Targeting of human DNA polymerase iota to the replication machinery via interaction with PCNA.

Human DNA polymerase iota (hPoliota) promotes translesion synthesis by inserting nucleotides opposite highly distorting or noninstructional DNA lesions. Here, we provide evidence for the physical interaction of hPoliota with proliferating cell nuclear antigen (PCNA), and show that PCNA, together with replication factor C (RFC) and replication protein A (RPA), stimulates the DNA synthetic activity of hPoliota. In the presence of these protein factors, on undamaged DNA, the efficiency (V(max)/K(m)) of correct nucleotide incorporation by hPoliota is increased approximately 80-150-fold, and this increase in efficiency results from a reduction in the apparent K(m) for the nucleotide. PCNA, RFC, and RPA also stimulate nucleotide incorporation opposite the 3'-T of the (6) thymine-thymine (T-T) photoproduct and opposite an abasic site. The interaction of hPoliota with PCNA implies that the targeting of this polymerase to the replication machinery stalled at a lesion site is achieved via this association.

Severe neuromuscular complications possibly associated with amlodipine.

OBJECTIVE: To document a case of severe, progressive myopathy, myalgias, arthralgias, and weakness possibly caused by amlodipine in a patient with benign essential hypertension. CASE SUMMARY: A 52-year-old white woman with asthma and newly diagnosed hypertension was initiated on zafirlukast therapy for asthma and amlodipine therapy for hypertension. Two months later, the patient reported severe, generalized muscle and joint pain, muscle stiffness, and weakness. The zafirlukast was discontinued without resolution of symptoms. Laboratory tests revealed an elevated C-reactive protein. The amlodipine dosage was increased. Her symptoms persisted and further laboratory tests revealed a positive anti-nuclear antibody screen, and negative single- and double-stranded DNA antibody tests. After another amlodipine dosage increase, the patient experienced a sudden onset of left-sided facial numbness, facial weakness, and a severe headache.The patient was admitted to rule out a possible cerebrovascular event or a metabolic neurologic process. Magnetic resonance imaging showed no abnormalities. The patient discontinued the amlodipine and reported complete resolution of the neurologic symptoms after 4 days. One month later, zafirlukast was reinitiated without a return of symptoms. CONCLUSIONS: Amlodipine was not initially suspected as a cause of these symptoms because these effects are not commonly associated with amlodipine therapy. However, due to the temporal relationship and progression of symptoms with increasing amlodipine dosage, drug-related causes were eventually explored. Review of the medical literature suggests myalgias and arthralgias may be adverse effects common to dihydropyridine calcium-channel antagonists.

Arthroscopic treatment of arthrofibrosis of the elbow joint.

Twenty-five patients with arthrofibrosis of the elbow were treated with arthroscopic debridement; 15 had post-traumatic arthrofibrosis and 10 had contractures caused by degenerative arthritis. At an average follow-up of 18 months, all patients had increased motion and decreased pain. One patient required reoperation because of continued stiffness and pain; she had moderate pain before surgery, mild pain after initial debridement, and occasional mild pain after the second operation. Patients with post-traumatic arthritis had more severe flexion contractures preoperatively than did those with degenerative arthritis, but they also had more improvement postoperatively. There were no perioperative or postoperative complications. Arthroscopic release and debridement of arthrofibrotic elbow joints appear to obtain improvement equal to that obtained by open techniques, with less morbidity and earlier rehabilitation.

Managing therapy and adverse effects with antihyperglycemic agents: a focus on metformin and acarbose.

Metformin and acarbose are novel antihyperglycemic agents indicated for the treatment of non-insulin-dependent diabetes mellitus. These agents offer new therapeutic options to control hyperglycemia that were previously unavailable. Common to both agents is a relatively high incidence of gastrointestinal adverse effects. Initiating therapy at a low dose and slowly titrating to therapeutic response may be the most effective way to minimize associated adverse effects. Recognition and proper management of these possible adverse effects can optimize therapy and maximize the potential for successful outcomes with these agents while limiting drug noncompliance.

Ruptures of the proximal biceps tendon in middle-aged patients.

Treatment of ruptures of the proximal biceps tendon has been based on clinical observations, with little objective data to substantiate treatment guidelines. Evaluation of 25 patients (all > 40 years of age) at an average of 7.9 years after injury found few objective or subjective differences between those treated nonoperatively and those treated operatively. Only 1 patient (treated nonoperatively) was dissatisfied with the result, and her dissatisfaction was with a cosmetic defect. Objective manual muscle testing and Cybex II (Cybex Corporation, Ronkonkoma, New York) evaluation of 19 patients found no significant differences in supination or elbow flexion strength in the two groups.

Electroencephalography in childhood conduct and behavior disorders.

The pathophysiology of behavior disorders in children is controversial. In particular, the relationship of episodic behavior disturbance to epilepsy and chronic behavior problems to subclinical neurologic disorder has been debated. It has been suggested that EEG may assist in this sometimes difficult determination. We report on routine screening EEGs in children hospitalized over an 18-month period for behavior problems. Eighty-six children were admitted for conduct disorder, attention deficit hyperactivity disorder, or both. Seventy-eight tracings (91%) were normal or showed normal variant patterns. Eight records (9%) were abnormal, showing background slowing or paroxysmal discharges not associated with behavioral manifestations. None of these neurologically normal, nonretarded patients had epilepsy or other known cerebral disorder. This suggests that routine EEG screening may be of limited value in childhood behavior problems without clinical evidence of neurologic disorder.

Neuropsychological and event-related potential correlates of nonepileptic seizures.

A retrospective study of 14 patients with epileptic seizures and 11 with nonepileptic seizures, all taking antiepileptic drugs, found epileptic patients had significantly longer P160, N200, and P300 latencies on auditory event-related potential recordings. Patients with nonepileptic seizures had generally higher IQs and significantly greater psychopathology on neuropsychological scales.

Passive long-latency event-related potentials in mental retardation.

Long-latency auditory event-related potentials (ERPs) were passively recorded in ten mental retardates and ten age-matched normal controls. Patients were mildly to moderately retarded and had epilepsy controlled with monotherapy, ERPs were recorded from CA-A1+A2, with 1000 and 3000 Hz tones in an "oddball" paradigm. Latency and amplitude of N1, N2, P2, and P3 components were compared in controls and retardates. All ten patients had reproducible AEPs, but these were attenuated in amplitude in four, although amplitudes did not differ significantly from controls. P3 was prolonged in latency in four patients, but patients and controls did not differ significantly. AEP latency and amplitude was not correlated with degree of retardation. These findings suggest that "cognitive" evoked potentials an be recorded passively in persons with impaired cognition, but are not correlated with intellectual ability and may not reflect specific cognitive functions.

Long-term ictal monitoring with subdural strip electrodes: prognostic factors for selecting temporal lobectomy candidates.

Long-term electrocorticographic (ECoG) monitoring data from subdural strip electrodes are analyzed to determine factors associated with seizure-free outcome from anterior temporal lobectomy. A total of 89 consecutive patients with complex partial seizures, in whom long-term ictal video/scalp electroencephalographic monitoring was insufficient to localize their epileptogenic focus, were subsequently evaluated with long-term ictal ECoG monitoring using subdural strip electrodes. Each patient underwent anterior temporal lobectomy based on the ictal ECoG data and has been followed for at least 1 year. The following parameters were found to be statistically significant in predicting a seizure-free outcome: unilateral onset, electrical onset pattern beginning as fast spike trains, absence of frontal lobe background desynchronization at onset, and an interhemispheric propagation time of greater than 8 seconds. Electrocorticographic criteria that were not associated with seizure outcome included: right- versus left-sided onset, time from electrical to clinical ictal onset, focality of onset (number of strip electrode contacts involved), and stereotypical ECoG onset. When present, the interictal focus was concordant with the ictal focus in most patients (96%), but was falsely lateralizing in 4% of cases. It is suggested that these data should improve patient selection for temporal lobectomy when subdural strip monitoring is used during preoperative evaluation.

Neuropsychological and psychiatric correlates of intractable pseudoseizures.

Psychogenic seizures can mimic convulsive epilepsy and with repetitive attacks, iatrogenic complications from aggressive treatment of status epilepticus can occur. We studied neuropsychiatric features of 20 patients in whom psychogenic seizures were intractable and at times continuous. Nineteen of 20 patients seen were female, and all but one were under 40 years of age. All had convulsive attacks resistant to various medications, normal neurological examinations, and negative imaging studies and electroencephalograms (EEGs). Sixteen had previous evidence of epilepsy and the other four had epileptic relatives. Seizures were atypically prolonged, included back arching and pelvic thrusting, and persisted despite intravenous diazepam and therapeutic phenytoin and phenobarbital levels. Seizures terminated spontaneously in five, were stopped by suggestion in four, and persisted until respiratory arrest or elective intubation in 11. Ten patients had conversion disorder, six borderline or mixed personality disorder and four mental retardation. Fifteen had had some precipitating stressor and the remainder had histories of exhibiting attention-seeking behaviour. Nine of 10 patients with conversion disorder had 'conversion V' Minnesota Multiphasic Personality Inventory (MMPI) profiles, while personality disorder patients had elevation of several psychopathological scales. Patients with conversion disorder gradually improved with anticonvulsant discontinuation, while retarded individuals were helped by behaviour modification, situational change or neuroleptics. Personality disorder patients continued to have attacks and eventually discontinued follow-up. Clinical evidence of non-epileptic seizures includes clinical atypicality and long duration, exacerbation by medications and frequent attacks despite normal examination and studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Auditory evoked potentials in borderline personality disorder.

Borderline personality disorder is an increasingly recognized condition and frequent management problem in psychiatric and nonpsychiatric practice. Paroxysmal changes in affect and behavior, high incidence of soft neurologic signs and frequent EEG alterations, and evidence of clinical response to antiepileptic drugs have suggested cerebral dysfunction, particularly involving the limbic system or reticular activating system. We recorded early latency brainstem auditory evoked potentials (BAEPs) and long-latency auditory event-related potentials (ERPs) in 20 patients fulfilling DSM-III-R criteria for this disorder. BAEPs were recorded from Cz to ipsilateral and contralateral ear reference, with rarefaction clicks presented at 11.1 per second and 70 dB SL. Two thousand averages were recorded and replicated for each ear, with filter band pass of 150-3000 Hz and 10 ms analysis time. ERPs utilized binaural stimulation with 1000 and 3000 Hz tones in an 80:20 ratio, with interstimulus interval 1.1 second, analysis time 1000 ms, and filter band pass 1-100 Hz. Two hundred averages were recorded and replicated from Cz with linked ear reference. No differences were evident in I-III, III-V, and I-V interpeak latencies between borderline patients and age-matched neurologically and audiologically normal controls. N1, P2, and N2 components of the AEPs were longer in latency and lower in amplitude in borderline patients, while P3 latency was longer and amplitude was attenuated in borderline patients as compared to controls. These findings may suggest differences from normals in attention maintenance and in limbic system function.

Sleep and sleep deprived EEG in partial and generalized epilepsy.

Sleep and sleep deprivation are often used for EEG activation in epilepsy. We compared postprandial naps and day-long sleep deprived EEGs in 36 patients with generalized seizures, 57 complex partial seizure patients, and 7 individuals with mixed seizure disorders. Ten of 36 generalized seizure patients had normal sleep and sleep deprived EEGs, while both were normal in 16 of 57 partial seizure patients. Both were abnormal in 18 of 36 generalized and 22 of 57 partial epileptics. Seven generalized seizure patients had epileptiform discharges or seizures during afternoon naps but normal sleep deprived EEGs. No partial seizure patients had normal sleep deprived EEGs and abnormal nap, but 29 of 57 had abnormalities or seizures only with sleep deprivation. All 7 mixed seizure patients had abnormal sleep and sleep deprived studies, and 6 had seizures, 4 on both studies. Natural sleep may facilitate the appearance of generalized seizures or epilepti-form discharges, while sleep deprivation may accentuate the yield of EEG abnormality in partial epilepsy. Either is likely to be abnormal in patients with mixed seizures and encephalopathy. Natural sleep and sleep deprived EEGs are an appropriate combination in the evaluation of refractory seizures.