Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia.

We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective "off-the-shelf" immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy.

Cognitive impairment in systemic lupus erythematosus: a follow-up study.

We evaluated outcome and the clinical value of cognitive impairment in systemic lupus erythematosus (SLE). Fifty-one consecutive SLE subjects with or without overt nervous system involvement received two comprehensive neuropsychiatric and neuropsychological assessments, including the Mental Deterioration Battery, the Mini Mental State Examination (MMSE), and tests from the Wechsler Adult Intelligence Scale. The two neuropsychological assessments were made when subjects were in stable neurological condition. Twenty-seven patients were found to have neuropsychiatric symptoms (NP-SLE) at the first assessment, and three others developed them during the follow-up. Fifteen patients (10 NP-SLE) had cognitive impairment at the first assessment. At retest the cognitive deficit persisted in all patients but one (non-NP-SLE) and had developed in four others. In the cognitively impaired subjects scores on MMSE approached the cutoff for an overt dementing condition. No progressively decreasing scores were found on any of the tests. No relationships were shown between neuropsychological diagnosis and neuropsychiatric disorder, neuroradiological findings, disease activity, or steroid and nonsteroid immunosuppressive therapy. Cognitive impairment thus seems to be a stable symptom of CNS involvement in SLE. It corresponds to the subjective complaint of intellectual difficulties and marginal performance on the MMSE. Intellectual deterioration may occur in patients without other symptoms of NP-SLE. Standardized neuropsychological testing methods should be used routinely to assess SLE patients.

Multisystem involvement of the central nervous system in Strümpell's disease. A neurophysiological and neuropsychological study.

The multisystem involvement of the central nervous system (CNS) in familial spastic paraplegia (FSP) has not been fully investigated by means of complete neurophysiological and neuropsychological examinations. The classification which distinguishes pure and complicated forms of FSP, is based on clinical features and does not take into account the possibility that clinically silent lesions of the CNS can be identified by means of adequate tests. The study was intended to assess the subclinical and multisystem involvement of the CNS in a group of 11 patients affected by FSP, clinically distinguished in 7 pure forms and 4 complicated forms. Neurophysiological tests included saccadic eye movements analysis, visual and auditory brain stem evoked responses. Neuropsychological examination was devised by means of a special purpose mental deterioration battery. Our results, showing a high incidence of multisystemic subclinical involvement of the CNS, confirm and extend the concept that FSP is a multisystemic degenerative disease of the CNS, and that the existence of "pure" forms should be reconsidered.

Influence of visual distractors on movement trajectory.

In the present study, we explored the influence of a visual distractor on the trajectory of movements made to join two dots. The two dots could be unconnected (D) or connected by a straight (L) or curved line, convex either to the left (LL) or to the right (RL). The connecting line constituted the visual distractor. In Experiment 1, subjects were asked to perform the joining movement as straight as possible. The results showed that hand trajectory moved to the left of the midsagittal axis in LL and to the right in RL, while it was almost straight both in L and D. In Experiment 2, subjects were explicitly required to follow the connecting line during their movements to verify whether, in the previous experiment, they had used curved lines as guide for their movements. An increase of movement time and different hand paths showed that this was not the case. In Experiment 3, subjects were asked to move as straight as possible without vision of their hand. Hand trajectories were shifted to the left in all experimental conditions, but the leftward shift was greater in LL than in all other conditions, and also greater in D and L than in RL. These findings suggest that the visual distractor influenced hand trajectory by attracting subject's attention and competing with target for motor response. It is hypothesized that the attracting influence operated by the distractor was sustained by involuntary attentional mechanisms.

The influence of semantic and perceptual factors on lexical comprehension in aphasic and right brain-damaged patients.

We investigated whether the errors made by aphasic patients and right brain-damaged (RBD) patients on a word-picture matching test were differently related to the semantic and perceptual difficulties of the task. To this effect, the target picture was presented in one condition along with two semantically similar distractors, in another condition with two perceptually similar distractors, and in a third condition with two distractors that were both semantically and perceptually similar. There were also two control conditions in which part of targets that had been originally shown with semantic distractors were now presented with perceptual distractors and vice versa. The findings were consistent with the hypothesis that aphasics mainly fail when the task involves semantic discrimination and RBD patients when it involves perceptual discrimination. In aphasics the semantic perceptual condition produced the highest number of errors, but this was due, it was argued, to an increase of the semantic demands of the task.

Disorders of classificatory activity in aphasia.

Two nonverbal tasks of classificatory activity ("class inclusion" and "class intersection") were administered to 46 aphasics, 28 normal controls, 19 nonaphasic left-brain-damaged and 17 right-hemisphere-damaged patients in order to study if aphasic patients are more impaired than nonaphasic brain-damaged patients on these two tasks of elementary logic and if a relationship exists within the aphasic patients between inability to perform the tasks of classifiactory activity and impairment of the semantic-lexical level of integration of language. Results were for the most part in line with expectations because aphasics scored worse than normal controls and nonaphasic brain-damaged patients (even if the difference reached the level of statistical significance only on the test of "class intersection") and within the aphasic patients the worst results were obtained by subjects presenting clear signs of semantic-lexical disintegration.

Movement velocity effects on kinaesthetic localisation of spatial positions.

In the present study, we examined how subjects locate spatial positions and code them in short-term memory. In the first experiment, blindfolded subjects were asked to perform movements in the near or far peripersonal space (criterion movement, CM). Then, subjects had to reach the end-point of CM (reproduction movement, RM). Movements could be performed either slowly or rapidly. Also, CM and RM could be performed with the same (congruent conditions) or different velocity (incongruent conditions). The results showed that performance was accurate in the two congruent conditions. Conversely, in the incongruent conditions, subjects made undershoot errors when the CM was fast and overshoot errors when it was slow. In the second experiment, blindfolded subjects also performed CM and RM in congruent or incongruent conditions. However, the CM and RM could start from the same or different position. We found again undershoot errors when the CM was fast and RM was slow and overshoot errors in the reverse condition. The results of both experiments suggest that the information about movement velocity contributes to the kinaesthetic coding in memory of a spatial location to be reached with arm movement.

Neuropsychological markers of dementia on visual-spatial tasks: a comparison between Alzheimer's type and vascular forms of dementia.

The incidence of the "closing-in" phenomenon and of the tendency to give "primitive answers" on the Raven's Colored Matrices was studied in 50 normal subjects and in two groups of Alzheimer's type (n = 41) and of vascular (n = 35) dementia patients, carefully matched as for the overall severity of dementia and the degree of visual-spatial impairment. The aims of this research were to determine if these patterns of behavior can be considered as neuropsychological markers of dementia and if their incidence is similar in the two dementia groups. Results show that both the closing-in phenomenon and the tendency to give globalistic and odd responses on the Raven's Colored Matrices are good markers of dementia and that, in particular, they point to a degenerative, rather than to a vascular form of dementia. From the clinical point of view, these data suggest that a qualitative analysis of the patient's behavior can increase the diagnostic efficacy of neuropsychological tests and that neuropsychological markers of dementia point more to Alzheimer's disease (considered as the most prototypic form of dementia) than to a vascular form of dementia even when the two groups of patients are well balanced in terms of visual-spatial impairment and the overall severity of dementia.

H-reflex behavior in glue (n-hexane) neuropathy.

The H-reflex response, and in particular the excitability cycle of spinal motor-neurones, were studied in a group of patients suffering from glue (n-hexane) neuropathy. Motor and sensitive nerve conduction, EMG, and clinical features were also considered. The results, showing an increased excitability of alpha-motorneurones, give evidence of spinal involvement in these patients.

Patterns of line bisection in patients suffering from unilateral spatial neglect.

Thirteen patients suffering from Unilateral Spatial Neglect and 6 Right Brain Damaged Control Patients were tested on a line bisection task in order to verify peculiar patterns of error. Stimuli were arranged in order to avoid confounding the effects of line length and line position in the space. Two parameters of rightward displacement of setting point were used: 1) the distance of patient's setting point from actual line midpoint, and 2) the deduced left end-point of the line that patient took into account. Results showed that: 1) the rightward extension of lines did not lead to a consistent rightward displacement of setting point; 2) error significantly increased as lines extended more than 10 cm in the left hemispace; 3) the USN severity amplified the degradation of leftmost portion of stimuli until the deduced left endpoint of all space/length conditions was aligned on the left of patient's sagittal midplane. The interpretation of these results points to the particular arrangement of neurons directing attention on specific portions of the visual field.

Dyscalculia in the early stages of Alzheimer's disease.

OBJECTIVE: To study mathematical deficits in the early stages of Alzheimer's disease (AD). METHODS: Sixty-eight patients with mild AD and 242 normal controls (NC) received a standardized battery (EC 301-R) assessing number processing and calculation abilities. AD patients also received testing for language, memory, visuo-spatial and executive-attentional domains. RESULTS: Sixty-four AD patients (94.1%) showed impaired performances on the EC 301-R. Mathematical deficits were evident both on calculation and number processing skills. Performance on the single tasks was related to attentional-executive resources and to impaired number representations. Heterogeneous patterns of preserved/impaired mathematical abilities were also observed in single cases. CONCLUSION: Dyscalculia is an early sign of AD. It should be included among the reliable clinical hallmarks for the diagnosis of AD. Identification of dyscalculic symptoms in these patients requires composite assessment procedure.

Recovery from moderate aphasia in the first year poststroke: effect of type of therapy.

OBJECTIVES: (1) To determine whether 2 model-based remediation programs affect writing performance in unselected subjects with moderate aphasia and whether there is consequent improvement in everyday life, and (2) to interpret the potential changes observed by recourse to a theoretical model. DESIGN: Consecutive sample, multiple baseline, within subject crossover study. SETTING: Ambulatory care units. PARTICIPANTS: Eight subjects with moderate aphasia from 6 to 12 months postonset. INTERVENTION: A standardized test for reading and writing skills was given at the beginning and the end of each therapy program and 1 month after therapy stopped. MAIN OUTCOME MEASURES: Functional outcome measures were the Communicative Abilities in Daily Living (CADL) test and subtests from standardized aphasia assessment. RESULTS: After the 2 programs, there was improved writing performance, which was maintained after therapy stopped. Patterns of improvement corresponded to each of the 2 programs. Learning transfer was observed on the CADL test and functional writing, but gains on oral language were limited. Only 1 program was effective for 6 of the 8 patients. CONCLUSION: Specific rehabilitation programs aid recovery from aphasic symptoms from 6 to 12 months postonset. Individual response is linked to type of treatment. The interpretation is linked to a model-based description of aphasic symptoms and mechanisms of functional recovery.

Calculation and number processing in mild Alzheimer's disease.

Calculation and number processing abilities in 17 patients suffering from a mild form of dementia of Alzheimer's type (DAT) were studied by means of a standardized multitask assessment battery, the EC301 (Deloche et al., 1994). Patients were selected from a larger sample by using a specific visuo-perceptive task to control the confounding effects of deficits in analysing digit serial order. Language and memory skills were evaluated by means of standardized testing procedures. The EC301 overall score showed impaired performance in 12 cases. Calculation and number processing scores were highly correlated with Mini-Mental State Examination and language performance. However, multiple single-case analyses indicated heterogeneous patterns of preserved/impaired abilities with respect to the three cognitive areas under investigation (calculation, memory, and language) and to the different components of the calculation and number processing system.

Stroke in two young siblings with congenital dysfibrinogenemia.

Two young siblings (a male of 21 and his sister of 26 years) suffered from arterial thrombosis episodes of the carotid and abdominal aorta documented by angiographic studies. In the absence of any known predisposing factor in the family and personal history, the laboratory investigation of both patients revealed coagulation abnormalities compatible with a dysfibrinogenemia. The occurrence of a similar defect also in plasma of one of the propositi's asymptomatic relatives is suggestive of an inherited fibrinogen disorder.

Natural killer lymphocytes: "null cells" no more.

Natural Killer (NK) lymphocytes were initially described as potent effector cells that, unlike T lymphocytes, were able to kill targets in the absence of a priori stimulation and without specific recognition mechanisms. Over the past ten years however, it has been clearly demonstrated that NK cell function is regulated by a number of surface receptors that bind specific ligands expressed by target cells. Some of these receptors display inhibitory functions and recognize MHC class I molecules expressed by normal autologous cells that, as a consequence, are spared from indiscriminate NK-mediated killing. Other receptors are involved in NK cell activation against allogeneic cells or cells that, upon viral infection or tumor transformation, down-regulate MHC Class I expression. Altogether these data provide important advances toward the understanding of the complexity of the molecular mechanisms that regulate NK-mediated functions.