The changing maternal "self" hypothesis: a mechanism for maternal tolerance of the fetus.

Recent advances in placental biology and immunology lead us to propose a novel hypothesis for maternal tolerance of the semi-allogeneic fetus and amelioration of rheumatoid arthritis (RA) during pregnancy. The initial event in this hypothesis is extrusion of placental apoptotic syncytiotrophoblast debris recently identified to contain intracellular fetal HLA Class II molecules, into maternal blood. The second event is uptake of apoptotic syncytiotrophoblast by immature maternal dendritic cells and presentation of fetal HLA class II peptides. In addition to presenting foreign antigens, HLA molecules also present HLA self-peptides. In the setting of the non-inflammatory environment of pregnancy, this process is expected to induce peripheral tolerance of fetal antigens through T cell death, anergy or induction of regulatory T cells in the lymph nodes. This hypothesis suggests a mechanism by which the simultaneous presentation of fetal and self (RA-associated) HLA peptides by tolerogenic dendritic cells during pregnancy may explain the observed amelioration of RA as a secondary benefit of fetal tolerance. After delivery, apoptotic syncytiotrophoblast debris disappears from maternal blood, autoimmunity returns and RA recurs. Thus, during pregnancy maternal immunologic "self" includes fetal HLA Class II as a result of apoptotic syncytiotrophoblast uptake by maternal tolerogenic dendritic cells.

LPS induces translocation of TLR4 in amniotic epithelium.

Toll-like receptor 4 (TLR4) mediates lipopolysaccharide (LPS) induced immune responses, which may contribute to preterm labor associated with intraamniotic gram-negative bacterial infections. The study objective was to investigate gestational age and LPS-induced changes in TLR4 subcellular localization within amniotic epithelium, the first line of host defense against intraamniotic bacteria. TLR4 localization in amniotic epithelium was assessed using immunohistochemistry on 24 placentas of different gestational ages: first trimester (n=6), second trimester (n=6), and third trimester (n=12). Immunofluorescence was used to determine TLR4 localization following ex vivo LPS stimulation of amnion from women undergoing cesarean section without labor at term. TLR4 was expressed in the cytoplasm of amniotic epithelium starting at 9weeks with apical polarization by 25weeks gestation. TLR4 localization to the basal membrane was significantly associated with chorioamnionitis (p=0.01). After LPS stimulation, TLR4 was expressed sequentially within the apical membrane, cytoplasm, and finally in the basal cellular compartment. This suggests that TLR4 expression in amniotic epithelium is poised to monitor amniotic fluid for pathogens. TLR4 translocation to the basal membrane may decrease LPS signaling early in an infection, but allow the amniotic epithelium to remain competent to invasive or intracellular bacteria.

Aging, abstinence, and medical risk factors in the prediction of neuropsychologic deficit among long-term alcoholics.

Halstead-Reitan assessments were conducted with 71 male alcoholics sober for four weeks, 65 alcoholics sober for four years, and 68 nonalcoholics. Recently detoxified alcoholics showed learning and problem-solving difficulties, as did older persons in all groups. Aging, not alcoholism, was related to psychomotor slowing. There were no age-alcohol interactions for any neuropsychologic test. Time since last drink predicted neuropsychologic performance modestly, as did head injury, age, and education. Long-term sober alcoholics were indistinguishable from controls. Our results suggest that alcoholics abstinent one month suffer a subacute alcohol-related organic mental disorder that might resolve with prolonged abstinence, that the neuropsychologic findings in such alcoholics are more consistent with an "independent decrements" rather than "premature aging" hypothesis, and that neuromedical and other risk factors must be considered before permanent neuropsychologic deficit among alcoholics can be attributed solely to neurotoxic effects of alcohol.

Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease.

In previous work we showed that patients with chronic obstructive pulmonary disease (COPD) suffered decrements in neuropsychologic functioning suggestive of organic mental disturbance. This study combined data from two multicenter clinical trials to explore the nature and possible determinants of such neuropsychologic change. Three groups of patients with COPD whose hypoxemia was mild (N = 86), moderate (N = 155), or severe (N = 61) were compared with age- and education-matched nonpatients (N = 99). The rate of neuropsychologic deficit rose from 27% in mild hypoxemia to 61% in severe hypoxemia. Various neuropsychologic abilities declined at different rates, suggesting differential vulnerability of neuropsychologic functions to progress of COPD. Multivariate analyses revealed a consistent significant relationship between degree of hypoxemia and neuropsychologic impairment, but the amount of shared variance was small (7%). Increasing age and lower education were also associated with impairment.

Psychologic effects of continuous and nocturnal oxygen therapy in hypoxemic chronic obstructive pulmonary disease.

The Nocturnal Oxygen Therapy Trial (NOTT) showed previously that patients with hypoxemic chronic obstructive pulmonary disease (COPD) frequently suffered from neuropsychologic deficit and experienced disturbed mood, personality, and life quality. The present study has followed up 150 NOTT patients six months after they were randomized to continuous oxygen treatment (COT) or nocturnal oxygen treatment (NOT). Tested off oxygen, 42% showed modest neuropsychologic improvement after six months of therapy, and the rates for COT and NOT were comparable. A subsample (n = 37) was examined a third time, after 12 months of treatment. At this point patients receiving COT registered better neuropsychologic performance than those receiving NOT. Concurrently, the COT group began showing improved survival. Despite mild neuropsychologic improvement, patients reported little change in emotional status or life quality. It is concluded that prolonged oxygen treatment is associated with small but definite improvement in brain functioning among patients with hypoxemic COPD, and that COT might have some advantage over NOT in enhancing neuropsychologic functioning as well as survival.

Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease.

As part of a six-center clinical trial of the effectiveness of continuous v nocturnal oxygen in the management of hypoxemic chronic obstructive pulmonary disease (COPD), we performed detailed neuropsychologic assessments of these patients prior to their beginning treatment. The 203 patients (age, 65 years; Pao2, 51 mm Hg; forced expiratory volume in 1 s, 0.74 L) performed significantly worse than controls on virtually all neuropsychologic tests. Moderate to severe test impairment suggestive of cerebral dysfunction was found in 42% of the patients, as compared with 14% of controls. Higher cognitive functions (abstracting ability, complex perceptual-motor integration) were most severely affected, although half the patients also showed decrements in motor speed, strength, and coordination. Low-order significant inverse correlations were found between neuropsychologic impairment and Pao2, resting arterial oxygen saturation and hemoglobin levels and maximum work. It is concluded that cerebral disturbance is common in hypoxemic COPD and may be related in part to decreased availability of oxygen to the brain.

Life quality of patients with chronic obstructive pulmonary disease.

Two hundred three patients with hypoxemic chronic obstructive pulmonary disease (COPD) and 73 healthy control subjects matched for age, sex, race, and neighborhood of residence were administered three self-report inventories concerned with the following four dimensions of life quality: emotional functioning, social-role functioning, activities of daily living, and recreational pastimes. An additional inventory was administered to a spouse or another close relative of each patient. The life quality of patients with COPD was found to be impaired relative to healthy subjects on all dimensions. Depression was the preponderant emotional disturbance reported; difficulties with home management and reduction in social interaction were the primary social-role deficits. Ambulation, mobility, sleep and rest, and a variety of recreational pastimes were also severely affected. Life quality exhibited moderate but significant relationships to neuropsychological, pulmonary, and cardiac functioning and to exercise capability. Age and socioeconomic status were found to be possible moderators of the relationship of COPD to life quality. A model to integrate these findings is proposed. Implications for the management of COPD and for the evaluation of medical treatments of chronic disabling conditions are described.

Failure of nonlinear models of drinking history variables to predict neuropsychological performance in alcoholics.

To test whether the relationship between drinking parameters and cognitive functioning can be visualized as a curvilinear surface (rather than as a line, which more traditional regression equations presuppose), the authors tested 84 recently detoxified and 72 longer-term abstinent alcoholic men with the Halstead-Reitan battery. Quadratic statistical models did not predict test performance in the first group; a few predictions were found in the second. When the multiple correlation was adjusted for number of cases and variables, the "nonlinear" results were statistically no more significant than those of simpler linear models. It is concluded that drinking history does not readily explain cognitive findings among sober alcoholics and that polynomial models can produce inflated correlation coefficients.

Neuropsychology in alcoholic men in their late thirties: one-year follow-up.

In a previous article the authors reported on two groups of alcoholic men in their late 30s who were remarkably free of neuropsychological impairment. In this article they present the results of a 1-year follow-up of many of these subjects. They found similarities in performance between alcoholic subjects who in the original study had been abstinent for 18 months and nonalcoholic control subjects who drank moderately. However, the group of alcoholic men who in the original study had been recently detoxified (about 3 weeks) failed to show practice-effect learning on follow-up. The authors interpret this failure as possibly indicative of a preclinical phase of what might ultimately become organic impairment.

Cross-study comparisons of self-reported alcohol consumption in four clinical groups.

Clinical research on the chronic effects of alcohol has been difficult to evaluate and compare because of the failure by investigators to quantify self-reported alcohol consumption. The authors describe four diverse groups of patients who were treated for alcohol and/or drug abuse. After devising a procedure for comparing the data from these studies, they found that patient self-reports of alcohol consumption may be less distorted than commonly assumed. The present findings are consistent with current research indicating that self-reports of alcohol use are reliable and clinically consistent. The authors also discuss the relationship between neuropsychological impairment and measures of alcohol and drug abuse.

Organic impairment in polydrug users: risk factors.

In a national collaborative study to assess the neuropsychological status of 151 polydrug users, the Halstead-Reitan Neuropsychological Battery showed deficits in 37% two to three weeks after they entered treatment and in 34% at three-month follow-up. Comparative rates for a group of psychiatric patients were 26% and 27%, and for nonpatients, 8% and 4%. Extensive and intensive use of CNS depressants and opiates correlated positively with neuropsychological deficit. Older, less-educated subjects with adverse medical or developmental histories were more likely to show polydrug-related organic impairment. Although there is some evidence that such impairment is reversible, the condition appears to be of at least intermediate duration and may be long lasting.

Impaired upper limb coordination in alcoholic cerebellar degeneration.

BACKGROUND: Alcoholic cerebellar degeneration (ACD) is a disorder resulting from severe chronic alcoholism and malnutrition and is characterized by cognitive disturbances, ataxia of gait, and truncal instability, with generally preserved coordination of the upper extremities. OBJECTIVES: To determine whether cognitive deficits in patients with ACD are the same as those seen in patients with severe chronic alcoholism without ACD and to determine whether upper limb motor coordination is different in the 2 groups. DESIGN: We examined cognitive function and upper limb coordination in 56 patients with severe chronic alcoholism, 13 with ACD and 43 without ACD, who had comparable levels of total alcohol intake. Neuropsychological and motor function was measured using an expanded Halstead-Reitan Neuropsychological Test Battery, including the Tactual Performance Test and Grooved Pegboard Test. RESULTS: Neither group had impaired coordination of upper limb function on clinical neurological examination. Both groups had impaired performance on neuropsychological tests involving executive function, but the patients with ACD had greater impairment of upper limb coordination than the patients without ACD as measured by the Tactual Performance Test and Grooved Pegboard Test. CONCLUSIONS: The findings suggest that these 2 groups have similar cognitive deficits but that upper extremity motor functions are more significantly impaired in the ACD group and that quantitative tasks of motor function reveal these impairments.

Spontaneous intracranial hypotension causing reversible frontotemporal dementia.

Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache.

Bispecific monoclonal antibodies produced by somatic cell fusion increase the potency of tissue plasminogen activator.

Bispecific monoclonal antibodies that bind simultaneously to human fibrin and tissue plasminogen activator (tPA) enhance the fibrinolytic potency of tPA. Two bispecific antibodies (F36.23 and F32.1) were generated by somatic cell fusion. Antibody F36.23 derives its tPA binding from monoclonal anti-tPA antibody TCL8 and its fibrin binding from monoclonal antifibrin antibody 59D8. After purification from cell supernatants and ascites by two steps of affinity chromatography, hybrid-hybridoma bispecific antibody F36.23 simultaneously bound tPA and fibrin in solution and in solid-phase assays. In an assay for the lysis of human fibrin monomer, F36.23 increased the fibrinolytic potency of tPA by 5 to 10 fold, regardless of whether the bispecific antibody had been combined with the tPA before or during the assay. Bispecific F36.23 F(ab')2 also bound tPA and fibrin simultaneously, and the enhancement in fibrinolysis in the presence of F36.23 F(ab')2 was identical to that in the presence of intact F36.23. The second bispecific antibody, F32.1, was produced by an alternative strategy that has a wider potential for application in other systems. Hybridoma bispecific antibody F32.1 was derived from the fusion of immune splenocytes (in mice immunized with a synthetic oligopeptide representing the amino terminus of the alpha-chain of human fibrin) with the anti-tPA cell line TCL8. The properties of hybridoma bispecific antibody F32.1 and its F(ab')2 were indistinguishable from those of hybrid-hybridoma bispecific antibody F36.23 in solid-phase binding assays and in assays of fibrinolysis. Bispecific antibodies produced by somatic cell fusion, particularly in the form of F(ab')2, may have potential for use in clinical thrombolysis.

Diagnosis of intermediate-duration and subacute organic mental disorders in abstinent alcoholics.

In a longitudinal study of 136 male alcoholics and controls, the authors found evidence of slowly reversible, subtle organic mental disorders in relation to prolonged abstinence from drinking by alcoholics. They suggest criteria for two new nosologic categories to describe these alcohol-related neuropsychiatric phenomena: (1) intermediate-duration organic mental disorder associated with alcoholism and (2) subacute organic mental disorder associated with alcohol abuse or alcoholism.

Long-term effects of severe penetrating head injury on psychosocial adjustment.

The long-term effects of severe penetrating head injury on adjustment levels were studied. Forty-one World War II veterans who suffered penetrating injury to the brain were interviewed 40 years after their initial injury using the Washington Psycho-Social Seizure Inventory (WPSI). The results support a comparable behavioral impact of right and left hemispheric lesions. Similarly, no significant relations were found between anterior and posterior locus of damage and psychosocial difficulties, although the results pertaining to the right-anterior group could be interpreted as suggestive of much greater maladjustment in all life dimensions assessed by the WPSI. Findings are discussed in terms of theoretical positions on hemispheric specialization and long-term expectancies that hold implications for planning rehabilitation programs for such patients.

Neuropsychological deficit in polydrug users. A preliminary report of the findings of the collaborative neuropsychological study of polydrug users.

The Collaborative Neuropsychological Study of Polydrug Users performed extensive neuropsychological assessments on 15 polydrug users 3 weeks after their enrollment in each of eight polydrug demonstration programs. Fifty-six (37%) of these subjects exhibited neuropsychological deficit. This deficit was partially related to increasing age, poor education and premorbid medical risk factors. The deficit was also associated with extensive and intensive use of two classes of drugs: sedatives (sleeping pills and minor tranquilizers) and opiates (heroin and other narcotic drugs). Seventeen (26%) of a comparison group of 66 psychiatric in-patients and day patients also demonstrated age- and education-correlated neuropsychological deficit. For these patients impairment was also related to lifetime experience with antipsychotic drugs and (perhaps) with clinical diagnosis of schizophrenia. Although both polydrug users and psychiatric patients revealed serious psychopathology as measured by the MMPI, the pattern of the neuropsychological test findings suggested that psychopathology alone did not account for impairment. The 3 month follow-up which is in progress should delineate further the time course and enduring features of neuropsychological deficit among polydrug users, and may establish more clearly the relationship of sedative and opiate use to such impairment. Changes in psychopathological status of both polydrug users and psychiatric patients should also help to clarify the influence of this variable on neuropsychological findings.

Can neuropsychological tests detect the sites of cerebrovascular stenoses and occlusions?

Conventional neuropsychological data may not mirror the site of cerebrovascular stenosis in a patient with mild to moderate symptoms. In this study, three groups of cerebral revascularization candidates failed to differ on an extended Halstead-Reitan battery: patients with symptoms and angiographic results referable to the carotid arterial system, subjects with clinical signs and neuroradiological findings referable to the vertebrobasilar arterial system, and patients with symptoms of cerebral ischemia but negative angiograms. Consistent with previous work, these patients generally were mildly impaired on neuropsychological tests, even though many were not symptomatic at the time of assessment. Neuropsychological tests seem to be sensitive to the presence and severity of cerebral ischemia, but in isolation may not be sufficient to determine the loci of vascular stenoses. The incongruence between angiographic and neuropsychological findings underlines the importance of distinguishing among different levels and types of measurements in defining subgroups of cerebral revascularization candidates. Collaboration among neuroscientists will further our understanding of the interrelationships among neurodiagnostic tests.

Accuracy of self-reported educational attainment among diverse patient populations: a preliminary investigation.

Despite speculation concerning the accuracy of self-reported information, particularly from certain patient populations, many neuropsychologists continue to estimate premorbid intellectual functioning on the basis of self-reported educational attainment. This study examined 116 individuals with diverse diagnoses [i.e., alcoholism, posttraumatic stress disorder (PTSD), schizophrenia or schizoaffective, and dementia] to determine the accuracy of their self-reported high school educational attainment. Results suggest that at least half of all participants were inaccurate as defined by discrepancies between actual and estimated GPA greater than.5 on a traditional 4-point grading scale. Most patients were inaccurate in the direction of overestimating their educational attainment. Patients diagnosed with alcoholism and PTSD were significantly less accurate in recalling their educational history when compared to a group of normal-control subjects. Several subjects, whose records could not be verified, were found to have not attended high school as they had claimed. These results underscore the potential inaccuracy that exists when estimating premorbid intelligence using self-reported information.

Cerebral angiography and neuropsychological measurement: the twain may meet.

In a sample of 31 cerebral revascularization candidates, severity and dissemination of atherosclerosis on the cerebral angiogram were correlated with two of three global indicators of neurobehavioral impairment. Additionally, the angiographic rating was correlated with age and with an index of medical risk factors, but not with duration of the longest symptomatic episode. It seems likely that several variables, particularly collateral circulation, help to determine whether a given pattern of stenoses results in neuropsychological dysfunction and what type of behavioral deficit occurs. In many cases, the configuration of neuropsychological test scores may not directly mirror the pattern of cerebrovascular stenoses.