Insulin-like growth factor 1 is a direct HOXA9 target important for hematopoietic transformation.

HOX homeobox proteins are key oncogenic drivers in hematopoietic malignancies. Here we demonstrate that HOXA1, HOXA6 and predominantly HOXA9 are able to induce the production of insulin-like growth factor 1 (Igf1). In chromatin immunoprecipitations, HOXA9 bound directly to the putative promoter and a DNase-hypersensitive region in the first intron of the Igf1 gene. Transcription rates of the Igf1 gene paralleled HOXA9 activity. Primary cells transformed by HOXA9 expressed functional Igf1 receptors and activated the protein kinase Akt in response to Igf1 stimulation, suggesting the existence of an autocrine signaling loop. Genomic deletion of the Igf1 gene by Cre-mediated recombination increased sensitivity toward apoptosis after serum starvation. In addition, the leukemogenic potential of Igf1-negative, HOXA9-transformed cells was impaired, leading to a significant delay in disease development on transplantation into recipient animals.

High-fat diet induces leptin resistance in leptin-deficient mice.

The occurrence of type II diabetes is highly correlated with obesity, although the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitiser and, in leptin-deficient, insulin insensitive, Lep(ob/ob) mice, leptin improves glucose tolerance, indicating that leptin resistance may link obesity to insulin insensitivity. Leptin resistance occurs in response to a high-fat diet (HFD) and both hyperleptinaemia and inflammation have been proposed as causative mechanisms. Scrutinising the role of hyperleptinaemia in this process, central hyperleptinaemia in Lep(ob/ob) mice was induced by chronic i.c.v. infusion of leptin (4.2 µg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake, as well as an improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Because Lep(ob/ob) mice are exquisitely sensitive to leptin, the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. HFD led to increased body weight and glucose intolerance compared to a low-fat diet (LFD). Older and heavier Lep(ob/ob) mice were used as body weight-matched controls. Mice in each group received either i.p. leptin (1.25 mg/kg) or vehicle, and glucose tolerance, food intake and the number of phosphorylated signal transducer and activator of transcription (pSTAT)3 immunoreactive cells in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) were analysed. Leptin improved glucose tolerance (P = 0. 019) and reduced food intake in Lep(ob/ob) mice on LFD (P ≤ 0.001) but was ineffective in mice on HFD. Furthermore, when leptin was administered centrally, the glucose tolerance of Lep(ob/ob) mice on HFD was significantly impaired (P = 0.007). Although leptin induced the number of pSTAT3 immunoreactive cells in the ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated pSTAT3 immunoreactivity in vehicle-treated Lep(ob/ob) mice that was unaffected by leptin treatment, suggesting central leptin resistance. Negating central inflammation by co-administering a c-Jun n-terminal kinase (JNK) inhibitor reinstated the glucose-lowering effects of leptin. These findings demonstrate that Lep(ob/ob) mice develop leptin resistance on a HFD independent of hyperleptinaemia and also indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced glucose intolerance.

Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3ß (Ser9), which are important markers of insulin signalling. Collectively, our data suggest that the acute inhibition of central JNK improves impaired glucose homeostasis and is associated with sensitisation of hypothalamic insulin signalling.

[Effect of a non-antihypertensive dose of ramipril on the plasma and tissue renin-angiotensin system in 27 TGR (mRen2) rats]. / Effets d'une dose non antihypertensive de ramipril sur les systèmes rénine-angiotensine plasmatique et tissulaire chez le rat TGR (mRen-2) 27.

It is admitted that low dose of angiotensin converting enzyme (ACE) inhibitors allows the regression of left ventricular hypertrophy (HVG) in experimental models where plasma renin activity (PRA) is high. The use of low dose of ramipril, an ACE inhibitor, make it possible to explore the place of cardiac renin-angiotensin system (RAS) in the regression of HVG independently of blood pressure (BP). Twenty rats TGR (mRen2) 27, heterozygous male, 10 weeks old were treated by daily oral gavage during 6 weeks by 10 micrograms/kg/jour ramipril or distilled water and compared to 10 normotensive Sprague Dawley (SD) rats. BP was measured. After the period of treatment, plasma, left kidney and the ventricles were removed. On each tissue samples and plasma, angiotensinogen (Aogen), the renin activity, angiotensins I (Ang I) and II (Ang II) were determined by radioimmuno assay and the activity of ACE was measured by fluorimetry. BP does not differ between treated and untreated groups during 6 weeks of treatment but is significantly higher compared to SD rats. PRA of untreated rats is high (36 +/- 5 ng Ang I/mL/h). However, treatment did not make it possible to decrease HVG. In plasma and kidney treatment's effect on SRA is confirmed by the increase in renin activity (plasma: 63 +/- 9 vs 36 +/- 5 ng Ang I/mL/h; kidney: 127 +/- 11 vs 92 +/- 7 micrograms Ang I/g/h) which is accompanied by an increase of Ang I rates (plasma: 297 +/- 31 vs 15 +/- 10 fmol/mL; kidney: 241 +/- 37 vs 160 +/- 12 fmol/g) and of the reduction in Aogen. An inhibition of ACE is perceptible with low dose of ramipril in heart (left ventricle: 1.7 +/- 0.1 vs 2.5 +/- 0.3 nmol HisLeu/min/mg protein), but it does not appear significant modifications of the other elements of the RAS in this tissue. The Ang II cardiac rates are probably not solely defined by cardiac ACE activity, other ways of synthesis being described. The absence of regression of the HVG in TGR (mRen2) 27 rat with low dose of ramipril could be related to the absence of effect on cardiac Ang II rates. In addition, the relation between high PRA rates and the effectiveness of low dose of ACE inhibitor in the HVG are not confirmed.

Brain mapping of bilateral visual interactions in children.

Interhemispheric interactions were studied with functional brain mapping of visual processing. Children performed a reaction time task with uni- and bilateral targets and nontargets. The visual evoked potential (VEP) was segmented into P1a, P1b, and N1 microstates using map rather than channel features. Map latencies, amplitudes and sources were tested for bilateral interactions. Bilateral targets yielded shorter VEP map latencies but later response onsets than unilateral ones. Source analyses of the unilateral VEPs indicated a transition from contra- (P1a) to ipsilateral (P1b) visual cortex activation (interhemispheric transfer). Bilateral VEPs were smaller than the summed unilateral VEPs in all microstates. indicating that interhemispheric interactions both precede and follow interhemispheric transfer. Brain mapping of uni- and bilateral VEPs in children thus revealed several distinct forms of interhemispheric interactions in the same, early time range.

Attentional and neuromotor deficits in ADHD.

In order to classify attention-deficit-hyperactivity disorder (ADHD) in 11-year-old children, the role of specific attentional and motor deficits was examined. Participants comprised 22 children with ADHD (19 male, 3 female; median age 11 years, range 8.8 to 13.5 years) and 20 control children (17 male, 3 female; median age 10.6 years, range 8.2 to 12.6 years). Neuromotor assessment indicated that while both groups needed more time to complete finger compared to hand movements, this increase was more pronounced in children with ADHD. Reaction-time testing with continuous-force recording identified both motor and attentional deficits in children with ADHD. Longer intervals between force onset and force peak, and higher rate of responses with multiple force peaks (particularly in the bilateral condition) revealed specific deficits in the speed and quality of their motor output. Increase in errors and variability of force onsets indicated attentional deficits. Prediction analysis indicated that force-onset variability contributed significantly to group classification which was 85.7% correct. Neither neuromotor assessment nor specific motor deficits contributed significantly to classification, indicating that pure motor-speed measures play a minor role in characterizing ADHD in this age range.

Brain mapping of bilateral interactions in attention deficit hyperactivity disorder and control boys.

OBJECTIVES: Children with attention deficit hyperactivity disorder (ADHD) are thought to have deficits in attentional control, whereas the status of deficits at visual and pre-motor processing stages is unclear. METHODS: The timing of such deficits was examined with event-related potential (ERP) microstates (stimulus- and response-related) and continuous force recordings in 15 ADHD and 16 control boys in a choice reaction time task. Unilateral and bilateral stimulus and response conditions were used to assess bilateral interactions at visual, central, and pre-motor stages. RESULTS: ADHD boys showed poorer performance, particularly in the bilateral conditions. In the visual P1 microstates, they exhibited less suppression of visual evoked potential (VEP) amplitudes but similar speeding of VEP latencies in the bilateral compared to the summed unilateral condition. The central P3 and pre-/post-response microstates were attenuated and topographically altered in ADHD boys. The attenuation was most pronounced in the bilateral condition and was similar for stimulus- and response-related averages. The lateralized readiness potential was also reduced in ADHD boys; this was most pronounced for the left hand responses. CONCLUSIONS: Brain mapping during uni- and bilateral stimulus and response conditions thus indicates multilevel deficits in ADHD boys affecting visuo-attentional, central, and pre-motor processes.

Electroencephalographic measurement of motor cortex control of muscle activity in humans.

OBJECTIVE: To detect and measure correlation between cortical and muscle activities, coherence analysis was used. METHODS: The electroencephalogram (EEG) and electromyogram (EMG) were recorded in 9 normal volunteers during tonic contraction of upper and lower limb muscles on the right side. Coherence between EEG and EMG was computed to analyze their linear association. RESULTS: EEG over the contralateral sensorimotor area was coherent with EMG, with peak coherence at 11-36 Hz (mean, 22 Hz). For the abductor pollicis brevis (APB) muscle, peak coherence, as determined by functional brain mapping with focal transcranial magnetic stimulation (TMS), was over or slightly posterior to the hand area on the primary motor cortex determined by focal transcranial magnetic stimulation (TMS). Peak coherence over the scalp was somatotopically organized. The temporal relation between EEG and EMG was analyzed with a new model for interpreting the phase shift ('constant phase shift plus constant time lag' model). For the APB muscle, the phase relation between cortical and muscular oscillations differed in the frequency ranges of 3-13 Hz and 14-50 Hz, respectively, suggesting that different coupling mechanisms operate in different bands. Only the phase shift between cortical and motoneuronal firing at 14-50 Hz was reliably estimated by a linear model. At 14-50 Hz, motoneuronal firing was led by surface-negative cortical activity with a constant time lag that depended on the cortical-muscular distance. For the APB muscle, the time lag was slightly shorter than the cortical-muscular conduction time determined by TMS. Vibratory stimulation (100 Hz) of a muscle tendon during tonic contraction had no significant effect on cortical-muscular coherence, indicating that cortical oscillation reflected motor rather than sensory activity. CONCLUSIONS: The present findings suggest temporal coding of the oscillatory motor control system (3-13 Hz vs. 14-50 Hz), and confirm the functional importance of cortical beta and gamma rhythms in the motor efferent command. Cortical-muscular synchronization is most likely mediated by the direct corticospinal pathway within the frequency range of 14-50 Hz.

Adult-onset angiofibroma and multiple endocrine neoplasia type I.

Multiple endocrine neoplasia type 1 (MEN 1) predisposes affected persons to neoplasms of the parathyroid glands, the endocrine pancreas, the anterior pituitary, and the duodenum. We report the first case of adult-onset multiple angiofibromas of the central face associated with MEN 1. Seven siblings also developed adult-onset angiofibromas, none with evidence of tuberous sclerosis. Basic fibroblast growth factor (BFGF) is elevated in many patients with MEN 1 and may play a pathogenetic role.

Neuroelectric mapping reveals precursor of stop failures in children with attention deficits.

Children with attention deficit disorders (ADD) may have specific problems with response inhibition in the STOP task. This task requires that subjects stop responses to a primary task if a second signal follows. However, it is unclear whether these problems reflect an impairment of the stopping process per se, whether they are related to reduced frontal lobe activation and whether they are confined to severe and pervasive forms of ADD. In 11 ADD and nine control children, 32 channel event-related EEG potentials (ERPs) were recorded in a STOP and a delayed GO task. Mapping revealed that both tasks evoked a similar sequence of neuroelectric microstates, i.e. of time segments with stable map topography. Adaptive segmentation identified the transition between these microstates. Reliable group differences were found in several microstates and in both tasks despite matched performance. In the GO task, ADD children had topographically altered P2/N2 microstates and attenuated P300-type microstates. In the STOP task, a topographically altered N1 microstate which coincided with the onset of the stop signal preceded the stop failures of ADD children. The timing of this microstate is too early to reflect deficits in actual stop signal processing and instead suggests altered initial orienting of attention to the primary signal in ADD children. Imaging with low resolution tomography (LORETA) during this microstate to stop failures indicated mainly posterior activation for both groups and increased rather than reduced frontal activation in ADD children. For a later microstate (P550), LORETA indicated strong frontal activation after successful stopping, but no group differences. The results suggest that information processing of ADD children deviates during activation of posterior mechanisms which may be related to the orienting of attention and which precedes and partly determines inhibitory control problems in ADD.

Lateral stability in sideward cutting movements.

Sideward cutting movements occur frequently in sports activities, such as basketball, soccer, and tennis. These activities show a high incidence of injuries to the lateral aspect of the ankle. Consequently, the lateral stability of sport shoes seems important. The purpose of this study was to show the effect of different shoe sole properties (hardness, thickness, torsional stiffness) and designs on the lateral stability during sideward cutting movements. A film analysis was conducted including 12 subjects performing a cutting movement barefoot and with five different pairs of shoes each filmed in the frontal plane. A standard film analysis was conducted; for the statistical analysis, various parameters such as the range of motion in inversion and the angular velocity of the rearfoot were used. The results showed a large difference between the barefoot and shod conditions with respect to the lateral stability. Two shoes performed significantly better (P < 0.05) than the others with a decreased inversion movement and less slipping inside the shoe. The two shoes differed mainly in the shoe sole design (hollow inner core) and the upper (high-cut). It is concluded that lateral stability may be improved by altering the properties and design of the shoe sole as well as the upper.

[Control of the rear foot in lateral movements in sports]. / Die Kontrolle des Rückfusses bei Seitwärtsbewegungen im Sport.

The goals of this investigation were to establish the frequency distribution of different movements in various ball sports (1) and to test the influence of altered shoe sole constructions on the stability in lateral breaking movements (2). Firstly, a video analysis was carried out to establish the frequency distribution of different movements in sporting activities such as volleyball, basketball, team handball and football (soccer). It is shown that a selected number of lateral cutting movements can represent more than half of all movements observed in one of the sporting activities. For part 2 an investigation with three systematically varied shoes was undertaken. The results show that with altered shoe sole constructions (torsion and change of shape of the shoe-sole) the supination movement with shoes comes close to the barefoot values. In respect of abduction/adduction of the foot the systematic changes of the shoe soles had no measurable influence.

Chromatographic methods for analysis of ethylene oxide in emissions from stationary sources.

Chromatographic methods of analysis with FID detection are investigated for quantitation of ethylene oxide in emissions from production plants and commercial sterilizers. A column with a stationary phase of 3% Carbowax 20M on 80-100 Chromosorb 101 is used to separate ethylene oxide from potential interferents in emissions from production plants. Two columns are found that allow accurate quantitation of ethylene oxide in emissions from commercial sterilizers. Both columns elute ethylene oxide before Freon 12, the diluent in the sterilization process. One column has a stationary phase of 1% SP-1000 on 60-80 Carbopack B and can be used to quantitate ethylene oxide over a wider range of concentrations than the other column, 5% Fluorcol (a fluorinated oil) on 60-80 Carbopack B. Graphitized carbon, the solid support in both of these columns, appears to participate in the ethylene oxide-Freon 12 separation with the SP-1000 column but not with the Fluorcol column.

[Experiences and clinical results following 99 kidney transplantations with kidneys from relatives]. / Erfahrungen und klinische Ergebnisse nach 99 Verwandtennierentransplantationen.

99 living related kidney transplantations were performed between January 1967 and December 1988. At the time of observation 4 of 94 organ donors had died; there was no correlation between unilateral nephrectomy and the patient's death. Intraoperative (2.9%) and postoperative (25%) complications did not result in severe physical consequences for the organ donors. Hypertension was found in 2 donors. There was no decrease in function of the remaining kidneys. The 3-year organ survival of the transplanted kidney was 60% with "conventional immunosuppression" and 93% with cyclosporin. No association was found between HLA DR-matching and graft survival. Rejection episodes occurred significantly more often in the HLA DR-mismatched grafts.

EMG scanning in the diagnosis of chronic pain.

A surface EMG diagnostic protocol was developed to assess the neuromuscular/postural contributions to pain states. The EMG activity of the right and left aspects of 11 muscle groups were monitored while the patient was in the sitting and standing positions. The diagnostic protocol was evaluated by comparing the patterns of EMG activity in four diagnostic groups: headache only, neck/shoulder/upper back pain only, low back pain only, and mixed pain states. The results suggest that (1) bilateral levels of EMG activity in the frontalis and masseter groups are of primary importance for the headache patients, (2) the discrepancy between the right and left EMG activity in the lumbar and cervical paraspinal muscle groups are of primary importance for low back pain patients, (3) position (sit/stand) may provide important diagnostic information, and (4) the data appear to support the notion of a postural disturbance as a contributing factor in low back pain.