Combination of selective androgen and estrogen receptor modulators in orchiectomized rats.

PURPOSE: Selective androgen and estrogen receptor modulators, ostarine (OST) and raloxifen (RAL), reportedly improve muscle tissue and offer therapeutic approaches to muscle maintenance in the elderly. The present study evaluated the effects of OST and RAL and their combination on musculoskeletal tissue in orchiectomized rats. METHODS: Eight-month-old Sprague Dawley rats were analyzed. Experiment I: (1) Untreated non-orchiectomized rats (Non-ORX), (2) untreated orchiectomized rats (ORX), (3) ORX rats treated with OST during weeks 0-18 (OST-P), (4) ORX rats treated with OST during weeks 12-18 (OST-T). Experiment II: 1) Non-ORX, (2) ORX, 3) OST-P, (4) ORX rats treated with RAL, during weeks 0-18 (RAL-P), 5) ORX rats treated with OST + RAL, weeks 0-18 (OST + RAL-P). The average daily doses of OST and RAL were 0.4 and 7 mg/kg body weight (BW). Weight, fiber size, and capillarization of muscles, gene expression, serum markers and the lumbar vertebral body were analyzed. RESULTS: OST-P exerted favorable effects on muscle weight, expression of myostatin and insulin growth factor-1, but increased prostate weight. OST-T partially improved muscle parameters, showing less effect on the prostate. RAL-P did not show anabolic effects on muscles but improved body constitution by reducing abdominal area, food intake, and BW. OST + RAL-P had an anabolic impact on muscle, reduced androgenic effect on the prostate, and normalized food intake. OST and RAL improved osteoporotic bone. CONCLUSIONS: The OST + RAL treatment appeared to be a promising option in the treatment of androgen-deficient conditions and showed fewer side effects than the respective single treatments.

C-reactive protein in spinal surgery: more predictive than prehistoric.

PURPOSE: In spinal surgery, surgical site infections (SSI) after dorsal spondylodesis lead to severe short- and long-term complications. Despite various clinical and serological evidence, the detection of a postoperative SSI remains crucial. In this retrospective cohort study, we determined the prognostic value of C-reactive protein (CRP) kinetics after open reduction and dorsal spondylodesis in the development of a SSI. METHODS: We retrospectively analyzed 192 patients from 2016 to 2018 undergoing open reduction and dorsal spondylodesis with and without SSI for 20 days at a level-I trauma center and assessed their serological and clinical characteristics. RESULTS: On day 7 and 8 after surgery, patients who developed a SSI displayed significantly higher CRP levels. A second peak after the initial maximum of CRP and a restricted failure to decline as well as a maximum CRP of more than 225 mg/l predict an infectious complication with a sensitivity of 92.9%, and a specificity of 78.2%. A binary logistic regression leads to 85.7% and 69.7%, respectively. A one-phase decay exponential regression can predict 75.6% of the variance after the initial peak of CRP. CONCLUSION: Our study demonstrates a high value of postoperative CRP kinetics in SSI detection after dorsal spondylodesis. Moreover, we observed typical CRP levels with a specific course as indicative predictors that may facilitate an early SSI detection in clinical practice.

Evaluation of ostarine as a selective androgen receptor modulator in a rat model of postmenopausal osteoporosis.

Selective androgen receptor modulators (SARMs) have shown beneficial effects on muscle wasting, general physical function and bone properties in male mammals. However, data on the effects of SARMs in postmenopausal osteoporotic bone are scarce. We evaluated the effects of the SARM drug ostarine on postmenopausal osteoporotic bone in a rat osteoporosis model. Ovariectomy was performed on 46 of 56 3-month-old female Sprague-Dawley rats. Eight weeks after ovariectomy, ostarine was orally administered daily for 5 weeks in dosages of 0.04 (low, OVX + Ost. 0.04), 0.4 (intermediate, OVX + Ost. 0.4), and 4 mg/kg (high, OVX + Ost. 4) body weight. Another ovariectomized group received no ostarine. Lumbar vertebrae and femora were removed for biomechanical, gene expression, ashing, and computer tomography analyses. Low dose showed no effects. The effects of intermediate and high doses were comparable overall. Improvements were mainly seen in structural properties such as bone mineral density and bone volume density. However, the effects in femora were superior to effects in vertebrae. Ostarine treatment for 5 weeks did not improve significantly biomechanical properties. mRNA expression of the receptor activator of NF-κB ligand decreased after treatment, and uterine weight increased. Serum levels of phosphorus increased following ostarine treatment in intermediate and high-dose groups. Short-term treatment of osteoporotic bone with ostarine leads to improvement of several microstructural bone indices. While we did not observe changes in biomechanics, it is conceivable that longer treatment may also improve biomechanical properties. Further studies are needed to characterize longer time effects and side effects of ostarine in osteoporosis.

Effect of Strontium Ranelate on the Muscle and Vertebrae of Ovariectomized Rats.

Osteoporosis is often accompanied by sarcopenia. The effect of strontium ranelate (SR) on muscle tissue has not been investigated sufficiently. In this study, the effect of different SR treatments on muscle was studied. Additionally, the lumbar vertebrae were analyzed. Three-month-old female rats were divided into five groups (n = 12): Group 1: untreated (NON-OVX); Group 2: ovariectomized and left untreated (OVX); Group 3: SR after OVX until the study ended (13 weeks, SR prophylaxis and therapy = pr+th); Group 4: OVX and SR for 8 weeks (SR prophylaxis = pr); Group 5: SR for 5 weeks from the 8 week after OVX (SR therapy = SR th). SR was applied in food (630 mg/kg body weight). The size of muscle fibers, capillary density, metabolic enzymes, and mRNA expression were assessed in soleus, gastrocnemius, and longissimus muscles. The vertebral bodies underwent micro-CT, biomechanical, and ashing analyses. In general, SR did not alter the muscle histological parameters. The changes in fiber size and capillary ratio were related to the body weight. Myostatin mRNA was decreased in Sr pr+th; protein expression was not changed. SR th led to increase in mRNA expression of vascular endothelial growth factor (Vegf-B). In lumbar spine, SR pr+th enhanced biomechanical properties, bone mineral density, trabecular area, density, and thickness and cortical density. The reduced calcium/phosphate ratio in the SR pr+th group indicates the replacement of calcium by strontium ions. SR has no adverse effects on muscle tissue and it shows a favorable time-dependent effect on vertebrae. A functional analysis of muscles could verify these findings.

Comparison of parathyroid hormone and strontium ranelate in combination with whole-body vibration in a rat model of osteoporosis.

We investigated the combinatorial effects of whole-body vertical vibration (WBVV) with the primarily osteoanabolic parathyroid hormone (PTH) and the mainly antiresorptive strontium ranelate (SR) in a rat model of osteoporosis. Ovariectomies were performed on 76 three-month-old Sprague-Dawley rats (OVX, n = 76; NON-OVX, n = 12). After 8 weeks, the ovariectomized rats were divided into 6 groups. One group (OVX + PTH) received daily injections of PTH (40 µg/kg body weight/day) for 6 weeks. Another group (OVX + SR) was fed SR-supplemented chow (600 mg/kg body weight/day). Three groups (OVX + VIB, OVX + PTH + VIB, and OVX + SR + VIB) were treated with WBVV twice a day at 70 Hz for 15 min. Two groups (OVX + PTH + VIB, OVX + SR + VIB) were treated additionally with PTH and SR, respectively. The rats were killed at 14 weeks post-ovariectomy. The lumbar vertebrae and femora were removed for biomechanical and morphological assessment. PTH produced statistically significant improvements in biomechanical and structural properties, including bone mineral density (BMD) and trabecular bone quality. In contrast, SR treatment exerted mild effects, with significant effects in cortical thickness only. SR produced no significant improvement in biomechanical properties. WBVV as a single or an adjunctive therapy produced no significant improvements. In conclusion, vibration therapy administered as a single or dual treatment had no significant impact on bones affected by osteoporosis. PTH considerably improved bone quality in osteoporosis cases and is superior to treatment with SR.

Visualization of Large-Scale Narrative Data Describing Human Error.

Objective Introduced is a visual data exploration technique for compiling, reducing, organizing, visually rendering, and filtering text-based narratives for detailed analysis. Background The analysis of data sets provides an increasingly difficult problem. The method of visual representation is considered an effective tool in many applications. The focus of this study was to determine if a latent semantic analysis-based projection of narrative data into a geographic information systems software program provided a useful tool for reducing and organizing large sums of narrative data for analysis. Method This approach utilizes latent semantic analysis to reduce narratives to a high-dimensional vector, truncates the vector to a two-dimensional projection through application of isometric mapping, and then visually renders the result with geographic information systems software. This method is demonstrated on aviation self-reported safety narratives sourced from the Aviation Safety Reporting System. Results Thematic regions from the corpus are illustrated along with the first five topics identified. Conclusion Shown is the ability to assimilate a large number of narratives, identify contextual themes, recognize common events and outliers, and organize resultant topics. Application Large narrative-based data sets present in aviation and other domains may be visualized to facilitate efficient analysis, enhance comprehension, and improve safety.

[Surgical treatment of a complex adolescent carpal fracture : A rare injury to the growing skeleton]. / Versorgung einer komplexen jugendlichen Handwurzelfraktur : Eine seltene Verletzung am wachsenden Skelett.

We report the case of a 15-year-old boy with combined fractures of the scaphoid, capitate, and hamate that represents a rare variation of the well-known Fenton's syndrome. Fixation was performed for the unstable fractures of the scaphoid and capitate with the use of cannulated Herbert screws and K­wires respectively. K­wires were removed after 6 months, with subsequent physiotherapy. After 6 months, CT confirmed complete consolidation of the two surgically treated carpal fractures and the conservatively treated fracture of the hamate. Regarding function, the patient is able to incorporate the hand into his school-related activities and has a good range of motion, with strong closure of the fist.

Continuous Lidocaine Infusions to Manage Opioid-Refractory Pain in a Series of Cancer Patients in a Pediatric Hospital.

BACKGROUND: Research on the safety and efficacy of continuous lidocaine infusions (CLIs) for the treatment of pain in the pediatric setting is limited. This article describes a series of pediatric oncology patients who received lidocaine infusions for refractory, longstanding, cancer-related pain. PROCEDURE: This is a retrospective review of patients who underwent lidocaine infusions to manage severe, opioid-refractory, cancer-related pain. Four patients ranging in age from 8 to 18 years were admitted to a pediatric hospital for their medical conditions and/or pain management. Structured chart review established demographic and diagnosis information, infusion rates, side effects, and efficacy of infusions in providing pain relief. Lidocaine bolus doses, infusion rates, serum concentrations, and subjective pain scores were analyzed. RESULTS: Median pain scores prior to lidocaine infusions were 8/10, falling to 2/10 at the infusion termination (P < 0.003), and rising to 3/10 in the first 24 hr after lidocaine (P < 0.029 compared to preinfusion pain). The infusions were generally well tolerated, with few side effects noted. In most cases, the improvement in pain scores persisted beyond termination of the infusion. CONCLUSIONS: CLIs were a helpful adjuvant in the four cases presented and may be an effective therapy for a more diverse array of refractory cancer pain. The majority of patients experienced pain relief well beyond the metabolic elimination of the lidocaine, corroborating a modulation effect on pain windup. Additional research regarding infusion rates, serum concentrations, side effects, and outpatient follow-up in a larger group of patients will provide additional insight into the role and safety of this therapy in children.

Management Practices for Standard-Risk and High-Risk Patients With Bronchiolitis.

OBJECTIVE: Management guidelines for bronchiolitis advocate for supportive care and exclude those with high-risk conditions. We aim to describe and compare the management of standard-risk and high-risk patients with bronchiolitis. METHODS: This retrospective study examined patients <2 years of age admitted to the general pediatric ward with an International Classification of Diseases, 10th Revision discharge diagnosis code of bronchiolitis or viral syndrome with evidence of lower respiratory tract involvement. Patients were defined as either standard- or high-risk on the basis of previously published criteria. The frequencies of diagnostic and therapeutic interventions were compared. RESULTS: We included 265 patients in this study (122 standard-risk [46.0%], 143 high-risk [54.0%]). Increased bronchodilator use was observed in the standard-risk group (any albuterol dosing, standard-risk 65.6%, high-risk 44.1%, P = .003). Increased steroid use was observed in the standard-risk group (any steroid dosing, standard-risk 19.7%, high-risk 14.7%, P = .018). Multiple logistic regression revealed >3 doses of albuterol, hypertonic saline, and chest physiotherapy use to be associated with rapid response team activation (odds ratio [OR] >3 doses albuterol: 8.36 [95% confidence interval (CI): 1.99-35.10], P = .048; OR >3 doses hypertonic saline: 13.94 [95% CI: 4.32-44.92], P = .001); OR percussion and postural drainage: 5.06 [95% CI: 1.88-13.63], P = .017). CONCLUSIONS: A varied approach to the management of bronchiolitis in both standard-risk and high-risk children occurred institutionally. Bronchodilators and steroids continue to be used frequently despite practice recommendations and regardless of risk status. More research is needed on management strategies in patients at high-risk for severe disease.

Addressing cervical cancer disparities in Texas: Expansion of a community-based prevention initiative for medically underserved populations.

Although cervical cancer is preventable, significant disparities exist in access to screening and prevention services. In medically underserved areas (MUAs) of Texas, these rates are 55% higher compared to the remainder of the US. In 2019, we expanded a multicomponent, comprehensive program to improve cervical cancer prevention in partnership with 13 clinics and mobile vans in MUAs of Texas. Our multicomponent intervention program consists of community education and patient navigation coupled with a training/mentoring program for local medical providers to perform diagnostic procedures and treatment for patients with abnormal screening results. Hands-on training courses to learn these skills are coupled with biweekly telementoring conferences using Project ECHO® (Extension for Community Healthcare Outcomes). This program was implemented in 2015 and expanded to other MUAs in Texas in 2019. From March 2019 to August 2022, 75,842 individuals were educated about cervical cancer screening and HPV vaccination. A total of 44,781 women underwent screening for cervical cancer, and 2,216 underwent colposcopy and 264 underwent LEEP. High-grade cervical dysplasia was diagnosed in 658 individuals and invasive cervical cancer in 33 individuals. We trained 22 providers to perform colposcopy and/or LEEP. In addition, 78 Project ECHO telementoring sessions were held with an average of 42 attendees per session, with 72 individual patient cases discussed. Our comprehensive community-based prevention initiative for medically underserved populations has led to a significant number of individuals undergoing cervical cancer screening in MUAs, as well as improved access to colposcopy and LEEP services.

Interprofessional geriatric and palliative care intervention associated with fewer hospital days.

BACKGROUND: With increasing complexity of our aging inpatient population, we implemented an interprofessional geriatric and palliative care intervention on a hospitalist service. This study aimed to measure the intervention's impact on length of stay (LOS), 30-day readmission, and the daily intensity of inpatient services utilization. METHODS: Using a nonrandomized controlled intervention at a 1000-bed U.S. academic quaternary medical center, we studied 13,941 individuals admitted to a general medicine hospitalist service (of which 5644 were age > =65 years); 1483 were on intervention teams (576 age > =65 years), 5413 concurrent controls, and 7045 historical controls. On 2 of 11 hospitalist teams, a geriatrician, palliative care physician and social worker attended multidisciplinary discharge rounds twice weekly, to recommend inpatient geriatric or palliative care consult (GPCC), postacute nursing or home care, versus postdischarge outpatient consultation. We measured the difference in improvement over time between intervention and control team patients for the following: (1) LOS adjusted for case-mix index, (2) 30-day readmissions, and (3) intensity of hospital service utilization (mean services provided per patient per day). RESULTS: Adjusted LOS (in hospital days) was decreased by 0.36 days (p = 0.039) for the 1483 patients in the intervention teams, with greater LOS reduction of 0.55 days per admission (p = 0.022) on average among the subset of 576 older patient admissions. Readmissions were unchanged (-1.17%, p = 0.48 for all patients; 1.91%, p = 0.46 for older patients). However, the daily relative value unit (RVU) utilization was modestly increased for both the overall and older subgroup, 0.35 RVUs (p = 0.041) and 0.74 RVUs (p < 0.001) per patient-day on average across the intervention teams, respectively. CONCLUSION: An interprofessional intervention of geriatric and palliative care consultation in collaboration with a hospitalist service may reduce LOS, especially for geriatric patients, without an increase in readmissions. This model may have broader implications for hospital care and should be further studied.

Obtaining buy-in for immediate postpartum long-acting reversible contraception programs in Texas hospitals: A qualitative study.

OBJECTIVE: To understand the specific ways in which champions lead efforts to obtain and sustain buy-in for immediate postpartum long-acting reversible contraception (LARC) programs. METHODS: We conducted a qualitative study with 60 semistructured interviews at 3 teaching hospitals in Texas with physicians, nurses, administrators and other staff who participated in the implementation of immediate postpartum LARC. Physicians self-identified as champions and identified other champion physicians and administrators. Two researchers analyzed and coded interview transcripts for content and themes. RESULTS: We found that champions draw on institutional knowledge and relationships to build awareness and support for immediate postpartum LARC implementation. To obtain buy-in, champions needed to demonstrate financial sustainability, engage key stakeholders from multiple departments, and obtain nurse buy-in. Champions also created buy-in by communicating goals for the service that focused on expanding reproductive autonomy, improving maternal health, and improving access to postpartum contraception. Some staff, especially nurses, identified reasons for the program that run counter to reproductive justice principles: reducing birth rates, poverty, and/or unplanned pregnancy among young women and high-parity women. Respondents at 2 hospitals noted that not all women had equitable access to immediate postpartum LARC. CONCLUSION: Physician and non-physician champions must secure long-term support across multiple hospital departments to successfully implement an immediate postpartum LARC program. For programs to equitably serve all women in need of postpartum contraceptive care, champions and other program leaders need to implement strategies to address access issues. They should also explicitly focus on reproductive justice principles during program introduction and training. IMPLICATIONS: Successfully implementing immediate postpartum long-acting reversible contraception programs requires champions with institutional networking connections, administrative and nursing support, and clearly communicated goals. Champions need to address access issues and focus on reproductive justice principles during program introduction and training to equitably serve all women in need of postpartum contraceptive care.

Predicting the disaster - The role of CRP in acetabular surgery.

OBJECTIVES: Acetabular fractures represent a complex surgical challenge. Given the heterogenous fracture pattern, the patient characteristics and spectrum of complications demand individual solutions. Surgical site infections (SSI) threaten osteosynthesis, and early detection of them and treatment remain crucial. What is the value of postoperative C-reactive protein (CRP) in this group of patients as well as its normal course? DESIGN & METHODS: 115 patients with isolated fractures of the acetabulum were retrospectively evaluated. CRP, white blood cell count (WBC) and fracture patterns as well as patient characteristics were assessed for 20 days following operative fixation of the acetabular fracture (n = 71) and in fractures that were managed conservatively (n = 44). RESULTS: Twelve patients suffered an infectious complication. With a one-phase decay, 70.55% of the variance of postoperative CRP kinetics was predicted. To anticipate maximum CRP as well as an infection, the preoperative CRP represented the best prognostic parameter. To predict an infection, the single variable "peak CRP value above 100 mg/l" resulted in a sensitivity and specificity of 91.67% and 36.21%, respectively. Combining a second peak of CRP with maximum CRP and day 5 CRP value for receiver-operating characteristic (ROC) analysis resulted in 83.3% and 88.1%, respectively. CONCLUSIONS: Predicting surgical site infections after an acetabular fracture is most predictive when analyzing the maximum overall CRP, the second peak and the CRP after day 5. With a combination of these parameters, a sensitivity and specificity of 83.3% and 88.1% to detect an infection was achieved.

The cost of improving care: a multisite economic analysis of hospital resource use for implementing recommended postpartum contraception programmes.

BACKGROUND: The costs of quality improvement efforts in real-world settings are often unquantified. Better understanding could guide appropriate resource utilisation and drive efficiency. Immediate postpartum contraceptive care (ie, placement of an intrauterine device or contraceptive implant during hospitalisation for childbirth) represents an excellent case study for examining costs, because recommended services are largely unavailable and adoption requires significant effort. We therefore evaluated the cost of implementing immediate postpartum contraceptive services at four academic centres and one private hospital in USA. METHODS: In this mixed-methods cost analysis, implementation activities were retrospectively identified using standardised data collection. Activities were categorised as preimplementation activities (infrastructure building, tool creation and stakeholder engagement) or execution activities (workforce training and process refinement). Costs were assigned based on national median salaries for the roles of individuals involved. Cross-case comparison and rapid qualitative analysis guided by the Consolidated Framework for Implementation Research were used to identify factors driving cost variation observed across sites. RESULTS: On average, implementation activities required 204 hours (range 119-368), with this time costing $14 433.94 (range $9955.61-$23 690.49), and involving 9 (range 7-11) key team members per site. Preimplementation activities required more resources than execution activities (preimplementation: average 173 hours, $11 573.25; execution: average 31 hours, $2860.67). Sites that used lower-cost employees (eg, shifting tasks from a physician to a project manager) observed lower costs per hour for implementation activities. Implementation activities and costs were associated with local contextual factors, including stakeholder acceptance, integration of employees and infrastructure readiness for the change effort. CONCLUSIONS: Our findings provide the first estimates of health system costs for adopting recommended contraceptive care in maternity units in USA. More broadly, our findings suggest that the budget impact of improvement efforts may vary widely depending on local context.

Crenarchaeota affiliated with group 1.1b are prevalent in coastal mineral soils of the Ross Sea region of Antarctica.

The objective of this study was to examine the presence and diversity of Archaea within mineral and ornithogenic soils from 12 locations across the Ross Sea region. Archaea were not abundant but DNA sufficient for producing 16S rRNA gene clone libraries was extracted from 18 of 51 soil samples, from four locations. A total of 1452 clones were analysed by restriction fragment length polymorphism and assigned to 43 operational taxonomic units from which representatives were sequenced. Archaea were primarily restricted to coastal mineral soils which showed a predominance of Crenarchaeota belonging to group 1.1b (> 99% of clones). These clones were assigned to six clusters (A through F), based on shared identity to sequences in the GenBank database. Ordination indicated that soil chemistry and water content determined archaeal community structure. This is the first comprehensive study of the archaeal community in Antarctic soils and as such provides a reference point for further investigation of microbial function in this environment.

Vulvar intravascular papillary endothelial hyperplasia or Masson's tumor: A case report.

Masson's tumor, also known as intravascular papillary endothelial hyperplasia (IPEH), is a rare and benign vascular disease in which there is a reactive hyperplasia of intravascular endothelial cells. This tumor is most commonly found in soft tissues in the head, neck and upper extremities. We report a rare case of IPEH on the vulva. A Hispanic woman in her mid-thirties presented with a painful and pruritic left vulvar mass. On physical examination, a pedunculated mass was visualized on the left labia majora. Under pathologic examination, it was concluded the lesion was IPEH and it was surgically excised. This is a rare case of IPEH located on the vulva. However, despite this rarity, a simple local excision could be used to manage IPEH.

Comparing Methadone Rotation to Consensus Opinion.

CONTEXT: Methadone is a complex but useful medication for pain management in palliative care. Recent expert opinions have been published on the safe and effective use of methadone. OBJECTIVES: To determine the success of methadone rotations and evaluate concordance with consensus recommendations by a palliative care consult service. METHODS: A retrospective study of methadone rotation practice by a palliative care consult service and outcomes for patients hospitalized between January 1, 2012 and December 31, 2018 at a single academic medical center. A successful rotation was defined as a 30% reduction in pain or as-needed medication use sustained for at least three consecutive days. Patient outcomes were compared with expert consensus recommendations. RESULTS: About 59 patients met the inclusion criteria. The study population was mostly Caucasian men and women of equal proportions who were started on methadone for inadequate pain control. Sixty-eight percent of patients were successfully rotated. Subjects who were rotated using a standardized protocol were six times more likely to have a successful rotation (odds ratio 6.28 [1.25-30.92]; P = 0.0238). CONCLUSION: The utilization of a standardized protocol was associated with better patient outcomes.

Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation.

Mesenchymal stem cells (MSCs) represent key contributors to tissue homeostasis and promising therapeutics for hyperinflammatory conditions including graft-versus-host disease. Their immunomodulatory effects are controlled by microenvironmental signals. The MSCs' functional response towards inflammatory cues is known as MSC-"licensing" and includes indoleamine 2,3-dioxygenase (IDO) upregulation. MSCs use tryptophan-depleting IDO to suppress T-cells. Increasing evidence suggests that several functions are (co-)determined by the cells' metabolic commitment. MSCs are capable of both, high levels of glycolysis and of oxidative phosphorylation. Although several studies have addressed alterations of the immune regulatory phenotype elicited by inflammatory priming metabolic mechanisms controlling this process remain unknown. We demonstrate that inflammatory MSC-licensing causes metabolic shifts including enhanced glycolysis and increased fatty acid oxidation. Yet, only interfering with glycolysis impacts IDO upregulation and impedes T-cell-suppressivity. We identified the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 pathway as a regulator of both glycolysis and IDO, and show that enhanced glucose turnover is linked to abundant STAT1 glycosylation. Inhibiting the responsible O-acetylglucosamine (O-GlcNAc) transferase abolishes STAT1 activity together with IDO upregulation. Our data suggest that STAT1-O-GlcNAcylation increases its stability towards degradation thus sustaining downstream effects. This pathway could represent a target for interventions aiming to enhance the MSCs' immunoregulatory potency.

A CD19-specific single-chain immunotoxin mediates potent apoptosis of B-lineage leukemic cells.

CD19 is a B-lineage-specific transmembrane signaling protein participating in the control of proliferation and differentiation. It is present at high surface density on chronic B-lymphocytic leukemia (B-CLL) cells and cells of other B-cell malignancies, and is a prime target for therapy with antibody-derived agents. Many attempts have been made to target malignant cells via CD19, but to date none of these agents have received drug approval. Here we report the design of a monovalent immunotoxin consisting of a CD19-specific single-chain Fv antibody fragment fused to a derivative of Pseudomonas Exotoxin A. This fusion protein induced efficient antigen-restricted apoptosis of several human leukemia- and lymphoma-derived cell lines including Nalm-6, which it eliminated at an effective concentration (EC(50)) of 2.5 nM. The agent displayed synergistic toxicity when used in combination with valproic acid and cyclosporin A in cell-culture assays. It induced apoptosis of primary malignant cells in 12/12 samples from B-CLL patients, including patients responding poorly to fludarabine, and of cells from one pediatric acute lymphoblastic leukemia patient. In NOD/SCID mice transplanted with Nalm-6 cells, the toxin prevented engraftment and significantly prolonged survival of treated mice. Owing to its efficient antigen-restricted antileukemic activity, the agent deserves further development towards clinical testing.