Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation.

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein. METHODS AND RESULTS: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5' Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes ("third hits") in some polyps. We found that the "third hit" probably initiated tumorigenesis. Somatic mutation spectra were similar in 5' and 3' mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, "third hits" were more common. Most "third hits" left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele. CONCLUSIONS: We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need "three hits" however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.

SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.

Valproate-ethosuximide combination therapy for refractory absence seizures.

Five patients had absence seizures refractory to treatment with either ethosuximide or valproate sodium. To determine their response to combination therapy with the two drugs, four of the five had serial 24-hour intensive monitoring studies that included cable telemetric EEG recording, closed-circuit television observation, and frequent antiepileptic drug (AED) serum level determinations. The resultant data confirmed the clinical and EEG effects of serial alterations in AED programs. All five became seizure free with combination therapy. Combination therapy with ethosuximide and valproate should be considered in patients whose absence seizures do not respond to standard therapeutic measures.

Seizure activity and anticonvulsant drug concentration.

Current methods permit frequent, accurate serum anticonvulsant drug concentration measurements and continuous, 24-hour electroencephalographic recording with minimal environmental restriction. These techniques were used to perform longitudinal, 24-hour recordings of electroencephalographic paroxysmal activity and sleep-wake state concurrently with frequent measurements of serum anticonvulsant drug concentrations in two patients with poorly controlled convulsions. Drug administration was designed with the intent of producing high serum concentrations at times of maximum electroencephalographic paroxysmal activity. The suppression of clinical seizures coincided with decreased numbers of paroxysmal bursts in the electroencephalogram and increased serum anticonvulsant drug concentration.

Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.

OBJECTIVE: To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS). DESIGN: Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase. SETTING: Twenty-one US medical centers. PATIENTS: Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs. INTERVENTIONS: Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily. MAIN OUTCOME MEASURES: Median change in 4-week CPS frequency and adverse events. RESULTS: Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P < .001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups. CONCLUSIONS: Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.

Reflections on the treatment of seizures in the elderly population.

Treatment of seizure disorders in older patients is an important problem because of the age-related increase in seizure incidence and the growing size of this segment of the population. Physiologic changes that occur with aging may influence drug dosing and safety. The standard antiepileptic drugs (AEDs) are not ideal for treating older patients because of their complex pharmacokinetics, multiple drug interactions, and possible increased susceptibility to adverse effects. Data are limited on the use of the newer AEDs--gabapentin, lamotrigine, topiramate, and tiagabine--in older patients. An ongoing clinical trial in this population is investigating the efficacy and safety of gabapentin and lamotrigine relative to carbamazepine for the treatment of new-onset partial seizures. Other trials are needed to evaluate the use of topiramate and tiagabine in older patients with epilepsy. In the absence of these data, AED selection in older patients must be made on the basis of current knowledge of efficacy and safety profiles. The newer agents now offer increased therapeutic options and some theoretical advantages over the older AEDs for elderly persons with seizures.

Transient global amnesia: clinical and electroencephalographic findings in 10 cases.

We studied 10 patients with transient global amnesia (TGA). Routine electroencephalograms (EEGs) were normal in six; two showed mild temporal lobe abnormalities, one had bitemporal delta activity with rare sharp waves, and one showed bioccipital rhythmic theta activity. Nasopharyngeal (NP) recordings were obtained in seven patients; five showed independent mesial temporal spike discharges during drug-induced sleep. The discharges are probably due to transient ischemia in deep temporal structures.

Daytime intensive monitoring: comparison with prolonged intensive and ambulatory monitoring.

We evaluated daytime (6- to 8-hour) intensive monitoring in a consecutive series of 166 studies. Overall success rate in answering clinical questions posed by referring physicians was 67%, and attacks were recorded in 55%. Daytime intensive monitoring provides a useful, cost-effective alternative to prolonged inpatient monitoring and ambulatory monitoring.

Contraversive seizures in occipital epilepsy: case report and review of the literature.

We studied a man with repeated seizures characterized by deviation of the head and eyes to the left. A right occipital focus was demonstrated in the EEG. Adversion is usually associated with frontal or temporal lobe seizures; the direction of adversion is equally likely to be ipsilateral as contralateral to the ictal focus. In all reports of occipital epilepsy, the ictal focus has been contralateral to the direction of head turning.

Epileptic aphasia.

We document a case of isolated epileptic aphasia with clear correlation between episodic clinical and electrographic events. This disorder is rarely recognized, perhaps because it is obscured by ictal motor activity or speech arrest, or by the lack of clinical manifestations if the seizure occurs when the patient is not attempting to speak.

The electroencephalogram in childhood basilar artery migraine.

In two pediatric patients with the clinical picture of basilar artery migraine, transient electroencephalographic disturbances were seen. Both children manifested posterior rhythmic delta activity in close temporal proximity to their attacks. Resolution of these abnormalities was documented by serial electroencephalographic tracings. These electroencephalographic findings are consistent with transient dysfunction in the neural structures supplied by the basilar artery and its branches. Pediatric patients in whom there is a clinical picture of basilar artery migraine and who have a family history of migraine and transient electroencephalographic changes of the type herein described need not undergo invasive neurodiagnostic study.

Sodium valproate: serial monitoring of EEG and serum levels.

The clinical and electroencephalographic (EEG) effects of sodium valproate were studied in four patients by means of serial 24-hour EEG recordings and simultaneous hourly determinations of serum drug concentrations. The patients all had frequent clinical seizures and generalized spike-wave discharges. Valproate appeared to reduce diurnal paroxysmal discharges (PD) and clinical seizures, but the effect on nocturnal PD was less marked. The extent and duration of the depression of PD and seizures varied. Altering the distribution of the total daily dose may change the pattern of clinical seizures and PD. Valproate concentrations fluctuated widely over 24 hours, and the significance of single estimations often cited in the literature appears dubious. Peak serum concentrations above 100 micrograms per milliliter may be necessary in some patients to achieve clinical and EEG improvement.

Telemetric EEG and video monitoring in epilepsy.

We report a clinical evaluation of EEG and video monitoring. In 181 consecutive records, the most common clinical indications were differentiation of epileptic and nonepileptic events (99), seizure recordings for locating a possible focus (23), seizure frequency determination (32), and investigation of possible trigger factors (19). Overall, useful information was obtained in 72% and the clinical question was answered in 67% of records. Prolonged EEG and video monitoring is therefore an important diagnostic aid in patients with proven or suspected epilepsy.

Supplementary motor seizures mimicking pseudoseizures: some clinical differences.

Supplementary motor seizures (SMS) are among the group of frontal lobe seizures that may often be misdiagnosed as pseudoseizures (PS). We designed this study to determine the value of clinical phenomena in distinguishing between the two. In a series of patients with SMS, we identified those with symptoms mimicking PS and compared the clinical phenomena with those of clinically similar PS. We found that SMS are short in duration, stereotypic, tend to occur in sleep, and often present with a tonic contraction of the upper extremities in abduction. This sign was specific for SMS, particularly when occurring at the onset. Conversely, PS are long in duration, nonstereotypic, and occur in the awake state. We conclude that clinical phenomena may be useful in distinguishing PS from SMS, although the final diagnosis must be documented by neurophysiologic means.

Characterisation of antibodies to urinary gonadotrophin peptide.

There is now general recognition that human chorionic gonadotropin (hCG), its beta subunit and its fragments are valuable diagnostic markers of trophoblastic and some non-trophoblastic malignancies. Urinary gonadotropin peptide (UGP) contains at least one epitope which cross-reacts with the beta-subunit of hCG. In order to assess the potential of UGP as a tumour marker in its own right, it was paramount that any measurements made could be regarded as specific for UGP and not cross-reactive with either hCG or human luteinising hormone (hLH). Four antibodies were tested, two polyclonal (AK12 and DR-Pool) and two monoclonal (2C2 and 6D3). Initial screening using radioiodinated (125I) UGP, hCG, hCG beta-subunit and hLH showed that the polyclonal antibodies bound to all four gonadotrophins, whilst the monoclonal antibodies bound only to the radioiodinated UGP. The antibodies were tested in both radioimmunoassay (RIA) and immunoradiometric assay (IRMA-sandwich assay) systems. The parameters measured were sensitivity and specificity for UGP. The polyclonal antibodies used in the RIA system produced a sensitive assay (0.2 ng/ml UGP) which was relatively specific; cross-reactions for the AK12 antibody (at 50% inhibition) were 5% for hCG, 11% for its beta-subunit, 0.4% for the alpha-subunit and 2.6% for hLH. The monoclonal antibodies performed optimally in the IRMA system. Immobilised 2C2 and radiolabelled (125I) AK12 produced a system that had a sensitivity of 0.4 ng/ml UGP and cross-reactivity (50% maximum binding) of 2% for the hCG beta-subunit and less than 1% for hCG, hLH and the hCG alpha-subunit.

Management of seizures in the elderly.

The elderly are a substantial and rapidly increasing proportion of the population. They also have a high frequency of seizures, which can lead to serious consequences. The elderly differ from the young in that they may have many medical conditions, take numerous concomitant drugs, have different metabolic characteristics, and are more likely to suffer from neurologic conditions such as stroke. The elderly are also more sensitive to adverse effects of prescription drugs. As available antiepileptic drugs (AEDs) have roughly equivalent efficacy, side-effect profiles are a major determinant in charting therapy. The older AEDs have a well-known collection of undesirable side effects. Newer AEDs have potential advantages for the elderly, particularly with respect to tolerability. The characteristics of seizures in the elderly and guidelines for their treatment are discussed.

Clinical and EEG prediction of seizure recurrence following antiepileptic drug withdrawal.

A prospective study is reported of antiepileptic drug withdrawal in 62 neurologically intact adult patients who had become seizure-free at least 3 years previously. No single clinical or laboratory finding was reliably predictive of outcome and in particular the presence of epileptiform EEG activity prior to AED withdrawal or appearance of such activity during withdrawal was not associated with relapse. A multivariate model was however developed which suggested that patients capable of remaining seizure-free without medication could be reliably identified at a much reduced cost of relapses in the remainder.

CNS oxidative stress associated with the kainic acid rodent model of experimental epilepsy.

The role of oxidative stress in seizure-induced brain injury was investigated in a kainic acid model of experimental epilepsy. Kainic acid (12.5 mg/kg) or saline was injected intraperitoneally into 12-week-old male Fischer 344 rats and sacrificed by decapitation at 4 and 24 h after injection. Markers of oxidative stress including protein carbonyls, thiobarbituric acid reactive material (TBARs), glutathione (GSH) and glutathione disulfide (GSSG) were measured in hippocampus, cortex, cerebellum and basal ganglia. Four hours after treatment, protein carbonyls were elevated by 103, 55, 52 and 32% in cortex, hippocampus, basal ganglia and cerebellum, respectively. TBARs were increased by 30-45% in all areas. After 24 h, elevated protein and lipid oxidative markers persisted in the hippocampus and cerebellum; by contrast, in the cortex, TBARs almost normalized to control values and protein carbonyls trended downward by one-half compared with measurements at 4 h, although this reduction relative to the 4 h timepoint did not reach statistical significance. In the basal ganglia, protein carbonyls approached control values at 24 h. GSSG levels were only increased statistically in the cortex after 4 h, GSH levels in all the regions were unchanged after treatment with kainic acid. However, in cortex, GSH levels correlated negatively with increases in protein and lipid oxidation (r = -0.69, P < 0.002). In contrast, significant correlations between GSH, protein carbonyls and TBARs measured in the hippocampus or cerebellum were not observed. Our data suggests that kainic acid induced similar oxidative stress in all of the brain regions that were examined, and that GSH plays a major antioxidant role in the cerebral cortex but not the hippocampus.

A comparative study of Norinyl 1/35 versus Brevicon in Panama City, Panama.

A comparative study of Norinyl 1/35 and Brevicon was conducted at the APLAFA clinic in Panama City, Panama. The study sought to evaluate the differences in continuation rates and the frequency of selected side effects which might contribute to method discontinuation. The 300 subjects were randomly allocated to one of the two oral contraceptives. Women in the Brevicon group reported significantly more (p less than 0.05) intermenstrual bleeding, nausea, headaches, dizziness and vaginal discharge than women in the Norinyl 1/35 group. The total discontinuation rate at 12 months was 28.0 for the Norinyl 1/35 group and 46.7 for the Brevicon group, and this difference was significant (p less than .01). Also, significantly more women (p less than .01) in the Brevicon group discontinued for menstrual problems than women in the Norinyl 1/35 group. No pregnancies were reported during this study. While both oral contraceptives appear safe and effective, Norinyl 1/35 was more acceptable to this group of Panamanian women.

A comparative study of Norinyl 1/35 versus Norinyl 1/50 in Belgrade, Yugoslavia.

A comparative study of Norinyl 1/35 and Norinyl 1/50 was conducted at the Dom Zdravlja Stari Grad in Belgrade, Yugoslavia. The study sought to evaluate the differences in continuation rates as well as the frequency of selected side effects which might contribute to method discontinuation. The trial included 299 women who were randomly allocated to one of the two oral contraceptives. In the Norinyl 1/35 group, significantly more women (p less than .05) reported a complaint of vaginal discharge as well as an increase in the occurrence of vaginal discharge compared to the Norinyl 1/50 group. There was no significant difference in continuation rates or for particular discontinuation reasons for the Norinyl 1/35 and Norinyl 1/50 groups. No accidental pregnancies were reported during this study. Both oral contraceptives appear to be safe and effective; there appears to be no difference in the acceptability of one oral contraceptive over the other among this group of Yugoslavian women.