Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia

Eighteen consecutive patients aged 5·5–24 years with Fanconi anaemia and diagnoses of aplastic anaemia ( n  = 8), myelodysplastic syndrome ( n  = 4), acute myeloid leukaemia ( n  = 6), received allogeneic haematopoietic stem cell transplants from alternative donors. All patients had been transfused, 13 had previously been treated with androgens and 14 had a history of infection. Donors were related human leucocyte antigen (HLA) mismatched for eight patients, unrelated HLA mismatched for seven patients and unrelated HLA matched for three patients. Cytoreduction included single dose total body irradiation (450 cGy), fludarabine (150 mg/m²) and cyclophosphamide (40 mg/kg). Immunosuppression included antithymocyte globulin and tacrolimus. Grafts were granulocyte colony-stimulating factor-mobilized, CD34⁺ T-cell-depleted peripheral blood stem cells in 15 patients and T-cell-depleted marrows in three. All 18 patients engrafted with 100% donor chimaerism; only one patient developed graft-versus-host disease (GVHD). With a median follow-up of 4·2 years, 13/18 patients were alive, 12 of these were disease-free. Five-year overall survival and disease-free survival were 72·2% and 66·6% respectively. Immune reconstitution was achieved at approximately 6 months post-transplant for most patients. These are encouraging results of T-cell-depleted transplants from alternative donors using fludarabine-based cytoreduction in 18 high-risk patients with Fanconi anaemia, with no evidence of rejection and minimal GVHD.     

Future Directions for Vascular Access for Hemodialysis

Hemodialysis vascular access is at the same time both the “Lifeline” and the “Achilles Heel” of hemodialysis. This review will initially summarize the vascular biology of dialysis vascular access dysfunction and then use this information to describe some novel and innovative ways (including advances in the process of care for vascular access) to prevent this problem.     

Variant human pancreas: aberrant uncinate process or an extended mesenteric process

Variations in the morphology of pancreas are not very common. We observed a rare variant of the uncinate process of the pancreas that extended in the mesentery of the small intestine. After its origin from the lower part of the head of the pancreas, the mesenteric process (MP) passed over the third part of the duodenum to enter the mesentery of the jejunum and ileum and extended up to the level of the pelvic brim. The branches of the superior mesenteric vessels were embedded in the extended MP of the pancreas. This aberrant extension of the pancreas was drained by a narrow duct, which joined the main pancreatic duct inside the head. We did not observe a separate uncinate process arising from the head. On histology normal acini and endocrine cells were observed in the extension. This variant is important as symptoms of pancreatic disease from such extensions may be confused with other commonly encountered acute or chronic abdominal conditions.     

A Prospective Patient-centred Evaluation of Urethroplasty for Anterior Urethral Stricture Using a Validated Patient-reported Outcome Measure

Background

Studies of interventions for urethral stricture have inferred patient benefit from clinician-driven outcomes or questionnaires lacking scientifically robust evidence of their measurement properties for men with this disease.

Objective

To evaluate urethral reconstruction from the patients’ perspective using a validated patient-reported outcome measure (PROM).

Design, setting, and participants

Forty-six men with anterior urethral stricture at four UK urology centres completed the PROM before (baseline) and 2 yr after urethroplasty.

Intervention

A psychometrically robust PROM for men with urethral stricture disease.

Outcome measurements and statistical analysis

Lower urinary tract symptoms (LUTS), health status, and treatment satisfaction were measured, and paired t and Wilcoxon matched-pairs tests were used for comparative analysis.

Results and limitations

Thirty-eight men underwent urethroplasty for bulbar stricture and eight for penile stricture. The median (range) follow-up was 25 (20–30) mo. Total LUTS scores (0 = least symptomatic, 24 = most symptomatic) improved from a median of 12 at baseline to 4 at 2 yr (mean [95% confidence interval (CI)] of differences 6.6 [4.2–9.1], p < 0.0001). A total of 33 men (72%) felt their urinary symptoms interfered less with their overall quality of life, 8 (17%) reported no change, and 5 (11%) were worse 2 yr after urethroplasty. Overall, 40 men (87%) remained “satisfied” or “very satisfied” with the outcome of their operation. Health status visual analogue scale scores (100 = best imaginable health, 0 = worst) 2 yr after urethroplasty improved from a mean of 69 at baseline to 79 (mean [95% CI] of differences 10 [2–18], p = 0.018). Health state index scores (1 = full health, 0 = dead) improved from 0.79 at baseline to 0.89 at 2 yr (mean [95% CI] of differences 0.10 [0.02–0.18), p = 0.012]).

Conclusions

This is the first study to prospectively evaluate urethral reconstruction using a validated PROM. Men reported continued relief from symptoms with related improvements in overall health status 2 yr after urethroplasty. These data can be used as a provisional reference point against which urethral surgeons can benchmark their performance.     

Construct Validity of the Mealtime Scan: A Secondary Data Analysis of the Making Most of Mealtimes (M3) Study

Long-term care (LTC) physical and psychosocial mealtime environments have been inconsistently assessed due to the lack of a standardized measure. The purpose of this study was to examine the construct validity of a new standardized observational measure, the Mealtime Scan (MTS), using the Making Most of Mealtimes data collected on 639 residents in 82 dining rooms in 32 LTC homes. The MTS includes physical, social, and person-centered care summary scales scored from 1 to 8. Mean ratings on these summary scales were moderate for physical (5.6 SD 0.9), social (5.0 SD 0.9), and person-centered care (PCC; 5.5 SD 0.8). Regression analyses determined which items within the MTS were associated with these summary scales: physical – music (B?=?0.27, p?=?0.04), number of staff passing food (B?=??0.11, p?=?0.03), number of residents (B?=??0.03, p?=?0.01); social – social sound (B?= 0.31 p?p?=?0.02); PCC – lighting (B?=?0.01 p?=?0.04), and total excess noise (B?=?0.05, p?相似文献   

Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis

Atherosclerosis is a chronic inflammatory disease of arteries. It is triggered by proinflammatory mediators which induce adhesion molecules (eg, vascular cell adhesion molecule [VCAM]-1) in endothelial cells (ECs) by activating p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases by phosphorylation. Blood flow influences atherosclerosis by exerting shear stress (mechanical drag) on the inner surface of arteries, a force that alters endothelial physiology. Regions of the arterial tree exposed to high shear are protected from endothelial activation, inflammation, and atherosclerosis, whereas regions exposed to low or oscillatory shear are susceptible. We examined whether MAP kinase phosphatase (MKP)-1, a negative regulator of p38 and JNK, mediates the antiinflammatory effects of shear stress. We observed that expression of MKP-1 in cultured ECs was elevated by shear stress, whereas the expression of VCAM-1 was reduced. MKP-1 induction was shown to be necessary for the antiinflammatory effects of shear stress because gene silencing of MKP-1 restored VCAM-1 expression in sheared ECs. Immunostaining revealed that MKP-1 is preferentially expressed by ECs in a high-shear, protected region of the mouse aorta and is necessary for suppression of EC activation at this site, because p38 activation and VCAM-1 expression was enhanced by genetic deletion of MKP-1. We conclude that MKP-1 induction is required for the antiinflammatory effects of shear stress. Thus, our findings reveal a novel molecular mechanism contributing to the spatial distribution of vascular inflammation and atherosclerosis.