Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.

The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin®. Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin® and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin® similarly secreted IL-6, TNF-α, IL-1ß, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin®, strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.

Long-term memory consolidation of new words in children with self-limited epilepsy with centro-temporal spikes.

Accelerated long-term forgetting has been studied and demonstrated in adults with epilepsy. In contrast, the question of long-term consolidation (delays > 1 day) in children with epilepsy shows conflicting results. However, childhood is a period of life in which the encoding and long-term storage of new words is essential for the development of knowledge and learning. The aim of this study was therefore to investigate long-term memory consolidation skills in children with self-limited epilepsy with centro-temporal spikes (SeLECTS), using a paradigm exploring new words encoding skills and their long-term consolidation over one-week delay. As lexical knowledge, working memory skills and executive/attentional skills has been shown to contribute to long-term memory/new word learning, we added standardized measures of oral language and executive/attentional functions to explore the involvement of these cognitive skills in new word encoding and consolidation. The results showed that children with SeLECTS needed more repetitions to encode new words, struggled to encode the phonological forms of words, and when they finally reached the level of the typically developing children, they retained what they had learned, but didn't show improved recall skills after a one-week delay, unlike the control participants. Lexical knowledge, verbal working memory skills and phonological skills contributed to encoding and/or recall abilities, and interference sensitivity appeared to be associated with the number of phonological errors during the pseudoword encoding phase. These results are consistent with the functional model linking working memory, phonology and vocabulary in a fronto-temporo-parietal network. As SeLECTS involves perisylvian dysfunction, the associations between impaired sequence storage (phonological working memory), phonological representation storage and new word learning are not surprising. This dual impairment in both encoding and long-term consolidation may result in large learning gap between children with and without epilepsy. Whether these results indicate differences in the sleep-induced benefits required for long-term consolidation or differences in the benefits of retrieval practice between the epilepsy group and healthy children remains open. As lexical development is associated with academic achievement and comprehension, the impact of such deficits in learning new words is certainly detrimental.

Efficacy and safety of intravenous lacosamide in refractory nonconvulsive status epilepticus.

BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) recently approved as an adjunctive therapy in the treatment of partial seizures in adults. LCM is available in oral and intravenous formulations, has linear pharmacokinetics and a unique mechanism of action. THE AIM OF THIS STUDY: To evaluate the safety and efficacy of intravenous LCM in the treatment of nonconvulsive status epilepticus (NCSE) after failure of conventional therapy. METHODS: We retrospectively reviewed all patients with NCSE treated with LCM. We reviewed the clinical and electrographic changes before and after LCM administration. We also noted any reported side effects including electrocardiographic changes. RESULTS: We report four cases of NCSE that were refractory to conventional treatment, but readily responsive to LCM. No side effects attributable to LCM were identified. CONCLUSIONS: Intravenous LCM may be safe and efficacious as an add-on AED for the treatment of NCSE when standard therapy fails.

Benign partial epilepsy of childhood: a longitudinal neuropsychological and EEG study of cognitive function.

The study combined prospective neuropsychological and EEG results of 22 children presenting with typical benign partial epilepsy with rolandic spikes (n=19) and occipital spikes (n=3). The aims were to assess the types of cognitive problems which may be encountered in this population, to evaluate the course of cognitive and learning capacities during the active phase of epilepsy, and to see if there was a correlation with paroxysmal activity on the EEG. Average age at entry in the study was 8.4 years and each child was seen two to four times over a period of 1 to 3 years. EEGs showed persistent spike foci in most cases that worsened in three cases, but there were no continuous spike-waves during sleep. No child had persistent stagnation, marked fluctuations, or a regression in cognitive abilities. Of 22 children, 21 had average IQ (>80). Eight children had school difficulties requiring special adjustment. No single cognitive profile was identified. Four children had delayed language development and eight children had transient weak scores in one isolated domain (verbal, visuospatial, memory) which improved or normalized during the course of the study with concomitant EEG improvement or normalization. In two of the three children with aggravation of the paroxysmal EEG activity, clinical changes were documented. A proportion of children with typical benign partial epilepsy with rolandic spikes showed mild, varied, and transient cognitive difficulties during the course of their epilepsy, and in most cases this probably had a direct relation with the paroxysmal EEG activity.

Active conservation of noncoding sequences revealed by three-way species comparisons.

Human and mouse genomic sequence comparisons are being increasingly used to search for evolutionarily conserved gene regulatory elements. Large-scale human-mouse DNA comparison studies have discovered numerous conserved noncoding sequences of which only a fraction has been functionally investigated A question therefore remains as to whether most of these noncoding sequences are conserved because of functional constraints or are the result of a lack of divergence time.

VISTA : visualizing global DNA sequence alignments of arbitrary length.

SUMMARY: VISTA is a program for visualizing global DNA sequence alignments of arbitrary length. It has a clean output, allowing for easy identification of similarity, and is easily configurable, enabling the visualization of alignments of various lengths at different levels of resolution. It is currently available on the web, thus allowing for easy access by all researchers. AVAILABILITY: VISTA server is available on the web at http://www-gsd.lbl.gov/vista. The source code is available upon request. CONTACT: vista@lbl.gov

Recognition of a protein fold in the context of the Structural Classification of Proteins (SCOP) classification.

A computational method has been developed for the assignment of a protein sequence to a folding class in the Structural Classification of Proteins (SCOP). This method uses global descriptors of a primary protein sequence in terms of the physical, chemical, and structural properties of the constituent amino acids. Neural networks are utilized to combine these descriptors in a way to discriminate members of a given fold from members of all other folds. An extensive testing of the method has been performed to evaluate its prediction accuracy. The method is applicable for the fold assignment of any protein sequence with or without significant sequence homology to known proteins. A WWW page for predicting protein folds is available at URL http://cbcg.lbl.gov/.

Plasma glucose alone does not predict neurologic dysfunction in hypoglycemic nondiabetic subjects.

STUDY OBJECTIVE: To assess the value of plasma glucose concentration alone as a predictor of neurologic dysfunction in nondiabetic subjects with normal baseline neurologic examination and electroencephalographic (EEG) findings. METHODS: Neurologic function and EEG results were evaluated in 17 subjects before and during insulin-induced hypoglycemia using relevant and reliable clinical tools for bedside use. RESULTS: Hypoglycemia (mean nadir concentration, 30 mg/dL) was without effect on level of consciousness or cranial nerve, motor, sensory, vestibulocerebellar, language, or simple visuospatial functions. Attention was minimally impaired in all subjects, but memory in only 3. EEG results remained normal in 5 subjects; minimal to moderate nonspecific changes occurred in the rest. All patients manifested signs of sympathetic stimulation from hypoglycemia, including tremor, tachycardia, and diaphoresis. The manifestations of neuroglycopenia did not correlate significantly with nadir plasma glucose or duration of hypoglycemia. CONCLUSION: Moderately severe hypoglycemia of short duration can be neurologically occult, or subtle inattention can be its first and only clinical manifestation. Our findings are at variance with reports in the emergency medicine literature in which marked deficits are universally present at glucose concentrations equal to those attained in this study. This discrepancy suggests that the expression of neuroglycopenia is multifactorially determined and that plasma glucose concentration alone does not predict neurologic dysfunction in nondiabetic subjects with normal baseline neurologic examinations.

[Complementary information from Doppler echocardiography in the electrocardiogram in the basic assessment of chronic coronary heart disease, especially following a myocardial infarct. Observations from an ambulatory cardiology clinic]. / L'apport complémentaire de l'écho-Doppler cardiaque à l'électrocardiogramme dans le bilan de base de la maladie coronarienne chronique, en particulier après un infarctus du myocarde. Reflets d'une consultation cardiologique ambulatoire.

In chronic ischemic heart disease, Doppler echocardiography (DE) at rest permits semiquantitative evaluation of scarring and remodelling processes, global ventricular function and, frequently, regional wall motion state. Late complications are detected, namely infarct expansion, true and false ventricular aneurysm, mitral insufficiency, thrombus formation, and associated valvular and aortic diseases are discovered. We studied 100 patients with known chronic coronary artery disease referred for noninvasive evaluation, including electrocardiogram (ECG) and DE. In all patients, the global left-ventricular function was satisfactorily assessable. In roughly two thirds of the documented infarctions. DE confirmed the ECG diagnosis and permitted a more precise diagnosis in the majority of them in terms of localization and/or dimension of the necrosis. In one third of the patients. DE clarified inconclusive ECG tracings. Thus, the baseline noninvasive investigation with ECG and DE is a potent tool in the management of chronic ischemic heart disease, serving as a guide to further investigation and to treatment adjustments.

Risk for definite neuroleptic malignant syndrome. A prospective study in 223 consecutive in-patients.

The occurrence of neuroleptic malignant syndrome (NMS) was studied prospectively in two series of consecutive psychiatric in-patients (n = 223). The first group (n = 120) suffered from schizophrenia and was treated only with haloperidol. The second group (n = 103) was treated with diverse neuroleptics. All patients were on a single antipsychotic agent with no anticholinergic drug as prophylaxis. The incidence of full NMS per admission and first neuroleptic exposure was 5/223 (2.2%). Patients with bipolar affective disorder and those treated with injections were significantly over-represented in the NMS group.

Diagnóstico por imágenes en la colecistectomía no quirúrgica / Imagings diagnostic in not surgical cholecystectomy

Fueron estudiados y clasificados in vitro cuarenta cálculos vesiculares provenientes de veitiocho pacientes por radiología, ecografía, tomografía axial computada y resonancia magnética. Se elaboraron cinco patrones tomográficos: hiperdenso, anular, heterogéneo, hipo e isodenso. Los restantes métodos no permitieron abrir juicio certero sobre la estructura química de los litos. La TC demostró ser el procedimiento de elección en la aproximación al diagnóstico de la composición química de los litos, en especial su contenido colesterínico. Cabe mencionar que veinticinco de los pacientes estudiados presentaron individualmente cálculos con patrones similares, siete de ellos con patrón hipodenso (28%), dos con patrón isodenso (8%) y ocho con patrón anular (37%). Los restantes tres pacientes mostraron individualmente cálculos con diferente composición química, combinando patrones anular, hipodenso o hiperdenso. Posteriomente se seleccionaron diferentes cálculos con patrones hipodensos, isodensos y anulares los cuales fueron sumergidos en diversas soluciones de metiltert-butil eter (MTBE), ácido etilen-diamino-tetra-acético (EDTA), dimetil sulfóxido (DMSO) en forma aislada, combinados y mezclados con bilis humana, en distintas proporciones. El MTBE demostró su efectividad ya sea en la disolución completa o reducción a finas partículas no mensurables de los cálculos con patrón hipo o isodenso (alto contenido colesterínico). Los restantes solventes, aislados o en combinación con MTBE, no mejoraron esta perfomance. Los cálculos con patrón anular sumergidos en MTBE redujeron los litos a delgadas cáscaras cálcicas que se desintegraron en partículas mensurables, pudiendo en tales casos condicionar patología vesicular o pancreática in vitro. La efectividad de los diferentes disolventes químicos utilizados en forma aislada o en combinación, guarda una íntima relación con la estructura y composición química de los cálculos. De tal forma resulta imprescindible una estricta selección de los pacientes pasibles de este tratamiento

[The value of color Doppler studies to conventional cardiac Doppler studies]. / Apport du Doppler couleur au Doppler cardiaque conventionnel.

Colour Doppler is a recent and important development among non-invasive diagnostic techniques in cardiology. A series of 500 adults has been studied in order to define the contribution made by colour Doppler to conventional Doppler. After elimination of patients with normal echo Doppler studies, colour Doppler contribution has been considered useful in 51% of the cases and was essential in 13%. Main contributions have been noted in valvular regurgitations, multiple valvular lesions, prosthetic valves and congenital cardiopathies. Colour Doppler appears as an useful, but not as an indispensable complement to conventional Doppler in adult cardiology.

[Ultrasonic diagnosis of aortic valve lesions in adults]. / Ultraschalldiagnostik der Aortenklappenläsionen beim Erwachsenen.

Based on a review of the literature and on a personal series of 136 cases the reliability of echocardiography and Doppler echocardiography in demonstrating aortic stenosis and regurgitation and its value for the analysis of aortic valve prosthesis is investigated.

[Echocardiographic and electrocardiographic evaluation of the effects of propranolol and verapamil in obstructive hypertrophic cardiomyopathy]. / Evaluation échocardiographique et électrocardiographique des effects du propranolol et du vérapamil dans la cardiomyopathie hypertrophique obstructive.

The purpose of this study is to compare M-mode echocardiographic and electrocardiographic modifications obtained by short-term therapy (6 weeks) with high doses (480 mg/day) of propranolol or verapamil in six patients with hypertrophic obstructive cardiomyopathy. Propranolol prevents heart rate acceleration and reduces significantly the echocardiographic obstruction index during provocative testing with isoprenaline, when verapamil doesn't. However verapamil seems to be more able than propranolol to suppress ventricular arrhythmias as demonstrated in Holter monitoring. Evaluation of each patient suffering from hypertrophic obstructive cardiomyopathy with echocardiography and 24-hours electrocardiography would permit to better define appropriate therapy.

[Acute renal insufficiency in children]. / Insuffisance rénale aiguë chez l'enfant.

Acute renal failure (ARF) implies a sudden decrease in glomerular filtration rate with consequent retention of nitrogen waste products, water and electrolytes normally excreted by the kidney. The causes of ARF fall into three main groups: prerenal, intrinsic, and postrenal. Prerenal or functional failure can usually be controlled by simple therapeutic measures. If unrelieved, it leads to the development of renal parenchymal damage. Early biochemical indices are useful in distinguishing prerenal from intrinsic renal failure. Potentially reversible obstruction must be searched for by ultrasonographic and radiological procedures, and rapidly relieved. Symptoms of ARF result from disturbance of physiological regulatory functions. Prerenal failure requires urgent vascular expansion and careful monitoring of fluid and electrolyte replacement. Established renal failure demands careful management of electrolyte and water overload, metabolic acidosis, anemia, hypertension, infections and nutrition. Peritoneal dialysis or hemodialysis should be prepared for whenever severe hypertension, pulmonary edema or worsening biochemistry occur. Acute renal failure has a generally good prognosis if properly treated.

[One- or two-dimensional echocardiography. A comparative study]. / Echocardiographie uni- ou bidimensionnelle? Une étude comparative.

A consecutive series of 300 M-mode and two-dimensional echocardiograms was reviewed retrospectively by 2 independent observers. These tests had been performed in adult patients who were either ambulatory or hospitalized in a community hospital. The diagnostic contribution of two-dimensional echo in comparison to M-mode was nil in three-quarters of the cases; it was rated as important or essential in only 20% of the cases. It is concluded that M-mode echocardiography in adults retains its value in everyday cardiac practice.