Changes in muscle cross-sectional area, muscle force, and jump performance during 6 weeks of progressive whole-body vibration combined with progressive, high intensity resistance training.

OBJECTIVES: We hypothesized that progressive whole-body vibration (WBV) superimposed to progressive high intensity resistance training has greater effects on muscle cross-sectional area (CSA), muscle force of leg muscles, and jump performance than progressive high intensity resistance training alone. METHODS: Two groups of healthy male subjects performed either 6 weeks of Resistive Vibration Exercise (RVE, squats and heel raises with WBV, n=13) or Resistive Exercise (RE, squats and heel raises without WBV, n=13). Squats under RVE required indispensable weight loading on the forefoot to damp harmful vibrations to the head. Time, intervention, and interaction effects were analyzed. RESULTS: After 6 weeks of training, knee extensor CSA, isometric knee extension force, and counter movement jump height increased equally in both groups (time effect, P⟨0.001, P≤0.02, and P≤0.03, respectively), whereas only in RVE ankle plantar flexor CSA and isometric ankle plantar flexion force reached significance or a tendency, respectively, (time effect, P=0.015 and P=0.069, respectively; intervention effect also for the latter, P=0.006). Drop jump contact time did significantly more improve in RVE (interaction effect, P=0.042). CONCLUSIONS: RVE showed better training effects than RE only in plantar flexor muscles. RVE seems to be suitable in professional sports with a special focus on calf muscles.

Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

Plasma concentration of high-mobility group box 1 (HMGB1) after 100 drop to vertical jumps and after a 1200-km bicycle race.

High-mobility group box 1 (HMGB1) has recently been reported to be involved in proinflammation and tissue repair. Therefore, we hypothesized that HMGB1 is released into the bloodstream after eccentric exercises or prolonged endurance activities. Blood samples from 11 participants that performed 100 drop to vertical jumps (DVJ) and from 10 participants that took part in the 1200-km 'Paris-Brest-Paris' bicycle race (PBP) were tested for HMGB1 and creatine kinase (CK) levels. CK increased after both DVJ (pre: 150.6 ± 81.5 U/L; post: 188.8 ± 95.5 U/L 8 h: 790.5 ± 346.4 U/L) and PBP (pre: 81.3 ± 36.4 U/L; post: 725.2 ± 229.5 U/L; 12 h: 535.8 ± 188.6 U/L), indicating membrane damage. However, HMGB1 plasma levels remained below the detection limit (78 pg/mL) of the applied enzyme-linked immunosorbent assay kit for all blood samples analysed. That is, neither high intensity eccentric exercises (DVJ) nor prolonged endurance events (PBP) seemed to affect HMGB1 levels in blood at selected time points.

Acute effects of superimposed electromyostimulation during cycling on myokines and markers of muscle damage.

OBJECTIVES: The purpose of the present study was to evaluate the effects of superimposed electromyostimulation (E) during cycling on myokines and markers of muscle damage, as E might be a useful tool to induce a high local stimulus to skeletal muscle during endurance training without performing high external workloads. METHODS: 13 subjects participated in three experimental trials each lasting 60 min in a randomized order. 1) Cycling (C), 2) Cycling with superimposed E (C+E) and 3) E. Interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), creatine kinase (CK) and myoglobin were determined before (pre) and 0', 30', 60', 240' and 24h after each intervention. RESULTS: Only C+E caused significant increases in levels of CK and myoglobin. BDNF and IL-6 significantly increased after C and C+E, however increases for IL-6 were significantly higher after C+E compared to C. CONCLUSION: The present study showed that superimposed E during cycling might be a useful tool to induce a high local stimulus to skeletal muscle even when performing low to moderate external workloads. This effect might be due the activation of additional muscle fibers and mild eccentric work due to the concomitant activation of agonist and antagonist. However the higher load to skeletal muscle has to be taken into account.

Acute metabolic, hormonal, and psychological responses to strength training with superimposed EMS at the beginning and the end of a 6 week training period.

OBJECTIVES: The aim was to determine metabolic and hormonal responses to strength training with or without superimposed electromyostimulation (EMS) at the beginning and the end of a 6 week training period. METHODS: 20 strength trained subjects were randomly assigned to two groups. The first group (S) performed 4 sets of back squats with a constantly adjusted additional load of their individual 10 repetition maximum (10 RM) twice a week over 6 weeks. The second group (S+E) did the same training program with superimposed EMS on leg and trunk muscles. Physiological responses were determined before and after the first (TS 1) and the last training session (TS 12). RESULTS: No significant differences of hormonal responses could be observed between groups and TSs. However, small to large effects on metabolism occurred between groups and TSs. Delayed onset muscle soreness (DOMS) was significantly higher 48h after TS 1 for S+E. CONCLUSIONS: Despite a higher DOMS after S+E, there is no acute effect of superimposed EMS on hormonal response to exhaustive resistance exercise. We suggest that, because of the high resistance during 10 RM bouts, most of the muscle fibers are already activated and superimposed EMS only activates few additional muscle fibers.

Electrically induced muscle cramps induce hypertrophy of calf muscles in healthy adults.

OBJECTIVES: Skeletal muscles usually cramp at short lengths, where the tension that can be exerted by muscle fibers is low. Since high tension is an important anabolic stimulus, it is questionable if cramps can induce hypertrophy and strength gains. In the present study we investigated if electrically induced cramps (EIMCs) can elicit these adaptations. METHODS: 15 healthy male adults were randomly assigned to an intervention (IG; n=10) and a control group (CG; n=5). The cramp protocol (CP) applied twice a week to one leg of the IG, consisted of 3x6 EIMCs, of 5 s each. Calf muscles of the opposite leg were stimulated equally, but were hindered from cramping by fixating the ankle at 0° plantar flexion (nCP). RESULTS: After six weeks, the cross sectional area of the triceps surae was similarly increased in both the CP (+9.0±3.4%) and the nCP (+6.8±3.7%). By contrast, force of maximal voluntary contractions, measured at 0° and 30° plantar flexion, increased significantly only in nCP (0°: +8.5±8.8%; 30°: 11.7±13.7%). CONCLUSION: The present data indicate that muscle cramps can induce hypertrophy in calf muscles, though lacking high tension as an important anabolic stimulus.

Motor point map of upper body muscles.

PURPOSE: The purpose of the present study was to systematically investigate the upper body motor point (MP) positions of selected muscles and to create an atlas of the identified MPs. METHODS: MPs were searched bilaterally in 15 male and 15 female subjects by scanning the skin with a special pen electrode at low stimulation frequency (3 Hz) and current amplitude (<10 mA). The following muscles were investigated: biceps brachii, triceps brachii, deltoideus, trapezius, latissimus dorsi, erector spinae (lumbar part), pectoralis minor and major, and rectus abdominis. RESULTS: A total of 1,563 MPs were identified. The MPs could be clustered into 31 distinct positions on each side of the body. However, the number of MPs per muscle varied between subjects: 2 MPs were found for the biceps brachii, 2-3 for the triceps brachii, 4-5 for the deltoideus, 2-3 for the pectoralis major, 1 MP for the pectoralis minor, 4-5 for the trapezius, 3-4 for the latissimus dorsi, 4-5 for the rectus abdominis, and 2-3 for the erector spinae in its lumbar part. Referring to the applied grid, upper limb and lower back muscles presented a low inter-individual variation, whereas MPs of the deltoideus, the pectoralis major, and the rectus abdominis were characterized by a poor homogeneity. All MPs were found to be highly symmetrical between both sides of the body (r = 0.96; p < 0.001). CONCLUSION: The presented data and the corresponding map will help physiotherapists, and conditioning specialists improve their neuromuscular electrical stimulation therapy or training, respectively.

Acute hormonal responses before and after 2 weeks of HIT in well trained junior triathletes.

The aim was to compare the acute hormonal response to a single HIT session at the beginning and end of a HIT shock microcycle. 13 male junior triathletes (15.8±1.8 yrs.) performed 16 HIT sessions within a 2 week period. Venous blood samples were collected before and after the first and last HIT session. Significant increases in cortisol (first session +89.7%; last session +70.3%) and hGH (first session +435.1%; last session +314.6%) concentrations were observed after both training sessions (P<0.05). The acute responses of cortisol, hGH, T3, and fT3 were not different between the first and last HIT sessions (P=1.00). Although no acute changes in testosterone were detected after the training sessions, testosterone concentrations were significantly higher at all time points (62.6-80.1%) during the last compared to first training session (P≤0.001). Findings from the present study reveal that 16 sessions of HIT led to significant increases in baseline concentrations of serum testosterone. This might indicate a heightened anabolic state even in junior triathletes. Based on the hormonal data, we conclude that at the end of this 2 week microcycle no familiarization effect was evident and that the training stimulus produced by HIT was still great enough to "stress" the athletes and induce positive training adaptations.

Active vs. passive recovery during high-intensity training influences hormonal response.

The aim of the present study was to compare the effects of active (A) vs. passive (P) recovery during high-intensity interval training on the acute hormonal and metabolic response. Twelve triathletes/cyclists performed four 4 min intervals on a cycle ergometer, either with A- or P-recovery between each bout. Testosterone, hGH, cortisol, VEGF, HGF and MIF were determined pre, 0', 30', 60' and 180' after both interventions. Metabolic perturbations were characterized by lactate, blood gas and spirometric analysis. A-recovery caused significant increases in circulating levels of cortisol, testosterone, T/C ratio, hGH, VEGF and HGF. Transient higher levels were found for cortisol, testosterone, hGH, VEGF, HGF and MIF after A-recovery compared to P-recovery, despite no differences in metabolic perturbations. A-recovery was more demanding from an athlete's point of view. Based on the data of testosterone, hGH and the T/C-ratio, as well as on the data of VEGF and HGF it appears that this kind of exercise protocol with A-recovery phases between the intervals may promote anabolic processes and may lead to pro-angiogenic conditions more than with P-recovery. These data support the findings that also the long term effects of both recovery modes seem to differ, and that both can induce specific adaptations.

Acute metabolic, hormonal, and psychological responses to different endurance training protocols.

In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4×4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4×4 min at 95% PPO; 3) 4×30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO3⁻, pO2, PCO2), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4×30 s training caused the highest increases in cortisol and hGH, followed by 4 × 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4×30 s, followed by 4×4 min and HVT. The 4×30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4×30 s and 4×4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols.

Randomized controlled study on resistive vibration exercise (EVE study): protocol, implementation and feasibility.

OBJECTIVES: A training intervention comparing resistance exercise with or without whole-body vibration (WBV) was conducted to compare acute and chronic effects on functional and molecular parameters. METHODS: A six-week training intervention was performed including 26 healthy males (26 years, SD=4). Two groups were analyzed in a parallel design performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training with weekly increasing vibration frequencies (20-40Hz). Resting and exercising blood pressure and heart rate were measured before and after the 6-week intervention. RESULTS: Both training interventions decreased resting systolic blood pressure (P=0.003). Resting diastolic blood pressure was significantly decreased only in the RVE group (P=0.01). Exercising diastolic blood pressure was significantly decreased during the final training (P<0.001) with no additional effect of superimposed vibrations. Resistance exercise with superimposed vibrations evoked back pain to a higher degree than resistance exercise alone when training at frequencies above 30Hz (P<0.01). CONCLUSIONS: These data suggest positive effects of resistance exercise upon cardiovascular health and vascular responsiveness and a further beneficial effect of superimposed vibrations in decreasing resting diastolic blood pressure. Finally, development of back pain may be fostered by superimposed vibrations to high training loads, particularly at higher frequencies.

Responses of angiogenic growth factors to exercise, to hypoxia and to exercise under hypoxic conditions.

The purpose of the present study was to compare the acute hormonal response of angiogenic regulators to a short-term hypoxic exposure at different altitudes with and without exercise. 7 subjects participated in 5 experimental trials. 2 times subjects stayed in a sedentary position for 90 min at 2000 m or 4000 m, respectively. The same was carried out again in combination with exercise at the same relative intensity (2 mmol∙L(-1) of lactate). The fifth trial consisted of 90 min exercise at sea level. Venous blood samples were taken under resting conditions, 0 and 180 min after each condition to determine VEGF, EPO, IL-6, IL-8 and IGF-1 serum concentrations. EPO, VEGF, and IL-8 showed increases only, when hypoxia was combined with exercise. IL-6 was increased after exercise, independent of altitude. IGF-1 showed no changes in any intervention. The present study suggests that short term hypoxic exposure combined with low intensity exercise is able to up-regulate angiogenic regulators, which might be beneficial to induce angiogenesis and to improve endurance performance. However, in some cases high altitudes are needed, or it can be speculated that exercise intensity needs to be increased.

Effects of load and training modes on physiological and metabolic responses in resistance exercise.

The aim of the study was to examine the effects of three different loads (LOAD) in combination with four different exercise modes (MODE) on physiological responses during and after one fatiguing bout of bench press exercise. Ten resistance-trained healthy male subjects performed bench press exercise each at 55% (LOW), 70% (MID) and 85% (HIGH) of 1 repetition maximum (1RM) for as many repetitions as possible and in four training modes: 4-1-4-1 (4-s concentric, 1-s isometric, 4-s eccentric and 1-s isometric successive actions), 2-1-2-1, 1-1-1-1 and MAX (maximum velocity concentric). Oxygen uptake [Formula: see text] was measured during exercise and for 30-min post-exercise. Maximum blood lactate concentration (blood LA(max)) and heart rate (HR(max)) were also determined. Number of repetitions (REPS) and exercise time (EXTIME) were recorded and accumulated lifted mass (MASS), defined by REPS × lifted mass, was calculated. LOAD had a significant effect on REPS (LOW > MID > HIGH, p < 0.01). A significant increase of REPS was obtained exercising at a faster MODE except from 1-1-1-1 to MAX (p < 0.01). EXTIME significantly decreased with increasing LOAD (LOW > MID > HIGH, p < 0.01 for all) and faster MODE (4-1-4-1, 2-1-2-1, 1-1-1-1 > MAX; p > 0.01). MASS decreased significantly with increasing LOAD (p < 0.01) but increased with a faster MODE (p < 0.05) with the exception of 1-1-1-1 to MAX. MODE had a significant effect on VO(2) (4-1-4-1 > MAX; p < 0.05). LOAD had a significant effect on consumed O(2) during exercise (LOW > MID and HIGH; p > 0.01) and on blood LA(max) (LOW and MID > HIGH; p < 0.01). The data indicate that physiological responses on different resistance exercises depend on both the load and the velocity mode.

Gravity Probe B: final results of a space experiment to test general relativity.

Gravity Probe B, launched 20 April 2004, is a space experiment testing two fundamental predictions of Einstein's theory of general relativity (GR), the geodetic and frame-dragging effects, by means of cryogenic gyroscopes in Earth orbit. Data collection started 28 August 2004 and ended 14 August 2005. Analysis of the data from all four gyroscopes results in a geodetic drift rate of -6601.8±18.3 mas/yr and a frame-dragging drift rate of -37.2±7.2 mas/yr, to be compared with the GR predictions of -6606.1 mas/yr and -39.2 mas/yr, respectively ("mas" is milliarcsecond; 1 mas=4.848×10(-9) rad).

Ergogenic effect of hyperoxic recovery in elite swimmers performing high-intensity intervals.

This investigation tested the hypothesis that breathing oxygen-enriched air (F(i)O(2) =1.00) during recovery enhances peak (P(peak)) and mean power (P(mean)) output during repeated high-intensity exercise. Twelve elite male swimmers (21 ± 3 years, 192.1 ± 5.9 cm, 79.1 ± 8.2 kg) inhaled either hyperoxic (HOX) or normoxic (NOX) air during 6-min recovery periods between five repetitions of high-intensity bench swimming, each involving 40 maximal armstrokes. Oxygen partial pressure (pO(2)) and saturation (SO(2)), [H(+)], pH, base excess and blood lactate concentration were measured before and after all intervals. The production of the reactive oxygen species (ROS) hydrogen peroxide was measured before, directly after and 15 min after the test. P(peak) and P(mean) with HOX recovery were significantly higher than with NOX throughout the third, fourth and fifth intervals (P<0.001-0.04). With HOX, electromyography activity was lower during the third, fourth and fifth intervals than during the first (P=0.05-0.001), with no such changes in NOX (P=0.99). There were no differences in blood lactate, pH, [H(+)] or base excess and ROS production at any time point with either HOX or NOX recovery. These findings demonstrate that the P(peak) and P(mean) of elite swimmers performing high-intensity intervals can be improved by exposure to oxygen-enriched air during recovery.

Are peak oxygen uptake and power output at maximal lactate steady state obtained from a 3-min all-out cycle test?

The aim of the study was to examine whether 1) the power output attained in the last 30 s of a 3-min all-out test (P (end)) correlates with the power output at maximal lactate steady state (P (MLSS)) and whether 2) peak oxygen uptake (VO (2peak)) can be obtained from a 3-min all-out test in well-trained cyclists. 18 cyclists (23±3 years; 186.1±6.9 cm; 79.1±8.2 kg; VO (2peak): 63.2±5.2 mL · kg (-1) · min (-1)) performed a ramp test, a 3-min all-out test and several submaximal constant 30 min-workload tests at +15, 0, -15, -30, -45, -60,-75, -90 W of P (end) to obtain P (MLSS). P (MLSS) was significantly lower compared to P (END) ( P<0.001; mean difference: 54±18 W) with a high correlation (r=0.93; R (2)=0.87; P<0.001) but great intra-individual variability (15-90 W). There were no mean differences between the ramp-VO (2peak) and 3-min all-out cycling VO (2peak) ( P=0.29; mean difference: 133±514 mL · min (-1)) showing significant correlation (r=0.60; R (2)=0.37; P=0.006) but great intra-individual variability (1 057-1 312 mL · min (-1)). We therefore suggest that in well-trained cyclists a 3-min all-out test is 1) not sufficient to obtain P (MLSS) and 2) should not be applied to assess VO (2peak).

Effects of high intensity exercise on isoelectric profiles and SDS-PAGE mobility of erythropoietin.

Exercise induced proteinuria is a common phenomenon in high performance sports. Based on the appearance of so called "effort urines" in routine doping analysis the purpose of this study was to investigate the influence of exercise induced proteinuria on IEF profiles and SDS-PAGE relative mobility values (rMVs) of endogenous human erythropoietin (EPO). Twenty healthy subjects performed cycle-ergometer exercise until exhaustion. VO (2)max, blood lactate, urinary proteins and urinary creatinine were analysed to evaluate the exercise performance and proteinuria. IEF and SDS-PAGE analyses were performed to test for differences in electrophoretic behaviour of the endogenous EPO before and after exercise. All subjects showed increased levels of protein/creatinine ratio after performance (8.8+/-5.2-26.1+/-14.4). IEF analysis demonstrated an elevation of the relative amount of basic band areas (13.9+/-11.3-36.4+/-12.6). Using SDS-PAGE analysis we observed a decrease in rMVs after exercise and no shift in direction of the recombinant human EPO (rhEPO) region (0.543+/-0.013-0.535+/-0.012). Following identification criteria of the World Anti Doping Agency (WADA) all samples were negative. The implementation of the SDS-PAGE method represents a good solution to distinguish between results influenced by so called effort urines and results of rhEPO abuse. Thus this method can be used to confirm adverse analytical findings.

Vibration training intervention to maintain cartilage thickness and serum concentrations of cartilage oligometric matrix protein (COMP) during immobilization.

OBJECTIVE: To test the hypotheses that 1) 14-days of immobilization of young healthy subjects using a 6 degrees -"head-down-tilt-bed-rest"-model (6 degrees -HDT) would reduce cartilage thickness in the knee and serum Cartilage oligometric matrix protein (COMP) concentration and 2) isolated whole body vibration training would counteract the bed rest effects. METHOD: The study was performed and designed in compliance with the Declaration of Helsinki and is registered as trial DRKS00000140 in the German Clinical Trial Register (register.germanctr.de). Eight male healthy subjects (78.0+/-9.5kg; 179+/-0.96cm, 26+/-5 years) performed 14 days of 6 degrees -HDT. The study was designed as a cross-over-design with two study phases: a training and a control intervention. During the training intervention, subjects underwent 2x5-min whole body vibration training/day (Frequency: 20Hz; amplitude: 2-4mm). Magnetic resonance (MR) images (slice thickness: 2mm; in-plane resolution: 0.35x0.35mm; pixels: 448x512) were taken before and after the 6 degrees -HDT periods. Average cartilage thicknesses were calculated for the load bearing regions on the medial and lateral articulating surfaces in the femur and tibia. RESULTS: While the control intervention resulted in an overall loss in average cartilage thickness of -8% (pre: 3.08mm+/-0.6mm post: 2.82mm+/-0.6mm) in the weight-bearing regions of the tibia, average cartilage thickness increased by 21.9% (pre: 2.66mm+/-0.45mm post: 3.24mm+/-0.63mm) with the vibration intervention. No significant differences were found in the weight-bearing regions of the femur. During both interventions, reduced serum COMP concentrations were observed (control intervention: -13.6+/-8.4%; vibration intervention: -9.9+/-3.3%). CONCLUSION: The results of this study suggest that articular cartilage thickness is sensitive to unloading and that vibration training may be a potent countermeasure against these effects. The sensitivity of cartilage to physical training is of high relevance for training methods in space flight, elite and sport and rehabilitation after illness or injury.

Computer simulations suggest that acute correction of hyperglycaemia with an insulin bolus protocol might be useful in brain FDG PET.

AIM: FDG PET in hyperglycaemic subjects often suffers from limited statistical image quality, which may hamper visual and quantitative evaluation. In our study the following insulin bolus protocol is proposed for acute correction of hyperglycaemia (>7.0 mmol/l) in brain FDG PET. (i) Intravenous bolus injection of short-acting insulin, one I.E. for each 0.6 mmol/l blood glucose above 7.0. (ii) If 20 min after insulin administration plasma glucose is

7-Bromoindirubin-3'-oxime induces caspase-independent cell death.

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.