What is the yield of breast MRI in the assessment of palpable breast findings?

AIM: To examine the contribution of magnetic resonance imaging (MRI) to characterise palpable breast masses after conventional imaging was found to be non-contributory. MATERIALS AND METHODS: The breast MRI database was reviewed for studies performed between January 2010 and December 2015 for the clinical indication of palpable breast finding with negative standard imaging. Medical files were reviewed for demographic data, clinical information, radiology, and pathology reports. Benign versus malignant outcomes were determined at histopathology or a minimum of 12 month follow-up. RESULTS: Investigation of palpable breast finding was the clinical indication for 167 of 7,782 (2%) examinations. Thirty-two (19%) women in the study had positive MRI findings. Most (20, 63%) findings corresponded to the palpable area, resulting in three carcinomas being diagnosed. Only one carcinoma required MRI-guided biopsy for diagnosis. Eighteen women with negative MRI underwent ultrasound-guided biopsy from the palpable area, which resulted in a diagnosis of one carcinoma. One carcinoma was incidentally detected in another location. Within the present population, the sensitivity for detecting malignancy was 80%, specificity 78%, negative predictive value 99%, and positive predictive value 13%. CONCLUSIONS: Although cancer was found in four cases in the palpable area, the biopsy was directed using MRI in only one case. A new palpable finding with non-contributory standard imaging should prompt a needle-guided biopsy and not further evaluation using MRI.

Does change in microcalcifications with neoadjuvant treatment correlate with pathological tumour response?

AIM: To determine whether change in microcalcification density and extent after neoadjuvant treatment (NAT) can predict tumour response. MATERIALS AND METHODS: This single-institution, retrospective study included all women with breast cancer who underwent NAT between 1 January 2008 and 31 December 2014, and fulfilled the following criteria: mammography before NAT with pathological microcalcifications, mammography performed after NAT, and tumour resection at Tel-Aviv Sourasky Medical Center. Correlation was made between mammography features and clinicopathological information. RESULTS: Fifty-four patients met the inclusion criteria. Post-NAT, the number of calcifications remained stable in 30 (55.5%) patients, decreased in 23 (42.6%) patients, and increased in one (1.9%) patient. Patients with a decreased number of malignant calcifications post-NAT had higher rates of pathological complete response compared to patients with no change (59% versus 20%, p=0.009). Patients with triple negative and human epidermal growth factor receptor 2 (HER2) receptor subtypes had higher rates of decreased number of calcifications post-NAT (50% versus 35%) and pathological complete response (57% versus 11%, p=0.007) compared to patients with luminal receptor subtype. In addition, patients who received a combination of chemotherapy and biological treatment had more cases of decreased number of calcifications compared to patients who received chemotherapy alone (56% versus 39%). No significant correlation was observed between calcification change post-NAT and calcification morphology or distribution pattern. CONCLUSIONS: Patients with breast carcinoma and decreased number of pathological calcifications post-NAT had higher rates of pathological complete response compared to patients with no change in calcifications; however, a substantial number of patients with complete pathological response had no change in microcalcification distribution with treatment, questioning the need to completely excise all calcifications post-NAT.

What do surrogate safety metrics measure? Understanding driving safety as a continuum.

Road safety is an important public health issue; technology, policy, and educational interventions to prevent crashes are of significant interest to researchers and policymakers. In particular, there is significant ongoing research to proactively evaluate the safety of new technologies, including autonomous vehicles, before enough crashes occur to directly measure their impact. We analyze the distributional form of five diverse datasets that approximate motor vehicle safety incident severity, including one dataset of hard braking events that characterizes the severity of non-crash incidents. Our empirical analysis finds that all five datasets closely fit a lognormal distribution (Kolmogorov-Smirnov distance < 0.013; significance of loglikelihood ratio with other distributions < 0.000029). We demonstrate a linkage between two well-known but largely qualitative safety frameworks and the severity distributions observed in the data. We create a formal model of the Swiss Cheese Model (SCM) and show through analysis and simulations that this formalization leads to a lognormal distribution of the severity continuum of safety-critical incidents. This finding is not only consistent with the empirical data we examine, but represents a quantitative restatement of Heinrich's Triangle, another heretofore largely qualitative framework that hypothesizes that safety events of increasing severity have decreasing frequency. Our results support the use of more frequent, low-severity events to rapidly assess safety in the absence of less frequent, high-severity events for any system consistent with our formalization of SCM. This includes any complex system designed for robustness to single-point failures, including autonomous vehicles.

Ambient temperature and congenital heart defects.

STUDY QUESTION: Does maternal exposure during pregnancy to higher ambient temperature increase the risk of congenital heart defects (CHDs)? SUMMARY ANSWER: Significant associations were found between maternal exposure during pregnancy to higher ambient temperature and CHDs risk especially during the cold season. WHAT IS KNOWN ALREADY: From rodents to non-human primates, a teratogenic effect of hyperthermic insult has been demonstrated. There are fewer data regarding the effect on the human fetus and specifically the association between maternal exposures during pregnancy to higher ambient temperature and CHDs. STUDY DESIGN, SIZE, DURATION: This population registry-based cohort study included 135 527 live and stillbirths in the Tel-Aviv region of Israel in 2000-2006. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two clinical diagnostic groups of isolated cardiac defects (atrial septal defects and ventricular septal defects: n = 542 and 481, respectively) and one group of multiple cardiac defects (defined by the presence of two or more cardiac malformations, n = 607) were studied. Temperature measurements were constructed from ambient stations and used to assess the impact of maternal exposure to average ambient temperature and extreme heat events (daily average temperature above the 90th percentile) during Weeks 3-8 of pregnancy on risk of CHDs. Logistic models, adjusted for sociodemographic covariates, were used to evaluate the associations between temperature and CHDs. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we found no significant associations between ambient temperature and CHDs throughout the year, with one exception for multiple CHDs. After stratifying by season of conception, continuous exposure to average ambient temperature and maximum peak temperature (1°C increase) during the cold season increased the risk for multiple CHDs [odds ratio (OR) 1.05, 95% confidence interval (CI): 1.00, 1.10 and OR 1.03, 95% CI: 1.01, 1.05, respectively]. A 1-day increase in extreme heat events increased the risk for multiple CHDs (OR 1.13, 95% CI: 1.06, 1.21) and also for isolated atrial septal defects (OR 1.10, 95% CI: 1.02, 1.19). LIMITATIONS, REASONS FOR CAUTION: Information both on CHD cases and on ambient temperature was based on registries and it is possible that this may cause some misclassification. In urban areas, pregnant women may be exposed to higher temperatures than recorded by ambient monitors because of the 'heat island effect'. Furthermore, data for the amount of time spent indoors were unavailable and this could have resulted in exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS: The findings are important within the context of global climate change, which may have implications for public health in countries with mild winters and hot summers. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Israeli Ministry of Environmental Protection (research grant-7-2-7) and by the Environment and Health Fund (PhD Fellowship Program). There are no competing interests.

Intrinsic oscillations of neocortex generated by layer 5 pyramidal neurons.

Rhythmic activity in the neocortex varies with different behavioral and pathological states and in some cases may encode sensory information. However, the neural mechanisms of these oscillations are largely unknown. Many pyramidal neurons in layer 5 of the neocortex showed prolonged, 5- to 12-hertz rhythmic firing patterns at threshold. Rhythmic firing was due to intrinsic membrane properties, sodium conductances were essential for rhythmicity, and calcium-dependent conductances strongly modified rhythmicity. Isolated slices of neocortex generated epochs of 4- to 10-hertz synchronized activity when N-methyl-D-aspartate receptor-mediated channels were facilitated. Layer 5 was both necessary and sufficient to produce these synchronized oscillations. Thus, synaptic networks of intrinsically rhythmic neurons in layer 5 may generate or promote certain synchronized oscillations of the neocortex.

Differential regulation of neocortical synapses by neuromodulators and activity.

Synapses are continually regulated by chemical modulators and by their own activity. We tested the specificity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which mediate the recombination of cortical information. Frequency-sensitive depression was much stronger in TC synapses than in IC synapses. The two synapse types were differentially sensitive to presynaptic neuromodulators: only IC synapses were suppressed by activation of GABA(B) receptors, only TC synapses were enhanced by nicotinic acetylcholine receptors, and muscarinic acetylcholine receptors suppressed both synapse types. Modulators also differentially altered the frequency sensitivity of the synapses. Our results suggest a mechanism by which the relative strength and dynamics of input and associational pathways of neocortex are regulated during changes in behavioral state.

Efficacy of thalamocortical and intracortical synaptic connections: quanta, innervation, and reliability.

Thalamocortical (TC) synapses carry information into the neocortex, but they are far outnumbered by excitatory intracortical (IC) synapses. We measured the synaptic properties that determine the efficacy of TC and IC axons converging onto spiny neurons of layer 4 in the mouse somatosensory cortex. Quantal events from TC and IC synapses were indistinguishable. However, TC axons had, on average, about 3 times more release sites than IC axons, and the mean release probability at TC synapses was about 1.5 times higher than that at IC synapses. Differences of innervation ratio and release probability make the average TC connection several times more effective than the average IC connection, and may allow small numbers of TC axons to dominate the activity of cortical layer 4 cells during sensory inflow.

Comparative properties of excitatory and inhibitory inter-laminar neocortical axons.

In recent years it has become increasingly clear that variations in voltage-gated channels, as well as highly diverse geometrical properties, shape the way axons conduct action potentials to their terminals. Numerous cell types in the mammalian neocortex form a dense network of connections, and the properties of their axons may have an effect on the processing performed by this network. We studied the conduction properties of local, inter-laminar axons emanating from regular-spiking (RS) pyramidal neurons and Martinotti type inhibitory neurons (MCs) in layer 5 of the mouse barrel neocortex by comparing the patterns of their antidromic activation from layer 1. Both types of axons had similarly slow conduction velocities ( approximately 0.3 m/s), compatible with thin unmyelinated fibers. In addition, in both types of neurons, subthreshold changes of the somatic membrane potential affected the stimulus threshold for evoking an antidromic spike in layer 1, a distance of 600-800 microm. However, the axons differed considerably in their antidromic activation profiles. 1) The antidromic latency in RS neurons was highly consistent while some MCs display considerable activation-latency jitter; 2) RS neurons displayed a steeper increase in excitability to repeated 40 Hz stimulation; 3) RS neurons displayed a sharp, step-like antidromic activation threshold to both somatic voltage and stimulus intensity, while MCs displayed a gradual recruitment pattern. Morphological differences in the branching pattern of the two types of neurons may account for some of these distinctions. These results suggest differences among excitatory and inhibitory neocortical neurons in the computational tasks of their local axons.

Enhanced stress reactivity in nitric oxide synthase type 2 mutant mice: findings in support of astrocytic nitrosative modulation of behavior.

Alterations of nitric oxide (NO) metabolism in the brain have been associated with modifications of stress-related behavior in animal models. It has been generally assumed that these behavioral changes are due to the neuronal nitrosative activity. On the other hand, glial NO production has been demonstrated mainly as a slow reaction to brain insults through the activity of an inducible nitric oxide synthase (NOS) isoform (NOS2). Recently we uncovered increased NOS activity in astrocytes of mice with a NOS2 mutation. Interestingly, these mice revealed a behavioral phenotype suggestive of increased susceptibility to stress. In the present study we investigated the responses of these mutants to stress by exposing them to predator scent. Seven days later, mutant mice exhibited significantly higher anxiety-like behavior in the elevated-plus maze, increased acoustic startle responses, and higher plasma corticosterone levels compared with their controls. Systemic administration of a NOS inhibitor prior to the stress exposure reversed these stress-related effects without affecting controls' behavior. These findings are in agreement with previous studies showing an association between increased NO levels and enhanced anxiety-like responses. In addition, mutant mice performed better in the Morris water maze prior to stress exposure, but the two animal groups performed alike in an object-recognition test. Taken together, our results suggest the involvement of astrocytic-derived NO in modulating behavior.

Beneficial effect of digoxin-specific Fab antibody fragments in oleander intoxication.

A 24-year-old man presented to the emergency department with nausea, vomiting, abdominal pain, and an acute confusional state of 6 hours' duration. Ten hours before admission, he had ingested a mixture of orange juice and six ground leaves, later identified as Nerium oleander (common pink oleander) leaves. His blood pressure was 100/80 mm Hg, and his pulse rate was irregular at 40/min. He was disoriented and his speech was dysarthric. Twelve-lead electrocardiography revealed a complete atrioventricular block, with a nodal escape rhythm of 40/min and diffuse ST depression. The presumptive diagnosis of acute oleander intoxication was confirmed by the detection of digoxin (1.0 nmol/L [0.8 ng/mL]) on radioimmunoassay. Despite intensive therapy, the patient's hemodynamic condition deteriorated. His blood pressure decreased to 70/40 mm Hg; he became oliguric and nonresponsive to external stimuli; and his potassium concentration rose to 6.8 mmol/L. Eighteen hours after admission, an empiric 480-mg dose of digoxin-specific Fab antibody fragments was administered intravenously over 30 minutes. Within minutes of the initiation of immunotherapy, the patient woke up; his blood pressure rose to 90/50 mm Hg; and he regained a sinus rhythm of 68/min with a prolonged PR interval. His potassium concentration decreased to 5.1 mmol/L within 15 minutes and normalized within 1 hour of therapy initiation. One day later, the 1 degree atrioventricular block disappeared, but the ST depression persisted for an additional 6 days. The value of digoxin-specific Fab antibody fragments in the treatment of plant glycoside and, in particular, oleander intoxication is discussed.

Tricyclic antidepressants in red cells and plasma: correlation with impaired intraventricular conduction in acute overdose.

OBJECTIVE: Tricyclic antidepressant levels in red blood cells and plasma in acute overdose and their association with cardiotoxicity were studied. METHODS: This was a prospective study in 15 patients with acute tricyclic antidepressant overdose. Tricyclic antidepressant parent compounds and metabolites were measured in red blood cells and plasma, and tricyclic antidepressant levels were correlated with ECG indexes of toxicity. RESULTS: Plasma levels of the parent compounds were higher than their red blood cell levels on admission (mean +/- SD, 691 +/- 409 and 337 +/- 220 ng/ml, respectively). Admission metabolite levels were higher in red blood cells than in plasma (264 +/- 180 and 190 +/- 164 ng/ml, respectively). QRS duration and the red blood cell levels of the metabolites were significantly correlated at the time of admission (r = 0.77, p < 0.01), as well as at 6 to 10 hours (r = 0.74, p < 0.01). CONCLUSIONS: In acute overdose, a shift of tricyclic antidepressants from plasma to red blood cells and increased levels of red blood cell metabolites reflect tissue redistribution of the drug. Tricyclic antidepressant red blood cell metabolites are the best markers for impaired intraventricular conduction.

A comparison of synapses onto the somata of intrinsically bursting and regular spiking neurons in layer V of rat SmI cortex.

Regular spiking (RS) and intrinsically bursting (IB) neurons show distinct differences in their inhibitory responses. Under various conditions, the synaptic responses of RS cells display marked inhibitory postsynaptic potentials (IPSPs), whereas the responses of most IB cells do not (Silva et al: Soc Neurosci Abstr 14:883, 1988; Chagnac-Amitai and Connors: J Neurophysiol 61:747, 62:1149, 1989; Connors and Gutnick: TINS 13:99, 1990). This investigation is designed to determine if differences in the inhibitory responses of RS versus IB cells are reflected in differences in the concentration of inhibitory synapses onto their somata. RS and IB neurons in rat somatosensory cortex were identified by using intracellular recording and labeling, examined with the light microscope, and then serial thin-sectioned prior to examination with the electron microscope. Axonal terminals presynaptic to their somata and proximal dendrites were identified and classified according to criteria described by Peters and coworkers (Peters et al: J Neurocytol 19:584, 1990; Peters and Harriman: J Neurocytol 19:154, 1990; 21:679, 1992). The locations of these boutons were displayed on the surfaces of 3-D reconstructions of the somata and proximal dendrites. The reconstructions were produced directly from the serial thin sections by using a novel, electron microscopic, image-processing computer resource. Our analysis showed no significant difference in the types and concentration of boutons presynaptic to the cell bodies and proximal dendrites of intrinsically bursting versus regular spiking neurons. We conclude that the differences observed in the inhibitory responses of intrinsically bursting versus regular spiking neurons cannot be explained by differences in the concentrations of synapses onto their somata.

Burst generating and regular spiking layer 5 pyramidal neurons of rat neocortex have different morphological features.

Intracellular recordings were obtained from pyramidal neurons in layer 5 of rat somatosensory and visual cortical slices maintained in vitro. When directly depolarized, one subclass of pyramidal neurons had the capacity to generate intrinsic burst discharges and another generated regular trains of single spikes. Burst responses were triggered in an all-or-none manner from depolarizing afterpotentials in most bursting neurons. Regular spiking cells responded to electrical stimulation of ascending afferents with a typical EPSP-IPSP sequence, whereas IPSPs were hard to detect in bursting cells. Orthodromic activation of the latter evoked a prominent voltage-dependent depolarization that could trigger a burst response. Intracellularly labelled bursting and regular spiking cells were located in layer 5b, but had distinctly different morphologies. Bursting neurons had a large pyramidal soma, a gradually emerging apical dendrite, and an extensive apical and basal dendritic tree. Their axonal collateral arborization was predominantly limited to layers 5/6. In contrast, regular spiking cells had a more rounded soma with abruptly emerging apical dendrite, a smaller dendritic arborization, and 2 to 8 ascending axonal collaterals that arborized widely in the supragranular layers. Both bursting and regular spiking cells had main axons that entered the subcortical white matter. These data show that some subgroups of pyramidal neurons within the deeper parts of layer 5 of rat cortex are morphologically and physiologically distinct and have different intracortical connections. Bursting cells presumably function to amplify and synchronize cortical outputs, whereas regular spiking output neurons provide excitatory feedback to neurons at all cortical levels and receive a more effective orthodromic inhibitory input. These data support the hypothesis that differences in gross neuronal structure, perhaps even the subtle differences that distinguish subclasses of neurons in a given lamina, are predictive of underlying differences in the type and distribution of ion channels in the nerve cell membrane and connections of cells within the cortical circuit.

Tea drinking and microcytic anemia in infants.

To evaluate the effect of tea drinking on the occurrence of microcytic anemia in infants, we studied 122 healthy infants who underwent routine blood counts at the age of 6-12 months. An overall high frequency of anemia (Hb less than 11 gm/dl-48.4%), microcytosis (MCV less than 70 Mm3-21.3%) and microcytic anemia (19%) was found in the whole group. The percentage of tea drinking infants with microcytic anemia (32.6%) was significantly higher than that of the non-tea drinkers (3.5%). The daily amount of tea drinking was 50-750 ml (median 250 ml). The tea drinkers had significantly lower mean levels of hemoglobin than that of the non-tea drinkers (10.5 +/- 1.2 gm/dl vs 11.2 +/- 0.8 gm/dl, respectively) and significantly lower mean levels of mean corpuscular volume than that of the non-tea drinkers (71.5 +/- 7.1 micron 3 vs 76.1 +/- 4.6 micron 3). There were no significant differences between the two groups in their sex distribution and in the duration of breast feeding. The two groups differed with regard to their ages and social class but a multivariate analysis had excluded the possible confounding effect of these differences on the hematological results. Based on our finding we do not recommend giving tea to infants whose main source of iron is from milk, grains, vegetables or medicinal sources.

Neuropsychological impairment from acute low-level exposure to carbon monoxide.

OBJECTIVE: To investigate the effects of acute low-level exposure to carbon monoxide on higher cognitive functions in healthy humans. DESIGN: An empirical study of the effects of low-level exposure to carbon monoxide on higher cognitive functions in young healthy volunteers and a matched nonexposed control group. SETTING: A dormitory at the Hebrew University campus in Jerusalem, Israel. PARTICIPANTS: Forty-five student volunteers who were exposed to carbon monoxide from residential kerosene stoves for 1.5 to 2.5 hours (air carbon monoxide concentrations of 17-100 ppm; mean +/- SD, 61 +/- 24 ppm) served as the experimental group and 47 nonexposed students served as the control group. MAIN OUTCOME MEASURES: A battery of neuropsychological tests was administered to each participant including digit span, the revised Wechsler Memory Scale for verbal and figural memory, Trail-Making Test parts A and B, digit symbol, block design, and the Rey Auditory Verbal Learning Test. RESULTS: Venous blood carboxyhemoglobin (Hbco) levels in participants of the study group ranged from 0.01 to 0.11 (mean +/- SD, 0.04 +/- 0.03) and correlated with air carbon monoxide concentrations (r = 0.39; P = .01). The experimental group scored significantly lower than controls on the following tests: digit span forward (P = .02), short-term (P = .008) and long-term semantic memory (P = .008), digit symbol (P = .004), block design (P = .009), recall of figural memory (P = .02), and Trail-Making part A (P = .04). No significant differences were found between the experimental and control groups in other tests. CONCLUSIONS: The lower scores on neuropsychological tests indicate dysfunctions in memory, new learning ability, attention and concentration, tracking skills, visuomotor skills, abstract thinking, and visuospatial planing and processing. These dysfunctions correspond with previous reports of carbon monoxide neurotoxic effects in patients with moderate carbon monoxide poisoning. Low-level exposure to carbon monoxide results in impairment of higher cognitive functions. Neuropsychological testing appears to be sensitive in the detection of subtle neurologic dysfunctions resulting from carbon monoxide poisoning.

Thalamocortical synaptic connections: efficacy, modulation, inhibition and plasticity.

The thalamic input to the neocortex is communicated by glutamatergic synapses. The properties and organization of these synapses determine the primary level of cortical processing. Similar to intracortical synapses, both AMPA and NMDA receptors in young and mature animals mediate thalamocortical transmission. Kainate receptors participate in thalamocortical transmission during early development. The shape of thalamocortical synaptic potentials is similar to the shape of intracortical potentials. On the other hand, thalamocortical synapses have on average a higher release probability than intracortical synapses, and a much higher number of release sites per axon. As a result, the transmission of each thalamocortical axon is significantly more reliable and efficient than most intracortical axons. Thalamic axons specifically innervate a subset of inhibitory cells, to create a strong and secure feed-forward inhibitory pathway. Thalamocortical connections display many forms of synaptic plasticity in the first postnatal week, but not afterwards. The implications of the functional organization of thalamocortical synapses for neocortical processing are discussed.

Membrane potential oscillations underlying firing patterns in neocortical neurons.

Membrane potential oscillations were studied in slices of rat somatosensory cortex maintained in vitro, using intracellular recordings from cells in layers 2/3 and 5. The cells were classified according to their firing patterns during long (0.8-1 s) depolarizing current steps. Subthreshold voltage oscillations were revealed by depolarizing the membrane to voltages around threshold for action potentials; however, these were obvious mainly in cells showing marked spike adaptation. When neurons of all firing patterns were stimulated to fire at 40-60 Hz for tens of seconds, spikes abruptly indicated. Hyperpolarizing the cells by 5-10 mV precipitated pronounced oscillations in 24 out of 35 cells. These oscillations existed in a narrow voltage range, and their frequency varied between 7 and 40 Hz, in a voltage-dependent manner. Spiking frequency was faster than the oscillation frequency for the same membrane potential in a given cell. The Na+ channel blocker tetrodotoxin abolished both the spikes and the oscillations, and blockade of K+ channels by tetraethylammonium converted the oscillations into prolonged and irregular plateaus. Blocking Ca2+ conductance with Co2+ reduced the oscillations amplitude and frequency in two out of three cells. The oscillations that followed spike inactivation varied in amplitude, frequency and persistence among different cells. Layer 5 nonadapting cells possessed the most periodic oscillations, as judged by autocorrelation analysis. Oscillations were also most persistent in this group, maintaining a stable steady-state. In other cell types, the oscillations were less regular and decayed with time. There was no difference among cell groups in the maximal peak to peak amplitude of the oscillations, or their frequency range. It is suggested that the oscillations are generated by ionic conductances that operate within the voltage range just above and below spike threshold, and thus can shape the cells' firing pattern. The prominence of the oscillations in a specific subset of layer 5 cells may indicate the mechanism that underlies the rhythmic firing pattern of those cells.

Injection of tetanus toxin into the neocortex elicits persistent epileptiform activity but only transient impairment of GABA release.

Focal injection of a minute quantity of tetanus toxin into the rat neocortex induces chronic epileptogenesis. Within a day, spontaneous and stimulus-evoked paroxysmal discharges appear in widespread regions of both hemispheres and this lasts for at least nine months. Tetanus toxin blocks transmitter release, apparently by catalysing the breakdown of synaptobrevin, a synaptic protein. It specifically binds to neuronal membranes but its potent epileptogenic properties have been ascribed to a higher affinity for inhibitory neurons. Following focal injection of tetanus toxin into the hippocampus a long-lasting epileptic syndrome also develops. During the early part of the syndrome GABA release is depressed in slices from the injected side, but not in slices from the contralateral, secondary focus. In the present experiments on neocortex, release of radiolabelled GABA was measured from primary and secondary epileptic foci induced by unilateral focal injection of tetanus toxin into the parietal cortex. By four weeks after the injection, no differences were detected in GABA release from any neocortical site in control or toxin-injected animals, despite the persistence of profound epileptic activity in slices from the latter. At earlier times (1.5 days) after the toxin injection, however, release was significantly depressed in both hemispheres. The results indicate that at first, the toxin induces focal neocortical epileptogenesis by directly impeding GABAergic synaptic transmission but that with time there is a recovery from this initial effect. We propose, as has also been suggested for other models, that the initial epileptogenesis leaves in its wake a long-lasting change in the local functional connectivity, such that the neocortex is rendered permanently epileptic.

Multiple dose activated charcoal for theophylline poisoning in young infants.

Five cases are presented in which multiple doses of activated charcoal were given to infants 6 months of age or less, as treatment of theophylline overdose. This therapy was tolerated in all cases with apparent enhancement of theophylline elimination. Use of multiple dose activated charcoal appears to be a viable option in the treatment of young infants with theophylline poisoning.

Ipecac-induced emesis and reduction of plasma concentrations of drugs following accidental overdose in children.

Syrup of ipecac is widely used following accidental drug overdosage in children. Proof of its efficacy, however, in reducing the risk of poisoning is limited. We prospectively studied the effect of early v late induction of emesis by ipecac in 50 children younger than 5 years of age with accidental acetaminophen poisoning. The mean estimated ingested dose was 165 mg/kg, and all patients vomited within 15 to 255 (mean 78) minutes postingestion. Although the predicted four-hour plasma acetaminophen concentration was 97 +/- 4 micrograms/mL (mean +/- SEM, calculated on the basis of the estimated ingested dose), the measured four-hour plasma acetaminophen concentration was 34 +/- 5 micrograms/mL (P less than .01). To assess the efficacy of early v late ipecac-induced emesis, we used the ratio of measured to predicted four-hour acetaminophen plasma concentration. The ratio of the measured to predicted four-hour level increased as the delay in time to vomiting increased (r = .60, P less than .001). Ipecac syrup was administered more promptly when available in the home than when obtained from a pharmacy or a medical facility (26 +/- 8 v 83 +/- 13 minutes postingestion, respectively; P less than .001) and vomiting occurred earlier (49 +/- 9 v 103 +/- 12 minutes postingestion; P less than .01). Although the mean estimated doses ingested were greater in patients who received ipecac syrup at home, their four-hour plasma acetaminophen concentrations were lower. These data suggest that prompt administration of ipecac syrup results in a greater reduction in plasma acetaminophen concentrations in potentially toxic overdosages in children.(ABSTRACT TRUNCATED AT 250 WORDS)