Allogeneic hematopoietic cell transplantation in chemotherapy‐induced aplasia in children with high‐risk acute myeloid leukemia or myelodysplasia

Relapse remains the most common cause of treatment failure after hematopoietic cell transplantation for acute myeloid leukemia. Inability to achieve hematologic complete remission has been a barrier to transplant for patients with refractory disease. We describe six children with refractory myeloid disease undergoing transplant in chemotherapy‐induced aplasia, as a strategy to facilitate curative therapy in refractory patients. Clofarabine‐ or high‐dose cytarabine‐based chemotherapy regimens were used to achieve marrow aplasia, followed by reduced‐intensity conditioning and allogeneic transplant before hematologic recovery. Long‐term disease control was achieved in five, with one transplant‐related mortality, suggesting the feasibility of this approach.     

Modulation of biliverdin dynamics and spectral properties by Sandercyanin

Biliverdin IX-alpha (BV), a tetrapyrrole, is found ubiquitously in most living organisms. It functions as a metabolite, pigment, and signaling compound. While BV is known to bind to diverse protein families such as heme-metabolizing enzymes and phytochromes, not many BV-bound lipocalins (ubiquitous, small lipid-binding proteins) have been studied. The molecular basis of binding and conformational selectivity of BV in lipocalins remains unexplained. Sandercyanin (SFP)–BV complex is a blue lipocalin protein present in the mucus of the Canadian walleye (Stizostedion vitreum). In this study, we present the structures and binding modes of BV to SFP. Using a combination of designed site-directed mutations, X-ray crystallography, UV/VIS, and resonance Raman spectroscopy, we have identified multiple conformations of BV that are stabilized in the binding pocket of SFP. In complex with the protein, these conformers generate varied spectroscopic signatures both in their absorption and fluorescence spectra. We show that despite no covalent anchor, structural heterogeneity of the chromophore is primarily driven by the D-ring pyrrole of BV. Our work shows how conformational promiscuity of BV is correlated to the rearrangement of amino acids in the protein matrix leading to modulation of spectral properties.

Biliverdin IX-alpha undergoes rotation around the D-ring pyrrole and displays a broad far-red absorbance on binding to monomeric Sandercyanin variant (orange) compared to the wild-type tetrameric protein (cyan).     

Protective effects of resveratrol on small intestines against intestinal ischemia–reperfusion injury in rats

Background and Aim:  The aim of this study was to determine whether resveratrol could prevent intestinal tissue injury induced by ischemia–reperfusion (I/R).
Methods:  Intestinal I/R was induced in rats' intestines by 60-min occlusion of the superior mesenteric artery, followed by a 60-min reperfusion. Thirty rats were divided into three groups as follows: sham (group 1), control (group 2), and the treatment groups (group 3). The rats in the treatment group received resveratrol both before ischemia and before reperfusion. In all groups, serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were determined. Total antioxidant capacity (TAC), catalase, total oxidative status (TOS), oxidative stress index (OSI), and myeloperoxidase (MPO) in the intestinal tissue were measured. Intestinal tissue histopathology was also evaluated by light microscopy.
Results:  The levels of liver enzymes in group 3 were significantly lower than those in group 2 ( P  < 0.05). TAC in the intestinal tissue was significantly higher in group 3 than in group 2 ( P  < 0.05). TOS, OSI, and MPO in the intestinal tissue were significantly lower in group 3 than in group 2 ( P  < 0.05 for all). Histological tissue damage was milder in the resveratrol treatment group than in the control group.
Conclusions:  The results of this study indicated that resveratrol treatment limits the oxidative injury of the small intestine induced by I/R in rats. However, more precise investigations are required to evaluate the antioxidative effect of resveratrol on small intestine tissue damage in clinical and experimental models.     

Rheumatology patient preferences for timing and location of out-patient clinics

OBJECTIVES: To determine the preferences of rheumatology patients for the time and location of their out-patient appointments. METHODS: All patients attending the rheumatology out-patient services at Dudley Group of Hospitals NHS Trust over a 2-week period were asked to complete a purpose-designed, scannable, previously piloted, self-administered questionnaire. RESULTS: Four hundred and nineteen patients completed questionnaires (response rate 87%). Age ranged from 16 to 92 yr; 38% of responders were over 65 yr, 72% were female, 57% had an inflammatory arthritis, 20% had a connective tissue disease, 8% had degenerative joint disease and 15% had another diagnosis; 29% were employed, 51% retired and 20% unemployed. Fewer than 1% of patients would like to be seen at community general practice centres (99.3% would prefer a hospital site). Proximity to their home was the main determinant of hospital choice. Monday was the most popular day for appointments, and days from Tuesday to Friday received equal rankings. Only 0.5% of patients would choose a weekend clinic. Fifty-eight per cent of patients would prefer morning appointments, 24% afternoon appointments and 2% evening appointments; 16% did not mind. Only being employed predicted out-of-hours preference. CONCLUSIONS: In this predominantly suburban, industrialized area, rheumatology out-patients prefer to be seen in the hospital rather than primary care environment, ideally close to their home, with appointments in the morning and on a weekday. These results may be generalizable to other districts and other chronic disease states, but we suggest that similar surveys become part of routine service provision and inform current and future planning.     

Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses

We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 x 106/kg) and PBSC (6 x 106/kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0.60, P = 0.033] and treatment failure (inverse of leukaemia-free survival, RR = 0.69, P = 0.032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0.5 x 109/l (RR = 1.38, P < 0.001) and platelets to > 20 x 109/l (RR = 1.34, P = 0.003), lower risk of relapse (RR = 0.62, P = 0.029) and treatment failure (RR = 0.74, P = 0.03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants.     

Nocturia: a risk factor for falls in the elderly.

OBJECTIVE: To determine if nocturia is a risk factor for reported falls and bone fractures in older persons. DESIGN: Cross-sectional study comparing falls in men and women with and without nocturia. SETTING: Longitudinal health screening program of ambulatory elderly participants. PARTICIPANTS: Participants included 988 (65.5%) women and 520 (34.5%) men who had completed their tenth annual visit to the program. MAIN OUTCOME MEASURES: Reported falls in the past year and reported bone fractures in the past 5 years. RESULTS: Participants who reported nocturia at least twice during the night were at significantly greater risk to report falls (Odds Ratio = 1.84; 95% CI = 1.05-3.22), and the risk increased in subjects reporting more than three nocturia events (Odds Ratio = 2.15; 95% CI = 1.04-4.44). The significant increase in falls reported by nocturia participants did not result in an increase in reported bone fractures in the past 5 years (P < 0.4360). CONCLUSIONS: Nocturia is an important risk factor for falls in ambulatory elderly persons. Preventive measures should be taken to decrease nocturia events and to decrease the risk of falling during these nocturia events.     

The effects of antioxidants on exercise-induced lipid peroxidation in patients with COPD

OBJEctive: The oxidant-antioxidant balance plays an important role in the pathogenesis of COPD. The aim of the present study was to evaluate the effects of exercise, as an oxidative stress factor on the oxidant-antioxidant balance and to investigate whether short-term antioxidant treatment affects lipid peroxidation products. METHODOLOGY: Twenty-one stable COPD patients and 10 control subjects were included in the study. Symptom-limited exercise tests were performed by all subjects. Blood was collected before and 1 h after exercise in control subjects and before, 1 and 3 h after exercise in COPD patients, for analysis of malondialdehyde (MDA), reduced glutathione (GSH) and vitamin E (VE) levels. VE and vitamin C treatments were added to the regular bronchodilator therapy in 10 COPD patients for 1 month. After the treatment period, an exercise test was performed and blood was collected again for MDA, GSH and VE levels. RESULTS: Baseline GSH and VE levels were significantly lower in the COPD group when compared with the control subjects. There was no statistically significant difference in MDA levels between the two groups. In the COPD group, MDA levels 3 h after exercise were significantly higher than at baseline. In contrast there were no significant differences in MDA, VE and GSH levels in the control group after exercise. VE and MDA levels increased significantly after exercise in COPD patients but there was no difference in GSH levels. Baseline exercise time was significantly lower in the COPD group than in the controls. In 10 COPD patients who were given antioxidant therapy, their exercise time increased significantly and there was no increase in MDA and VE levels after the repeated exercise test. CONCLUSIONS: Antioxidant levels were significantly lower in COPD patients than in control subjects. In these patients, exercise results in more significant oxidative stress and lipid peroxidation than in control subjects and antioxidant therapy may decrease lipid peroxidation following exercise and improve exercise capacity.     

Coronary cyclic flow variations "precondition" ischemic myocardium.

BACKGROUND. Repeated brief episodes of myocardial ischemia performed by mechanical clamping of a coronary artery "precondition" the heart and reduce infarct size after a subsequent sustained ischemia. It is not known, however, whether spontaneous episodes of transient ischemia caused by formation of platelet thrombi, which may occur in unstable angina, have a similar cardioprotective effect. METHODS AND RESULTS. Therefore, our objective was to determine whether brief spontaneous thrombotic episodes of ischemia/reperfusion could limit infarct size and preserve contractile function following 60 minutes (protocol 1) or 90 minutes (protocol 2) of sustained ischemia and 4-4.5 hours of reperfusion in the canine model. Before the sustained coronary occlusion, dogs underwent a 30-minute "treatment" period consisting of: no intervention (control group), four repeated episodes of 3-minute mechanical occlusion plus 5-minute reperfusion (preconditioned group), or coronary artery stenosis and endothelial injury, resulting in a mean of four spontaneous episodes of cyclic flow variations (CFV group) caused by formation and dislodgment of platelet thrombi. In protocol 1 (60-minute sustained ischemia plus 4.5-hour reperfusion), infarct size was significantly smaller in both the preconditioned and CFV groups compared with controls (3.5 +/- 1.4%,* 3.4 +/- 2.1%,* and 9.9 +/- 2.7% of the myocardium at risk, respectively; *p less than 0.05 versus control). In contrast, neither preconditioning nor CFV preserved contractile function: Segment shortening during sustained occlusion was equally depressed at -15% to -20% of baseline values among the three groups and equally stunned at +12% to +18% of baseline during the 4.5 hours of reflow. In protocol 2 (90-minute sustained ischemia plus 4-hour reperfusion), only CFV continued to exert a cardioprotective effect: Infarct size averaged 15.0 +/- 4.1%, 7.4 +/- 2.5%,* and 16.5 +/- 4.4% of the region at risk in the preconditioned, CFV, and control groups, respectively (*p less than 0.05 versus control). Contractile function, however, was similar among all three groups both during 90 minutes of sustained occlusion and throughout 4 hours of reperfusion. CONCLUSIONS. We therefore conclude that repeated coronary thrombus formation preconditions the ischemic myocardium: In fact, in contrast to mechanical preconditioning, cardioprotection provided by CFV persisted following 90 minutes of sustained coronary occlusion. However, preconditioning by thrombotic or mechanical occlusion neither preserved myocardial contractile function during sustained coronary occlusion nor prevented stunning after reperfusion. These data raise the possibility that clinical episodes of unstable angina prior to acute myocardial infarction may precondition the ischemic myocardium.