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Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality., (© 2023. The Author(s).)

Objective: Examine pre-existing learning disorders (LD) and attention deficit/hyperactivity disorders (ADHD) as risk factors for prolonged recovery and increased symptomology following pediatric mild traumatic brain injury (mTBI)., Methods: We conducted a retrospective cohort study of children/adolescents (5-17 years) with mTBI who presented to a Children's Minnesota Concussion Clinic between April 2018 and March 2019. Differences across strata of pre-existing conditions (present vs. absent) in time to recovery measures were estimated via Kaplan-Meier and Cox proportional hazards analyses and differences in symptom trajectories were examined via linear mixed-effects regression models. Regression models were adjusted for age, sex and other confounders., Results: In our cohort of 680 mTBI patients, those with LD (n = 70) or ADHD (n = 107) experienced significantly longer median durations of symptoms (58 and 68 days, respectively) than those without (43 days). Accordingly, LD was significantly associated with delayed symptom recovery (adjusted hazard ratio (aHR) = 1.63, 95% CI: 1.16-2.29), return to school (1.47, 1.08-2.00), and return to physical activity (1.50, 1.10-2.04). Likewise, ADHD was associated with delayed recovery (1.69, 1.28-2.23), return to school (1.52, 1.17-1.97) and physical activity (1.55, 1.19-2.01). Further, patients with LD or ADHD reported, on average, significantly more concussion symptoms and higher vision symptom scores throughout recovery versus those without. There was no evidence that concussion or vision symptom recovery trajectories varied over time between those with/without LD or ADHD (joint P-interactions > 0.05)., Conclusion: Pre-existing LD and ADHD are risk factors for prolonged and more symptomatic mTBI recovery in youth. These results can inform clinical concussion management and recovery expectations.

We hypothesize that first trimester circulating micro particle (CMP) proteins will define preeclampsia risk while identifying clusters of disease subtypes among cases. We performed a nested case-control analysis among women with and without preeclampsia. Cases diagnosed < 34 weeks' gestation were matched to controls. Plasma CMPs were isolated via size exclusion chromatography and analyzed using global proteome profiling based on HRAM mass spectrometry. Logistic models then determined feature selection with best performing models determined by cross-validation. K-means clustering examined cases for phenotypic subtypes and biological pathway enrichment was examined. Our results indicated that the proteins distinguishing cases from controls were enriched in biological pathways involved in blood coagulation, hemostasis and tissue repair. A panel consisting of C1RL, GP1BA, VTNC, and ZA2G demonstrated the best distinguishing performance (AUC of 0.79). Among the cases of preeclampsia, two phenotypic sub clusters distinguished cases; one enriched for platelet degranulation and blood coagulation pathways and the other for complement and immune response-associated pathways (corrected p < 0.001). Significantly, the second of the two clusters demonstrated lower gestational age at delivery (p = 0.049), increased protein excretion (p = 0.01), more extreme laboratory derangement (p < 0.0001) and marginally increased diastolic pressure (p = 0.09). We conclude that CMP-associated proteins at 12 weeks' gestation predict the overall risk of developing early preeclampsia and indicate distinct subtypes of pathophysiology and clinical morbidity.

Objective: To examine pre-existing anxiety disorders as a risk factor for increased concussion symptomology and prolonged recovery in children and adolescents., Methods: In this retrospective cohort study, we abstracted medical record data for 637 children/adolescents (5-17 years) presenting to three tertiary concussion clinics between April 2018 and March 2019. Primary outcomes were mean concussion symptom and vision symptom severity scores measured at clinic visits. Linear mixed-effects regression models were employed to investigate differences in average symptom load, vision symptom score and symptom recovery trajectories across anxiety strata, adjusted for random effects (time), age and sex. Secondary outcomes, time to concussion symptom recovery and time to return to academics and sports, respectively, were examined via log-rank tests and multivariable Cox regression., Results: Among 637 eligible concussion patients, 155 (24%) reported pre-existing anxiety. On average, patients with anxiety reported an additional 2.64 (95% CI 1.84 to 3.44) concussion symptoms and 7.45 (95% CI 5.22 to 9.68) higher vision symptom severity scores throughout recovery versus those without, after adjusting for age and sex. There was no evidence that concussion or vision symptom trajectories varied over time between those with/without anxiety after accounting for baseline dissimilarities in symptom scores (all p interaction >0.05). Anxiety was significantly associated with delayed symptom recovery (adjusted HR 3.34, 95% CI 2.18 to 5.12), return to school (adjusted HR 2.01, 95% CI 1.59 to 2.53) and return to physical activity (adjusted HR 1.88, 95% CI 1.49 to 2.37)., Conclusions: Pre-existing anxiety disorders were associated with more severe symptomology and prolonged recovery after concussion in children and adolescents. These results can be referenced by providers to manage patients' recovery expectations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We have previously shown that protein biomarkers associated with circulating microparticles proteins (CMPs) obtained at the end of the first trimester may detect physiologic changes in maternal-fetal interaction such that the risk of spontaneous preterm delivery ≤35 weeks can be stratified., Objectives: We present here a study extension and validation of the CMP protein multiplex concept using a larger sample set from a multicenter population that allows for model derivation in a training set and characterization in a separate testing set., Materials and Methods: Ethylenediaminetetraacetic acid (EDTA) plasma was obtained from 3 established biobanks (Seattle, Boston, and Pittsburgh). Samples were from patients at a median of 10-12 weeks' gestation, and the CMPs were isolated via size-exclusion chromatography followed by protein identification via targeted protein analysis using liquid chromatography-multiple reaction monitoring-mass (LC-MRM) spectrometry. A total of 87 women delivered at ≤35 weeks, and 174 women who delivered at term were matched by maternal age (±2 years) and gestational age at sample draw (±2 weeks). From our prior work, the CMP protein multiplex comprising F13A, FBLN1, IC1, ITIH2, and LCAT was selected for validation., Results: For delivery at ≤35 weeks, the receiver operating characteristic (ROC) curve for a panel of CMP proteins (F13A, FBLN1, IC1, ITIH2, and LCAT) revealed an associated area under the ROC curve (AUC) of 0.74 (95% CI, 0.63-0.81). A separate panel of markers (IC1, LCAT, TRFE, and ITIH4), which stratified risk among mothers with a parity of 0, showed an AUC of 0.77 (95% CI, 0.61-0.90)., Conclusion: We have identified a set of CMP proteins that provide, at 10-12 weeks gestation, a clinically useful AUC in an independent test population. Furthermore, we determined that parity is pertinent to the diagnostic testing performance of the biomarkers for risk stratification., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Psychogenic non-epileptic seizures (PNES) are diagnosed in at least 10-40% of the patients seen for long-term monitoring of epilepsy, and it is no surprise that patients with PNES are often treated for epilepsy. Given the substantial economic costs and mental health burden of misdiagnosis, it is imperative to establish early identification, correct diagnosis, and effective treatment of PNES in order to provide the greatest opportunity for remission of events, improved psychological functioning, and social-vocational outcome. This article outlines an informed, practical approach to diagnosing this common condition and provides a summary of factors, based on medical history and semiology, that may suggest PNES. We discuss also the issues of communicating the diagnosis to the patient and making treatment recommendations which should ideally be coordinated using a multi-disciplinary team approach, involving the disciplines of neurology, psychiatry, psychology, social work, and nursing.

Background: The analysis of circulating microparticles in pregnancy is of revolutionary potential because it represents an in vivo biopsy of active gestational tissues., Objective: We hypothesized that circulating microparticle signaling will differ in pregnancies that experience spontaneous preterm birth from those delivering at term and that these differences will be evident many weeks in advance of clinical presentation., Study Design: Utilizing plasma specimens obtained between 10 and 12 weeks' gestation as part of a prospectively collected birth cohort in which pregnancy outcomes are independently validated by 2 board-certified maternal-fetal medicine physicians, 25 singleton cases of spontaneous preterm birth ≤ 34 weeks were matched by maternal age, race, and gestational age of sampling (±2 weeks) with 50 uncomplicated term deliveries. Circulating microparticles from these first-trimester specimens were isolated and analyzed by multiple reaction monitoring mass spectrometry for potential protein biomarkers following previous studies. Markers with robust univariate performance in correlating spontaneous preterm birth were further evaluated for their biological relevance via a combined functional profiling/pathway analysis and for multivariate performance., Results: Among the 132 proteins evaluated, 62 demonstrated robust power of detecting spontaneous preterm birth in a bootstrap receiver-operating characteristic curve analysis at a false discovery rate of < 20% estimated via label permutation. Differential dependency network analysis identified spontaneous preterm birth-associated coexpression patterns linked to biological processes of inflammation, wound healing, and the coagulation cascade. Linear modeling of spontaneous preterm birth using a multiplex of the candidate biomarkers with a fixed sensitivity of 80% exhibited a specificity of 83% with median area under the curve of 0.89. These results indicate a strong potential of multivariate model development for informative risk stratification., Conclusion: This project has identified functional proteomic factors with associated biological processes that are already unique in their expression profiles at 10-12 weeks among women who go on to deliver spontaneously ≤ 34 weeks. These changes, with further validation, will allow the stratification of patients at risk of spontaneous preterm birth before clinical presentation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Magnetoencephalography (MEG)/magnetic source imaging (MSI) is a noninvasive functional neuroimaging procedure used to localize language-specific regions in the brain. The Wada test, or intracarotid amobarbital procedure (IAP), is the gold standard in determining speech/language lateralization for presurgical planning, although it is invasive and associated with morbidity. The purpose of this study is to provide further validation on the use of MSI for presurgical language lateralization by comparing results against the IAP., Methods: The sample consisted of 35 patients with epilepsy and/or brain tumor undergoing presurgical evaluation at the Minnesota Epilepsy Group. All patients received both an IAP and MSI to determine hemispheric language dominance. For MSI, a 148-channel MEG system was used to record activation of language-specific cortex by an auditory word-recognition task., Results: The MSI and IAP were concordant in determining language in the hemisphere to be treated in 86% of the cases with sensitivity and specificity values of 80% and 100%, respectively., Conclusions: The results from this study are consistent with prior research findings comparing functional neuroimaging procedures to the IAP in determining language lateralization in presurgical patients. The current study provides an important replication and support for Papanicolaou et al.'s findings in 2004 using a consecutive clinical sample from a different institution. An unusually high rate of atypical IAP language cases in this sample and differences between the two procedures are believed to explain the noted discrepancies. MSI is a viable noninvasive alternative to the IAP in the presurgical determination of language lateralization.

Background: The recent interest of clinical laboratories in developing serum testosterone assays based on isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) stems from the lack of accuracy of direct immunoassays. In this study, we assessed the accuracy and state of standardization (traceability) of 4 published ID-LC-MS/MS procedures in a method comparison with an ID-gas chromatography (GC)-MS reference measurement procedure listed in the database of the Joint Committee for Traceability in Laboratory Medicine., Methods: The study used 58 specimens from different patient categories. Each specimen was measured in triplicate (ID-LC-MS/MS) and quadruplicate (ID-GC-MS) in independent runs., Results: The testosterone concentrations by ID-GC-MS were 0.2-4.4 nmol/L (women), 0.2-2.0 nmol/L (hypogonadal man), and 10.1-31.3 nmol/L (normogonadal men). For ID-GC-MS, the CV was nearly constant, with a median of 1.0%; for ID-LC-MS/MS, it was concentration-dependent, with a median of up to 8%. Weighted Deming regression gave mean slopes, intercepts, and correlation coefficients of 0.90-1.11, -0.055-0.013 nmol/L, and 0.993-0.997, respectively. The % difference plot showed between 7% and 26% of the results outside a total error limit of 14%, with median deviations from ID-GC-MS between -9.6 and 0.4%., Conclusions: This study demonstrated fairly good accuracy and standardization of the tested ID-LC-MS/MS procedures. Performance differences between procedures were evident in some instances, due to improper calibration and between-run calibration control. This emphasizes the need for thorough validation, including traceability, of new ID-LC-MS/MS procedures.

Background: Measurement of estradiol (E(2)) plays a critical role in the diagnosis and clinical management of reproductive disorders. The challenge for all currently available direct methods for measuring E(2) is to provide accuracy and precision across a wide dynamic range., Methods: We describe the development and multi-site performance evaluation of a direct E(2) assay on the Architect i2000. Assay performance and method comparisons were performed by testing specimens from men, healthy women with regular menstrual cycles, and post-menopausal women using the Architect assay and isotope dilution, gas chromatography-mass spectrometry (ID/GC-MS). Reference intervals were established by testing prospectively collected daily blood draws from 42 healthy women, 72 postmenopausal women and 101 males., Results: No unexpected cross-reactivity or interference was observed for over 40 compounds tested. Recovery was 100+/-10% in the presence of estrone and estriol. Functional sensitivity (%CV<20%) was <15 pg/ml.(1) The imprecision of the assay was <7.1% (total CV), <2.5%, and <2.3% for control sera containing 45, 190, and 600 pg/ml estradiol, respectively. The assay had a correlation of y=1.033 x+0.3156, r(2)=0.99, n=131 compared to ID/GC-MS. Reference intervals for the current Architect Estradiol assay are reported., Conclusions: Format changes resulted in dramatic improvement in the performance and accuracy of this direct, fully automated assay. The assay is standardized by ID/GC-MS. The assay is clinically useful for serum concentrations from 15 to >4000 pg/ml.

A 70-year-old man presented to us in 1994 with a three-year history of worsening dementia. With the exceptions of a Mini-Mental State exam score of 20 and an inability to tandem walk, his physical and neurological examinations were normal. His past medical history revealed that in 1992 he had been evaluated at another institution for memory impairment and bifrontal headaches. A spinal tap had been done in 1992 showing elevated protein, reduced glucose, and a pleocytosis; his CSF fungal culture and cryptococcal antigen test were negative. He subsequently was lost to follow-up, and although his headaches had resolved, his mental status had continued to worsen. In 1994 his CSF cryptococcal antigen was positive, and his CSF fungal culture grew C. neoformans. He gradually improved with treatment for cryptococcal meningitis (CM). With the exception of mild memory impairment, in 2003 he and his family thought that his mental status had returned to normal. This case emphasizes that: 1) CM should always be kept in the differential diagnosis of dementia; 2) CM may be extremely insidious and difficult to diagnose; and 3) if one is to rule out unequivocally all possible reversible causes of dementia, one should perform a spinal tap.

We examined performances on the Wechsler Memory Scale-3rd Edition (WMS-III) among patients who underwent temporal lobectomy for the control of medically intractable epilepsy. There were 51 right (RTL) and 56 left (LTL) temporal lobectomy patients. All patients were left hemisphere speech-dominant. The LTL and RTL patients were comparable in terms of general demographic, epilepsy, and intellectual/attention factors. Multivariate analyses revealed a significant crossover interaction (p <.001), with the RTL group scoring significantly lower on the visual than auditory indexes while the LTL group scored significantly lower on the auditory than visual memory indexes. Within-group pairwise analyses revealed statistically significant auditory versus visual index score comparisons (all p <.001) for both surgical groups. Discriminant analysis (p <.001) identified Verbal Paired Associates I, Faces I, and Family Pictures II to significantly discriminate RTL and LTL patients, with an overall correct classification rate of 81.3%. Our findings suggest that the WMS-III is sensitive to modality-specific memory performance associated with unilateral temporal lobectomy.

The long-term prognosis of pharmacological therapy in patients with mesial temporal sclerosis (MTS) is generally considered poor. On the contrary, successful surgical therapy is frequently reported. We performed a retrospective case record survey of patients with MTS in a comprehensive epilepsy center between 1993 and 1999 in order to develop treatment strategies. The time period allowed access to high-resolution qualitative magnetic resonance imaging (MRI) and a minimum of 1-year outcome assessment. Eighty-three patients with intractable partial epilepsy with MRI and electroencephalograph (EEG) abnormalities and seizure semiology consistent with temporal lobe epilepsy were identified. Thirty-six patients were treated pharmacologically and surgically and 47 patients received only pharmacotherapy. The number of patients who became seizure free was in total 37 (45%); in the surgical group 26 and in the non-surgical group 11. The proportions of seizure-free patients in each group were 72% (surgical) and 23% (non-surgical). Clinical factors such as age, gender, lesion side, previous medical history, duration of illness, seizure frequency and IQ did not correlate to prognosis. A good seizure outcome was associated with early age of seizure onset, low number of previously used antiepileptic drugs (AEDs) and surgical treatment. There is a better long-term outcome in patients with MTS receiving surgical therapy in comparison with medical therapy.

We examined whether differences between the expanded standardization protocol (SP) used to derive norms for the final published version (PB) of the Wechsler Memory Scale - Third Edition (WMS-III; Wechsler, 1997a) would result in differences on the Primary Indexes in a neurologic sample. Specifically, we examined the comparability of the performances of 63 patients with temporal lobectomy (TL) who were administered either the expanded SP protocol (n = 33: 22 left TL and 11 right TL) or the PB battery (n = 30: 11 left TL and 19 right TL). Patients who were administered the SP or PB were comparable in terms of age, sex, education, seizure duration, postsurgical seizure status, and Full Scale IQ. Postoperative intervals were significantly longer for the SP group, although correlational analyses demonstrated no significant relationship between postoperative follow-up interval and WMS-III performance. A series of t tests revealed no significant differences on any of the eight Primary Index scores between patients taking the two versions of the WMS-III for either left or right TL groups. Furthermore, repeated measures analyses of variance failed to show significant differences on modality-specific memory scores between the SP and PB for the left and right TL groups. The current study indicates that temporal lobectomy patients obtained comparable scores on the two versions of the WMS-III.

This study investigated the cognitive estimations test (CET) in patients with frontotemporal dementia (FTD) and Alzheimer's disease (AD). The CET consists of questions which reflect judgment and reasoning. FTD patients, who have predominant frontotemporal atrophy, may give more extreme estimates on the CET compared toAD patients, who have greater temporoparietal pathology. The CET was administered to 31 FTD and 31 AD patients of comparable dementia severity plus 31 normal elderly controls. Both dementia groups gave significantly more extreme estimates on the CET than did the controls, and, contrary to expectations, AD patients gave more extreme estimates than did FTD patients. Extreme CET scores correlated with poor savings and calculations scores on neuropsychological tests. In conclusion, the CET may be particularly impaired in AD because it reflects impaired memory and numerical ability as well as disturbed judgment and reasoning. The CET may also be helpful in discriminating some patients in moderate stages of AD from those with FTD.

Two synthetic peptides 31 and 32 amino acids in length were prepared as deduced from a known amino acid sequence of penicillin-binding protein 2' (PBP2') of methicillin-resistant Staphylococcus aureus. Two monoclonal antibodies were generated from fused cells of myeloma cells and splenic cells of mice immunized with the synthetic peptides. Western blot (immunoblot) analysis demonstrated specific binding of the antibodies to PBP2' of a methicillin-resistant S. aureus strain. An immunoradiometric assay was developed by using these antibodies for simple detection of PBP2'.

We report the neurobehavioral aspects of the delayed encephalopathy of carbon monoxide (CO) intoxication in a 29 year old woman and review the literature. Four weeks after CO poisoning, the patient developed a frontal lobe syndrome, visuoperceptual impairment, and diffuse white matter lesions with an otherwise normal neurological examination. In contrast, patients with the classical syndrome also have a parkinsonian state or an akinetic-mute state. The delayed encephalopathy of CO poisoning usually results from demyelination of subcortical white matter, necrosis of the globus pallidus, or both. The clinical aspects, risk factors, neurobiological features, and therapy and prognosis are discussed.

New-onset epileptic seizures occur in patients with Alzheimer's disease (AD), but the nature and underlying reasons for these seizures are unclear. We identified new-onset, nonsymptomatic seizures in 77 (17%) of 446 patients with uncomplicated, definite AD on autopsy. Among these seizure patients, 69 had generalized tonic-clonic seizures, and 55 had less than three total seizures. The seizure patients had a younger age of dementia onset than did the remaining AD patients; however, at seizure onset, they averaged 6.8 years into their AD and had advanced dementia. When further compared to 77 AD controls, matched for age of onset and duration, the seizure patients did not differ on medical illnesses, amount of medications, and degree of focal neuropathology. We conclude that a few unprovoked generalized seizures frequently occur late in the course of AD, and that AD patients with a younger age of dementia onset are particularly susceptible to seizures.

Patients with epilepsy often have depressive disorders. This association may be particularly prominent in secondary epilepsy from a left hemisphere lesion. Among 1611 outpatients with epilepsy 272 patients were identified whose seizures originated from a structural brain lesion other than mesial temporal sclerosis. Sustained depressive disorders had occurred in 25 (9%) of these patients with secondary epilepsy. The depressed patients were compared with the remaining patients without depression with regard to location of lesion laterality and seizure variables. The only group difference was unilateral left hemisphere lesions in 58% of the patients with depression compared with only 21% of the non-depressed patients (chi 2 = 10.4, p = 0.006). This finding supports the idea of a relation of depression with epileptogenic lesions in the left hemisphere.

Interictal violence among epileptic patients could result from factors other than epileptiform activity. We characterized 44 patients who presented for psychiatric evaluation because of violent behavior. Most violent acts consisted of verbal or minor physical aggression. Twenty (45%) of these patients met criteria for a schizophrenic disorder, and one committed murder during a paranoid schizophrenic relapse. In addition to schizophrenia, the violence patients had significantly more mental retardation when compared with 88 age- and sex-matched epileptic patients without prior violent behavior. However, violent and nonviolent patients did not differ on seizure variables such as type and frequency of seizures, auras, electroencephalographic changes, epilepsy age of onset, or anticonvulsant therapy. These findings suggest that interictal violence is associated more with psychopathology and mental retardation than with epileptiform activity or other seizure variables.

Interictal depression is common among epilepsy patients and may have a relationship to seizure variables. Among 1339 epileptic outpatients, we identified 101 (7.5%) patients who had a depressive disorder that required psychiatric evaluation, compared with only 105 (5.3%) of 1991 migraine patients from the same clinic (p = .01). The 101 epilepsy-depression patients were compared retrospectively with 202 seizure patients without depression on six seizure variables. The epilepsy-depression group had significantly fewer patients with generalized tonic-clonic seizures, a decreased frequency of generalized tonic-clonic seizures, and more patients on multiple anticonvulsant medications. We conclude that interictal depression in epilepsy may result from the use of more anticonvulsant drugs resulting in the prevention of secondary generalization from a seizure focus.

Among epileptic patients, personality disorders may be associated with specific seizure manifestations. In an epilepsy clinic, we identified 42 idiopathic epilepsy patients diagnosed with various DSM-III-R personality disorders, including borderline, atypical or mixed, explosive, and dependent. When compared with 42 age- and sex-matched epileptic control subjects on six seizure variables, the personality disorder group had more patients with epileptic auras (P = 0.001), particularly "cephalic" auras, and fewer with secondarily generalized tonic-clonic seizures (P < 0.05). These findings suggest that the experience of epileptic auras contributes to the development of personality disorders, especially when auras are not masked by secondarily generalized seizures.

Prior studies have incompletely established a relationship between epilepsy and schizophrenia, primarily because of methodological difficulties. We undertook a two-part retrospective investigation of neurology clinic patients with epilepsy and schizophrenia. Part I: Interictal schizophrenic disorders occurred in 149 (9.25%) of 1,611 epileptic outpatients, compared with only 23 (1.06%) of 2,167 migraine outpatients. Part II: Among age- and sex-matched groups, we compared 62 epilepsy-with-schizophrenia patients with 62 epilepsy patients on six seizure variables, and we compared them with 62 schizophrenia patients on 10 psychosis variables. The epilepsy-with-schizophrenia group had a later epilepsy age of onset with more complex partial seizures, more patients with auras, and fewer patients with generalized epilepsy. Except for increased suicidal behavior, epileptic patients did not differ from controls on psychosis variables; however, psychotic symptoms often emerged with increased seizure activity. Together these results support a distinct association of schizophrenic disorders with epilepsy, particularly with seizures emanating from the temporal limbic system.

This research assessed whether individual differences in anterior brain asymmetry are linked to differences in basic dimensions of emotion. In each of 2 experimental sessions, separated by 3 weeks, resting electroencephalogram (EEG) activity was recorded from female adults during 8 60-s baselines. Mean alpha power asymmetry across both sessions was extracted in mid-frontal and anterior temporal sites. Across both regions, groups demonstrating stable and extreme relative left anterior activation reported increased generalized positive affect (PA) and decreased generalized negative affect (NA) compared with groups demonstrating stable and extreme relative right anterior activation. Additional correlational analyses revealed robust relations between anterior asymmetry and PA and NA, particularly among subjects who demonstrated stable patterns of EEG activation over time. Anterior asymmetry was unrelated to individual differences in generalized reactivity.

Objective: To evaluate the ictal and psychiatric aspects underlying the high risk of suicide among epileptic patients., Method: We surveyed the records of 1611 epileptic patients seen in a neurology clinic during an eight-year period, found four who died by suicide, and characterized their ictal and psychiatric features., Results: All four epileptic patients had partial complex seizures and temporal lobe foci. Two had an associated paranoid schizophrenia with suicidal ideation, and good or improving seizure control at the time of their deaths. Another patient killed himself during a brief psychotic episode associated with increasing epileptiform discharges. The fourth patient had ictal depression and committed suicide during a flurry of partial complex seizures., Conclusions: These findings suggest that the high suicide rate among epileptic patients has a greater association with psychotic behaviors and psychic auras than with major depression or the psychosocial burden of being epileptic. We further review other reported risk factors for suicide in epilepsy.

5'-Nucleotidase (5'-ribonucleotide phosphohydrolase, EC 3.1.3.5) of bovine milk fat globules can be solubilized by deoxycholate from either isolated globule membranes or washed cream. The solubilized and membrane-bound enzymes exhibit similar Km values and are inhibited by concanavalin A by an apparent noncompetitive process. The soluble enzyme shows positive cooperativity for the inhibition (Hill coefficient of 2) at 37 degrees C, but the membrane enzyme exhibits essentially no cooperation effect. At lower temperatures (5 or 20 degrees C) the cooperative effect in the inhibition of the soluble enzyme is lost. Colchicine and cytochalasin D failed to induce cooperativity of the concanavalin A inhibition of the membrane enzyme, but induction cooperativity occurred when membranes were extracted with glycine/EDTA/mercaptoethanol, releasing a major protein component with a polypeptide molecular weight of 155 000. We suggest that the interaction of this component with the membrane imposes restraints on the behavior of the nucleotidase which are reflected in the cooperativity of the inhibition of the enzyme by concanavalin A.

Exposure of postconfluent 1321N1 human astrocytoma cells to 1.0 microM isoproterenol for 12-24 hr results in a 90% loss of beta-adrenergic receptors. Upon removal of agonist, recovery of beta-receptors to control levels occurs within 72 hr. The recovery of receptors is completely blocked by cycloheximide [R. C. Doss, J. P. Perkins, and T. K. Harden, J. Biol. Chem. 256:12281-12286 (1981)]. In contrast cycloheximide does not block recovery of beta-receptors after down-regulation in preconfluent cultures. To determine unambiguously if beta-receptor synthesis accounts for the recovery of receptors after down-regulation, post confluent cultures were incubated with isoproterenol and then transferred to agonist-free medium containing either normal or "heavy" (2H, 13C, 15N) amino acids. The rate and extent of beta-receptor recovery were similar in both normal and heavy amino acid-containing medium. When beta-receptors that had recovered in the heavy amino acid-containing medium were labeled with 125I-cyanopindolol, solubilized in Lubrol PX, and subjected to centrifugation on a 5-15% sucrose density gradient, they exhibited an increased mass compared to beta-receptors that recovered in the presence of normal amino acids. These results confirm that the density shift method is a useful approach for the study of beta-receptor synthesis and that new receptor synthesis occurs during recovery of beta-receptors from catecholamine-induced down-regulation in postconfluent cultures.

Differences in cell morphology, concanavalin A-induced receptor redistributions, and the cooperativity of the inhibition of 5'-nucleotidase (AMPase) by concanavalin A (Con A) have been investigated in ascites sublines of the 13762 rat mammary adenocarcinoma cells treated with microfilament- and microtubule-perturbing drugs. By scanning electron microscopy MAT-C1 cells exhibit a highly irregular surface, covered with microvilli extending as branched structures from the cell body. MAT-A, MAT-B, and MAT-B1 cells have a more normal appearance, with unbranched microvilli, ruffles, ridges, and blebs associated closely with the cell body. MAT-C cells have an intermediate morphology. Treatment of MAT-A, MAT-B, or MAT-B1 cells with Con A causes rapid redistribution of Con A receptors. Both cytochalasins and colchicine cause alternations in the receptor redistributions. Receptors on MAT-C1 cells are highly resistant to redistribution, even in the presence of cytoskeletal perturbant drugs. The cooperativity of the inhibition of AMPase by Con A was investigated in MAT-A and MAT-C1 cells. Untreated cells exhibit no cooperativity. If either subline is treated with colchicine, cytochalasin B or D, or dibucaine, cooperativity is observed. Lumicolchicine has no effect. Theophylline or dibutyryl cyclic AMP prevents the effects of either colchicine or cytochalasin. The concentration required for half-maximal induction of cooperativity is 0.3--0.4 microM for both colchicine and cytochalasin D, which is in the appropriate range for specific microtubule and microfilament disruptions. The effectiveness of the cytochalasins (E greater than D greater than B) is consistent with their known effects on microfilaments. No direct correlation was observed between the induction of cooperativity and drug-induced changes in Con A receptor redistribution or cell morphology. The morphology of MAT-A cells is grossly altered by cytochalasins or dibucaine and somewhat less by colchicine. MAT-C1 cells exhibit more minor alterations in morphology as a result of these drug treatments. The results of this study indicate that the inhibition of AMPase, which is a Con A receptor, is a different process from the redistribution of the bulk of the Con A receptors, possibly short range membrane interactions rather than global effects on the cell.

Tunicamycin, which inhibits formation of asparagine-linked glycoproteins, caused a concentration-dependent blockade of beta-adrenergic receptor (beta-AR) accumulation in 1321N1 human astrocytoma cells during growth in culture. A concentration of tunicamycin (0.1 microgram/ml) that inhibited receptor accumulation and [3H]mannose or [3H]glucosamine incorporation into glycoproteins by 90% had only a small effect (10%) on [3H]leucine incorporation into protein, and reduced the rate of cell growth. Incubation in drug-free medium subsequent to treatment of 1321N1 cells with tunicamycin for 48 hr resulted in recovery of beta-AR to control levels within an additional 48 hr. Exposure of cultures to isoproterenol (0.1 microM, 12 hr) caused an 80-90% loss of beta-AR in both pre- and postconfluent cultures; beta-AR recovered to control levels upon removal of isoproterenol. Although both tunicamycin and the protein synthesis inhibitor cycloheximide blocked beta-AR accumulation during growth of 1321N1 cells, neither agent inhibited the appearance of beta-AR during recovery from the down-regulated state in preconfluent cultures. However, cycloheximide, but not tunicamycin, blocked recovery of beta-AR after isoproterenol-induced loss of receptors in postconfluent cultures. In a previous report (Mol. Pharmacol. 26:424-429, 1984), we provided direct evidence that recovery of beta-AR from down-regulation in postconfluent cultures requires de novo synthesis of receptor protein. Thus, the results with tunicamycin are consistent with the idea that recovery of beta-AR in postconfluent cultures requires the synthesis of new beta-AR molecules, but as aglycoproteins that exhibit radioligand-binding characteristics similar to those of native glycoprotein beta-AR.

As a part of the process of agonist-induced desensitization, 1321N1 human astrocytoma cells lose up to 95% of their beta-adrenergic receptors, as detected by 125I-hydroxybenzylpindolol (125IHYP) binding, after 12-24 h of exposure to isoproterenol. In preconfluent cultures the loss of beta-receptors is completely reversible upon removal of isoproterenol, with receptor levels reaching 100% of control levels within 48-72 h. Addition of cycloheximide (5 micrograms/ml) upon removal of agonist does not prevent the recovery of receptors. After an initial 4-h lag, receptors accumulate in the presence of cycloheximide until the same receptor level is reached that was present at the onset of desensitization. Confluent cultures, which have a reduced number of receptors per cell, recover beta-receptors to only 60 to 70% of control levels following removal of isoproterenol. In addition, cycloheximide blocks the recovery of receptors in these cultures. The effects of cycloheximide on the accumulation of receptors during cell growth suggest that receptors are stable in preconfluent cultures and that turnover only occurs later when cultures are confluent. The data also indicate that long term exposure of cells to catecholamine results in a form of the beta-adrenergic receptor that is undetectable by 125IHYP binding but, nonetheless, retains its primary amino acid structure. The undetectable receptors appear to be retained until agonist is removed, whereupon they become detectable by 125IHYP binding with a t1/2 of about 36 h in the presence of cycloheximide.

A new TSH immunoenzymometric assay was found to be capable of discriminating between the serum TSH values of normal subjects [2.28 +/- 1.02 (+/-SD); range, 0.6-6.5 microU/ml] and those of clinically euthyroid, antithyroid drug-treated (n = 22) or clinically thyrotoxic (n = 34) patients. While a wide spectrum of basal TSH values was found in the antithyroid drug group [ranging from undetectable (less than 0.05 microU/ml: 57%) to 17.9 microU/ml], all clinically thyrotoxic patients had undetectable values. In 33 patients receiving chronic oral T4 therapy for treatment of goiter (n = 15) or thyroid cancer (n = 18), 48% (6 of 33) had undetectable basal TSH levels and no TSH response to TRH stimulation. Detectable TSH levels were found in 42% (14 of 33), and TRH responsiveness was found in 52% (17 of 33). The TSH response to TRH stimulation was less than 2.0 microU/ml in 7 patients. Serum free T4 index, free T3 index, and free T4 levels and oral T4 dosage were inferior predictors of TRH responsiveness compared to the basal TSH value. No patient receiving more than 0.2 mg T4 daily or having a free T4 index above 18, a free T3 index above 205 or a free T4 level above 3.0 ng/dl had a TSH response to TRH. Seventy-six percent (16 of 21) of the patients, when reevaluated 1-6 weeks after increased oral T4 dosage, had a significant reduction in their serum thyroglobulin level. This was true of both patients with initially detectable (11 of 14) as well as undetectable (5 of 7) basal serum TSH levels. These findings support the concept that subnormal and, for that matter, as yet undetectable levels of circulating TSH may exert stimulatory effects on thyroid tissue.