Efficacy and tolerability of mycophenolate mofetil in a pediatric Rasmussen syndrome.

Rasmussen syndrome (RS) is a chronic encephalopathy with uncertain etiology and immune-mediated pathogenesis. The only definitive treatment is represented by functional hemispherectomy. We describe the case of a 6.5-year-old female patient who developed several episodes of focal, unilateral clonic seizures. Following laboratory and instrumental investigations, the patient was diagnosed as having RS. A treatment with corticosteroids, intravenous immunoglobulin, and the antiseizure medication (carbamazepine and levetiracetam) did not completely control the seizures. Therefore, the patient was treated with mycophenolate mofetil (MMF), showing a good clinical response, with reduction of the seizures, and stability of the radiological findings. This case suggests the potential utility of MMF in the immune approach to RS.

A robotic Intelligent Towing Tank for learning complex fluid-structure dynamics.

We describe the development of the Intelligent Towing Tank, an automated experimental facility guided by active learning to conduct a sequence of vortex-induced vibration (VIV) experiments, wherein the parameters of each next experiment are selected by minimizing suitable acquisition functions of quantified uncertainties. This constitutes a potential paradigm shift in conducting experimental research, where robots, computers, and humans collaborate to accelerate discovery and to search expeditiously and effectively large parametric spaces that are impracticable with the traditional approach of sequential hypothesis testing and subsequent train-and-error execution. We describe how our research parallels efforts in other fields, providing an orders-of-magnitude reduction in the number of experiments required to explore and map the complex hydrodynamic mechanisms governing the fluid-elastic instabilities and resulting nonlinear VIV responses. We show the effectiveness of the methodology of "explore-and-exploit" in parametric spaces of high dimensions, which are intractable with traditional approaches of systematic parametric variation in experimentation. We envision that this active learning approach to experimental research can be used across disciplines and potentially lead to physical insights and a new generation of models in multi-input/multi-output nonlinear systems.

EEG complexity drug-induced changes in disorders of consciousness: a preliminary report.

The goal of this work is to investigate EEG (ElectroEncephaloGram) dynamics after drug intake in patients being in states of Disorders Of Consciousness (DOC) after brain injury. Four patients were involved in the study. All the patients exhibit cerebral lesions located in the same anatomical region. Two nonlinear indexes, such as Lempel-Ziv Complexity (LZC) and Approximate Entropy (ApEn), along with power spectra, were calculated for EEG signals gathered from electrodes placed on both injured and non-injured regions. Experimental results show that after drug administration the two nonlinear indexes calculated from EEG taken from injured regions increase (p < 0.001) while power spectra decrease or remain unchanged. These results do not pretend to draw conclusions about consciousness level either suggest promising therapeutical treatments, but represent only an experimental evidence about the change in the EEG complexity after drug administration.

Spontaneous blinking behaviour in persistent vegetative and minimally conscious states: relationships with evolution and outcome.

There is evidence that spontaneous blinking correlates with cognitive functions. This arises from the observation that blinking rate (BR) is modulated by arousal levels, basic cognitive processes (e.g., attention, information processing, memory, etc.) and more complex cognitive functions (e.g., reading, speaking, etc.). The aim of this work was to test the role of BR evaluation in the assessment of cognitive network functioning in awake patients with consciousness deficits. Thirteen patients were recruited for the study, and were assessed by the Glasgow coma scale (GCS) and Glasgow outcome scale (GOS) on admittance and discharge, respectively. A level of cognitive functioning scale (LCFS) score was assigned at every change in awareness or at least every 2 weeks. At the same time as the clinical tests, the BR was observed for a 5-min period. Ten healthy subjects, observed throughout three non-consecutive days, formed the control group. The BR underwent a different temporal behaviour in the two diagnostic categories. In the persistent vegetative state (PVS) group it remained stable throughout time and linked with the clinical conditions of the patients; whereas in the non-persistent vegetative state (NPVS) group it decreased over time as the cognitive conditions improved. Moreover, a strong inverse correlation was found between overall BR values and LCFS scores. We have concluded that the blinking behaviour changes manifested in PVS and NPVS patients reflect different evolution phases of a cholinergic-dopaminergic imbalance, and that a reduced BR characterizes the early stages of consciousness recovery.

Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass.

OBJECTIVES: We sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization. RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients ( P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group. CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

Impaired agonists recruitment during voluntary arm movements in patients affected by spasmodic torticollis.

We have investigated the electromyographic (EMG) and kinematic characteristics of horizontal arm extension movements in patients affected by idiopathic cervical dystonia (ICD) as well as in normal subjects. In spite of the lack of an overt dystonic involvement of the muscles acting at upper arm level, all these patients were considerably bradykinetic. Although the degree of bradykinesia observed was comparable to that previously reported for the body segment directly affected by this patholgy (21,15,8), the EMG analysis of the agonist muscles indicated a specific pathophysiological mechanism. In particular, the recruitment of the posterior deltoid (pD) in ICD patients was severely impaired within the initial phase (130 ms) of the movement. On the other hand, within the same time span, the activation of the mD, a muscle that plays a more important postural role than the pD, was not significantly different between patients and normal subjects. This reduced recruitment in the initial phase of the AG1 appears responsible of the slowness of voluntary movements.

Asymmetric scalp distribution of pattern visual evoked potentials during interictal phases in migraine.

The N70 and P100 components of transient pattern visual evoked potentials (P-VEPs) were measured in migraine patients, with and without aura, and in normal subjects in order to evaluate their latency, amplitude and occipital scalp distribution. The aim was to find any typical electrophysiological abnormalities in migraine. P-VEP N70 and P100 were analyzed in 59 patients without any known visual field defect. Mean latency and amplitude values were within normal ranges for either N70 and P100 all over the occipital scalp; the only significant abnormality we found was related to the absolute right-left amplitude ratio either for N70 and P100 waves, providing an asymmetry in P-VEP scalp distribution; this finding was detected in 78.9% of patients with aura and 72.5% without aura. Our results show that in migraine patients, both P-VEP waves N70 and P100, have an asymmetric topographic distribution, even during interictal phases, that can be explained by a cortical disturbance in agreement with the neural hypothesis of headache.

Effects of grating spatial orientation on visual evoked potentials and contrast sensitivity in multiple sclerosis.

Previous studies suggest a delay of pattern visual evoked potentials (PVEPs) in multiple sclerosis (MS) depending on grating orientation. We examined a group of 14 patients with definite MS recording PVEPs to vertical and horizontal grating and analysing latency and amplitude of P60, N70 and P100 waves. We evaluated contrast sensitivity (CS) to dark and bright bars of several spatial frequencies (SF). The aim was to evaluate the diagnostic value of evoked responses and CS in revealing involvement of cortical structures. PVEPs to 1 degrees cycle/degree (c/d) vertical bars were abnormal in 25% for P60, in 32% for N70 and in 36%, for P100; in 25%, 36% and 42% respectively at 4 c/d; as regards horizontal bars at 1 c/d we found alterations of P60, N70 and P100 in 11%, 19% and 27% respectively; at 4 c/d in 19%, 27%) and 35%. CS resulted more abnormal for vertical grating, with a maximum impairment for 3.7 c/d SF. We may conclude that the use of vertical grating in clinical routine is more reliable both for PVEPs and CS testing; in addition CS can be abnormal even with normal PVEPs: this could mean an early impairment of CS and provide useful indications about a subclinical involvement of visual cortex.

Changes in long-latency reflexes onset latencies across full-wave rectified and non-rectified recordings.

Electrically elicited long-latency reflexes (LLRs) were obtained from thenar muscles by either fully rectified or non-rectified raw recordings in 10 healthy volunteers. The LLR II onset latencies were significantly (P < 0.0001) delayed on rectified (mean +/- SD: 49.8+/-2.9 ms) compared to raw (45.3+/-2.3 ms) recordings, with a mean difference of 4.4 ms. These data show that, according to the recording technique employed, the LLR II onset latencies can change considerably. The possible implications on cortical relay time (CRT) calculation and the understanding of the intracortical connections physiology are discussed.

Impaired ascendant central pathways conduction in impotent diabetic subjects.

OBJECTIVES: Diabetic impotence is generally due to peripheral neuropathy, but a central pathway impairment has also been suggested. We evaluated somatosensory transmission in a group of impotent diabetic men to assess the role of central nervous system (CNS) involvement. MATERIALS AND METHODS: Somatosensory evoked potentials (SEPs) of pudendal (pdn) and posterior tibial (ptn) nerves were recorded in 74 patients. Type and duration of diabetes, severity of sexual dysfunction, medium term metabolic control, occurrence of microangiopathic chronic complications and autonomic neuropathy were evaluated. RESULTS: Our data show an impairment of central conduction times in pdn (25.7%) and ptn (39.2%) greater than peripheral nervous impairment (pdn 12.2%, ptn 8.1%), in impotent diabetic patients without any further major complication. Central nervous conduction delay resulted to be correlated with poor glycemic control. Significant evident autonomic dysfunction was found only in a minority of cases. CONCLUSION: Our data might suggest that altered conduction along CNS and somatic peripheral neuropathy might develop independently. We confirm the hypothesis of a "central diabetic neuropathy" and suggest that central sensory pathways involvement, not related to peripheral impairment, could play a role in the pathogenesis of erectile dysfunction in diabetic patients.

Expression of the paired-box genes Pax-1 and Pax-9 in limb skeleton development.

Vertebrate Pax genes encode a family of transcription factors that play important roles in embryonic patterning and morphogenesis. Two closely related Pax genes, Pax-1 and Pax-9, are associated with early axial and limb skeleton development. To investigate the role of these genes in cartilage formation we have examined the expression profiles of Pax-1 and Pax-9 in developing chick limb mesenchyme in vivo and in vitro. Both transcripts are detected by reverse transcription polymerase chain reaction and Northern blotting throughout chick limb development, from the early bud stages (Hamburger-Hamilton 20-23) to fully patterned appendages (stage 30). Whole-mount in situ hybridization reveals complex, nonoverlapping expression domains of these two genes. Pax-1 transcripts first appear at the anterior proximal margin of the limb buds, while Pax-9 is expressed more distally at what will be the junction of the autopod and the zeugopod. In situ hybridization to serial sections of the girdles reveals that in the pectoral region Pax-1 is expressed proximally in condensed mesenchyme surrounding the junction of the developing scapula, humerus, and coracoid. In the pelvis, Pax-1 is expressed between the femur and the developing acetabulum and along the ventral edge of the ischium; this transcript was also found in the distal hindlimb along the posterior edge of the fibula. Pax-9 transcripts were not detected in the pectoral girdle at any stage, and only weakly in the pelvis along the ventral ischial margin. In the distal parts of both wings and legs, however, Pax-9 is strongly expressed between the anterior embryonic cartilages (e.g., distal radius or tibia) and the anterior ectodermal ridge. The expression of both genes was strongest in undifferentiated cells of precartilage condensations or at the margins of differentiated cartilages, and was absent from cartilage itself. In micromass cultures of chondrifying limb bud mesenchyme expression of Pax-1 and Pax-9 is maintained for up to 3 days in vitro, most strongly at the end of the culture period during chondrogenic differentiation. As seen in vivo, transcripts are found in loose mesenchyme cells at the outer margins of developing cartilage nodules, and are absent from differentiated chondrocytes at the nodule center. Taken together, these investigations extend previous studies of Pax-1 and Pax-9 expression in embryonic limb development while validating limb bud mesenchyme culture as an accessible experimental system for the study of Pax gene function and regulation. Our in vivo and in vitro observations are discussed with reference to 1) the relationship between somitic and limb expression of these two Pax genes, 2) what regulates this expression in different regions of the embryo, and 3) the putative cellular functions of Pax-1 and Pax-9 in embryonic skeletogenesis.

Changes in pain perception and pain-related somatosensory evoked potentials in humans produced by exposure to oscillating magnetic fields.

Nociception has been reported to be influenced by exposure to magnetic fields (MFs). The aim of this study was to investigate the effects of 2 h exposure to weak, oscillating MFs on pain perception thresholds and on pain-related somatosensory evoked potentials (SEPs). In 11 healthy volunteers, pain perception thresholds and pain-related SEPs were assessed by intracutaneous electrical stimulation. After sham treatment, pain thresholds significantly increased, whereas after MFs a slight non-significant decrease in thresholds was found. After both treatments pain-related SEP amplitude was reduced, but this decrease was more evident and statistically significant only after MF exposure. The increase found in thresholds after sham exposure may be due to stress-induced analgesia (SIA) and the contrasting behaviour recorded after MF exposure might indicate a suppression of SIA. The significant reduction in pain-related SEP amplitude observed after MF exposure provides the first evidence that human SEPs are influenced by MFs.

Mitochondrial tRNA(Cys) gene mutation (A5814G): a second family with mitochondrial encephalopathy.

We report an Italian family with maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiological evidence of brainstem dysfunction. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 5814 in the tRNA gene for cysteine (A5814G), previously reported in a 5-year-old girl of Portuguese origin. The mutation was very abundant (> 95%) in both muscle and blood from the proposita and was present in lower proportions (average 85 +/- 6%) in blood from three less severely affected maternal relatives. This observation confirms pathogenicity for the A5814G mutation.

T lymphocyte benzodiazepine binding is reduced in demented patients.

Blood cells, especially platelets and lymphocytes, are used in neuropsychiatric research as tools for investigating systemic derangements in neuropsychiatric disorders, and as peripheral models for studying central nervous system biochemistry. In the present work, we determined T lymphocyte peripheral-type benzodiazepine binding: a significant reduction of Bmax values was observed in demented patients as compared with healthy controls, whereas Kd values were similar in the two subjects' groups. A significant negative correlation was found between Bmax values and illness severity. These data, which seem to be related to an impairment of immune response and cell energy metabolism in demented patients, may represent a state-dependent marker in monitoring disease course and treatment efficacy.

Neanderthal parietal, vertebrate fauna, and stone artifacts from the Upper Pleistocene deposits of Contrada Ianní di San Calogero (Catanzaro, Calabria, Italy).

Human skeletal remains recovered at a new archaeological site, dating back to the Italian Mousterian age are analyzed. The finds consist of a left parietal of a child about 2-3 years old. The metrical, morphometrical, and morphological traits of this parietal are compared to those of other Neanderthal children. The geological features of the site, its fauna, and stone artifacts recovered there during quarry operations are also analyzed.