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Background: Patients with major depressive disorder (MDD) who do not adequately respond to antidepressant treatment (ADT) may benefit from adjunctive atypical antipsychotics; however, certain agents target specific symptoms of depression and not the full syndrome. The aim of this analysis was to examine the effects of brexpiprazole, adjunct to ADT, on the core symptoms of MDD, defined using Montgomery-Åsberg Depression Rating Scale (MADRS) items.Methods: This was a post hoc analysis of data from two 6-week, randomized, double-blind studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (n = 1056). Efficacy was assessed using the MADRS core symptom subscale (MADRS6) and individual items (apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts).Results: At Week 6, adjunctive brexpiprazole showed a greater effect than adjunctive placebo on the MADRS6 (within-group Cohen's d effect sizes: brexpiprazole, 1.05; placebo, 0.71; p < 0.001 between groups) and on each of the six core symptoms (effect sizes: brexpiprazole, 0.64-0.94; placebo, 0.39-0.64; all p < 0.001). At Week 2, adjunctive brexpiprazole already showed a greater effect than adjunctive placebo on the MADRS6, and on five of the core symptoms (all p < 0.01).Limitations: This was a post hoc analysis of studies that were not designed for this purpose. Correction for multiple comparisons was not performed.Conclusions: Brexpiprazole, as adjunct to ADT, produced a statistically significant and clinically meaningful improvement on the core symptoms of MDD. Brexpiprazole is thought to exert its effects in MDD by treating the core symptoms of the disease. [ABSTRACT FROM AUTHOR]

Background Non-alcoholic fatty liver disease ( NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis ( NASH). Aim To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. Methods A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA- IR level. Results The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. Conclusions These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1 β and IL-6 suppression. [ABSTRACT FROM AUTHOR]

Background Lithium augmentation of antidepressants for treatment of unipolar major depression was one of the first adjunctive strategies based on a neuropharmacologic rationale. Randomized controlled trials supported its efficacy but most trials added lithium to tricyclic antidepressants (TCAs). Despite its efficacy, use of lithium augmentation remains infrequent. The current systematic review and meta-analysis examines the efficacy of lithium augmentation as an adjunct to second generation antidepressants as well as to TCAs and considers reasons for its infrequent use. Method A systematic search of Medline and the Cochrane Clinical Trials database was performed. Randomized, placebo-controlled trials of lithium augmentation were selected. A fixed-effects meta-analysis was performed. Odds ratios for response were calculated for each treatment-control contrast, for the trials grouped by type of initial antidepressant (TCA or second generation antidepressant), and as a meta-analytic summary for all treatments combined. Results Nine trials that included 237 patients were selected. The odds ratio for response to lithium vs. placebo in all contrasts combined was 2.89 (95% CI 1.65, 5.05, z=3.72, p=0.0002). Heterogeneity was very low, I²=0%. Adjunctive lithium was effective with TCAs (7 contrasts) and with second generation agents (3 contrasts). Discontinuation due to adverse events was infrequent and did not differ between lithium and placebo. Limitations The meta-analysis is limited by the small size and number of trials and limited data for treatment resistant patients. Conclusions Adjunctive lithium appears to be as effective for second generation antidepressants as it was for the tricyclics. [ABSTRACT FROM AUTHOR]

Background: Uncontrolled antidepressant trials suggest that anxious patients with major depressive disorder (MDD) are less responsive to antidepressant treatment than less anxious patients. The objective of this study is to determine whether specific antidepressant effects, estimated by drug-placebo differences, are reduced in anxious depression during treatment of MDD with duloxetine. Methods: This is a retrospective secondary pooled analysis of all placebo-controlled trials of duloxetine at therapeutic doses conducted by the sponsor in outpatients with nonpsychotic unipolar MDD, using the Hamilton Depression Rating Scale (HAMD). Anxious depression was defined by ≥7 on the anxiety/somatization factor of the HAMD. Response was defined as ≥50% improvement from baseline to endpoint on the HAMD. Remission was defined as an endpoint HAMD≤7. Analyses were performed in the intent-to-treat sample with at least one post-treatment rating. Results: Eleven trials included 2,841 patients of whom 1,326 were classified as anxious and 1,515 as nonanxious. Change on the HAMD was greater with duloxetine than placebo in both anxious (9.91 versus 7.55, P<.001) and nonanxious (6.65 versus 5.23, P<.001) patients. Level of anxiety had no effect on the drug–placebo differences. Response and remission rates were significantly greater in duloxetine than placebo-treated patients and drug–placebo differences were unaffected by anxious status. Use of HAMD items psychic and somatic anxiety to define anxious subgroups had similar outcomes. Conclusions: Duloxetine was more effective than placebo in achieving response and remission in both anxious and nonanxious patients. Anxious status did not affect the magnitude of the drug effect. Depression and Anxiety, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Within 3-tier behavioral models, universal interventions are expected to prevent the onset of problem behavior in a majority of children altogether and to sustain improvements in child outcomes by the selected and indicated interventions. A cohort longitudinal design was used to assess the extent to which a 3-tier model achieves these expected outcomes. The respective universal, selected, and indicated interventions included Behavior and Academic Support and Enhancement, First Step to Success, and MultiSystemic Therapy. A total of 407 children in Grades K-3 from 1 of 4 longitudinal cohorts participated. The results of 2-level linear growth analyses indicate that the 3-tier behavior model achieved the anticipated outcomes with respect to social behavior. The results, limitations, and implications are discussed. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation causes significant morbidity and mortality. An important site of GVHD is the gastrointestinal (GI) tract because development of acute GI GVHD is prognostic of overall survival. The standard of care to treat acute GI GVHD is systemic corticosteroids and immunosuppressants; however, the use of these therapies can cause life-threatening opportunistic infections. To limit the adverse effects of systemic immunosuppression, the topically active corticosteroid beclometasone dipropionate has been investigated in case studies and in randomized placebo-controlled trials for the treatment of acute GI GVHD. In this review, we appraise these studies with beclometasone dipropionate, and discuss future randomized studies to clarify the role of beclometasone dipropionate for the treatment and prevention of acute GVHD. At present, more data are required before the addition of beclometasone dipropionate to systemic corticosteroids for the treatment of acute GVHD can be considered the standard of care. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of adjunctive ziprasidone in treatment for major depression and adjunctive atypical antipsychotics. Information about the randomized controlled trial in patients who received adjunctive ziprasidone, is provided. An overview on the comparison of ziprasidone with other atypical antipsychotics, is also examined.

Abstract: The goal of the present work was to conduct a meta-analysis comparing reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n =2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and reboxetine (59.2%)-treated groups (p =0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p =0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p =0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD. [Copyright &y& Elsevier]

Introduction Treatment studies of depression in the very oldest patients are infrequent. For these reasons, this study of mirtazapine orally disintegrating tablets was carried out in nursing home residents ≥85 years old with physician-diagnosed depression. The naturalistic conditions of the study allowed us to include patients with cognitive impairment, concomitant medications and comorbid illness. Methods This was a subgroup analysis of nursing home residents ≥85 years old who took part in a larger 12-week open-label trial. Patients were eligible if they had physician-diagnosed depression, and a Mini-Mental State Exam score ≥10. The physician or nurse coordinator obtained data from healthcare professionals in daily contact with the patient to complete the Clinical Global Impression (CGI) scale, a modified 16-item Hamilton Depression Scale (HAM-D), and the Cornell Scale for Depression in Dementia (CSDD). Treatment-emergent adverse events were recorded. Results Of the 50 patients enrolled at 23 sites, 72% completed the 12-week trial. The mean age of the participants was 89.3 years. The mean HAM-D score declined from 16.9 at baseline to 7.3 at endpoint (ITT, LOCF analysis) For the CSDD, the mean score declined from 15.1 to 7.1. The percentage of responders on the CGI-Improvement (CGI-I) scale increased at each assessment reaching 55% at endpoint. Only 10% of the patients discontinued treatment because of adverse events. There was a mean increase in weight of 1.32 lbs (0.6 kg) at day 84. Conclusion Although lacking a placebo control, this naturalistic study suggests that mirtazapine orally disintegrating tablets were effective and well tolerated in this sample of depressed nursing home residents ≥85 years of age. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This article systematically reviews the available research on rational emotive behavioral therapy (REBT) with children and adolescents. Meta-analytic procedures were applied to 19 studies that met inclusion criteria. The overall mean weighted effect of REBT was positive and significant. Weighted zr effect sizes were also computed for five outcome categories: anxiety, disruptive behaviors, irrationality, self-concept, and grade point average. In terms of magnitude, the largest positive mean effect of REBT was on disruptive behaviors. Analyses also revealed the following noteworthy findings: (a) there was no statistical difference between studies identified low or high in internal validity; (b) REBT appeared equally effective for children and adolescents presenting with and without identified problems; (c) nonmental health professionals produced REBT effects of greater magnitude than their mental health counterparts; (d) the longer the duration of REBT sessions, the greater the impact, and (e) children benefited more from REBT than adolescents. The findings are discussed in terms of several important limitations along with suggestions for future research. [ABSTRACT FROM AUTHOR]

Objective: There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients. This placebo-controlled study of sertraline was designed to confirm the results of non-placebo-controlled trials. Method: The subjects were outpatients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher. The patients were randomly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline. The primary outcome variables were the Hamilton scale and Clinical Global Impression (CGI) scales for severity and improvement. Results: A total of 371 patients assigned to sertraline and 376 assigned to placebo took at least one dose. At endpoint, the patients receiving sertraline evidenced significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales. The mean changes from baseline to endpoint in Hamilton score were -7.4 points (SD=6.3) for sertraline and -6.6 points (SD=6.4) for placebo. The rate of CGI-defined response at endpoint was significantly higher for sertraline (45%) than for placebo (35%), and the time to sustained response was significantly shorter for sertraline (median, 57 versus 61 days). There were few discontinuations due to treatment-related adverse events, 8% for sertraline and 2% for placebo. Conclusions: Sertraline was effective and well tolerated by older adults with major depression, although the drug-placebo difference was not large in this 8-week trial. [ABSTRACT FROM AUTHOR]

Background. When a cryogen spurt is applied to the skin surface for an appropriately short period of time (on the order of tens of milliseconds), the cooling remains localized in the epidermis, while leaving the temperature of the deeper port-wine stain (PWS) blood vessels unchanged. Objective. The objective of this study was to compare the efficacy and safety of noncooled laser treatment (NC-LT), and cryogen spray cooled laser treatment (CSC-LT) of PWS birthmarks in a large series of patients. Methods. A retrospective review was conducted of 196 patients with head or neck PWS birthmarks treated with the pulsed dye laser (λ = 585 nm; τp = 450 μsec) over a 7-year period. Subjects' ages ranged between 2 months and 62 years; there were 109 females and 87 males, all of whom were Asian. Ninety-eight patients received NC-LT using light dosages of 5–7 J/cm2. Subsequently, 98 patients received CSC-LT using light dosages of 8–10 J/cm2. The primary efficacy measure was the quantitative assessment of the blanching response scores of NC-LT PWSs as compared, on a blinded basis, to CSC-LT PWSs. Results. Based on chi-squared analysis, there were clinical, and statistically significant, differences in the blanching response scores favoring PWS receiving CSC-LT as compared to the NC-LT group (P < .001). Permanent scarring was noted in 3.1% (n = 3) of the patients in the NC-LT group. Permanent scarring was not observed in the CSC-LT treatment group. Transient hyperpigmentation was noted in 57% (n = 56) and 48% (n = 47) of the patients in the NC-LT and CSC-LT groups, respectively. In both groups, the transient hyperpigmentation resolved in all patients within 1 year. Two patients in the NC-LT group developed delayed permanent hypopigmentation. Permanent hypopigmentation was not observed in the CSC-LT group. Conclusion. CSC permitted the use of higher incident light dosages leading to improved PWS clearance without... [ABSTRACT FROM AUTHOR]

Treatment of refractory depression is a common challenge for mental health professionals. To assure optimal treatment, the clinician should first determine that adequate dosage has been employed for an adequate duration. Next there are a variety of augmentation strategies or alternative antidepressants that could be considered. This report reviews the evidence supporting these strategies, describes their implementation, compares their effectiveness, and offers suggestions for approaching the array of treatments available. Depression and Anxiety 5:165–174, 1997. © 1997 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The author reflects on a study which demonstrates the successful use of adjunctive L-methylfolate as treatment for patients with major depressive disorder. He says that study involved two trials, the comparison of L-methylfolate and placebo in 148 patients with nonpsychotic unipolar depression and the use of 15 milligrams per day (mg/day) L-methylfolate or placebo in 75 patients. He is interested on the impact of L-methylfolate's long-term administration in depressed individuals.

El autor ofrece sus opiniones sobre el tratamiento de la depresión ansiosa. El autor cuestiona los resultados del estudio "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D). Se discute el significado del termino "ansiosa" según los médicos y los autores de estudios que abordan el trastorno.

This article presents an overview of the study regarding anxious depression. The study demonstrates that among 2,876 patients with major depression, those who were more anxious were more likely to experience adverse events and were less likely to respond and remit during citalopram treatment. The difference in response rates between anxious and nonanxious groups in the Sequenced Treatment Alternative to Relieve Depression sample is 41.7 percent and 52.8 percent, respectively, considering the magnitude of differences observed in recent placebo-controlled trials in depression and antidepressant comparison studies.

Background. The treatment of medium-sized (1.5–20 cm diameter) congenital melanocytic nevi (CMN) has been the concern of dermatologists for decades. Although many techniques have been described and utilized, no single treatment has emerged as applicable under all circumstances. Methods The Q-switched ruby laser (QSRL) at 694 nm, a wavelength well absorbed by melanin relative to other optically absorbing structures in skin, causes highly selective destruction of pigment-laden cells. In addition, the 20-nanosecond pulse duration produced by this laser approximates the thermal relaxation time for melanosomes, thereby confining the energy to the targeted cells. Results. In the present report, treatment using the QSRL resulted in complete clinical removal of a biopsy-documented medium-sized compound CMN with no recurrence after 5 years. In contrast to other therapeutic modalities, complications such has hypertrophic scarring, dyspigmentation, or atrophy were not observed. [ABSTRACT FROM AUTHOR]

Pulsed dye laser irradiation in the wavelength range of 585 to 600 nm is currently the gold standard for treatment of port-wine stains (PWSs). However, this treatment method is often ineffective for deeply seated blood vessels and in individuals with moderate to heavy pigmentation. Use of optical particles doped with the FDA-approved near-infrared (NIR) absorber, indocyanine green (ICG), can potentially provide an effective method to overcome these limitations. Herein, we theoretically investigate the effectiveness of particles derived from erythrocytes, which contain ICG, in mediating photothermal destruction of PWS blood vessels. We refer to these particles as NIR erythrocyte-derived transducers (NETs). Our theoretical model consists of a Monte Carlo algorithm to estimate the volumetric energy deposition, a finite elements approach to solve the heat diffusion equation, and a damage integral based on an Arrhenius relationship to quantify tissue damage. The model geometries include simulated PWS blood vessels as well as actual human PWS blood vessels plexus obtained by the optical coherence tomography. Our simulation results indicate that blood vessels containing micron- or nano-sized NETs and irradiated at 755 nm have higher levels of photothermal damage as compared to blood vessels without NETs irradiated at 585 nm. Blood vessels containing micron-sized NETs also showed higher photothermal damage than blood vessels containing nano-sized NETs. The theoretical model presented can be used in guiding the fabrication of NETs with patient-specific optical properties to allow for personalized treatment based on the depth and size of blood vessels as well as the pigmentation of the individual's skin. [ABSTRACT FROM AUTHOR]

Presents case studies of patients who underwent corticosteroid therapy for diffuse alveolar hemorrhage after autologous bone marrow transplantation. Medical history of the patients; Details of the treatment; Discussion on the occurrence of the complication.

Residual symptoms of major depressive disorder ( MDD) following treatment are increasingly recognized as having a negative impact on the patient because of their association with lack of remission, poorer psychosocial functioning, and a more chronic course of depression. Although the effects of specific residual symptoms have not been as systematically studied, several symptoms, including fatigue, sleep disturbance, anxiety, and concentration difficulties, commonly occur as part of the residual state in MDD. In particular, the relatively high prevalence of residual fatigue suggests that this symptom is not being adequately addressed by standard antidepressant therapies. A review of the clinical relevance of residual fatigue was undertaken, using the published literature with respect to its assessment, neurobiology, and treatment implications. The findings of this review suggest that fatigue is highly prevalent as a residual symptom; its response to treatment is relatively poor or delayed; and the presence of residual fatigue is highly predictive of inability to achieve remission with treatment as well as impaired psychosocial functioning. Recognition of the significant consequences of residual fatigue should reinforce the need for further therapeutic interventions to help reduce the impact of this symptom of MDD. [ABSTRACT FROM AUTHOR]

In our previous research (Benner, Nelson, Sanders, & Ralston, 2012), elementary schools were randomly assigned to either a primary-level behavior intervention directed at externalizing behavior (treatment, n = 7 schools) or to business-as-usual condition (control, n = 6 schools). A screening procedure was used to identify K through 3-grade students who exhibited externalizing behavior. The results showed that treatment students (h = 44) exhibited lower levels of problem behavior (ES = -0.99) and higher rates of on-task behavior (F.S = 0.61) compared to controls (n = 26). The results also suggested that individual baseline behavior and school context as measured by free and reduced-priced meal rates moderated the findings. Given this latter finding, our interest in the current study was to test whether individual and school aggregate baseline behavior levels moderate students' response to two years of the behavior intervention. Schools originally assigned to treatment continued to implement the intervention during the subsequent academic year; schools in the control condition continued with their business-as-usual behavior management approaches. During the winter of the second year, students who remained in their schools were re-assessed on their behavior (r\ = 35 and n = 19 in treatment and control conditions, respectively). Analyses involving multilevel context modeling showed that students with relatively high initial baseline behavior levels (pretreatment) were more responsive to the intervention if they were in schools with higher school aggregate baseline behavior levels. Conversely, students tended to be less responsive to intervention if they were in schools with lower school aggregate baseline behavior levels. Limitations and practical implications are discussed. [ABSTRACT FROM AUTHOR]

The turbidity of most biologic tissues hinders the use of lasers for diagnostic and therapeutic purposes. Hyperosmotic agents such as glycerol have been used to alter the optical scattering properties of turbid tissues. The mechanism of this effect, “optical clearing”, however, remains incompletely understood. Multiphoton microscopy utilizing second harmonic generation can be used to monitor collagen structural changes in the presence of glycerol. This study suggests that the use of glycerol for tissue “optical clearing” screens noncovalent intermolecular interactions between low-order collagen structures, resulting in fiber disassembly. Dissociation of collagen fibers in native and engineered tissues in the presence of glycerol and reassociation with the application of saline are imaged dynamically. Collagen fiber reassembly is governed by the displacement of glycerol by saline in native and engineered skin. These results reveal the assembly process of high-order collagen structures and propose a molecular mechanism for the increase in tissue transparency observed after glycerol application. [ABSTRACT FROM AUTHOR]

Background: The majority of port-wine stain (PWS) patients treated with the pulsed dye laser (PDL) do not achieve complete blanching. Safe administration of higher fluences has been proposed as a means of improving treatment efficacy. Objective: To determine the safety and efficacy of PWS treatment with the 1.5-msec PDL at high fluences in conjunction with cryogen spray cooling. Methods: Twenty PWS patients were treated with the PDL in combination with cryogen spray cooling utilizing a 7 or 10 mm spot size and fluences ranging from 6 to 15 J/cm[sup 2] . Before and after treatment photographs were compared on a blinded basis. Results: No scarring or skin textural changes occurred. Blanching scores were as follows: 20% of patients achieved 75% or greater blanching after an average of 3.3 treatments, 30% achieved 50–74% blanching, 20% achieved 25–49% blanching, and 30% achieved less than 25% blanching. Conclusion: In conjunction with cryogen spray cooling, the PDL can be safely used at high fluences. At this time it is not clear that the use of higher fluences improves treatment efficacy; however, as other aspects of PWS laser treatment are optimized, safe administration of higher fluences is likely to be advantageous. [ABSTRACT FROM AUTHOR]

Background: Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs) from radiation injury is an important goal in the development of medical countermeasure agents (MCM). We recently identified thioredoxin (TXN) as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI) and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. Methods: We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs), red blood cells (RBCs), hemoglobin, and platelets. Colony forming unit (CFU) assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. Results: We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin- (KSL) cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced double-strand DNA breaks in both murine bone marrow lineage-negative (Lin-) cells and primary fibroblasts. Furthermore, TXN decreased the expression of p16 and phosphorylated p38. Our data suggest that TXN modulates diverse cellular processes of HSCs. Conclusions: Administration of TXN 24 h following irradiation mitigates radiation-induced lethality. To the best of our knowledge, this is the first report demonstrating that TXN reduces radiation-induced lethality. TXN shows potential utility in the mitigation of radiation-induced hematopoietic injury. [ABSTRACT FROM AUTHOR]

Treatment-related mortality (TRM) remains elevated in adult patients undergoing umbilical cord blood transplantation (UCBT), including an early rise in TRM suggestive of excessive toxicity associated with the standard myeloablative total body irradiation (TBI), fludarabine, and cyclophosphamide regimen. In an attempt to reduce regimen-related toxicity, we previously studied a modified myeloablative regimen with TBI (1350 cGy) and fludarabine (160 mg/m 2 ); TRM was decreased, but neutrophil engraftment was suboptimal. Therefore, to improve engraftment while still minimizing regimen-related toxicity, we piloted a myeloablative regimen with the addition of thiotepa (10 mg/kg) to TBI and fludarabine conditioning. Thirty-one adult patients (median age, 46 years; range, 19 to 65) with hematologic malignancies (acute leukemia/myelodysplastic syndrome, 77%; lymphoid malignancy, 23%) underwent single (n = 1) or double (n = 30) UCBT from 2010 to 2015 at our institution. The cumulative incidence of neutrophil engraftment was 90% (95% confidence interval [CI], 70% to 97%) by 60 days, with a median time to engraftment of 21 days (95% CI, 19 to 26). The cumulative incidence of platelet engraftment was 77% (95% CI, 57% to 89%) by 100 days, with a median time to engraftment of 47 days (95% CI, 37 to 73). Cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease (GVHD) at day 100 were 45% (95% CI, 27% to 62%) and 10% (95% CI, 2% to 23%), respectively. The overall incidence of chronic GVHD at 2 years was 40% (95% CI, 22% to 57%), with 17% of patients (95% CI, 6% to 33%) experiencing moderate to severe chronic GVHD by 2 years. TRM at 180 days was 13% (95% CI, 4% to 27%), at 1 year 24% (95% CI, 10% to 41%), and at 3 years 30% (95% CI, 13% to 49%). Relapse at 1 year was 13% (95% CI, 4% to 27%) and at 3 years 19% (95% CI, 6% to 38%). With a median follow-up of 35.5 months (95% CI, 12.7 to 52.2), disease-free and overall survival at 3 years were 51% (95% CI, 29% to 69%) and 57% (95% CI, 36% to 73%), respectively. This regimen represents a reasonable alternative to myeloablative conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study. [ABSTRACT FROM AUTHOR]

Comprehensive recommendations for maintenance therapy after autologous stem cell transplantation (ASCT) for patients with multiple myeloma (MM) have yet to be defined. Bortezomib has been utilized as maintenance therapy after ASCT, but data attesting to the safety and efficacy of this agent compared with lenalidomide in the post-ASCT setting are limited. Therefore, we retrospectively analyzed the outcomes of 102 patients with MM who received maintenance therapy with bortezomib after ASCT at Duke University's adult bone marrow transplant clinic between 2005 and 2015. Maintenance with bortezomib was initiated between 60 and 90 days after ASCT as a single agent 1.3 mg/m 2 once every 2 weeks (n = 92) or in combination with lenalidomide (10 mg/day) (n = 10). The median age at ASCT was 64 (range, 31 to 78). Of the 99 patients with molecular data available, 42% had high-risk cytogenetics (including d17p, t(4;14), +1q, and t(14;16) by fluorescein in situ hybridization). Overall, 46% of patients experienced side effects from maintenance therapy, with 31% of all patients experiencing peripheral neuropathy. In total, 2% of patients required discontinuation of bortezomib maintenance because of adverse events. No secondary malignancies were reported from the therapy. The median progression-free survival (PFS) for patients receiving maintenance therapy with bortezomib after ASCT was 36.5 months (95% confidence interval [CI], 21.3 to not available) and median overall survival was 72.7 months (95% CI, 63.9 to not available). The PFS of patients with high-risk cytogenetics was not statistically significantly different from those with standard-risk cytogenetics, suggesting that maintenance with bortezomib may help overcome the impact of high-risk cytogenetics on early progression. These results indicate that maintenance therapy with bortezomib represents a safe, well-tolerated, and efficacious option for patients with high-risk cytogenetics, renal insufficiency, an inability to tolerate lenalidomide, or a previous history of another cancer. [ABSTRACT FROM AUTHOR]

Background: Due to the clinical challenges of treatment-resistant depression (TRD), we evaluated the efficacy of mindfulness-based cognitive therapy (MBCT) relative to a structurally equivalent active comparison condition as adjuncts to treatment-as-usual (TAU) pharmacotherapy in TRD.Methods: This single-site, randomized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program (HEP), comprising physical fitness, music therapy and nutritional education, as adjuncts to TAU pharmacotherapy for outpatient adults with TRD. The primary outcome was change in depression severity, measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D17), with secondary depression indicators of treatment response and remission.Results: We enrolled 173 adults; mean length of a current depressive episode was 6.8 years (SD = 8.9). At the end of 8 weeks of treatment, a multivariate analysis showed that relative to the HEP condition, the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 (36.6 vs. 25.3%; p = 0.01) and a significantly higher rate of treatment responders (30.3 vs. 15.3%; p = 0.03). Although numerically superior for MBCT than for HEP, the rates of remission did not significantly differ between treatments (22.4 vs. 13.9%; p = 0.15). In these models, state anxiety, perceived stress and the presence of personality disorder had adverse effects on outcomes.Conclusions: MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates. MBCT appears to be a viable adjunct in the management of TRD. [ABSTRACT FROM AUTHOR]

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia. [ABSTRACT FROM AUTHOR]

Background Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes. Methods GBM was applied to pooled data from 12 randomised clinical trials of 4987 participants experiencing an acute depressive episode who were treated with duloxetine, an SSRI or placebo to predict treatment remission. Additional analyses were conducted on the same dataset using the logistic regression model for comparison between these two methods. Results With GBM, there were noticeable differences between treatments when identifying which and to what extent variables were associated with remission. A single logistic regression only revealed a decreasing or increasing relationship between predictors and remission while GBM was able to reveal a complex relationship between predictors and remission. Limitations These analyses were conducted post-hoc utilising clinical trials databases. The criteria for constructing the analyses data were based on the characteristics of the clinical trials. Conclusions GBM can be used to identify and quantify patient variables that predict remission with specific treatments and has greater flexibility than the logistic regression model. GBM may provide new insights into inter-individual differences in treatment response that may be useful for selecting individualised treatments. Trial registration IMPACT clinical trial number 3327; IMPACT clinical trial number 4091; IMPACT clinical trial number 4689; IMPACT clinical trial number 4298; NCT00071695; NCT00062673; NCT00036335; NCT00067912; NCT00073411; NCT00489775; NCT00536471; NCT00666757 (note that trials with IMPACT numbers predate mandatory clinical trial registration requirements) [ABSTRACT FROM AUTHOR]

Abstract: Background: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. Methods: Data from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25–30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. Results: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, −2.5 [−4.0 to −1.1]; moderate, −3.2 [−4.9 to −1.6]; severe, −4.5 [−6.8 to −2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. Limitations: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. Conclusions: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. Clinical trial registration: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758. [Copyright &y& Elsevier]

Abstract: We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression. [Copyright &y& Elsevier]

Laser cartilage reshaping (LCR) with cryogen spray cooling is a promising modality for producing cartilage shape change while reducing cutaneous thermal injury. However, LCR in thicker tissues, such as auricular cartilage, requires higher laser power, thus increasing cooling requirements. To eliminate the risks of freeze injury characteristic of high cryogen spray pulse rates, a carbon dioxide (CO) spray, which evaporates rapidly from the skin, has been proposed as the cooling medium. This study aims to identify parameter sets which produce clinically significant reshaping while producing minimal skin thermal injury in LCR with CO spray cooling in ex vivo rabbit auricular cartilage. Excised whole rabbit ears were mechanically deformed around a cylindrical jig and irradiated with a 1.45-μm wavelength diode laser (fluence 12-14 J/cm per pulse, four to six pulse cycles per irradiation site, five to six irradiation sites per row for four rows on each sample) with concomitant application of CO spray (pulse duration 33-85 ms) to the skin surface. Bend angle measurements were performed before and after irradiation, and the change quantified. Surface temperature distributions were measured during irradiation/cooling. Maximum skin surface temperature ranged between 49.0 to 97.6 °C following four heating/cooling cycles. Significant reshaping was achieved with all laser dosimetry values with a 50-70 °C difference noted between controls (no cooling) and irradiated ears. Increasing cooling pulse duration yielded progressively improved gross skin protection during irradiation. CO spray cooling may potentially serve as an alternative to traditional cryogen spray cooling in LCR and may be the preferred cooling medium for thicker tissues. Future studies evaluating preclinical efficacy in an in vivo rabbit model are in progress. [ABSTRACT FROM AUTHOR]

Purpose: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. Experimental Design: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m2 or 1.3 mg/m2 IV bolus on days 1 and 8 of a 21-day cycle). Results: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. Conclusion: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) re-mains the most common cause of nonrelapse-related morbidity and mortal-ity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosup-pression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recur-rence. In this study, we showed that hepa-ran sulfate (HS), an extracellular matrix component, can activate Toll-like recep-tor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell matura-tion and alloreactlve T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor «1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and corre-lated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD. [ABSTRACT FROM AUTHOR]

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness. [ABSTRACT FROM AUTHOR]

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: To evaluate the immunological impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPS) at 12 months, for children who have received zero to three infant doses of seven-valent pneumococcal conjugate vaccine (PCV), on responses to a subsequent exposure to a small dose of 23vPPS (mPPS). Methods: Five hundred and fifty-two Fijian infants were stratified by ethnicity and randomized into eight groups to receive zero, one, two, or three PCV doses at 14 weeks, six and 14 weeks, or six, ten, and 14 weeks. Within each group, half received 23vPPS at 12 months and all received mPPS at 17 months. Sera were taken prior and one month post-mPPS. Findings: By 17 months, geometric mean antibody concentrations (GMC) to all 23 serotypes in 23vPPS were significantly higher in children who had received 23vPPS at 12 months compared to those who had not. Post-mPPS, children who had not received the 12 month 23vPPS had a significantly higher GMC for all PCV serotypes compared with those who had (each p <0.02). For the non-PCV serotypes, children who had not received the 12 month 23vPPS had significantly higher GMC for six of 16 non-PCV serotypes (7F, 9N, 12F, 19A, 22F, 33F) than those who did (each p <0.02). After adjusting for the pre-mPPS level, exposure to 23vPPS was associated with a lower response to mPPS for all serotypes (each p <0.001). Interpretation: Despite higher antibody concentrations at 17 months in children who had received 23vPPS at 12 months, the response to a re-challenge was poor for all 23 serotypes compared to children who had not received the 12 month 23vPPS. [Copyright &y& Elsevier]

Abstract: Fijian infants aged 6 weeks were stratified by ethnicity and randomized to receive 0, 1, 2, or 3 PCV-7 doses with or without the 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months. Strong booster effects for all 7 PCV-7 serotypes were elicited, and for 4/7 serotypes these responses were highest in the single PCV-7 group. There were fourfold rises in GMC for all non-PCV-7 serotypes. By 17 months the PPV-23 group still had significantly higher GMC (each p <0.001) for all serotypes. The PPV-23 was well tolerated and induced excellent responses for all serotypes which were greatest in the single PCV-7 group. [Copyright &y& Elsevier]

Currently, no agents are approved by the United States Food and Drug Administration (FDA) for either prevention or treatment of acute graft-versus-host disease (aGVHD). Formal precedents establishing a comparative basis for assessing the efficacy and safety of new investigational agents are still lacking. As a step toward addressing this problem, a panel of experts met on 2 occasions to reach consensus on recommendations for terminology describing a clinically meaningful primary endpoint in studies assessing treatment for aGVHD. The panel recommended terminology for “very good partial response” (VGPR) that includes both diagnostic and functional criteria. The central hypothesis leading to this proposal is that the potential harm of giving more treatment than needed to produce or maintain complete response exceeds the harm of slight undertreatment that may be associated with less than complete response. VGPR clearly cannot be used as the sole outcome measure in GVHD treatment trials, and must be considered in the context of survival and safety. The proposed use of VGPR as the primary endpoint in GVHD treatment trials will remain provisional until its use has been validated through experience. [Copyright &y& Elsevier]

Abstract: We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at ≤1 month or noncompliance. The adverse events included serum creatinine ≥2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin’s efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials. [Copyright &y& Elsevier]

Treatment with myeloablative chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation followed by vaccination with autologous dendritic cells (DCs) treated with tumor antigens is a promising therapeutic strategy for several types of cancer. Obtaining sufficient numbers of both PBSCs and DCs is central to this approach. Previously, it has been shown that administration of Flt-3-Ligand (FL) combined with either G-CSF or GM-CSF mobilizes large numbers of PBSCs in patients with cancer. In the current study, we sought to determine whether these same cytokines could simultaneously mobilize DCs into the PBSC leukapheresis collection. DCs were analysed in PBSC leukapheresis samples obtained from five patients with high-risk breast cancer who received G-CSF alone as priming prior to leukapheresis, four patients who received FL+G-CSF and five patients who received FL+GM-CSF. DCs were defined as cells with a lindim/- HLA-DR+ CD11c+ phenotype. The proportions of DCs in the FL+G-CSF and FL+GM-CSF samples were significantly higher than in pre-mobilization peripheral blood and G-CSF leukapheresis samples. The mean yield of DCs/kg in the FL+GM-CSF samples was also significantly higher than the mean yield of DCs in the G-CSF samples. The FL+G-CSF and FL+GM-CSF mobilized DCs were immature by morphologic and phenotypic criteria but stimulated allogeneic T-cells at levels similar to DCs generated in culture from PBMCs. Overnight culture?of the immature DCs obtained from patients receiving either FL+G-CSF or FL+GM-CSF in TNF-α?resulted in the generation of mature DCs. In summary, administration of FL in combination with GM-CSF and G-CSF to patients with breast cancer can mobilize large numbers of immature DCs into PBSC leukapheresis collections. [Copyright &y& Elsevier]

Aminoguanidine (AG) is an inhibitor of protein modification by the advanced Maillard reaction. We evaluated its effects in preventing age-related collagen cross-linking, glycation, and glycoxidation in Fischer 344 rats by administering the drug in their drinking water at 1 g/l from the time they were 6 months until they were 24 months of age. Body weight and food and water consumption were consistently recorded throughout the study. Plasma glucose was measured by the glucose oxidase method, and collagen cross-linking was assessed by tail tendon break time (TBT) in urea. Glycation (furosine) and glycoxidation (pentosidine and carboxymethyllysine) were assessed by high-performance liquid chromatography in acid hydrolysates of skin and tendon collagen. Water consumption dramatically increased (p <.0001) after 20 months of age and was accelerated in the control versus AG-treated rats (p <.0001). Plasma glucose increased approximately 20% at age 19 months in both groups (p <.0001). TBT, glycation, and glycoxidation all increased significantly (p <.0001) with age. However, except for a modest decrease of TBT at all ages that approached significance (p =.077), AG had no effect on collagen glycation or glycoxidation. These results are important because they suggest that alpha,beta-dicarbonyl compounds that can be trapped by aminoguanidine do not play a major role in collagen aging in the rat. Instead, post-Amadori pathways involving oxidative or nonoxidative fragmentation of the Amadori product emerge as the more likely mechanism of collagen cross-linking in aging. [ABSTRACT FROM AUTHOR]

Sumatriptan succinate (Imitrex) is a 5-HT (5-hydroxytryptamine) agonist used for relief of migraine symptoms. Some individuals experience short-lived side-effects, including heaviness of the limbs, chest heaviness and muscle aches and pains. The effects of this drug on skeletal muscle energy metabolism were studied during short submaximal isometric exercises. We studied ATP flux from anaerobic glycolysis (An Gly), the creatine kinase reaction (CK) and oxidative phosphorylation (Ox Phos) using 31P nuclear magnetic resonance spectroscopy (31P MRS) kinetic data collected during exercise. It was found that side-effects induced acutely by injection of 6 mg sumatriptan succinate s.c. were associated with reduced oxygen storage in peripheral skeletal muscle 5-20 min after injection as demonstrated by a transient reduction in mitochondrial function at end-exercise. These results suggest that mild vasoconstriction in peripheral skeletal muscle is associated with the action of sumatriptan and is likely to be the source of the side-effects experienced by some users. Migraine with aura patients were more susceptible to this effect than migraine without aura patients. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE. The objective of this study was to determine the effectiveness of a dynamic cooling device (DCD), spraying the skin with a brief spurt of cryogen prior to the laser pulse, in reducing transient pain associated with 585-nm pulsed dye laser (PDL) treatment of port-wine stains (PWS), and reducing epidermal damage (hypo/hyperpigmentation) caused by this laser during PWS treatment.MATERIALS AND METHODS. Matched treatment sites were compared with and without the use of the cryogen spray in 47 patients at two investigational sites. Pain ratings, clearance of the PWS, and pigmentation changes were assessed. The results were analyzed by skin type and patient age. RESULTS. A statistically significant reduction in pain ratings was found in all patient groups using the DEC without changing the efficacy of PWS clearance. Pain reduction was most remarkable in patients with darker skin types. Dynamic cooling prevented the occurrence of epidermal damage or pigmentation change in moist cases. CONCLUSIONS. This study suggests that dynamic cooling can dramatically diminish pain during PWS treatment with the 585-nm PDL without reducing treatment efficacy. The absence of epidermal damage in most patients suggests that precooling with the DCD may allow the use of higher laser fluences to expedite clearance without inducing epidermal change. Dynamic cooling has potential use with other lasers and different lesions where discomfort and epidermal effects limit therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND. Successful laser treatment of hemangiomas requires selective photothermal destruction of dilated cutaneous vessels without damaging the overlying epidermis. Delivering a short cryogen spurt, on the order of milliseconds, has been shown to result in localized cooling of the superficial skin structures during laser irradiation. OBJECTIVE.The purpose of this study was to examine the effectiveness of cryogen spray cooling (CSC) in protecting superficial tissue structures during continuous Nd:YAG laser irradiation of an in vivo model hemangioma. METHODS. The highly vascularized chicken comb was selected as the animal model for hemangioma. The ND:YAG laser irradiation ranged from 2.6 to 35.1 1/mm². A feedback system utilizing infrared rediometry monitored the comb surface temperature and controlled delivery time to the cryogen spurt. When comb surface temperature during laser irradiation reached 36-42°C, a 30-100 msec cryogen spurt was delivered. Animals were euthanized 1 hour to 21 days following each experiment. Gross and histologic analyses were performed. RESULTS. Nd:YAG laser irradiation resulted in deep (up to 6.1 mm) tissue photocoagulation, which CSC preserved the overlying epidermis and papillary dermis. CONCLUSION. The results demonstrate that CSC is effective in protecting the epidermis and papillary dermis and papillary dermis, while achieving deep tissue photocoagulation during ND:YAG laser irradiation. Further pilot studies in humans appear warranted. [ABSTRACT FROM AUTHOR]

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation. [ABSTRACT FROM AUTHOR]