Cognitive development in benign focal epilepsies of childhood

Benign focal epilepsy of childhood (BFEC) is the most common form of epilepsy, in children from 3 to 12 years. Its prognosis is always favourable as far as the epilepsy is concerned. Nevertheless, recent clinical data suggest that children affected by BFEC are more likely to show learning difficulties and behavioural disturbances than their peers. We report here the preliminary findings of a prospective study of 22 children affected with BFEC. Electroclinical and neuropsychological changes observed during the first 18 months of the follow-up strengthen the conclusion of recent neuropsychological studies stressing the correlation between epilepsy and cognitive performances. The cognitive deficits affecting mainly non-verbal functions were significantly correlated with the frequency of seizures and spike-wave discharges and to the lateralization of the epileptic focus in the right hemisphere, whereas frontal functions like attention control, response organization and fine motor speed, were impaired in the presence of active BFEC independently of the lateralization of the epileptic focus. Our results indicate that maturing cognitive functions subserved by a cortical area distant from the epileptic focus are susceptible to interference with epilepsy. Copyright Copyright 1999 S. Karger AG, Basel     

Electric nerve stimulation: analysis of two clinical cases of failed nerve electrolocation by using sheathed needles.

The aim of this work was to explain the reasons of two unsuccessful blocks of sciatic nerve even if anaesthetic solution was injected through insulated needle on elicited twitch. The clinical cases were two outpatients undergoing diagnostic arthroscopy of knee under anaesthetic block of sciatic and femoral nerves. In both patients, the muscular twitch appeared when the ischiatic bone was kept in unexpected touch with needle tip. In spite of the attempt to locate correctly the needle (the touch with bone means that the nerve is not in front of the needle tip), the injection of anaesthetic solution was unsuccessful. In clinical environment, when electroinsulated needles gathered total amount of administered current on the needle tip, it was not possible to elicit a twitch just at the moment of touch of the needle with the bone. Referred events disagree with some experimental works performed out of clinical environment, which found that total amount of administered current through an insulated needle gathers always in front of the tip. Our clinical observations seems to confirm an electrolocation mistake called "electrical shadow". The ability of sheathed needles to work as occasional capacitor due to the alternation of two conductor layers (needle shaft and tissue) and of a dielectric (coating material) can explain some missing electrolocations, as the appearance of electric fields within dielectric needle sheathing.     

Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions

The thienobenzodiazepine derivative etizolam (CAS 40054-69-1, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo-(3,4-c)thienol(1 ,4) diazepine) is a potent anxiolytic with a pharmacological profile similar to that of classical benzodiazepines. In order to rationalize the therapeutic use of etizolam, its pharmacodynamics properties on GABAA receptors were investigated by a comparative study with other ligands on human recombinant GABAA as well as rat brain native receptors. Etizolam inhibited in a concentration-dependent manner [3H]flunitrazepam (CAS 1622-62-4) binding to rat cortical membranes, with an affinity of 4.5 nmol/l greater than that of alprazolam (CAS 28981-97-7) (7.9 nmol/l). Ethizolam enhanced GABA-induced Cl- currents in oocytes expressing human cloned GABAA receptors. With alpha 1 beta 2 gamma 2S subunit combination, etizolam produced a 73% increase in GABA-induced currents with an EC50 of 92 nmol/l. At the same receptor type, alprazolam showed a higher degree of potentiation and potency (98%, EC50 56 nmol/l). At alpha 2 beta 2 gamma 2S or alpha 3 beta 2 gamma 2S subunit constructs, the effects of etizolam were similar to those of alprazolam. Flumazenil (CAS 78755-81-4) completely blocked both etizolam and alprazolam effects on GABA-induced currents. Etizolam, administered i.p., was uneffective in changing ex vivo t-[35S]butylbicyclophosphorothionate ([35S]-TBPS) binding to rat cerebral cortex, whereas alprazolam and abecarnil (CAS 111841-85-1) significantly reduced this parameter. However, etizolam similarly to abecarnil and alprazolam, antagonized isoniazid-induced increase (61%) in [35S]-TBPS binding to rat cortical membranes. Further, etizolam inhibited in a dose-dependent manner basal acetylcholine release from both hippocampus and prefrontal cortex, and reversed foot-shock-induced increase of basal acetylcholine release to a control level. Altogether, these results suggest that etizolam may have a reduced intrinsic activity, at least at specific subpopulations of GABAA receptors. This property, together with the pharmacokinetic indication of a short-acting drug, may characterize etizolam as a ligand endowed with less side-effects typical of full agonits such as diazepam (CAS 439-14-5) and alprazolam. Finally, given its marked efficacy under conditions of GABAergic deficit, etizolam may represent a possible drug of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.     

Neo-adjuvant organ-preserving chemotherapy in the management of locally advanced oral cavity and oropharynx cancer

We designed an open, non-randomized clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neo-adjuvant chemotherapy (NAG) in oral cavity and oropharynx cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. Moreover, an attempt was made to scale the extent of surgery by means of an Arbitrary Scale assigning different percentages to the different extents of surgical resection. Twenty-five patients with primary oral cavity and oropharynx cancer (stage III-TV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (1) (n=15) or to a regimen (2) consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2-5 and vinorelbine 20 mg/m(2) on days 2 and 8 (n=10). The 25 patients were all evaluable for response to NAC and 20 of them were evaluable for organ preservation. The overall response (OR) rate was 86.6% (13/15 patients) for regimen 1 (cisplatin + 5-FU) and 80% (8/10 patients) for regimen 2 (cisplatin + 5-FU + vinorelbine). The median follow-up duration was 20.6 months. 5/20 (25%) patients completely avoided surgery, 5/20 (25%) patients had a reduced extent of surgical resection, while: 10/20 (50%) patients received the previously planned surgical resection. Altogether, 10/20 (50%) patients treated with NAC either avoided or achieved a reduction in the previously planned surgical resection. Moreover, organ function was evaluated to support the assessment of treatment outcome in our patients. For this purpose we selected the Performance Status Scale for Head and Neck Cancer Patients: as expected, no significant impairment was detected in the area of comprehensibility of speech, but we were rather surprised that no significant impairment was found in the two areas of eating in public and normalcy of diet. NAG-associated toxicity was moderate and similar in the two chemotherapy regimens. The most relevant contributions offered by our study are represented by i) a Scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) an attempt to support the results with an assessment of treatment outcome.     

Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer

Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.     

Oral iron absorption in infantile protein-energy malnutrition.

The ability of infants with protein-energy malnutrition to absorb iron was assessed using the serum iron response to a dose of ferrous sulfate providing 3 mg elemental iron per kg body weight. Responses were grouped as flat (delta serum Fe less than 30 microgram/dl), intermediate (30 to 100 microgram/dl), and normal (greater the 100 microgram/dl). Of 25 consecutively admitted children studied, seven had a flat, five an intermediate, and 13 a normal curve (mean delta serum Fe: 10 microgram/dl, 66 microgram/dl, and 175 microgram/dl, respectively). There were no differences among the three groups in hematocrit, fasting serum iron or transferrin saturation, severity of malnutrition, or evidence of other malabsorption sufficient to explain these differences. Although hematocrits, fasting serum iron, and transferrin saturations did not change appreciably during nutritional rehabilitation, all children with initially abnormal responses subsequently had normal tests.     

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],