Multiphasic renal CT: comparison of renal mass enhancement during the corticomedullary and nephrographic phases

We report a combined EEG-single-photon emission CT (SPECT) study on a patient with epileptic negative myoclonus (ENM). Clinically, the ENM was characterized by brief repetitive lapses in postural tone of the right upper extremity when the arms were held outstretched, whereas no movement effect was observed during rest. Ictal EEG showed repetitive left frontal spikes with a maximum at electrodes EC1 and F1. EMG silent periods lasting from 100 to 200 ms followed the onset of the EEG transients by a latency of 20 to 40 ms. The N20 component of median nerve somatosensory evoked potentials-representing a biological marker of the location of central fissure-showed a phase reversal between electrodes P3 and C1 and thus was located considerably posterior to the spike maximum. We obtained accurate anatomic reference of cerebral blood flow changes visible on SPECT by a special coregistration technique of MRI and SPECT. SPECT performed during ENM showed a marked regional hyperperfusion in the left middle frontal gyrus and a less pronounced increase in tracer uptake in the left supramarginal gyrus. Our results suggest that ENM is generated by epileptic activity in the premotor area in the middle frontal gyrus corresponding to Brodmann's area 6.     

Clinical case report: multiple idiosyncratic adverse effects of antiepileptic drugs in trisomy 9p

We report the case of a mentally retarded 30 y.o. patient with partial trisomy of chromosome 9, affected by epilepsy. Following treatment with antiepileptic drugs (AEDs), the patient developed several rare complications: after beginning therapy with phenytoin, the patient developed pseudolymphoma; after monotherapy with carbamazepine (CBZ), the patient thereafter developed myoclonic jerks of upper and lower limbs upon awakening; after one year of treatment with valproate (VPA) the patient developed clinical and immuno-haematological signs of SLE. Gradual withdrawal of AED, obtained clinical remission. The possibility that the chromosomal abnormality of the patient was responsible for the three rare complications observed during AED therapy is considered.     

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.     

Antiepileptic drug therapy and sexual function in men with epilepsy

PURPOSE: To study the effects of antiepileptic drugs (AEDs) on sex hormone levels and sexual activity in a group of men attending a hospital-based epilepsy clinic. METHODS: One hundred eighteen men being treated with AED therapy, 32 with epilepsy but not receiving AEDs, and 34 controls were recruited. All subjects were aged 18-65 years. Blood (20 ml) was removed for hormone assays, after which each subject completed a validated questionnaire [Sexuality Experience Scores (Frenken and Vennix, 1981)] aimed at exploring the individuals' sexual activity and attitudes to sexual morality. RESULTS: Men taking carbamazepine (CBZ) only had significantly higher mean sex hormone-binding globulin (SHBG) levels than the control group. The CBZ group also had a significantly lower mean DHEAS concentration than the control, untreated, and sodium valproate (VPA) monotherapy groups. The phenytoin monotherapy group (PHT) had a significantly higher mean SHBG than both the control and untreated groups, and had a significantly higher mean total testosterone (TT) value than the control untreated, CBZ, and VPA groups, and a significantly lower mean DHEAS than the controls, untreated, and VPA groups. Men receiving more than one AED had significantly higher mean SHBG concentrations compared with control, untreated, and VPA groups. In addition, the polytherapy group's mean TT was significantly higher than the control and VPA groups, although its mean DHEAS concentration was lower than the control, untreated, and VPA groups. There were no significant differences between the study groups in mean FT, Budrostenedione (AND), or estradiol levels. But the CBZ, PHT, and polytherapy groups had significantly lower mean free and rogen index (FAI) than the controls. The CBZ group had a lower mean FAI than the VPA group. The polytherapy group had a lower FAI than the untreated group. Sexuality Experience Scores (SES) showed that those men receiving AEDs embraced a stricter sexual morality than the controls and untreated, and expressed greater satisfaction with their marriages than the control and untreated groups. CONCLUSIONS: Seizure type did not affect SES scores. Multiple regression showed men who had received further education were less accepting of strict sexual morality.     

Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity

OBJECTIVE: To investigate whether the stiff limb syndrome may be separated from the stiff man syndrome and progressive encephalomyelitis with rigidity on simple clinical grounds, and whether such a distinction has implications for aetiology, treatment, and prognosis. METHODS: Twenty three patients referred over a 10 year period with rigidity and spasms in association with continuous motor unit activity, but without evidence of neuromyotonia, extrapyramidal or pyramidal dysfunction or focal lesions of the spinal cord were reviewed. The patients were divided into those with an acute or subacute illness, leading to death within 1 year, and those with a chronic course. The latter were divided into those in whom rigidity and spasms dominated in the axial muscles, or in one or more distal limbs, at the time of their first assessment. RESULTS: This simple division identified three distinct groups of patients. (1) Progressive encephalomyelitis with rigidity: two patients had a rapidly progressive condition characterised by widespread rigidity which resulted in death within 6 and 16 weeks. One patient had negative anti-GAD and anti-neuronal antibodies, but had markedly abnormal CSF and widespread denervation. The principal pathological findings in this case were a subacute encephalomyelitis which primarily affected the grey matter. In the remaining patient anti-GAD antibodies were not tested, and postmortem was refused. (2) Stiff man syndrome: eight patients had rigidity and painful spasms of the lumbar paraspinal, abdominal, and occasionally proximal leg muscles associated with a lumbar hyperlordosis. There was no involvement of the upper limbs, distal lower limbs, sphincters or cranial nerves. Seven had anti-GAD antibodies and most had additional evidence of autoimmune disease. Neurophysiologically there was continuous motor unit activity with abnormal exteroceptive reflexes, but a normal interference pattern during spasms. The patients all responded to baclofen/diazepam and remained ambulant. (3) Stiff limb syndrome: thirteen patients had rigidity, painful spasm, and abnormal postures of the distal limb, ususphincter or brainstem involvement. Generalised myoclonic jerks were not a feature. Only two had truncal rigidity, and another two had anti-GAD antibodies. Most had no evidence of autoimmune disease. Neurophysiologically they had continuous motor unit activity in the affected limb, abnormal exteroceptive reflexes, and abnormally segmented EMG activity during spasms. The disease ran a protracted course, and most patients had only a partial response to baclofen or diazepam. About half became wheelchair bound. CONCLUSIONS: The stiff limb syndrome seems distinct from the stiff man syndrome or progressive encephalomyelitis with rigidity, and is an important cause of rigidity and spasm in the setting of continuous motor unit activity.     

Postural stability in diabetic polyneuropathy

OBJECTIVE: To examine whether sensory changes in lower limbs associated with diabetic sensory polyneuropathy compromise postural stability in different visual sensory conditions. RESEARCH DESIGN AND METHODS: The presence and severity of sensory neuropathy was evaluated with a clinical scale and measures of nerve conduction velocity in the lower limbs. Balance control was evaluated by testing subjects' postural stability (with a force platform) with vision, without vision, and during a recovery period after being without vision. RESULTS: Neuropathic patients showed larger ranges of sway, a faster sway speed, and a greater dispersion of sway than control subjects in all conditions. They also exhibited similar or less stable postural performance with vision than that of control subjects without vision. There was a strong relationship between the severity of the neuropathy and the postural stability. CONCLUSIONS: This experiment highlights that even with vision, the postural stability of neuropathic patients is impaired and may put them at higher risk of falling when performing more challenging daily tasks.     

Effects of dopamine on postural control in parkinsonian subjects: scaling, set, and tone

1. This study investigates the effects of parkinsonism and of dopamine replacement therapy (levodopa) on scaling the magnitude of automatic postural responses based on sensory feedback and on predictive central set. Surface reactive torques and electromyographic (EMG) activity in response to backward surface translations were compared in patients with parkinsonism ON and OFF levodopa and in elderly control subjects. Correlations between the earliest postural responses [initial rate of change of torque and integrated EMG (IEMG)] and translation velocity provided a measure of postural magnitude scaling using somatosensory feedback. Correlations of responses with expected translation amplitude provided a measure of scaling dependent on predictive central set because the responses preceded amplitude completion. 2. Parkinsonian EMG responses in six leg and trunk muscles were not later than in elderly control subjects. In fact, quadriceps antagonist latencies were earlier than normal, resulting in coactivation at the knee not present in control subjects. EMG activation was fragmented, with short burst durations and high tonic levels that often returned to baseline with multiple bursts. In addition, parkinsonian responses showed smaller-than-normal agonist extensor bursts and larger-than-normal activation in tibialis and rectus femorus antagonist flexors. 3. Although parkinsonian subjects scaled postural responses to both displacement velocities and amplitudes, their torque response were smaller than those of elderly controls, especially in response to the largest displacement amplitudes. The gain (slope) of postural response magnitude scaling to displacement velocity was similar for parkinsonian and control subjects, although parkinsonian subjects had smaller torques. Parkinsonian subjects were also able to use prediction to scale responses to small expected displacement amplitudes, but many patients did not generate the larger plantarflexion torques required at larger displacement amplitudes. Reduced torque at large amplitudes was associated with less agonist gastrocnemius IEMG, increased tibialis antagonist burst responses, and increased tibialis tonic background activity. 4. Levodopa further reduced the already low magnitude of initial torque and IEMG responses to displacement velocities and amplitudes in parkinsonian patients. The ability to scale postural responses to velocity feedback was not affected by levodopa, but the ability to scale responses to large displacement amplitudes based on central set was worsened by levodopa. Levodopa also significantly reduced the tonic, background levels of EMG, particularly the distal gastrocnemius and tibialis activity. 5. High baseline muscle tone was apparent in parkinsonian subjects from their high background EMG activity in quiet stance, especially in tibialis and quadriceps, and the slow initial velocity of center of mass falling in response to displacements. By reducing tone, levodopa reduced passive stiffness to perturbations without increasing EMG burst magnitudes, resulting in less resistance to external displacements and thus faster center of body mass (COM) displacements. 6. The biggest postural deficit in parkinsonian subjects was not in response latency, pattern, or reactive or predictive scaling of response magnitude, but in quickly generating an adequate level of postural force. Dopamine improved tonic background postural tone but further weakened automatic postural responses to external displacements. Thus the basal ganglia may participate in postural control by regulating appropriate levels of background postural tone and by enabling adequate force generation for resisting external displacements.     

Therapeutic failure, treatment and non-treatment of childhood epilepsy

INTRODUCTION: The classification of epileptic syndromes defines the prognosis and offers some orientation about treatment in childhood epilepsy. OBJECTIVE: To study the medical therapy according to epileptic syndromes in the everyday practice of a hospital based outpatient neuropediatric clinic. METHODS: Survey of the database using an algorithm to define therapeutic failure, treatment and spontaneous evolution, according to syndrome and drug, of all epileptic patients attended at the clinic during 1966. RESULTS: 465 patients with: monotherapy 38%, politherapy 20%, therapeutic success (follow-up after drug discontinuation) 21%, spontaneous evolution 22% (54% of partial idiopathic epilepsies). Most used antiepileptic drugs (VPA > CBZ > VGB > CLB > PB > PHT > LTG > ESM > PRM > GBT) are those with lowest failure rate and highest percentage of patients on monotherapy. Percentages of monotherapy in treated patients and of previous failure out of total number of patients are: idiopathic partial epilepsies: 85% and 10%; remote symptomatic partial: 58% and 43%; cryptogenic partial: 53% and 50%; idiopathic generalized: 83% and 25%; symptomatic-cryptogenic generalized: 34% and 63%; undetermined: 45% and 43%. CONCLUSIONS: Screening of the database serves as a quality control but the use of an algorithm offers only an approximation to reality. In idiopathic partial epilepsy treatment can be avoided in half of the patients and failure is lowest for VPA and CBZ. In idiopathic generalized epilepsies VPA predominance is almost absolute with a very low failure rate. In all other epileptic syndromes the therapeutic failure rate is about 50% regardless of drug, except for VPA which shows a moderately better outcome.     

Modulation of postural tremors at the wrist by supramaximal electrical median nerve shocks in essential tremor, Parkinson's disease and normal subjects mimicking tremor

The response of postural wrist tremors to supramaximal median nerve stimulation was examined in patients with hereditary essential tremor (n = 10) and Parkinson's disease (n = 9), and in normal subjects mimicking wrist tremor (n = 8). The average frequency of on-going tremor was the same in all three groups. Supramaximal peripheral nerve shocks inhibited and then synchronised the rhythmic electromyographic (EMG) activity of all types of tremor. The duration of inhibition ranged from 90 to 210ms, varying inversely with the frequency of on-going tremor. There was no significant difference in mean duration of inhibition or in the timing of the first peak after stimulation on the average rectified EMG records between the three groups. The degree to which supramaximal peripheral nerve shocks could modulate the timing of rhythmic EMG bursts in the forearm flexor muscles was also quantified by deriving a resetting index. No significant difference in mean resetting index of the three groups was found. These results suggest that such studies cannot be used to differentiate between the common causes of postural wrist tremors.     

Experience with oral methylprednisolone in the treatment of refractory hyperemesis gravidarum

OBJECTIVE: Our purpose was to describe the effect of oral methylprednisolone on the course of refractory hyperemesis gravidarum. STUDY DESIGN: Patients with intractable hyperemesis gravidarum were candidates for oral methylprednisolone. Forty-eight milligrams per day was given for 3 days followed by a tapering dose over 2 weeks. If vomiting recurred after 2 weeks of therapy or during tapering, the medication was restarted or extended but not longer than 1 month total. RESULTS: Seventeen of 18 patients (94%) were free of vomiting and were able to tolerate a regular diet within 3 days. Seven did not have further symptoms during their pregnancies. Nine vomited during or after tapering, but 7 of these responded to extension or reinstitution of therapy. Four of 6 patients on total parenteral nutrition at the start of therapy had a complete response within 3 days. CONCLUSIONS: A short course of oral methylprednisolone appears to be a reasonable therapeutic alternative for intractable hyperemesis.     

Phenobarbital in comparison with carbon tetrachloride and phenobarbital-induced cirrhosis in rat liver regeneration

PURPOSE: Status epilepticus (SE) is a major medical and a neurologic emergency associated with significant morbidity and mortality. The current definition of SE is continuous seizure activity or intermittent seizure activity without regaining consciousness, lasting > or =30 min. Epilepsy monitoring unit data indicate that many seizures self-terminate within minutes. Thus consideration was recently given to include seizure episodes lasting > or =10 min in the definition of SE. Because no large studies have been conducted on seizures lasting 10-29 min, this study was initiated to compare cases of SE and 10 to 29-min seizure episodes seen within the same period. METHODS: Patients seen at the Medical College of Virginia Hospitals of Virginia Commonwealth University over the same 2-year period were studied. Two hundred twenty-six prospective SE cases (91 children and 135 adults) and 81 retrospective 10- to 29-min seizure episodes (31 children and 50 adults) were compared. A standardized data-entry-form system was compiled on each patient and was used to evaluate the data collected. RESULTS: The 10- to 29-min seizure patients and the SE cases had similar demographic characteristics, such as sex, race, and age, and also had similar etiologies. The majority (93%) of SE cases required anticonvulsant (AED) treatment to control and stop seizure activity. In the 10- to 29-min group, 43% stopped seizing spontaneously, and the remainder (57%) required AED treatment to stop seizure activity. The mortality for the SE patients was 19% compared with 2.6% for 10- to 29-min group (p<0.001). In the 10- to 29-min group that stopped seizing spontaneously, the mortality was 0. In the 10- to 29-min patients that required AED treatment, the mortality was 4.4%. CONCLUSIONS: The results demonstrate that a significant number of patients experience seizure activity lasting from 10- to 29-min. Approximately half of these seizure events stopped spontaneously and did not require AED treatment. The other half of the patients responded quickly to medications and stopped seizing before the 30-min definition for SE. The overall mortality of this group was significantly lower than that of the patients with SE. The results demonstrate that further studies on the 10- to 29-min seizure group are needed to differentiate seizures that will stop spontaneously and those that will only stop with AED treatment. Because almost half of the prolonged seizures stopped spontaneously, further studies are needed before including prolonged seizure activity in the definition of SE.     

Cortical activation during fast repetitive finger movements in humans: steady-state movement-related magnetic fields and their cortical generators

OBJECTIVE: To study the cortical physiology of fast repetitive finger movements. METHODS: We recorded steady-state movement-related magnetic fields (ssMRMFs) associated with self-paced, repetitive, 2-Hz finger movements in a 122-channel whole-head magnetometer. The ssMRMF generators were determined by equivalent current dipole (ECD) modeling and co-registered with anatomical magnetic resonance images (MRIs). RESULTS: Two major ssMRMF components occurred in proximity to EMG onset: a motor field (MF) peaking at 37+/-11 ms after EMG onset, and a postmovement field (post-MF), with inverse polarity, peaking at 102+/-13 ms after EMG onset. The ECD for the MF was located in the primary motor cortex (M1), and the ECD for the post-MF in the primary somatosensory cortex (S1). The MF was probably closely related to the generation of corticospinal volleys, whereas the post-MF most likely represented reafferent feedback processing. CONCLUSIONS: The present data offer further evidence that the main phasic changes of cortical activity occur in direct proximity to repetitive EMG bursts in the contralateral M1 and S1. They complement previous electroencephalography (EEG) findings on steady-state movement-related cortical potentials (ssMRCPs) by providing more precise anatomical information, and thereby enhance the potential value of ssMRCPs and ssMRMFs for studying human sensorimotor cortex activation non-invasively and with high temporal resolution.     

No evidence for inhibition of human glutathione reductase by valproic acid

The human red blood cell enzyme glutathione reductase (GR) was reported to be inhibited by the anticonvulsant drug valproic acid (VPA) [Cotariu et al., Biochem Pharmacol 43: 425-429, 1992]. When attempting to reproduce and extend these experiments, we could not detect any significant effect of VPA on glutathione reductase in haemolysates from 20 healthy children and 10 children under VPA therapy, no matter which concentration of the drug (0.9 or 1.8 mM in a haemolysate diluted by a factor of 50 or 1.8 mM directly in the assay), which incubation time (0-60 min) and which assay system were chosen. An influence of VPA on FAD-free apoglutathione reductase was also excluded. GR-activities of 10 children under VPA therapy (1.08 +/- 0.14 U/mL blood or 7.57 +/- 0.94 U/g Hb) were almost identical with the activities of age- and sex-matched controls (1.04 +/- 0.17 U/mL or 7.79 +/- 1.32 U/g Hb). No correlation between erythrocyte GR activity and serum levels of VPA was observed. Finally, incubation of crystalline human GR with VPA did not lead to enzyme inhibition; rather, in most experiments the enzyme was stabilized by incubation with VPA. Possible explanations for the discrepancies between the results of Cotariu et al. and our data are discussed.     

Eccentric knee flexor torque following anterior cruciate ligament surgery

The purposes of this study were to compare eccentric knee flexor torque and muscle activation in the limbs of normal (NOR) subjects and in subjects who had undergone unilateral ACI, autograft surgical reconstruction (INJ) and to assess the effect of movement speed on EMG/ torque ratios and eccentric-concentric actions. Fourteen subjects (7 NOR and 7 INJ) were tested for knee eccentric flexor torque and EMG activity at four isokinetic speeds (15 degrees, 30 degrees, 45 degrees and 60 degrees.s-1). Results revealed that post-surgical limbs (ACL) produced significantly less (P < 0.05) eccentric torque and flexor EMG activity at 60 degrees.s-1 than uninjured (UNI) contralateral limbs. Eccentric torque rose significantly as speed increased from 45 degrees to 60 degrees.s-1 for surgical group uninjured limbs and NOR group left and right limbs. Eccentric flexor torque increased with speed for both groups and approximated equality with concentric extensor torque at 60 degrees.s-1 for INJ group ACL and UNI limbs. Concentric flexor muscle EMG/torque ratios were 30-191% greater than eccentric muscle actions across groups and speeds. The results suggest that ACL dysfunction may result in reduced eccentric flexor torque at rapid movement speeds, that eccentric flexor torque increases with movement speed and may have the capacity to counter forceful extensor concentric torque, and that eccentric muscle actions produce less muscle activation per unit force than concentric actions which may reflect reduced energy cost.     

Comparative study of the effects of auranofin and aurothiomalate on laboratory and clinical indicators in patients with rheumatoid arthritis

We studied the changes in the anticipatory postural adjustments (APAs), associated with dropping a load from extended arms and during fast bilateral shoulder flexion movements, when movements were performed in a self-paced manner and under a simple reaction-time instruction. The latter instruction applied time pressure and did not allow the regular pattern of APAs to be used. In particular, the following questions were asked: (1) are there changes in the relative timing of APAs under the reaction time condition; (2) are changes in the relative timing of APAs associated with changes in APAs themselves; (3) can different postural strategies be used to maintain stability under self-paced and reaction time conditions; and (4) are changes in APAs related to actual reaction time or to a change in the instruction? In particular, under reaction-time conditions, APAs occurred later in time, typically simultaneously with the initiation of the focal movement. Additional changes in electromyographic (EMG) patterns in postural muscles included an increase in the amplitude of EMG bursts and "speeding-up" some of the tri-phasic patterns in postural dorsal-ventral muscle pairs. This was accompanied by a smaller early shift of the center of pressure followed by its more rapid delayed displacement. There was considerable variability in the changes of EMG and dynamic characteristics across subjects. Some of the changes in the EMG patterns in postural muscles depended on actual reaction time, while others were related to a change in the instruction and occurred even if actual reaction times were long enough to allow for the typical self-paced APA patterns to occur. These findings can be interpreted as supporting the parallel control hypothesis for the focal movement and postural adjustments. Alternatively, they can be interpreted within a framework that implies the generation of a single control function, which is transformed into two components, one directed at the focal muscles/joints and the other directed at postural muscles/joints.     

Developmental features of 4-aminopyridine induced epileptogenesis

4-Aminopyridine (4-AP, 50 microM), perfused in rat hippocampal slices from postnatal days 2-30 (P2-P30), induced in the CA3 area the appearance of spontaneous epileptiform discharges, short (interictal-like) and sustained (ictal-like), as well as slow potential. The duration of epileptiform discharges decreased and their rate of occurrence (frequency) increased with maturation: their duration during the 1st postnatal week was 4-6 times longer and their frequency 5 times lower, compared to those of the 4th postnatal week. Ictal discharges gradually disappeared at the end of the 4th postnatal week. Spontaneous synchronous activity-as a whole-often appeared in clusters separated by equal or longer length inactive periods, during the first two postnatal weeks. At the same period, ictal discharges were often followed by repetitive afterdischarges, forming sequences which lasted 0.7-1.5 min. Sectioning experiments showed that epileptiform discharges were generated in CA3, and their presence in CA1 depended on the integrity of CA1-CA3 synaptic connections. In conclusion, these findings demonstrate that (i) immature CA3 can generate synchronous epileptiform discharges as early as P2, (ii) such discharges are longer lasting and more complex during the early developmental stages and (iii) there are two time points (end of 2nd, end of 4th postnatal weeks), when maturational changes alter the epileptogenic properties of immature hippocampus.     

Chlorambucil in chronic lymphocytic leukemia: mechanism of action

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.     

Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic leukemia by inhibition of DNA-dependent protein kinase activity using wortmannin

In this study, we examined the ability of wortmannin to modulate chlorambucil (CLB) cytotoxicity in lymphocyte samples from patients with B-cell chronic lymphocytic leukemia (B-CLL). It has been suggested previously that enhanced cross-link repair is a primary mechanism of resistance to nitrogen mustards (NMs) in B-CLL. DNA-dependent protein kinase (DNA-PK) is involved in the repair of double-strand breaks and in rejoining steps in recombination mechanisms. Mutants defective in this process are hypersensitive to alkylating agents. We have recently demonstrated that the activity of DNA-PK is a determinant in the cellular response of B-CLL to CLB. The DNA-PK gene has homology to the P110 phosphatidylinositol 3-kinase (PI 3-K). Wortmannin, an inhibitor of P110 PI 3-K, also inhibits DNA-PK activity in vitro. We investigated the effect of wortmannin on DNA-PK activity and CLB toxicity in the lymphocytes from 11 patients with B-CLL. Our results demonstrate that DNA-PK activity is decreased after exposure to wortmannin in a dose-dependent manner. Wortmannin, at nontoxic concentrations, synergistically sensitized B-CLL lymphocytes to the effects of CLB. Moreover, we observed a significant correlation when we compared the fold decrease in DNA-PK activity and the synergistic value (I), obtained when wortmannin was used at 0.1 microM. In the resistant B-CLL lymphocyte samples, there was a highly significant correlation between the ability of wortmannin at 0.1 and 0.25 microM to decrease the level of DNA-PK activity and to increase CLB sensitivity. In a model of primary human tumor cells, our findings suggest that the inhibition of DNA-PK activity may be a powerful way to overcome resistance to NMs such as CLB and point to new possibilities to improve the effectiveness of NM therapy.     

Social anxiety and peer relations among adolescents: testing a psychobiological model

The START cell cycle transition in the budding yeast Saccharomyces cerevisiae is catalyzed by the Cdc28 cyclin-dependent kinase associated with Cln-type cyclins. Since ectopic expression of the B-type cyclin CLB5 can efficiently rescue the inviability that results from CLN depletion, we tested the specificity of the CLN and CLB classes of cyclins for promoting START-associated events. Several aspects of the regulation of the mating factor response were compared for cells in which START activity was provided by either Cln-cyclins or Clb5. Unlike Cln1 and Cln2, high level expression of Clb5 was unable to repress the activity of the mating factor response pathway at START. Downregulation of Far1 protein at START is normal in cln- GAL1::CLB5 cells. Even though the Clb5-Cdc28 kinase activity in cln- GAL1::CLB5 cells is not downregulated in response to mating factor, cells arrest in the first cycle after addition of mating factor with a similar sensitivity as wild-type cells. However, whereas wild-type cells treated with mating factor arrest specifically in G1 phase as unbudded cells with unreplicated DNA (pre-START), most cln- GAL1::CLB5 cells arrest as budded post-START cells with replicated DNA. Our findings demonstrate the ability of post-START cells to arrest in response to mating factor and provide novel evidence for mechanisms that contribute to restrict mating factor-induced arrest in wild-type cells to the G1 phase of the cell cycle.     

Necrolytic migrating erythema without glucagonoma

INTRODUCTION: The glucagonoma syndrome is an uncommon but well-known entity associating erythema necroticans migrans (ENM) with glucagonoma. CASE REPORT: A 43-year-old man with a past history of alcoholic cirrhosis and ascitis was hospitalized for skin disorders which had developed over the past 4 months. Centrifugal erythematous skin lesions were observed, some with non-turgid bullae and marginal desquamation, others with an erosive center. Lesions first appeared on the hands then diffused widely without involving the periorifical areas, folds and lower limbs. Laboratory results revealed an anemia, hypovitaminosis K, cholestatic liver failure, a beta-gamma block and low zinc levels. Histology study of the skin biopsy demonstrated a < Neapolitan trench > image suggestive of ENM. A paraneoplasic syndrome and pancreas tumor were not found. Despite supplementation with zinc, amino acids and vitamins, the patient died from his liver disease. DISCUSSION: There have been 4 cases of ENM reported in the literature, all in cirrhosis patients, two of which had low zinc levels. Our case is thus the third with cirrhosis and low zinc. Bazex's syndrome, acrodermatitis enteropathica, annular chronic lupus erythematosis and annular superficial pemphigus were eliminated as possible diagnoses. The failure of zinc and amino acid supplementation would favor the secondary nature of the zinc deficiency and the predominant role of cirrhosis in this skin disease. The possible role of essential fatty acids in ENM is raised.