Reaching Ambulatory Older Adults with Educational Tools: Comparative Efficacy and Cost of Varied Outreach Modalities in Primary Care.

BACKGROUND: Providing patients with access to health information that can be obtained outside of an office visit is an important part of education, yet little is known about the effectiveness of outreach modalities to connect older adults to online educational tools. The objective was to identify the effectiveness and cost of outreach modalities providing online information about advance care planning (ACP) for older adults. METHODS: Six different outreach modalities were utilized to connect patients to online educational tools (ACP video decision aids). Participants were 13,582 patients aged 65 and older of 185 primary care providers with appointments over a 30-month period within a large health system in the greater New York City area. Main outcome measures were number of online video views and costs per outreach for each modality. KEY RESULTS: There were 1150 video views for 21,407 remote outreach events. Text messages, sent to the largest volume of patients (8869), had the highest outcome rate (9.6%) and were the most economical ($0.09). Characterization of phone calls demonstrated 21.7% engagement in the topic of ACP but resulted in minimal video views (<1%) and incurred the highest cost per outreach ($2.88). In-office handouts had negligible results (<1%). CONCLUSIONS: Text was the most cost-effective modality to connect older adults to an online educational tool in this pragmatic trial, though overall efficacy of all modalities was low.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

[A 44-year-old woman with hereditary nonpolyposis colon carcinoma: screening examinations for non-colonic tumors]. / 44-jährige Patientin mit hereditärem nichtpolypösem Kolonkarzinom: Vorsorgeuntersuchungen nichtkolonischer Tumoren.

A 44-year-old woman presented in March 2010 for surveillance esophagogastroduodenoscopy (EGD). In October 2004, rectal cancer had been diagnosed and treated by resection of the rectum with adjuvant chemotherapy. A diagnosis of hereditary nonpolyposis colon carcinoma (HNPCC) was established on the basis of the Amsterdam II criteria. Due to a lack of clear guidelines we decided to perform annual systematic surveillance examinations of the stomach and the most frequent tumor manifestations. Until 2009, extracolonic tumors were not observed in the patient. In March 2010, EGD showed a discrete erosive lesion in the gastric antrum, which was biopsied. Most notably, the histopathological examination revealed a poorly differentiated mucinous adenocarcinoma. Due to the poor differentiation, we decided against technically possible, endoscopic resection. The patient underwent subtotal gastrectomy and is still doing fine 28 months after surgery. This case prompted us to evaluate our surveillance approach in HNPCC patients and to review the literature.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Development of the mandibular, hyoid arch and gill arch skeleton in the Chinese barb Puntius semifasciolatus: comparisons of ossification sequences among Cypriniformes.

The morphogenesis and sequence of ossification and chondrification of skeletal elements of the jaws, and hyoid arch and gill arches of Puntius semifasciolatus are described. These data provide a baseline for further studies and enable comparisons with other described cypriniforms. Some general patterns of ossification in the hyoid arch and branchial arches in cypriniforms were notable. First, the overall development is from anterior to posterior, with the exception of the fifth ceratobranchial bone, which ossifies first. Second, where ossification of iterated elements is sequential, it tends to proceed from posterior to anterior, even when more posterior chondrifications are the smallest in the series. Ossification of the ceratobranchial, epibranchial and pharyngobranchial bones tends to proceed from ventral to dorsal. The comparisons revealed small sets of skeletal elements whose ossification sequence appears to be relatively conserved across cyprinid cypriniforms. Several potentially key timing changes in the ossification sequence of the jaws, hyoid arch and gill arches were identified, such as the accelerated timing of ossification of the fifth ceratobranchial bone, which may be unique to cypriniforms.

[Is there a role for risk-scoring methods in ruptured abdominal aortic aneurysm (rAAA)?]. / Was leisten Risiko-Scores beim rupturierten abdominellen Aortenaneurysma (rAAA)?

BACKGROUND: Rupture of an abdominal aortic aneurysm (rAAA) is associated with a high mortality both before and after admission to hospital. In spite of the use of expensive intensive medical therapeutic interventions 30 - 50 % of the operated patients still die. The ASA score is one of the most used scores world-wide. Use of the Glasgow aneurysm score (GAS) and the Hardman index (HI) is frequently reported in the literature to predict survival after surgical management of rAAA. With regard to the comorbidity factor severity score (CSS) no evaluated data on the mortality in cases of rAAA are available. On the basis of our own patient collective we intended to assess to what extent the risk score could give an answer to the question of therapeutic options. METHODS: In a retrospective study (7/1998 - 8/2007), 94 patients (m : f = 78 : 16) were assessed after operative management of rAAA. The validity of preoperative risk assessments on the basis of the ASA score, the CSS, the GAS and the HI with regard to intra- or postoperative death in the initial hospitalisation period was examined. Sensitivity and specificity of the score systems were determined by receiver operating characteristics (ROC) analyses. RESULTS: The age of the patients was 72.3 ±â€†9.5 years (mean ±â€†SD). Thirty-five (37.2 %) patients died in the immediate postoperative period. The areas under the receiver operating characteristics curves for ASA, GAS, HI and CSS were 0.598, 0.787, 0.742 and 0.614, respectively. CONCLUSIONS: This study revealed clear differences in the prognostic predictions of the various scores. In accord with the literature, no score gave a 100 % positive result with regard to mortality. Thus, an individual decision or, respectively, a therapeutic option cannot be reached with the help of the investigated scores. Further parameters need to be evaluated in order to make decisions about postoperative therapy.

The effect of scoliosis support orthosis bracing on adult spinal deformity patients: evaluation of gait and dynamic balance.

Non-operative treatment is regarded as the first-line therapy for patients with adult spinal deformity (ASD) without neurologic deficits or significant impairment. While there is high-level evidence supporting the use of rigid bracing in adolescent idiopathic scoliosis, there is a paucity of literature pertaining to the use of scoliosis support orthosis (SSO) in ASD patients. To investigate the impact of an SSO on pain, gait parameters, and functional balance measures in symptomatic ASD patients. Thirty ASD patients (26 Females, Age: 72.7, Cobb Angle: 47.1°) were evaluated on 3 different occasions: first day of bracing: baseline (Pre), and 45-min post fitting (Post45m), and after 8-weeks of bracing for 4 hours a day (Post8w). Each patient performed a 6-minute walk (over-ground gait), a dynamic balance test, and completed VAS, ODI, and SRS22r. Significant short- and long-term improvements using SSO were found in the 6-minute walk (Pre: 278.6; Post45m: 322.2; Post8w: 338.8 m, p<0.001), walking speed (Pre: 0.88; Post45m: 0.97; Post8w: 0.97 m/s, p<0.001), head total sway distance during the balance test (Pre: 81.33; Post45m: 68.63; Post8w: 60.72 cm, p=0.048), low-back pain (VAS: Pre: 5.5; Post45m: 3.5; Post8w: 3.3, p<0.001), and for the ODI (Pre: 41.9; Post45m: 32.9; Post8w: 30.1, p=0.005).This study demonstrated clinically significant improvements in PROMs, spatiotemporal gait measures, and functional balance measures after continuous use of a SSO. These improvements were observed immediately following brace-fitting and maintained at an 8-week follow-up. Given these results, it is reasonable to consider a SSO for conservative management of patients with mild symptoms of pain and deformity, and who have not yet progressed to meet surgical indications.

A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study).

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The co-primary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.

Primary cytomegalovirus ileitis complicated by massive gastrointestinal haemorrhage in a patient with steroid refractory Crohn's disease.

A young man with known steroid refractory terminal ileal Crohn's disease developed torrential gastrointestinal bleeding necessitating an emergency ileal resection. Serology was indicative of primary cytomegalovirus (CMV) infection and this was confirmed with histopathology of the resected ileum. We highlight the difficulty in clinical practice of distinguishing between CMV infection and CMV disease as well as the different investigations available to aid in the diagnosis of pathogenic CMV disease.

Thrombolytic therapy for management of complicated catheter-related Candida albicans thrombophlebitis.

In immunocompromised patients, endovascular infection due to Candida albicans is associated with significant morbidity and mortality. Recommended management includes removal of any existing central venous catheter. Rarely, complications of endocarditis or infected mural thrombi may arise, with poorer clinical outcomes. For large endoluminal lesions, particularly of the great vessels or those that are intra-atrial, thrombolysis has been used in paediatric populations or before surgery for dissolution of infected thrombus. We describe the case of an adult patient with lung carcinoma who developed persisting candidaemia with a large endovascular fungal lesion adherent to the tip of a peripherally inserted central venous catheter. Local urokinase infusion enabled safe removal of the catheter without embolization. As an adjunct to antifungal therapy, local thrombolysis may play a contributory role in the management of central venous catheter-related candidal septic thrombosis.

Tracking ultrafast hot-electron diffusion in space and time by ultrafast thermomodulation microscopy.

The ultrafast response of metals to light is governed by intriguing nonequilibrium dynamics involving the interplay of excited electrons and phonons. The coupling between them leads to nonlinear diffusion behavior on ultrashort time scales. Here, we use scanning ultrafast thermomodulation microscopy to image the spatiotemporal hot-electron diffusion in thin gold films. By tracking local transient reflectivity with 20-nm spatial precision and 0.25-ps temporal resolution, we reveal two distinct diffusion regimes: an initial rapid diffusion during the first few picoseconds, followed by about 100-fold slower diffusion at longer times. We find a slower initial diffusion than previously predicted for purely electronic diffusion. We develop a comprehensive three-dimensional model based on a two-temperature model and evaluation of the thermo-optical response, taking into account the delaying effect of electron-phonon coupling. Our simulations describe well the observed diffusion dynamics and let us identify the two diffusion regimes as hot-electron and phonon-limited thermal diffusion, respectively.

The GABAAα5-selective Modulator, RO4938581, Rescues Protein Anomalies in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is the most common genetic cause of intellectual disability (ID). There are no treatments for the cognitive deficits. The Ts65Dn is a partial trisomy mouse model of DS that shows learning and memory (LM) impairments and other abnormalities relevant to those seen in DS. Many drugs and small molecules have been shown to rescue the LM deficits, but little is known about the associated molecular responses. Here, patterns of protein expression are described in hippocampus of Ts65Dn and euploid littermate controls exposed to a battery of LM and behavior tests with and without chronic treatment with the GABAA receptor α5 subunit-selective negative allosteric modulator, RO4938581, that rescued LM deficits. Levels of 91 proteins/protein modifications, selected for relevance to LM and synaptic plasticity, were measured: 44 of 52 abnormalities present in vehicle-treated Ts65Dn were corrected by RO4938581. Superimposing protein data onto the molecular pathway defining long-term potentiation (LTP) shows that profiles are consistent with both abnormal LTP in vehicle-treated Ts65Dn and its observed rescue by RO4938581. Lastly, comparing these results with those from Ts65Dn treated, using a different protocol, with the NMDA receptor antagonist, memantine, that also rescues LM impairments, identifies common and divergent responses to the two drugs. Expansion of this approach to include additional drugs and DS models would aid in determining critical protein abnormalities and in identifying cocktails of drugs and/or new drug targets that would be effective in clinical trials for ID in DS.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Prevention of phorbol ester receptor down modulation in human myeloblastic leukemia ML-1 cells by differentiation-stimulating serum components.

The phorbol esters 12-O-tetradecanoylphorbol-13-acetate, phorbol 12,13-didecanoate, phorbol 12,13-dibutyrate (PDB), and phorbol 12,13-dibenzoate were found to compete with [20-3H]-PDB binding to human myeloblastic leukemia ML-1 cells in approximate proportion to their differentiation-inducing capacity. Fetal bovine serum decreased the down modulation of phorbol ester receptor sites on these cells and increased PDB-induced differentiation. These two activities coeluted upon chromatography of fetal bovine serum on a Sephadex G-150 column. A partially purified fraction from pokeweed mitogen-stimulated human leukocyte-conditioned medium which effectively induced ML-1 cell differentiation also prevented the down modulation of PDB receptors. As indicated by Scatchard analysis, prevention of down modulation was due to stabilization of the number of binding sites rather than to a change in receptor affinity. In view of the previously observed modulation of growth factor binding by phorbol esters, the currently described alteration of phorbol ester receptor activity by differentiation-inducing factors implies an interaction between growth and differentiation factors in receptor modulation.

Reduced cytocidal efficacy for adriamycin in cultured human carcinoma cells depleted of polyamines by difluoromethylornithine treatment.

We have studied the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to Adriamycin (ADR). The cell lines utilized included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48-h DFMO pretreatment reduced putrescine and spermidine content to less than 10 and less than 1% of control levels and decreased spermine to between 70 and 30% of controls. Plating efficiency assays were used to generate ADR dose-response survival curves for DFMO-treated and control cultures. The DFMO pretreatment significantly protected human adenocarcinoma cells from the lethal effects of ADR. Addition of exogenous putrescine to the DFMO-treated cultures 24 h before treatment with ADR restored their cytocidal response to ADR to near control levels. Putrescine had no effect on cell survival in cultures that were not pretreated with DFMO. These observations suggest that DFMO-induced protection from ADR may be a specific consequence of DFMO-induced inhibition of polyamine biosynthesis. Alternatively, since ADR efficacy varies directly with cellular growth rates and DFMO inhibits proliferation, the protection may have resulted from DFMO-induced growth inhibition. Comparison of ADR uptake in DFMO-pretreated and control cells showed that the protection did not result from decreased intracellular accumulation of ADR.

Altered cell cycle phase distributions in cultured human carcinoma cells partially depleted of polyamines by treatment with difluoromethylornithine.

We have studied the effects of partial polyamine depletion, induced by treatment with alpha-difluoromethylornithine (DFMO) on cell cycle phase distributions in five cultured human carcinoma cell lines. We used flow cytometry of cells stained with chromomycin-A3 and computer analysis to measure phase distributions of treated and control cultures. All five lines respond to 1-5 mM DFMO treatment with a total absence of measurable putrescine, a loss of greater than 90% of spermidine, and a 30-40% decline in spermine by 48 h after DFMO addition. The proliferation of all five lines is inhibited as well. Nonetheless, only four of the cell lines (HuTu-80, HT-29, MCF-7, and A-427) show a marked increase in the G1-phase fraction and decrease in the S-phase fraction as a consequence of DFMO treatment. Small, but significant, decreases in the G2-M populations of these cell lines also occurred after DFMO treatment. Exogenous putrescine (5-50 microM) reversed both the polyamine depletion and the perturbed phase distributions of DFMO-treated cultures but was without effect on phase distributions of cultures not treated with DFMO. The fifth cell line (ME-180) showed no effect of polyamine depletion on cell cycle phase distributions in DFMO-treated cultures and also no effect of exogenous putrescine on phase fractions of either control or DFMO-treated cells. These observations indicate that some human tumor cell lines are dependent upon adequate intracellular polyamine content for maintenance of cell cycle traverse. They also imply that human tumor cell lines are heterogeneous with regard to their cell cycle response to DFMO-induced polyamine deficiency.

Comparison of DNA interstrand cross-linking and strand breakage by 1,3-bis(2-chloroethyl)-1-nitrosourea in polyamine-depleted and control human adenocarcinoma cells.

Recent evidence from our laboratory and from others suggested that pretreatment with alpha-difluoromethylornithine (DFMO) sensitizes some human and rodent tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Many human tumor cells are resistant to chloroethylnitrosourea-induced DNA interstrand cross-linking and cell kill due to their high levels of the DNA repair protein O6-alkylguanine DNA alkyltransferase. We therefore investigated DFMO-mediated sensitization to BCNU in BCNU-sensitive and -resistant cells. Colony formation assays were used to compare BCNU cytotoxicity in DFMO-pretreated and control cultures of two colon tumor lines, HT-29 cells, which have high alkyltransferase levels and thus are BCNU-resistant, and BE cells, which are deficient in this repair capacity and thus are BCNU-sensitive. Polyamine depletion significantly enhanced BCNU cytotoxicity only for the repair-proficient HT-29 cell line. BE cells were 40-fold more sensitive to BCNU than were HT-29 cultures. However, in BE cells, no effect of polyamine depletion was found on cellular response to BCNU treatment at 72 h after DFMO treatment. Reverse-phase high-performance liquid chromatography assays of polyamine concentrations in cell extracts verified that DFMO produced comparable degrees of polyamine depletion for both cell lines. DNA alkaline elution analysis was used to monitor BCNU-induced formation of DNA single strand breaks, DNA interstrand cross-links, and DNA-protein cross-links. Equal concentrations of BCNU produced similar levels of strand breaks and DNA-protein cross-links in DFMO-pretreated and control cultures for both cell lines. These data suggest that DNA in polyamine-deficient HT-29 and BE cells is not more accessible to BCNU than is DNA in controls. No DNA interstrand cross-links were detected in either DFMO-pretreated or control HT-29 cells after BCNU treatment. Further, in BE cells which accumulate BCNU-induced DNA interstrand cross-links, no increase in the measureable levels of cross-links resulted from polyamine deficiency. Our observations suggest that mechanisms other than increased DNA interstrand cross-link formation may be mediating the enhanced efficacy of BCNU in polyamine-deficient HT-29 cell cultures. Our findings may also imply that cellular targets for BCNU other than DNA damage may be responsible for DFMO-induced chemosensitization in the repair-proficient cells.

Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.

Hematopoietic cytokine receptor signaling pathways involve activation of signal transducers and activators of transcription (STAT) proteins, which are postulated to be involved in cellular differentiation. Aberrant STAT isoforms (beta forms rather than the normal alpha forms) have been described and have been found to block the normal signaling pathway from the receptor. Bcr/Abl proteins have been suggested to directly activate STATs, without exposure to growth factors. We asked whether STATs play a role in leukemogenesis. We analyzed constitutive and induced patterns of STAT activity in pretreatment blasts from 36 newly diagnosed acute myeloid leukemia (AML) patients and studied protein tyrosine kinases (PTKs) that may be involved in STAT activity, using in vitro and in-gel kinase assays. The beta forms were expressed in 21 of 27 samples (78%). Constitutive STAT3 and STAT5 activity was found in samples from 28 and 22% of patients, respectively. Response to exogenous cytokines identified two groups. STAT activity in one group was modulated by exogenous cytokines: constitutive STAT activity increased in some patients but decreased or disappeared in response to cytokines in others. The second group was cytokine insensitive. Additionally, we found constitutive PTK activity in two patients whose blasts demonstrated constitutive STAT activity, suggesting that PTKs use cytokine receptor signal pathways to activate STATs in AML blasts without exposure to exogenous cytokines. Our data suggest that (a) constitutive expression of aberrant STATs may be involved in blocking differentiation of AML blasts, (b) exogenous cytokines may activate STAT-inhibitory pathways, and (c) STATs may be activated by PTKs in some AML blasts.