Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?

BACKGROUND: Glatiramer acetate (GA) 20 mg/day (GA20) is associated with immediate post-injection reactions (PIRs). For convenience of use, approved GA 40 mg three times weekly (GA40) delivers a similar weekly dose. The dose and concentration of a single GA40 injection are, however, twice as high as for GA20, and post-injection adverse events may differ. Cases of atypical PIRs to GA40 prompted us to systematically monitor such events. OBJECTIVE: The aim was to characterize atypical PIRs in multiple sclerosis (MS) patients treated with GA40. METHODS: Clinical practice data were prospectively collected in consecutive relapsing-remitting MS patients. Descriptive statistics for categorical and continuous variables, Mann-Whitney and Chi-squared tests for baseline comparisons, and Cox regression models for association of variables to first atypical PIRs were applied. RESULTS: Forty-six out of 173 patients (26.6%) given GA40 experienced any PIRs. Of those, 38 (22.0%) had atypical, 14 (8.1%) had combined typical and atypical, and 26 (15.0%) had recurrent atypical PIRs, most frequently shivering (13.3%) and nausea/vomiting (8.1%). Compared to typical PIRs, onset of atypical PIRs was significantly delayed (median 30 vs 1 min, p < 0.0001), and their median duration longer (median 120 vs 6 min, p = 0.00013). Previous exposure to GA20 was associated with a lower risk of atypical PIRs [hazard ratio (HR) = 0.35, 95% confidence interval (CI) 0.17-0.72, p = 0.0039]. Patients experiencing PIRs with GA20 were at elevated risk for atypical PIRs with GA40 (HR = 5.75, 95% CI 1.66-19.94, p = 0.0059). CONCLUSIONS: Atypical PIRs with GA40, especially gastrointestinal symptoms and/or fever/shivering, had a delayed onset and occurred in a significant proportion of our patients. Their real prevalence should be assessed in appropriately designed studies accounting for  nocebo responses. Initial dose titration might reduce PIR frequency.

Impact of the spatial structure of the hydraulic conductivity field on vorticity in three-dimensional flows.

A material fluid element within a porous medium experiences deformations due to the disordered spatial distribution of the Darcy scale velocity field, caused by the heterogeneity of hydraulic conductivity. A physical consequence of this heterogeneity is the presence of localized kinematical features such as straining, shearing and vorticity in the fluid element. These kinematical features will influence the shape of solute clouds and their fate. Studies on the deformation of material surfaces highlighted the importance of stretching and shearing, whereas vorticity received so far less attention, though it determines folding, a deformation associated with the local rotation of the velocity field. We study vorticity in a three-dimensional porous formation exploring how its fluctuations are influenced by the spatial structure of the porous media, obtained by immersing spheroidal inclusions into a matrix of constant hydraulic conductivity. By comparing porous formations with the same spatial statistics, we analyse how vorticity is affected by the different shape and arrangement of inclusions, defined as the medium 'microstructure'. We conclude that, as microstructure has a significant impact on vorticity fluctuations, the usual second-order statistical description of the conductivity field is unable to capture local deformations of the plume.

A theoretical framework for modeling dilution enhancement of non-reactive solutes in heterogeneous porous media.

Spatial heterogeneity of the hydraulic properties of geological porous formations leads to erratically shaped solute clouds, thus increasing the edge area of the solute body and augmenting the dilution rate. In this study, we provide a theoretical framework to quantify dilution of a non-reactive solute within a steady state flow as affected by the spatial variability of the hydraulic conductivity. Embracing the Lagrangian concentration framework, we obtain explicit semi-analytical expressions for the dilution index as a function of the structural parameters of the random hydraulic conductivity field, under the assumptions of uniform-in-the-average flow, small injection source and weak-to-mild heterogeneity. Results show how the dilution enhancement of the solute cloud is strongly dependent on both the statistical anisotropy ratio and the heterogeneity level of the porous medium. The explicit semi-analytical solution also captures the temporal evolution of the dilution rate; for the early- and late-time limits, the proposed solution recovers previous results from the literature, while at intermediate times it reflects the increasing interplay between large-scale advection and local-scale dispersion. The performance of the theoretical framework is verified with high resolution numerical results and successfully tested against the Cape Cod field data.

Stochastic analytical modeling of the biodegradation of steady plumes.

We present a stochastic analytical framework to assess the contaminant concentration of a steady plume undergoing biodegradation. The method is focused on heterogeneous formations, and it embeds both fringe and core degradation. The Lagrangian concentration approach of Fiori (2001) was employed, which is suited for describing the interplay between the large scale advection caused by heterogeneity and the local dispersion processes. The principal scope of the model is to provide a relatively simple tool for a quick assessment of the contamination level in aquifers, as function of a few relevant, physically based dimensionless parameters. The solution of the analytical model is relatively simple and generalizes previous approaches developed for homogeneous formations. It is found that heterogeneity generally enhances mixing and degradation; in fact, the plume shear and distortion operated by the complex, heterogeneous velocity field facilitates local dispersion in diluting the contaminant and mixing it with the electron acceptor. The decay of the electron donor concentration, and so the plume length, is proportional to the transverse pore-scale dispersivity, which is indeed the parameter ruling mixing and hence degradation. While the theoretical plume length is controlled by the fringe processes, the core degradation may determine a significant decay of concentration along the mean flow direction, thus affecting the length of the plume. The method is applied to the crude oil contamination event at the Bemijdi site, Minnesota (USA).

[Identifying language and communication disorders as part of the medical curriculum]. / Erkennen von Sprach- und Sprechstörungen als Lerninhalt des Medizinstudiums.

BACKGROUND: Like hearing loss, language and speech disorders can also lead to impaired communication. Speech and language disorders can occur at any age, for example as a specific language impairment, stuttering, dysarthria, and aphasia. Hence, irrespective of their speciality, there is a high probability that physicians will at some point encounter communication-impaired patients, be required to classify their disorder and refer them for appropriate therapy. METHODS: A new module entitled 'communication disorders' consisting of two teaching units was integrated in the practical course 'ENT--phoniatrics--pedaudiology' for undergraduate clinical students in 2008. The learning objective of the first unit was to identify and classify communication disorders, presented using sound and video data, by means of simple criteria. The module was evaluated on the basis of questionnaires completed by 164 students. RESULTS: On a scale of 1-7, the evaluation showed overall positive results with 6.54 (highest score) for professional competence and 5.32 (lowest score) for discussion. The overall score was 12.28 out of a possible maximum of 15 points. CONCLUSION: The ability to identify communication impairments is an important medical skill. Since communication disorders are common diseases we suggest that this skill be incorporated in the medical curriculum. Thus we have introduced a module for communication disorders; its evaluation by students shows a high level of satisfaction in each category. After developing specific diagnostic indicators students were able to independently describe and identify communication disorders.

[Deviant language development following cochlear implantation? Applicability of the parent questionnaire ELFRA-2]. / Abweichende Sprachentwicklung nach Cochleaimplantation? Zur Anwendbarkeit des Elternfragebogens ELFRA-2.

BACKGROUND: The parent questionnaire ELFRA-2 is considered a valid tool for early detection of delayed language development in 2-year-old children. Applicability for children treated with cochlear implants (CI) is to be investigated. METHODS: By means of the ELFRA-2 we documented longitudinally for up to 24 months post implantation language development in 27 children treated before 3 years of age. The critical developmental criteria (related to age) were applied to CI children (related to duration of CI use) and gender-related normative data were taken as a reference. RESULTS: Only two boys were identified as showing a language delay after 2 years of CI use. However, using normative data 11-44% of the children performed below average. Development in girls was faster than in boys. The influence of preoperative hearing experience declined over time. CONCLUSION: The critical developmental criteria of ELFRA-2 have proved to be unreliable for the identification of varying development after CI. Modified and gender-related evaluation is necessary.

[Do children with cochlear implants read or write differently?: literacy acquisition after cochlear implantation]. / Lesen und schreiben CI-Kinder anders?: Schriftspracherwerb nach Versorgung mit einem Cochlear implant.

BACKGROUND: Despite the fact that literacy acquisition in hearing impaired children is frequently hampered, reading and writing competences continue not to be regularly evaluated and documented in children fitted with cochlear implants (CI). In this 2-year longitudinal study literacy acquisition in children fitted with CI was investigated. PATIENTS AND METHODS: In total, 18 pre- and primary school children fitted with CI who had suffered prelingual deafness were examined. Subjects' ages at CI fitting ranged from 0.9 to 5.9 years; they were raised orally and monolingual German and showed normal intellectual achievement. Familial risk of developing dyslexia was ruled out. To assess subjects' literacy acquisition precursor and partial abilities in reading and writing according to dual route and developmental models were examined three times within 2 years. Precursor abilities included development of vocabulary and phonological awareness. Partial abilities were mastery in sublexical and lexical word processing in reading and writing as well as auditory and visual working memory. RESULTS: Subjects showed a broad range in performance regarding vocabulary development as well as literacy. Discrepant results in terms of age equivalent visual and underachievement in auditory working memory as well as good achievement in implicit phonological awareness and weakness in explicit demands on phoneme analysis and manipulation of phonemes can be described. Indications were that subjects tended towards lip reading the instructor's item presentation. Performance in the administered writing test reveals a preference for lexical word processing, whereas sublexical word processing seems to make relatively higher demands on subjects. CONCLUSIONS: Easier processing of visual information in partial and precursor abilities are consistent with a tendency to prefer a visual-lexical processing strategy. The presented study stresses the importance of generally assessing reading and writing skills when evaluating language development in children supplied with cochlear implants. Partial and precursor abilities should be included in order to identify any delay in development promptly. Thus, individual qualitative characteristics can be addressed in therapeutic intervention.

Nanocrystalline diamond films grown in nitrogen rich atmosphere: structural and field emission properties.

The field emission behaviour of a series of nanocrystalline N-doped diamond films has been investigated and interpreted on the basis of the structural and compositional characteristics of the layers. The diamond films, formed by crystallites with grain size in the range 20-100 nm were produced from CH4/H2 mixtures using a HF-CVD apparatus. Nitrogen was added to the gaseous reactants in form of both N2 and of Urea. Micro-Raman spectroscopy and cathodoluminescence have been used to define the structure of the deposits on a nanometric scale. The field emission measurements have been carried out under a pressure of 10(-6) mbar using a sphere-to-plane anode-cathode configuration. The characteristics of the emission from the various nanodiamond samples and from different regions of the same sample are discussed in terms of field threshold, current density, current stability.

Hybrid carbon nanotube/nanodiamond structures as electron emitters for cold cathodes.

The field emission properties of hybrid carbon nanotubes/nanodiamond structures produced by one-step chemical vapor deposition (CVD) process have been investigated in order to assess their application as electron emitters for cold cathodes. The electron emission properties of a series of samples have been investigated by current-pressure, current-voltage and current-time measurements with the aim of testing the emission stability under working conditions relevant to technological applications. Stable emission, high values of current density and lack of arcing have been observed during prolonged working cycles, and without degradation of the material structure.

[Model oriented assessment of literacy performance in children with cochlear implants]. / Vorschläge zur modellgeleiteten Erhebung der Schriftsprachkompetenzen bei Schulkindern nach Cochlea Implantation - eine Pilotstudie.

BACKGROUND: Although most hearing-impaired children lag behind normally hearing children in literacy acquisition, this aspect has hardly been addressed in the evaluation of language acquisition after cochlear implantation. The present study investigated written language abilities in 8 school-age children with cochlear implants. Neurolinguistic dual-route-models of written language processing indicate that literacy acquisition leads to the establishment of two distinct reading and writing strategies: a lexical one for the quick processing of known words and a sublexical one for decoding unfamiliar words or nonwords letter by letter. PATIENTS: 8 school-aged children were investigated, a very heterogeneous group concerning age of onset of hearing impairment, educational placement, and competences in sign language. However, this range is typical of the group of CI-children. METHODS: The aim was to investigate if children with cochlear implants are able to establish both strategies or if they need to find a differential and individual access to written language. Performance within the Salzburger Lese-Rechtschreib-Test was evaluated. Individual performance of each subject was analysed. RESULTS: Performance varied substantially ranging from only rudimentary spoken and written language abilities in two children to age-equivalent performance in three of them. Severe qualitative differences in written language processing were shown in the remaining three subjects. Suggestions for remediation were made and a re-test was carried out after 12 months. Their individual profiles of performance are described in detail. CONCLUSIONS: The present study stresses the importance of a thorough investigation of written language performance in the evaluation of language acquisition after cochlear implantation. The results draw a very heterogeneous picture of performance. Model-oriented testing and analysis of performance prove to be sensible in at least a subpopulation of children with cochlear implants. Based on a better understanding of their acquired word-processing strategies, remediation programs meeting the needs of each individual child can be derived.

Ultrasonographic evaluation of cervical length in pregnancies complicated by preterm premature rupture of membranes.

OBJECTIVE: To evaluate the usefulness of transvaginal ultrasonography in the determination of the risk of preterm delivery and chorioamnionitis in pregnancies affected by preterm premature rupture of membranes preterm premature rupture of membranes. DESIGN: One hundred and one singleton pregnancies with preterm premature rupture of membranes were included in this prospective study over a 3-year period. Patients underwent cervical length measurement by transvaginal ultrasonography at admission and thereafter, in the absence of chorioamnionitis, were managed expectantly. RESULTS: The median time interval between admission and delivery (latency period) was 48 h. A cervical length of less than 20 mm was associated with a significant risk of early delivery (mean latency period was 59.44 +/- 159.93 h vs. 240.94 +/- 364.67; P < 0.05). There was no relation between cervical length and occurrence of chorioamnionitis or neonatal sepsis. CONCLUSIONS: These data suggest that the use of transvaginal ultrasonography for cervical length measurement during preterm premature rupture of membranes may predict an early delivery but cannot anticipate the risk of chorioamnionitis or neonatal sepsis.

Inhibitory effect of somatostatin on neutral amino acid transport in isolated brain microvessels.

In the presence of somatostatin-14 or some of its receptorial agonists, the uptake of large neutral amino acids by isolated brain microvessels was found to be inhibited up to 50%, no other transport system being affected. Although the luminal and abluminal sides of brain endothelial cells are both capable of taking up large neutral amino acids, only uptake from the abluminal side appears to be inhibited by somatostatin. The involvement of a type-2 somatostatin receptor was suggested by assays with a series of receptor-specific somatostatin agonists, and was confirmed by the release of inhibition caused by a specific type-2 receptor antagonist. A type-2-specific mRNA was indeed shown to be present in both bovine brain microvessels ex vivo and primary cultures of endothelial cells from rat brain microvessels.

Isolation and molecular characterization of KlCOX14, a gene of Kluyveromyces lactis encoding a protein necessary for the assembly of the cytochrome oxidase complex.

The yeast Kluyveromyces lactis was mutagenized with ethyl methane sulphonate and mutants unable to grow on respiratory carbon sources were isolated. Functional complementation of one of these mutants led to the isolation of KlCOX14, a gene encoding a 64 amino acid protein which is the functional homologue of Saccharomyces cerevisiae Cox14p, a protein necessary for the assembly of the cytochrome oxidase holoenzyme (Glerum et al., 1995). The disruption of KlCOX14 resulted in the absence of the absorption bands relative to cytochromes a and a(3) and in the complete loss of respiratory activity. Klcox14 mutants display the typical phenotype of pet mutants and have a reduced growth rate. In addition, unlike the wild-type, Klcox14 mutants are able to grow by fermentation also in the presence of low glucose. The nucleotide sequence of KlCOX14 has been deposited in the EMBL databank with Accession No. AJ238801.

Disruption of six novel genes from chromosome VII of Saccharomyces cerevisiae reveals one essential gene and one gene which affects the growth rate.

Six ORFs of unknown function located on chromosome VII of Saccharomyces cerevisiae were disrupted in two different genetic backgrounds, and the phenotype of the generated mutants was analysed. Disruptions of ORFs YGR256w, YGR272c, YGR273c, YGR275w and YGR276c were carried out using the disruption marker kanMX4 flanked by short homology regions, whereas ORF YGR255c was inactivated with a long flanking homology (LFH) disruption cassette (Wach et al., 1994). Tetrad analysis of the heterozygous disruptants revealed that ORF YGR255c, previously identified as COQ6 and encoding a protein involved in the biosynthesis of coenzime Q (Tzagoloff and Dieckmann, 1990), is an essential gene. The same analysis also revealed that sporulation of the ygr272cDelta heterozygous diploid produced two small colonies per ascus that were also G418-resistant, indicating that the inactivation of ORF YGR272c could result in a slower growth rate. This result was confirmed by growth tests of the haploid disruptants and by complementation of the phenotype after transformation with a plasmid carrying the cognate gene. No phenotypes could be associated to the inactivation of ORFs YGR256w, YGR273c, YGR275w and YGR276c. Two of these genes have recently been further characterized: ORF YGR255w, renamed RTT102, encodes a regulator of the Ty1-element transposition, whereas ORF YGR276c was found to encode the 70 kDa RNase H activity and was renamed RNH70 (Frank et al., 1999).

Deltorphin transport across the blood-brain barrier.

In vivo antinociception studies demonstrate that deltorphins are opioid peptides with an unusually high blood-brain barrier penetration rate. In vitro, isolated bovine brain microvessels can take up deltorphins through a saturable nonconcentrative permeation system, which is apparently distinct from previously described systems involved in the transport of neutral amino acids or of enkephalins. Removing Na+ ions from the incubation medium decreases the carrier affinity for deltorphins (-25%), but does not affect the Vmax value of the transport. The nonselective opiate antagonist naloxone inhibits deltorphin uptake by brain microvessels, but neither the selective delta-opioid antagonist naltrindole nor a number of opioid peptides with different affinities for delta- or mu-opioid receptors compete with deltorphins for the transport. Binding studies demonstrate that mu-, delta-, and kappa-opioid receptors are undetectable in the microvessel preparation. Preloading of the microvessels with L-glutamine results in a transient stimulation of deltorphin uptake. Glutamine-accelerated deltorphin uptake correlates to the rate of glutamine efflux from the microvessels and is abolished by naloxone.

Developmental study of ultrastructural and biochemical changes in isolated chick brain microvessels.

The morphology of the endothelial junctions, the expression of the alkaline phosphatase (ALKP) and gamma-glutamyltranspeptidase (GGT) activities, and the transport systems for neutral amino acids (NAA) and for d-glucose were studied in parallel in isolated microvessels from the brains of 9-, 12-, and 21-day chick embryos and 30-day chickens using freeze-fracturing and biochemical techniques. In the 9-day embryos, the endothelium junctional plasma membranes show alignments of discrete intramembrane particles (Imps) on the replica P-faces. In the 12-day embryos, the junctional membranes show short fibrils of loosely interconnected fused Imps. In the 21-day embryos, the junction is characterized by simple networks, and in the 30-day chickens, by very dense meshworks of continuous, fibrillary strands. In early embryonic life, the ALKP activity is expressed at high levels, more markedly in the microvessels than in the whole brain. ALKP progressively declines in later embryos and even more in adulthood, when the activity is fivefold higher in the microvessels than in the whole brain. No GGT activity is expressed in either embryonic or adult microvessels. The transport systems for NAA and for d-glucose are most active in 12-day embryonic microvessels, and progressively less expressed by the 21st day and in the adult. The results taken as a whole suggest a close relationship between the morphological and the metabolic maturation of the endothelial barrier of cerebral vessels.

Evaluation of cocaine use during pregnancy through toxicological analysis of hair.

Toxicological analysis of hair was used to detect cocaine use in a group of 615 pregnant women. Hair samples were washed, enzymatically digested, and analyzed by radioimmunoassay for cocaine. Positive results were confirmed by gas chromatography-mass spectrometry after a solid-phase extraction. Benzoylecgonine (BZE) and cocaine were detected after derivatization with pentafluoropropionic-anhydride-pentafluoropropanol. Deuterated cocaine and BZE were used as internal standards. This study demonstrated a mean frequency of 1.9% cases positive for cocaine in all the hair samples examined. The positive rate was 6% among women admitted for spontaneous abortion (66 cases), and the positive rate was 1.4% for those who carried to full term (549 cases). These data underline the usefulness of hair analysis for the diagnosis of drug abuse and demonstrate that there is significant use of cocaine in the Italian population.

Cocaine abuse in pregnancy: its evaluation through hair analysis of pathological new-borns.

Cocaine abuse in pregnancy has been evaluated through toxicological analysis of hair from 123 pathological new-borns admitted in an intensive care division. The new-borns were affected with malformations, low gestational age, low birth weight, respiratory distress. A control group of 39 healthy new-borns was also analysed. Hair samples (about 50 mg) were enzymatically digested and directly analysed by RIA. Samples positive to the preliminary screening were extracted by SPE columns and injected in GC/MS. Results obtained showed 3 positive samples (2.4%). All cocaine babies had low gestational age, low birth weight, two of them showed heart malformation, one kidney malformation and one genital malformation. None of the control new-born resulted positive for cocaine. These results show a worrying trend of cocaine diffusion in the Italian population.

Cocaine during pregnancy: a critical review of the literature.

A number of epidemiological indices suggest that the use of cocaine in Italy is increasing, thus explaining the importance of scientific interest in this field. There is considerable disparity between the scientific papers published in the literature concerning the damaging effects on fetus and mother linked to the use of cocaine during pregnancy. The main problem consists of the method used to identify those patients using cocaine. These methods are burdened by a high level of false negatives: subjects who often use a variety of active pharmacological substances are identified and the methods are not always suitable for classifying subjects according to useful clinical parameters. This is reflected in the poor quality of data concerning the epidemiology and clinical aspects of cocaine abuse during pregnancy. A careful selection of the best scientific papers published in the literature shows that the effects on the maternal organism are slight, whereas those on the fetus are more severe. Compared to controls, the use of cocaine is associated with a high percentage of cardiac malformations, preterm delivery, low birth weight and minor anomalies of the nervous system. Results relating to sudden neonatal death are discordant. This paper shows that the use of cocaine is often underestimated both in epidemiological terms and from the fetal point of view. This behaviour is linked to the belief that the effects of cocaine are benign.