[Psychometric validation of the brief Humanizar Scale on the meaning of suffering]. / Validación psicométrica de la Escala Humanizar breve sobre el sentido del sufrimiento.

OBJECTIVE: To develop the short version of the brief Humanizar Scale, including reducing the dimensionality and the number of items. METHODS: The Humanizar Scale (24 items with Likert scale), consists of five factors that give meaning to suffering; significance, punishment, catalyst for change, masochism, inherent to life. A parallel analysis and exploratory factor analysis (EFA) were carried out on a first sample (n=529) and, using a different sample (n=182) the two-dimensional structure of the scale was confirmed using confirmatory factor analysis (CFA). RESULTS: The parallel analysis procedure obtained two factors. After the EFA, 15 items were retained with greater than 0.4 commonalities. The CFA confirmed the two-dimensional model including the first factor, the sense of suffering as a change (8 items) and the second, the sense of suffering as a burden (6 items). The goodness of fit were suitable: RMSEA=0.07; SRMR=0.08; CFI=0.96, and GFI=0.99. The weight factor of all items was significant and greater than 0.5. Cronbach Alpha was 0.75 for the first factor, and 0.74 for second. The factors showed a correlation of 0.56 (P<.01). Significant differences were found (P<.05) between the factor means according to beliefs (Christian vs. atheists/agnostics) and practice or not of prayer/meditation, the means being higher for both factors among believers (2 points of difference in each factor) and practitioners of prayer/meditation (3 points for Change factor and 1.5 for Burden factor). CONCLUSIONS: The two-dimensionality and the usefulness of the scale on the meaning of suffering have been well-defined.

Immunocytochemical analysis of valproic acid induced histone H3 and H4 acetylation during differentiation of rat adipose derived stem cells into neuron-like cells.

Valproic acid (VPA) is an inhibitor of histone deacetylases (HDACs) that can regulate differentiation and proliferation of stem cells by epigenetic mechanisms. We investigated VPA induced histone H3 and H4 acetylation in adipose derived stem cells (ADSCs) transdifferentiated into neuron-like cells (NLCs). Rat ADSCs were transdifferentiated into neural stem cells (NSCs) that had been generated from neurospheres. The NSCs were differentiated into NLCs by induction with different concentrations of VPA at 24, 48 and 72 h. The NLCs were evaluated using anti-H3 and -H4 antibodies, and ADSCs, NSCs and NLCs were evaluated using immunofluorescence. The ADSCs were immunoreactive to CD90 and CD49d, but not to CD45 and CD31. Both the neurospheres and NSCs were immunostained with nestin and neurofilament 68. The neurospheres expressed Musashi1, Sox2 and Neu N genes as determined by RT-PCR. Our dose-response study indicated that the optimal concentration of VPA was 1 mM at 72 h. Histone acetylation levels of H3 and H4 immunostaining intensities in NLCs were significantly greater than for ADSCs and NSCs. VPA alters H4 and H3 acetylation immunoreactivities of ADSCs transdifferentiated into NLCs.

[Validation of the Scale of Hope in Terminal Illness for relatives brief version (SHTI-b). Validity and reliability analysis.] / Validación de la Escala de Esperanza en Enfermedad Terminal (EEET-fb). Análisis de validez y fiabilidad.

BACKGROUND: Bermejo and Villacieros' Scale of Hope in Terminal Disease (SHTD) specifically collects meanings of hope facing terminal disease, including considerations relating to psycho-emotional support and that have a transcendental sense. The objective of this paper is to validate the SHTD abbreviated and rephrased to adapt all the items to a single domain. METHODS: Starting from the published SHTD, an exploratory factor analysis (EFA) was carried out with a sample of 177 valid questionnaires. In a second study, with another sample of 180 valid questionnaires, a confirmatory factor analysis (CFA) and a correlation analysis with other measurements of spiritual wellbeing (Functional Assessment of Chronic Illness Therapy-Sp) and hope (Herth Hope Index) were done. RESULTS: A bidimensional model with satisfactory goodness of fit index values was obtained (GFI = 0.991; CFI = 0.984; SRMR = 0.08; RMSEA = 0.057); the Relations of Transcendence factor obtained a Cronbach's alpha of 0.872 and Personal Relations an alpha of 0.762. The correlations of the SHTI-rb with external measures were: r = 0.527with FACIT; r = 0.266 with HHI; r = 0.667 with the Spirituality subscale of FACIT; and r = 0.348 with the Interrelation factor of HHI. The Relations of Transcendence subscale correlated with both Layout and Expectation and Interrelation of HHI (r = 0.162 and r = 0.329 respectively), while the scale of Personal Relations only correlated with Interrelation of HHI (r = 0.244). CONCLUSIONS: The Scale of Hope in Terminal Illness for relatives (brief version) is a valid and reliable specific instrument for terminal patients.

Long-term event-free and overall survival after risk-adapted melphalan and SCT for systemic light chain amyloidosis.

Stem cell transplantation (SCT), an effective therapy for amyloid light chain (AL) amyloidosis patients, is associated with low treatment-related mortality (TRM) with appropriate patient selection and risk-adapted dosing of melphalan (RA-SCT). Consolidation after SCT increases hematologic complete response (CR) rates and may improve overall survival (OS) for patients with

Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study.

Cyclophosphamide plus G-CSF (C+G-CSF) is one of the most widely used stem cell (SC) mobilization regimens for patients with multiple myeloma (MM). Plerixafor plus G-CSF (P+G-CSF) has demonstrated superior SC mobilization efficacy when compared with G-CSF alone and has been shown to rescue patients who fail mobilization with G-CSF or C+G-CSF. Despite the proven efficacy of P+G-CSF in upfront SC mobilization, its use has been limited, mostly due to concerns of high price of the drug. However, a comprehensive comparison of the efficacy and cost effectiveness of SC mobilization using C+G-CSF versus P+G-CSF is not available. In this study, we compared 111 patients receiving C+G-CSF to 112 patients receiving P+G-CSF. The use of P+G-CSF was associated with a higher success rate of SC collection defined as ⩾5 × 10(6) CD34+ cells/kg (94 versus 83%, P=0.013) and less toxicities. Thirteen patients in the C+G-CSF arm were hospitalized owing to complications while none in the P+G-CSF group. C+G-CSF was associated with higher financial burden as assessed using institutional-specific costs and charges (P<0.001) as well as using Medicare reimbursement rates (P=0.27). Higher rate of hospitalization, increased need for salvage mobilization, and increased G-CSF use account for these differences.

Catalog of total excitation-emission and total synchronous fluorescence maps with synchronous fluorescence spectra of homologated fluorescent pesticides in large use in Morocco: development of a spectrometric low cost and direct analysis as an alert method in case of massive contamination of soils and waters by fluorescent pesticides.

The purpose of this research is to develop a direct spectrometric approach to monitor soils and waters, at a lower cost than the widely used chromatographic techniques; a spectrometric approach that is effective, reliable, fast, easy to implement, and without any use of organic solvents whose utilization is subject to law limitation. It could be suitable at least as an alert method in case of massive contamination. Here, we present for the first time a catalog of excitation-emission and total synchronous fluorescence maps that may be considered as fingerprints of a series of homologated pesticides, in large use in Morocco, aiming at a direct detection of their remains in agricultural soils and neighboring waters. After a large survey among farmers, agricultural workers and product distributors in two important agricultural regions of Morocco (Doukkala-Abda and Sebou basin), 48 commercial pesticides, which are fluorescent, were chosen. A multi-component spectral database of these targeted commercial pesticides was elaborated. For each pesticide, dissolved in water at the lowest concentration giving a no-noise fluorescence spectrum, the total excitation-emission matrix (TEEM), the total synchronous fluorescence matrix (TSFM) in addition to synchronous fluorescence spectra (SFS) at those offsets giving the highest fluorescence intensity were recorded. To test this preliminary multi-component database, two real soil samples, collected at a wheat field and at a vine field in the region of Doukkala, were analyzed. Remains of the commercial Pirimor (Carbamate) and Atlantis (Sulfonylurea) were identified by comparison of the recorded TEEM, TSFM, and SFS to those of the preliminary catalog at one hand, and on the basis of the results of a field pre-survey. The developed approach seems satisfactory, and the fluorimetric fingerprint database is under extension to a higher number of fluorescent pesticides in common use among the Moroccan agricultural regions.

Factors impacting stem cell mobilization failure rate and efficiency in multiple myeloma in the era of novel therapies: experience at Memorial Sloan Kettering Cancer Center.

Thalidomide, lenalidomide and bortezomib have increasingly been incorporated in first-line induction therapies for multiple myeloma. Concerns regarding the impact of these agents, especially lenalidomide, on stem cell mobilization prompted us to re-evaluate the risk factors that impact mobilization, including exposure to novel induction regimens. Among 317 patients who proceeded to stem cell collection after induction therapy between 2000 and 2009, the rate of mobilization failure, defined as the inability to collect 5 × 10(6) CD34+ cells/kg following the first collection attempt, was 13%. By multivariate analysis, independent risk factors associated with mobilization failure included older age (P=0.04), lower platelet count (P=0.002) and use of single-agent G-CSF for mobilization (P<0.0001). When considering for outcome measurement stem cell collection efficiency measured by the number of CD34+ cells yielded per pheresis performed during first collection attempt, lower platelet count, use of single-agent G-CSF and older age were also associated with lower efficiency. In this population mobilized mostly with cyclophosphamide and G-CSF, the use of lenalidomide during induction was not associated with a lower stem cell collection efficiency by multivariate analysis. The data support the current International Multiple Myeloma Working Group guidelines recommending the use of cyclophosphamide and G-CSF based mobilization for patients previously exposed to lenalidomide.

Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis.

To improve the efficacy of risk-adapted melphalan (MEL) in patients with amyloidosis (AL), we conducted a phase II trial using bortezomib and dexamethasone (BD) as consolidation. Forty untreated patients with renal (70%), cardiac (65%), liver/gastrointestinal (15%) or nervous system (13%) AL were assigned MEL 100, 140 or 200 mg/m(2) based on age, renal function and cardiac involvement. Hematological response was assessed at 3 months post stem cell transplant (SCT); patients with less than complete hematological response (CR) received BD consolidation. Four patients with advanced cardiac AL died within 100 days of SCT (10% treatment-related mortality). Survival at 12 and 24 months post treatment start was 88 and 82% overall and was 81 and 72% in patients with cardiac AL. At 3 months post SCT, 45% had ≥ partial response (PR) including 27% CR. Twenty-three patients received consolidation and in 86% response improved; all patients responded in one cycle. At 12 and 24 months, 79 and 60% had ≥ PR, 58 and 40% CR. Organ responses occurred in 55 and 70% at 12 and 24 months. Eight patients relapsed/progressed. One patient with serologic progression had organ impairment at time of progression. In newly diagnosed AL, BD following SCT rapidly and effectively improves responses resulting in high CR rates and maintained organ improvement.

A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma.

Patients with asymptomatic (smoldering) multiple myeloma (AMM) have a high risk of transformation to active multiple myeloma (MM). Bisphosphonates such as zoledronic acid (ZLD) reduce skeletal events in MM and the immunomodulatory agent thalidomide (Thal) has proven effectiveness in active MM. We hypothesized that treatment with Thal and ZLD would prolong the time to progression (TTP) to MM over ZLD alone. Eligible patients had asymptomatic MM and all patients received ZLD 4 mg intravenous monthly; the treatment arm also received Thal 200 mg per day. The TTP was superior for Thal/ZLD (n=35) patients compared with ZLD alone (n=33); median TTP of 2.4 years (95% confidence interval (CI): 1.4-3.6) versus 1.2 years (95% CI: 0.7-2.5) (hazard ratio (HR), 2.05; 95% CI: 1.1-3.8; P-value: 0.02). At 1 year, 86% of Thal/ZLD patients were progression free compared with 55% on ZLD alone (P=0.0048). The overall response rate after year 1 was 37% for Thal/ZLD with a median duration of response of 3.3 years (95% CI: 1.1-NA); there were no confirmed responses to ZLD alone (P=0.0004). The addition of Thal to standard ZLD produces anti-tumor responses whereas ZLD alone does not. Thal/ZLD also prolongs TTP from AMM to MM. This study provides the rationale for further studies in patients with AMM to delay chemotherapy.

Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients' monitoring after transplantation.

Auto-SCT (ASCT) is widely used in first-line treatment of multiple myeloma (MM). However, most patients eventually relapse or have progression of disease (R/POD). Although precise knowledge of R/POD patterns would be important to generate evidence-based surveillance recommendations after ASCT, such data is limited in the literature, especially after introduction of the free light chain assay (FLCA). This retrospective study examined the patterns of R/POD after first-line ASCT in 273 patients, using established criteria. At the time of R/POD, only 2% of patients had no associated serological evidence of R/POD. A total of 85% had asymptomatic R/POD, first detected by serological testing, whereas 15% had symptomatic R/POD with aggressive disease, early R/POD and short survival, with poor cytogenetics and younger age identified as risk factors. Although occult skeletal lesions were found in 40% of asymptomatic patients tested following serological R/POD, yearly skeletal surveys and urine testing were poor at heralding R/POD. We found a consistent association between paraprotein types at diagnosis and R/POD, allowing informed recommendations for appropriate serological monitoring and propose a new needed criterion using FLCA for patients relapsing by FLC only. Our findings provide important evidence-based recommendations that strengthen current monitoring guidelines after first-line ASCT in MM.

Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects.

BACKGROUND: Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL). METHODS: In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response. RESULTS: During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a ≥ 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment. CONCLUSION: AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.

Predictors of survival in patients with systemic light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone.

The treatment of systemic light-chain (AL) amyloidosis with symptomatic cardiac involvement at diagnosis remains a challenge. We report the results of 40 consecutive newly diagnosed AL cardiac patients who were not candidates for stem cell transplant and therefore received monthly oral melphalan and dexamethasone. Median survival was 10.5 months and baseline predictors of survival included gender, troponin I and interventricular septal thickness. The most significant predictor of survival was response to therapy. The haematological response rate was 58% (23/40) with 13% (5/40) complete responses; most responses were noted in <3 cycles. Achievement of a rapid response to therapy extends survival.

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease.

The treatment of monoclonal Ig deposition disease (MIDD) is controversial and not standardized. We report our experience with high dose melphalan and auto-SCT (HDM/auto-SCT) in seven patients with MIDD associated with underlying Durie-Salmon stage IB multiple myeloma, including five with light chain deposition disease, one with light and heavy chain deposition disease and one with light chain crystal deposition disease. The median age of these patients was 50 years; six of them were male subjects. A monoclonal kappa-light chain was detected by Serum Free Light Chain Assay in all seven. The patients received melphalan 140 mg/m(2) followed by auto-SCT. All patients are alive and six remain in hematologic CR with a median follow up of 23.6 months (7.9-69.8 months). Renal function has improved compared to pre-HDSM/auto-SCT in five patients--two of whom had a renal transplant and became dialysis independent--remained stable in one and worsened in one leading to hemodialysis despite hematologic CR. Our results corroborate previous experience with HDM/auto-SCT in MIDD and argue in favor of kidney transplantation in patients who achieve hematologic CR after HDM/auto-SCT. Although this approach appears effective, multi-center studies are needed to define the optimal treatment for patients with MIDD.

Results of a phase I/II trial adding carmustine (300 mg/m2) to melphalan (200 mg/m2) in multiple myeloma patients undergoing autologous stem cell transplantation.

Autologous stem cell transplantation (SCT) with high-dose melphalan (HDM, 200 mg/m2) is the most effective therapy for multiple myeloma. To determine the feasibility of combining carmustine (300 mg/m2) with HDM, we enrolled 49 patients with previously treated Durie-Salmon stage II/III myeloma (32M/17W, median age 53) on a phase I/II trial involving escalating doses of melphalan (160, 180, 200 mg/m2). The median beta2-microglobulin was 2.5 (0-9.3); marrow karyotypes were normal in 88%. The phase I dose-limiting toxicity was > or =grade 2 pulmonary toxicity 2 months post-SCT. Other endpoints were response rate and progression-free survival (PFS). HDM was safely escalated to 200 mg/m2; treatment-related mortality was 2% and > or =grade 2 pulmonary toxicity 10%. The complete (CR) and near complete (nCR) response rate was 49%. With a median post-SCT follow-up of 2.9 years, the PFS and overall survival (OS) post-SCT were 2.3 and 4.7 years. PFS for those with CR or nCR was 3.1 years while for those with stable disease (SD) it was 1.3 years (P=0.06). We conclude that carmustine can be combined with HDM for myeloma with minimal pulmonary toxicity and a high response rate.

Hematopoietic stem cell mobilization with intravenous melphalan and G-CSF in patients with chemoresponsive multiple myeloma: report of a phase II trial.

Multiple myeloma (MM) is an incurable hematologic malignancy for which autologous hematopoietic stem cell transplantation (HCT) is a standard therapy. The optimal method of stem cell mobilization is not defined. We evaluated intravenous melphalan (60 mg/m2), the most effective agent for MM, and G-CSF (10 microg/kg/day) for mobilization. End points were safety, adequacy of CD34+ collections, MM response, and contamination of stem cell components (SCC). In total, 32 patients were mobilized. There were no deaths or significant bleeding episodes; 14 patients (44%) required hospitalization for neutropenic fever. Median days of grade 3 or 4 neutropenia or thrombocytopenia were 7 (2-20) and 8 (3-17). Median mobilization days, CD34+ cells/kg and total leukaphereses were 16 (12-30), 12.1 million (2.6-52.8), and 2 (1-5) respectively. Four patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in five leukaphereses. Reduction in myeloma was seen in 11 patients (34%) with 3 (9%) achieving complete response; 15 (47%) maintained prior responses. Estimated MM contamination per SCC (N=48) was 0.0009% (range 0-0.1) and 0.21 x 10(4) cells per kg (range 0-41.2). Increased contamination was associated with increased patient age. This strategy for mobilization is feasible, frequently requires hospitalization and transfusion, and controls disease in most patients.

Heme oxygenase-1 induction by hemin protects against gut ischemia/reperfusion injury.

BACKGROUND: We have shown that both intraischemic hypothermia and hypertonic saline resuscitation provide dramatic protection against gut ischemia/reperfusion (I/R) injury that is in part mediated by heme oxygenase-1 (HO-1). We therefore hypothesized that induction of HO-1 by hemin would lessen damage and improve function after gut I/R. MATERIALS AND METHODS: Male Sprague-Dawley rats were treated with 50 micromol/kg hemin (HO-1 inducer ferric protoporphyrin IX chloride) sq or vehicle 2 h before superior mesenteric artery occlusion for 60 min or sham laparotomy. After 6 h of reperfusion, transit was determined by quantitation of percentage of tracer in 10 equal segments of small intestine 30 min following injection into the duodenum (expressed as mean geometric center). Ileum was harvested for assessment of mucosal histologic injury (Chiu score 0-5 by blinded observer), myeloperoxidase activity (MPO, index of inflammation), and HO-1 protein expression. RESULTS: Hemin treatment was associated with increased HO-1 protein expression, lessened mucosal injury, decreased MPO activity, and improved intestinal transit following gut I/R. CONCLUSION: These data corroborate that HO-1 plays an important role in protecting the gut against I/R-induced injury.

Chronic aortic dissection not a risk factor for neurologic deficit in thoracoabdominal aortic aneurysm repair.

OBJECTIVE: chronic aortic dissection has long been considered a risk factor for neurologic deficit following thoracoabdominal aortic aneurysm (TAA) surgery. We reviewed our experience with regard to aneurysm extent and the use of adjunct, (distal aortic perfusion/cerebrospinal fluid drainage), and examined the impact of these factors on neurologic deficit among chronic dissection and non-dissection cases. METHODS: between February 1991 and March 2001, we repaired 800 aneurysms of the descending thoracic and thoracoabdominal aorta. Seven hundred and twenty-nine cases were elective; 196 chronic dissection, 533 non-dissection. 182/729 (24.9%) were TAA extent II. Among these, 61/182 (33%) involved chronic dissection. Adjunct was used in 507/729 (69.6%). We conducted detailed multivariate analyses to isolate the impact of chronic aortic dissection on neurologic morbidity, with other important risk factors taken into account. RESULTS: overall, 32/729 (4.4%) patients had neurologic deficit upon awakening; 7/196 (3.6%) in chronic dissections, and 25/533 (4.7%) in non-dissections. Adjunct had a major effect, reducing neurologic deficit in TAA extent II from 10/36 (27.8%) to 10/146 (6.9%) (p=0.001). However, in univariate and multivariate analysis, chronic dissection did not increase the risk of neurologic deficit, regardless of extent or mode of treatment. CONCLUSION: in contrast to previous reports, we determined that chronic aortic dissection is not a risk factor in TAA patients.

beta-Spectrin S(ta) Bárbara: a novel frameshift mutation in hereditary spherocytosis associated with detectable levels of mRNA and a germ cell line mosaicism.

Hereditary spherocytosis (HS) is a common inherited anaemia characterized by the presence of spherocytic red cells and by a heterogeneous nature in terms of its clinical presentation, molecular basis and inheritance. Defects in several membrane protein genes have been involved in the pathogenesis of HS, including defects in the beta-spectrin gene. We detected a novel frameshift mutation in the beta-spectrin gene, a C deletion at codon 638, in a patient presenting with HS and spectrin deficiency. The mutant protein was not detected in the membrane or in other cellular compartments, but detectable levels of mutant mRNA were found in the patient. Interestingly, this mutation was not present in the patient's parents, suggesting a genetic mosaicism, especially as the patient has an affected brother with the same molecular defect. We analysed DNA from different tissues of the parents and the mutation was absent from all tissues analysed. This mutation seems to be confined to the germ cell lineage of the patient's mother and must present a mosaic pattern in these cells as the patient also has unaffected siblings.