Does the amount of lower extremity movement variability differ between injured and uninjured populations? A systematic review.

Movement variability during repetitive performance of a dynamic activity (eg, running, jumping, kicking) is considered an integral characteristic of optimal movement execution; however, its relationship with musculo-skeletal injury is not known. The primary aim of this study was to review published comparison trials to determine whether movement variability differs between uninjured controls and subjects with a lower limb musculo-skeletal injury. A systematic search of online databases; MEDLINE, Sports Discus, Scopus, and Web of Science was conducted from July to November 2016. Studies were selected if they (a) included participants with a lower limb injury, (b) compared injured participants to uninjured controls, (c) examined movement variability for at least one dependent variable, and (d) provided a statistical between-group comparison when comparing measures of movement variability. Studies were excluded if they (a) investigated neurological disorders, (b) examined musculo-skeletal injury in the upper extremity or spine, and (c) used nonlinear measures to examine variability (ie, complexity). A significant difference between injured and uninjured populations was reported in 73% of the included studies, and of these, 64% reported greater movement variability in the injured group. This is the first systematic review with a best-evidence synthesis investigating the association between movement variability and musculo-skeletal injury. Findings suggest that movement variability in those with a musculo-skeletal injury differs from uninjured individuals. Interestingly, there was an overall trend toward greater movement variability being associated with the injured groups, although it should be noted that this trend was not consistent across all subcategories (eg, injury type). For a clearer insight into the clinical application of variability, greater methodological homogeneity is required and prospective research is recommended.

Is stiffness related to athletic groin pain?

Athletic groin pain (AGP) is a common injury prevalent in field sports. One biomechanical measure that may be of importance for injury risk is stiffness. To date, [corrected] however, stiffness has not been examined in AGP. The primary aim was to determine whether AGP affects vertical and joint stiffness and if so, whether successful rehabilitation is associated with a change in stiffness. Sixty-five male patients with AGP and fifty male controls were recruited to this study. Assessment included a biomechanical examination of stiffness during a lateral hurdle hop test. Subjects with AGP were tested pre- and post-rehabilitation, while controls were tested once. AGP subjects were cleared for return to play in a median time of 9.14 weeks (5.14-29.0). Stiffness was significantly different at pre-rehabilitation in comparison with controls for three [corrected] of the ten stiffness values examined: ankle plantar flexor, knee extensor, hip abductor, and vertical stiffness (P <  .05, D = 0.38-0.81). [corrected]. Despite clearance for return to play, of these four variables, only hip abductor stiffness changed significantly from pre- to post-rehabilitation (P = .05, D = 0.36) [corrected] to become non-significantly different to the uninjured group (P = .23, D = 0.23). [corrected]. These findings suggest that hip abductor stiffness may represent a target for AGP rehabilitation. Conversely, given the clearance for return to play, the lower sagittal plane and vertical stiffness in the AGP group in comparison with the uninjured controls likely represents either a compensatory mechanism to reduce the risk of further injury or a consequence of neuromuscular detraining.

Athletic groin pain (part 2): a prospective cohort study on the biomechanical evaluation of change of direction identifies three clusters of movement patterns.

BACKGROUND: Athletic groin pain (AGP) is prevalent in sports involving repeated accelerations, decelerations, kicking and change-of-direction movements. Clinical and radiological examinations lack the ability to assess pathomechanics of AGP, but three-dimensional biomechanical movement analysis may be an important innovation. AIM: The primary aim was to describe and analyse movements used by patients with AGP during a maximum effort change-of-direction task. The secondary aim was to determine if specific anatomical diagnoses were related to a distinct movement strategy. METHODS: 322 athletes with a current symptom of chronic AGP participated. Structured and standardised clinical assessments and radiological examinations were performed on all participants. Additionally, each participant performed multiple repetitions of a planned maximum effort change-of-direction task during which whole body kinematics were recorded. Kinematic and kinetic data were examined using continuous waveform analysis techniques in combination with a subgroup design that used gap statistic and hierarchical clustering. RESULTS: Three subgroups (clusters) were identified. Kinematic and kinetic measures of the clusters differed strongly in patterns observed in thorax, pelvis, hip, knee and ankle. Cluster 1 (40%) was characterised by increased ankle eversion, external rotation and knee internal rotation and greater knee work. Cluster 2 (15%) was characterised by increased hip flexion, pelvis contralateral drop, thorax tilt and increased hip work. Cluster 3 (45%) was characterised by high ankle dorsiflexion, thorax contralateral drop, ankle work and prolonged ground contact time. No correlation was observed between movement clusters and clinically palpated location of the participant's pain. CONCLUSIONS: We identified three distinct movement strategies among athletes with long-standing groin pain during a maximum effort change-of-direction task These movement strategies were not related to clinical assessment findings but highlighted targets for rehabilitation in response to possible propagative mechanisms. TRIAL REGISTRATION NUMBER: NCT02437942, pre results.

Stressful life events, hopelessness, and suicidal intent in patients admitted with attempted suicide in a tertiary care general hospital.

BACKGROUND: Suicide is a psychiatric emergency. Stressors in life and social variables (like marital status, family, and social support) are among the determinants of suicide. Hopelessness and suicidal intent are among the psychological variables that have shown promise in the prediction of suicide. AIMS AND OBJECTIVES: To assess stressful life events, hopelessness, suicidal intent, and sociodemographic variables in patients of attempted suicide. MATERIALS AND METHODS: Fifty consecutive patients admitted with attempted suicide were interviewed. Presumptive Stressful Life Event Scale, Beck Hopelessness Scale, and Beck Suicidal Intent Scale were used along with a semistructured pro forma for interview. Data were analyzed with statistical tests. RESULTS: Sixty-six percent of the participants were females, 72% were less than 30 years of age. Sixty-six percent of the patients had stressful life event score between 101 and 200 with the mean score of 127. The stressful life event score in those who considered they are in need of psychiatric help was significantly high. Most of the patients had mild (34%) and moderate (40%) degrees of hopelessness, and the mean score was 9.64. The mean suicidal intent in the participants was 25.14, when correlated with hopelessness score significant positive correlation was found. CONCLUSION: Lethality of the attempt increases with the increase in hopelessness.

PDBe: Protein Data Bank in Europe.

The Protein Data Bank in Europe (PDBe; pdbe.org) is a partner in the Worldwide PDB organization (wwPDB; wwpdb.org) and as such actively involved in managing the single global archive of biomacromolecular structure data, the PDB. In addition, PDBe develops tools, services and resources to make structure-related data more accessible to the biomedical community. Here we describe recently developed, extended or improved services, including an animated structure-presentation widget (PDBportfolio), a widget to graphically display the coverage of any UniProt sequence in the PDB (UniPDB), chemistry- and taxonomy-based PDB-archive browsers (PDBeXplore), and a tool for interactive visualization of NMR structures, corresponding experimental data as well as validation and analysis results (Vivaldi).

The effects of rehabilitation on the biomechanics of patients with athletic groin pain.

This study sought to investigate the kinematic and kinetic variables that change in patients with athletic groin pain (AGP) after a successful exercise intervention. The kinematic and kinetic measures of subjects with AGP (n = 65) that completed a lateral hurdle hop, pre and post an exercise rehabilitation program were compared to a control group of matched uninjured individuals (n = 50). Analysis of Characterising Phases was used to identify differences in kinematic and kinetic measures between the groups. AGP subjects returned to pain-free participation in sport in a median time of 9.14 weeks (5.14-29.0). In total 18 different biomechanical variables were significantly different between the AGP group and the uninjured group pre-rehabilitation. Of these, seven variables were no longer significantly different between the AGP group post-rehabilitation and the uninjured group. These seven variables may represent the factors most related to return to play in this cohort and are potential targets for rehabilitation.

Crystal chemistry and single-phase synthesis of Gd3+ substituted Co-Zn ferrite nanoparticles for enhanced magnetic properties.

Rare earth (RE) ions are known to improve the magnetic interactions in spinel ferrites if they are accommodated in the lattice, whereas the formation of a secondary phase leads to the degradation of the magnetic properties of materials. Therefore, it is necessary to solubilize the RE ions in a spinel lattice to get the most benefit. In this context, this work describes the synthesis of Co-Zn ferrite nanoparticles and the Gd3+ doping effect on the tuning of their magnetic properties. The modified sol-gel synthesis approach offered a facile way to synthesize ferrite nanoparticles using water as the solvent. X-ray diffraction with Rietveld refinement confirmed that both pure Co-Zn ferrite and Gd3+ substituted Co-Zn ferrite maintained single-phase cubic spinel structures. Energy dispersive spectroscopy was used to determine the elemental compositions of the nanoparticles. Field and temperature dependent magnetic characteristics were measured by employing a vibration sample magnetometer in field cooled (FC)/zero field cooled (ZFC) modes. Magnetic interactions were also determined by Mössbauer spectroscopy. The saturation magnetization and coercivity of Co-Zn ferrite were improved with the Gd3+ substitution due to the Gd3+ (4f7)-Fe3+ (3d5) interactions. The increase in magnetization and coercivity makes these Gd3+ substituted materials applicable for use in magnetic recording media and permanent magnets.

Analysis on sliding helices and strands in protein structural comparisons: a case study with protein kinases.

Protein structural alignments are generally considered as 'golden standard' for the alignment at the level of amino acid residues. In this study we have compared the quality of pairwise and multiple structural alignments of about 5900 homologous proteins from 718 families of known 3-D structures. We observe shifts in the alignment of regular secondary structural elements (helices and strands) between pairwise and multiple structural alignments. The differences between pairwise and multiple structural alignments within helical and beta-strand regions often correspond to 4 and 2 residue positions respectively. Such shifts correspond approximately to "one turn" of these regular secondary structures. We have performed manual analysis explicitly on the family of protein kinases. We note shifts of one or two turns in helix-helix alignments obtained using pairwise and multiple structural alignments. Investigations on the quality of the equivalent helix-helix, strand-strand pairs in terms of their residue side-chain accessibilities have been made. Our results indicate that the quality of the pairwise alignments is comparable to that of the multiple structural alignments and, in fact, is often better. We propose that pairwise alignment of protein structures should also be used in formulation of methods for structure prediction and evolutionary analysis.

WITHDRAWN: Rice-based oral rehydration solution for treating diarrhoea.

BACKGROUND: Oral rehydration therapy is used to treat dehydration caused by diarrhoea. However the rehydration solution does not reduce stool loss or length of illness. A solution able to do this may lessen the use of ineffective diarrhoea treatments as well as improve morbidity and mortality related to diarrhoea. OBJECTIVES: The objective of this review was to assess the effects of rice-based oral rehydration salts solution compared with glucose-based oral rehydration salts solution on reduction of stool output and duration of diarrhoea in patients with acute watery diarrhoea. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, Lilacs and the reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomized trials comparing standard World Health Organization oral rehydration solution with an experimental oral rehydration salts solution in which glucose (20 grams per litre) was replaced by 50-80 grams per litre of rice powder, with the electrolytes remaining unchanged. DATA COLLECTION AND ANALYSIS: Data were extracted independently by a statistician and a clinician. MAIN RESULTS: Twenty-two trials were included. Concealment of allocation was adequate in 15 of these trials. Irrespective of age, people with cholera who were given rice oral rehydration salts solution had substantially lower rates of stool loss than those given oral rehydration salts solution in the first 24 hours. Mean stool outputs in the first 24 hours were lower by 67 millilitres/kg of body weight (weighted mean difference -67.40, 95% confidence interval -94.26 to -41.53) in children, and by 51 millilitres/kg of body weight (weighted mean difference -51.07, 95% confidence interval -65.87 to -36.27) in adults. The rate of stool loss in infants and children with acute non-cholera diarrhoea was reduced by only four millilitres/kg of body weight (weighted mean difference -4.29, 95% confidence interval -9.36 to 0.78). AUTHORS' CONCLUSIONS: Rice-based oral rehydration appears to be effective in reducing stool output in people with cholera. This effect was not apparent in infants and children with non-cholera diarrhoea.

PRODOC: a resource for the comparison of tethered protein domain architectures with in-built information on remotely related domain families.

PROtein Domain Organization and Comparison (PRODOC) comprises several programs that enable convenient comparison of proteins as a sequence of domains. The in-built dataset currently consists of approximately 698 000 proteins from 192 organisms with complete genomic data, and all the SWISSPROT proteins obtained from the Pfam database. All the entries in PRODOC are represented as a sequence of functional domains, assigned using hidden Markov models, instead of as a sequence of amino acids. On average 69% of the proteins in the proteomes and 49% of the residues are covered by functional domain assignments. Software tools allow the user to query the dataset with a sequence of domains and identify proteins with the same or a jumbled or circularly permuted arrangement of domains. As it is proposed that proteins with jumbled or the same domain sequences have similar functions, this search tool is useful in assigning the overall function of a multi-domain protein. Unique features of PRODOC include the generation of alignments between multi-domain proteins on the basis of the sequence of domains and in-built information on distantly related domain families forming superfamilies. It is also possible using PRODOC to identify domain sharing and gene fusion events across organisms. An exhaustive genome-genome comparison tool in PRODOC also enables the detection of successive domain sharing and domain fusion events across two organisms. The tool permits the identification of gene clusters involved in similar biological processes in two closely related organisms. The URL for PRODOC is http://hodgkin.mbu.iisc.ernet.in/~prodoc.

Study of inheritance of diabetes mellitus in Western Indian population by pedigree analysis.

OBJECTIVES: To study the inheritance pattern of diabetes mellitus in Western Indian population by analysing the pedigree of diabetes patients. METHODS: 3,921 individuals from 300 families were interviewed for family history in this study, out of which 770 were diabetic individuals. Statistical analysis of the data was carried out using T-test and Chi-square test. RESULTS: 37% cases of Type 1 DM and 58% cases of Type 2 DM showed family history of the disease. Of the cases showing family history for diabetes, 92% in case of Type 1 DM and 59% in case of Type 2 DM showed family history of Type 2 DM with a decrease in age of onset in the successive generations. Both the parents, when diabetic conferred equal risk of inheriting diabetes in offspring. The sex ratio of offspring suffering from diabetes was not influenced when only one of the parents was diabetic. However it was observed that the male offspring were highly susceptible when both parents were diabetic (Chi-square value=4.55 with 1 d.f.). The age of onset of diabetes did not show significant correlation with whether one or both the parents were diabetic. However, it was noteworthy that in case of familial history of diabetes there was a decrease in the age of onset in successive generations. CONCLUSION: This study suggests that family history of diabetes results in predisposition to early onset of the disease in successive generations and a cluster of genes involved in Type 2 DM may show a parental effect for predisposition to Type 1 DM in the offspring in this set of Indian population.

Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides.

Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.

Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and outcome.

The optimal means of combining breast-conserving surgery, radiation therapy, and chemotherapy for the treatment of patients with early-stage, node-positive breast cancer is not known. We reviewed the results in 295 patients treated at the Joint Center for Radiation Therapy and affiliated institutions from 1976 to 1985. All patients had positive axillary nodes on dissection, had no gross residual disease in the breast or axilla after surgery, and received breast irradiation (with or without nodal irradiation) and three or more cycles of a cyclophosphamide, methotrexate, and fluorouracil (CMF)-based or doxorubicin-containing regimen. Median follow-up in patients without any failure was 78 months. Breast failure rates were assessed in relation to the sequencing of radiotherapy and chemotherapy. The different sequences were not randomly assigned, and the characteristics of the sequence groups differed. The actuarial 5-year breast failure rate was 4% in 99 patients receiving radiotherapy before chemotherapy; 8% in 54 patients sequentially receiving some chemotherapy, then radiotherapy without concurrent chemotherapy, then further chemotherapy; and 6% in 116 patients receiving concurrent chemotherapy and radiotherapy. However, the failure rate was 41% in 26 patients who received all chemotherapy before radiotherapy. The crude incidences of local failure within 4 years of treatment in these groups were 3%, 2%, 4%, and 15%, respectively (P = .065 for all four groups not being the same). The actuarial 5-year local failure rate was 5% for 252 patients irradiated within 16 weeks after surgery compared with 35% for 34 patients irradiated more than 16 weeks after surgery. The 4-year crude incidences were 4% and 12% for the two groups, respectively (P = .06). These results suggest that delaying the initiation of radiotherapy may result in an increased likelihood of local failure. Formal randomized controlled trials will be needed to confirm these results and to improve the integration of these treatment modalities.

Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

PURPOSE: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. PATIENTS AND METHODS: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved. RESULTS: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. CONCLUSION: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

Identification of growth factor-responsive acute myelogenous leukemia based on factor-dependence for survival and proliferation.

To determine whether a requirement for exogenous growth factors (GFs) for survival and proliferation could identify cases of AML which would respond best to GFs, singly and in combination, primary AML bone marrow samples were grown in suspension. Samples were classified as GF-dependent (61%), or GF-independent (39%) based on maintenance of Ki67+ cell number (proliferating cells) in the absence of exogenous GFs. GF-dependent samples had significant proliferative responses to steel factor (SF), GM-CSF and IL-3; mean Ki67+ cell number increased by 4.1-, 3.3-, and 5.2-fold, respectively. Significant stimulation was not seen for GF-independent cases; several were inhibited by exogenous GFs. SF was additive or synergistic with GM-CSF or IL-3 among GF-dependent cases; however, combinations were no more effective than single cytokines among the GF-independent group. GM-CSF plus IL-3 or the hybrid protein PIXY 321 did not increase the mean Ki67 ratio compared to the individual cytokines for any population. Flow cytometric determination of GF receptor expression was less predictive of GF response than was survival and proliferation in the absence of GFs. Suspension cultures in the absence of GFs can select patients most likely to benefit from therapeutic strategies using GFs for cell cycle recruitment.

Flow cytometric detection of rare normal human marrow cells with immunophenotypes characteristic of acute lymphoblastic leukemia cells.

Rare subpopulations of normal marrow B lymphoid cells expressing immunophenotypes typically found in B-lineage acute lymphoblastic leukaemias (ALL) were sought by multiparameter flow cytometry. First, CD34+ marrow leukocytes were isolated by immune adherence using immunomagnetic microspheres, and analyzed for coexpression of the following pairs of membrane antigens: CD34 CD22; CD34 CD20; and CD10 CD22. Terminal deoxynucleotidyl transferase expression was not assessed. All three antigen combinations were found on small percentages of the CD34-enriched cell population. Second, unseparated normal low density marrow leukocytes were examined by 'gating' on cells with the right-angle light scatter of lymphoid cells, plus either CD34+ or CD10+ immunofluorescence. This independent approach confirmed that rare subsets of normal cells coexpress 'immature' and 'mature' differentiation antigens. In addition, remission marrow cells were examined from two children who had completed therapy for ALL two and four months earlier. Both specimens had a more than threefold increase in CD34+ cells over normal marrow, and cells coexpressing immature and mature cell surface antigens were easily detected. These findings demonstrate that immunophenotypes characteristic of B-lineage ALL, previously labeled 'asynchronous' with respect to the developmental sequence of the majority of normal B lymphoid cells, exist at low frequency in normal human bone marrow.

Augmentation of phenylbutyrate-induced differentiation of myeloid leukemia cells using all-trans retinoic acid.

Despite preliminary evidence of clinical activity of the putative differentiating agent sodium phenylbutyrate (PB) in the treatment of myeloid neoplasms, it has proven difficult to maintain therapeutic levels of PB above 0.5 mM, well below the ED50 of 1-2 mM. We have studied the impact of combining PB with all-trans retinoic acid (ATRA) on the ML-1 myeloid leukemia cell line. ATRA augmented PB-induced differentiation, cell-cycle arrest, and apoptosis. ATRA augmented PB induction of the myelomonocytic marker CD11b at all doses of ATRA tested (0.0025-1 microM). Although ATRA did not significantly affect the ED50 of PB, the combination of ATRA (1 microM) and PB (0.5 mM) augmented PB-induced CD11b expression eight-fold. Compared to PB alone, this combination of ATRA and PB induced greater cell cycle arrest (S-phase 14% vs 38%; G0/G1-phase cells 72% vs 52%) and greater apoptosis (24% vs 16% by TUNEL assay). Treatment with ATRA (0.5 microM) in combination with PB (0.5 mM) led to significantly greater inhibition of colony formation (4.8% vs 48% inhibition). ATRA combined synergistically with PB to augment CD11b expression and inhibit colony formation. This combination also showed significant interaction in terms of S-phase inhibition. However, this interaction varied as a function of ATRA concentration: antagonistic at low concentrations of ATRA, synergistic at higher concentrations of ATRA. These data suggest that retinoids may significantly augment the cytostatic and differentiating activity of PB, leading to increased potency of the latter drug at clinically achievable doses.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), given concurrently with induction therapy for acute myelogenous leukemia (AML), augments the syndrome of T-lymphocyte recovery.

A transient lymphocytosis precedes myeloid recovery in many patients with AML treated with intensive chemotherapy. We describe the kinetics, clinical features, and immunology of lymphocyte recovery which is markedly augmented by the inclusion of GM-CSF in induction therapy. Lymphocyte recovery from 19 patients receiving GM-CSF as part of induction therapy was compared to a historical control of 25 patients treated with identical chemotherapy in the absence of cytokine. Kinetics and clinical features of lymphocyte recovery were analyzed. Peripheral blood was studied by flow cytometry, chromium release assays, and Southern analysis of the T-cell antigen receptor, beta chain gene. Patients treated with GM-CSF to recruit cells into cycle, exhibit markedly increased peaks of lymphocyte recovery. Recovering lymphocytes demonstrated an activated memory T-cell phenotype suggestive of a cytokine release syndrome. Lymphoid recovery was often associated with rash, fever, and lymphadenopathy. Study patients who developed peak lymphocyte counts > or = 1000 microliters were more likely to achieve remission than those with a lower peak. Recovery lymphocytes did not lyse pretreatment autologous bone marrow cells. Southern analysis demonstrated dominant potentially clonal rearrangements in the majority of patients studied. Lymphocyte recovery, which appears to include oligoclonal expansion of memory T cells is markedly augmented by administration of GM-CSF during chemotherapy. This may represent a non-specific response by a limited repertoire of T cells surviving therapy, or a specific clonal response to a powerful exogenous or endogenous antigen. Possible antileukemic activity of these cells remains to be elucidated.