of first-time patellar dislocation with a concomitant osteochondral fracture.
A 29-question, multiple-choice, case-based survey was developed by 20 members of the Patellofemoral Research Interest Group of the Pediatric Research in Sports Medicine Society. The survey consisted of questions related to demographic information, management of first-time patellar dislocation without an osteochondral fracture, and management of first-time patellar dislocation with a 2 cm osteochondral fracture. The survey underwent 2 rounds of iterations by Patellofemoral Research Interest Group members and the final survey was administered to Pediatric Research in Sports Medicine members, using REDCap. Consensus-based guidelines were generated when more than 66% of respondents chose the same answer.
Seventy-nine of 157 (50%) eligible members responded. Sixty-one were orthopaedic surgeons and 18 were primary sports medicine physicians. Eleven consensus-based guidelines were generated based on survey responses. Those that met the criteria for consensus included initial knee radiographs (99% consensus), nonoperative treatment for first-time patellar dislocation without an osteochondral fracture (99%), physical therapy starting within the first month postinjury (99%), with return to sport after 2 to 4 months (68%) with a brace (75%) and further follow-up as needed (75%). Surgical treatment was recommended if there were patellar subluxation episodes after 6 months of nonoperative treatment (84%). Patellar stabilization should be considered for a first-time dislocation with an osteochondral fracture (81.5%).
Consensus-based guidelines offer recommendations for the management of first-time patellar dislocation with or without an osteochondral fracture. Several changing trends and areas of disagreement were noted in clinical practice.
In the absence of high-level evidence, consensus-based guidelines may aid in clinical decision-making when treating patients following a first-time patellar dislocation. These guidelines highlight the evolving trends in clinical practice for the management of first-time patellar dislocation. Areas not reaching consensus serve as topics for future research.
PDF
