Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis

Neurofilaments are cytoskeletal proteins localized within axons, which may interact with the immune system during and following tissue destruction in multiple sclerosis (MS). Antibodies against the medium neurofilament subunit synthesized intrathecally may reflect axonal damage in MS patients. Both immunoglobulin G (IgG) and M (IgM) responses against the purified native medium subunit of neurofilaments (NFM) using enzyme-linked immunosorbent assay (ELISA) were determined in paired serum and cerebrospinal fluid samples obtained from 49 MS patients, 16 normal controls (CN), 21 control patients with miscellaneous diseases (CD) and 14 patients with neurodegenerative disorders (CDEG). Intrathecal production of IgM and IgG antibodies to NFM were elevated in MS patients compared with the CN or CD groups (p < 0.04 for IgM, p < 0.01 for IgG). The increase was present in all the MS courses (relapsing-remitting, primary and secondary progressive). Similar local anti-NFM IgG and IgM synthesis occurred in the MS and CDEG groups. MS patients with short and long disease duration did not differ in terms of their anti-NFM IgM and IgG responses. Repeated examinations showed stable intrathecal anti-NFM production. Intrathecal IgG and IgM antibodies against NFM were increased in MS patients and may serve as a potential marker for axonal pathology. The extent of anti-NFM levels did not correspond to any individualized clinical profiles of MS patients.     

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.     

The patient with schizophrenia and his father. The father's role and personality traits in the dynamics of the family with a son suffering from schizophrenia

The role of the father in the onset and development of schizophrenic disorder/disturbance is very often secondary as compared to that of the mother. This study deals with the father's sphere in the family with a patient/son suffering from schizophrenia, the traits of his personality and his relationship with his son/patient, and with his wife/the mother of the patient. The methods applied were clinical interview, structured interview and semantic differential. The following statistical procedures were used: correlation, componential, discriminative, factor and quasicanonical analyses. The results include some characteristic excerpts from clinical interviews with patients/sons and their fathers, projective perception of current family relationships, quasicanonical analysis of the father's, mother's and son's experiences of the patient's/son's early childhood, and the projective view of the father. Among the conclusions reached, the phenomenon of "dead father" is emphasized as one of the main factors in the onset and development of schizophrenic disorder/disturbance.     

The sea urchin embryo, an invertebrate model for mammalian developmental neurotoxicity, reveals multiple neurotransmitter mechanisms for effects of chlorpyrifos: therapeutic interventions and a comparison with the monoamine depleter, reserpine

Lower organisms show promise for the screening of neurotoxicants that might target mammalian brain development. Sea urchins use neurotransmitters as embryonic growth regulatory signals, so that adverse effects on neural substrates for mammalian brain development can be studied in this simple organism. We compared the effects of the organophosphate insecticide, chlorpyrifos in sea urchin embryos with those of the monoamine depleter, reserpine, so as to investigate multiple neurotransmitter mechanisms involved in developmental toxicity and to evaluate different therapeutic interventions corresponding to each neurotransmitter system. Whereas reserpine interfered with all stages of embryonic development, the effects of chlorpyrifos did not emerge until the mid-blastula stage. After that point, the effects of the two agents were similar. Treatment with membrane permeable analogs of the monoamine neurotransmitters, serotonin and dopamine, prevented the adverse effects of either chlorpyrifos or reserpine, despite the fact that chlorpyrifos works simultaneously through actions on acetylcholine, monoamines and other neurotransmitter pathways. This suggests that different neurotransmitters, converging on the same downstream signaling events, could work together or in parallel to offset the developmental disruption caused by exposure to disparate agents. We tested this hypothesis by evaluating membrane permeable analogs of acetylcholine and cannabinoids, both of which proved effective against chlorpyrifos- or reserpine-induced teratogenesis. Invertebrate test systems can provide both a screening procedure for mammalian neuroteratogenesis and may uncover novel mechanisms underlying developmental vulnerability as well as possible therapeutic approaches to prevent teratogenesis.     

Methodological issues in conducting treatment trials for psychological nonepileptic seizures

A randomized, placebo-controlled trial has yet to be completed in patients with psychological nonepileptic seizures (NES). Treatment publications for NES are limited to class III trials and class IV reports. Little is written on the methodology of treatment trials in NES. The authors describe the procedures and limitations of such a trial to inform future NES treatment trials, based on their prospective, open-label pharmacological, feasibility trial. The authors review the recruitment, enrollment, completion of surveys, compliance, and follow-up of patients with NES. The majority of patients who enrolled, readily completed surveys and took the medication during the trial. Twelve patients were screened, eight enrolled, and six completed the trial. The authors discuss the use of outcomes and the various symptoms scales in the trial. A comprehensive neuropsychiatric initial assessment and assessing cognitive, emotional, behavioral, and psychosocial measures are important for monitoring the outcomes in NES treatment RCTs.     

Modulation of neuronal responses in macaque primary visual cortex in a memory task

The primary visual cortex, a relatively early station in the visual pathway, has long been considered mainly as a site of basic feature detection but evidence is emerging that is consistent with the existence of feedback influences from higher cortical areas. We show that in a delayed match-to-sample memory task, where the monkey needs to remember both the visual pattern and its location, there is significant modulation of neuronal activity in the primary visual cortex suggestive of a feedback signal. Responses to identical patterns are remarkably different depending upon their place in the memory task. These modulatory influences are significantly less when the same visual patterns are shown during a simple fixation task, where these stimuli can be ignored and not attended to. The results indicate that neural processing specific to attentional and mnemonic functions can involve even primary sensory areas.     

Modifications of cognitive and motor tasks affect the occurrence of event-related potentials in the human cortex

This study concerns the question of how task modification affects the frequency occurrence of event-related potentials (ERP) inside the active cortical areas. In 13 candidates for epilepsy surgery, 156 sites in the temporal (74), frontal (73), and parietal (9) cortices were recorded by means of depth and subdural electrodes. Four modifications of the somatosensory evoked P3-like potentials were performed; (i) an oddball paradigm with silent counting of target stimuli (P3c); (ii) an oddball paradigm with a hand movement in response to target stimuli (P3m); (iii) an S1-S2 paradigm, ERP in the P300 time window after the S2 stimulus, with silent counting of target stimuli (S2c), and (iv) an S1-S2 paradigm with a hand movement in response to target stimuli (S2m). In comparing the oddball paradigms with the S1-S2 (contingent negative variation, CNV) paradigms, four regions emerge that are significantly linked with the oddball P3; the prefrontal cortex, the cingulate, the amygdalo-hippocampal complex, and the lateral temporal cortex. A prominent role of the cingulate and the fronto-orbital cortex in the cognitive processing of movement was supported when tasks with identical cognitive loads but different required responses were compared. Even relatively simple cognitive tasks activate many cortical regions. The investigated areas were activated in all tests; however, small regions in each field were active or inactive in relation to the nature of the task. The study indicates a variable and task-dependent internal organization of a highly complex and widely distributed system of active cortical areas.     

Cyclin-dependent kinase inhibitors as potential targeted anticancer agents

Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Genes involved in cell cycle are frequently mutated in human cancer and deregulated CDK activity represents a hallmark of malignancy. This knowledge provides a rationale for regarding CDKs and their associated molecules as potential targets for new drug development in anticancer research. The present article will review the most relevant CDK inhibitors with emphasis on the newer molecules in clinical development and the biological rationale of this therapeutic approach.