Systemic lupus erythematosus and dementia.
Comparison of Trail-making Parts A and B and the Shipley Conceptual Quotient of 18 index patients (M age = 29 years) and 18 controls indicated no dementia for the index patients.
Adolescent↗
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Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL.
Acute myelogenous leukemia (AML) remains a deadly disease for most adult patients, due primarily to the emergence of chemoresistant cells. Defects in apoptosis pathways make important contributions to chemoresistance, suggesting a need to restore apoptosis sensitivity or to identify alternative pathways for apoptosis induction. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity, including 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-m). We explored the effects of CDDO and CDDO-m in vitro on established AML cell lines (HL-60, U937, AML-2) and on freshly isolated AML blasts. CDDO and CDDO-m reduced the viability of all AML cell lines tested in a dose-dependent manner, with effective doses for killing 50% of cells (ED(50)) within 48 h of approximately 1 and 0.5 muM, respectively. CDDO or CDDO-m also induced substantial increases in cell death in five out of 10 samples of primary AML blasts. Cell death induced by CDDO and CDDO-m was attributed to apoptosis, based on characteristic cell morphology and evidence of caspase activation. Immunoblot analysis demonstrated proteolytic processing of caspase-3, -7, and -8, but not caspase-9, suggesting the involvement of the 'extrinsic' pathway, linked to apoptosis induction by TNF-family death receptors. Accordingly, CDDO and CDDO-m induced concentration-dependent reductions in the levels of FLIP protein, an endogenous antagonist of caspase-8, without altering the levels of several other apoptosis-relevant proteins. Reductions in FLIP were rapid, detectable within 3 h after exposure of AML cell lines to CDDO or CDDO-m. CDDO and CDDO-m also sensitized two of four leukemia lines to TRAIL, a TNF-family death ligand. The findings suggest that synthetic triterpenoids warrant further investigation in the treatment of AML, alone or in combination with TRAIL or other immune-based therapies.
Antineoplastic Agents↗
Could different directions of infant stepping be controlled by the same locomotor central pattern generator?
This study examined the idea of whether the same central pattern generator (CPG) for locomotion can control different directions of walking in humans. Fifty-two infants, aged 2-11 mo, were tested. Infants were supported to walk on a treadmill at a variety of speeds. If forward stepping was elicited, stepping in the other directions (primarily sideways and backward) was attempted. The orientation of the infant on the treadmill belt determined the direction of stepping. In some infants, we also attempted to obtain a smooth transition from one direction to another by gradually changing the orientation of the infant during a stepping sequence. Limb segment motion and surface electromyography from the muscles of the lower limb were recorded. Most infants who showed sustained forward walking also could walk in all other directions. Thirty-three of 34 infants tested could step sideways. The success of eliciting backward stepping was 69%. Most of the infants who did not meet our backward stepping criteria did, however, make stepping movements. The different directions of stepping had similar responses to changes in treadmill speed. The relationship between stance and swing phase durations and cycle duration were the same regardless of the direction of stepping across a range of speeds. Some differences were noted in the muscle activation patterns during different directions of walking. For example, the hamstrings were much more active during the swing phase of backward walking compared with forward walking. The quadriceps was more active in the trailing leg during sideways walking. In some infants, we were able to elicit stepping along a continuum of directions. We found no discrete differences in either the electromyographic patterns or the temporal parameters of stepping as the direction of stepping was gradually changed. The results support the idea that the same locomotor CPG controls different directions of stepping in human infants. The fact that most infants were able to step in all directions, the similarity in the response to speed changes, and the absence of any discrete changes as the direction of stepping was changed gradually are all consistent with this hypothesis.
Brain Stem↗
Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss.
BACKGROUND: The role of sex hormones in the prevention of cognitive decline is uncertain. Animal studies suggest mechanisms for sex hormones including testosterone to maintain optimal cognitive function. But, there are studies to suggest that endogenous testosterone levels are associated with aggression in men with cognitive impairment. METHODS: In this pilot study, 11 men (mean age 80 +/- 5 years, range 73-87 years) with early cognitive decline and bioavailable testosterone levels below 128 ng/dl (lower limit for adult normal range) were randomized to receive intramuscular testosterone (200 mg every 3 weeks) or placebo for 12 weeks. Outcome measures included sex hormones (testosterone, bioavailable testosterone, sex hormone binding globulin, estradiol, and estrone), Behave AD Questionnaire, Katz Activities of Daily Living, Geriatric Depression Scale, Digit Span, Clock Face Drawing, Clock Face Perception, Verbal Fluency, Trail-Making B, and International Prostate Symptom Score at baseline, 4 weeks, and 10 weeks. RESULTS: All men completed the study. Total and bioavailable testosterone, estrone, and estradiol levels increased in men receiving testosterone, but no changes were detected in men receiving placebo. No significant changes were found in behavior following testosterone supplementation, nor was there evidence of change in depression or activities of daily living. No discernable changes were found in any of the cognitive tests. Symptoms of prostate hyperplasia remained unchanged in the testosterone (6.6 + 5.8 to 5.2 + 3.6; p =.39) and placebo (8.8 + 6.4 to 6.4 + 3.8; p =.15) groups, and prostate-specific antigen levels did not change significantly. CONCLUSION: No significant changes in behavior, function, depression, or cognitive performance occurred following 12 weeks of testosterone replacement in men with low testosterone levels and early-to-moderate cognitive impairment. This pilot work suggests that testosterone can be given to men with early cognitive impairment without significant concern about worsening aggressive or unwanted behaviors.
Aged↗
Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen.
STUDY OBJECTIVE: Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN: We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS: The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS: In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION: DNS after CO poisoning cannot be predicted on the basis of a patient's clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.
Adolescent↗
A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array.
A method has been developed for the manufacture of a "three-dimensional" electrode array geometry for chronic intracortical stimulation. This silicon based array consists of a 4.2 x 4.2 x 0.12 mm thick monocrystalline substrate, from which project 100 conductive, silicon needles sharpened to facilitate cortical penetration. Each needle is electrically isolated from the other needles, and is about 0.09 mm thick at its base and 1.5 mm long. The sharpened end of each needle is coated with platinum to facilitate charge transfer into neural tissue. The following manufacturing processes were used to create this array. 1) Thermomigration of 100 aluminum pads through an n-type silicon block. This creates trails of highly conductive p+ silicon isolated from each other by opposing pn junctions. 2) A combination of mechanical and chemical micromachining which creates individual penetrating needles of the p+ silicon trails. 3) Metal deposition to create active electrode areas and electrical contact pads. 4) Array encapsulation with polyimide. The geometrical, mechanical, and electrical properties of these arrays should make them well suited as interfaces to cortical tissue.
Animals↗
Neurobehavioral and respiratory findings in jet engine repair workers: A comparison of exposed and unexposed volunteers.
Workers repairing jet engines had respiratory, rheumatic, and neurobehavioral symptoms. They had welded and ground stainless steel parts using hard metal tools and cleaned metal with chlorinated and fluorinated organic solvents. We compared 154 workers and 112 unexposed subjects, all volunteers of similar ages and with similar educational levels, for abnormalities on chest radiographs, spirometric measurements, and questionnaires. Also appraised were performance of reaction time, balance, blink reflex latency, color discrimination, Culture Fair, vocabulary, slotted pegboard, trail making A and B, profile of mood states (POMS), and frequencies of 35 symptoms. Compared to unexposed subjects, workers had significantly more respiratory symptoms but no differences in pulmonary function. They had significantly prolonged simple and choice reaction time (P<0.0001), and abnormal balance with eyes open and eyes closed (P<0. 0001), and abnormal color discrimination. Blink reflex latency was abnormal in both exposed workers and in local unexposed compared to other reference groups. Focus of the inquiry on lung disease helped ensure that for neurobehavioral tests confounding factors were minimal and known biases were small. We tentatively attribute the neurobehavioral impairments and increased symptom frequencies to chlorinated solvent exposure. Excessive respiratory symptoms are attributed to welding stainless steel combined with cigarette smoking. Specifically, manganese exposure may have affected the respiratory and the central nervous systems.
Adult↗
Visual information processing during controlled hypoglycaemia in humans.
A general impairment of cognitive performance occurs during acute insulin-induced hypoglycaemia, but little objective evidence is available for disruption of more specific cognitive processes. The effect of controlled hypoglycaemia on the early stages of visual information processing and contrast sensitivity was examined in a homogeneous group of 20 nondiabetic human subjects. Hypoglycaemia caused a significant disruption in general cognitive performance as assessed by a digit symbol task (P < 0.001) and the trail making B task (P < 0.05). Hypoglycaemia also produced a highly significant deterioration in performance on all of the visual information processing tasks, namely inspection time (IT) (P = 0.01), visual change detection (VCD) (P < 0.005) and visual movement detection (VMD) (P < 0.005). A significant deterioration in contrast sensitivity was observed during hypoglycaemia (P < 0.005). In contrast, no significant effect of hypoglycaemia was demonstrated on standard clinical measures of visual acuity or stereoscopic vision. Thus, although hypoglycaemia caused no detectable deterioration in visual acuity as measured by Snellen-type tests, a marked deterioration occurred in the speed of visual information processing and in contrast sensitivity. As many decisions are made under conditions of limited perceptual time and low visual contrast (e.g. when driving), the disruptive effect of moderate insulin-induced hypoglycaemia on visual perception will have important practical implications in diabetic humans exposed to this metabolic stress. The present results are congruent with other evidence which shows that the early stages of visual information processing are susceptible to deterioration by general cerebral insults.
Adult↗
Effects of hydrogen sulfide on neurobehavioral function.
BACKGROUND: Nineteen hydrogen sulfide (H2S)-exposed patients were compared with 202 unexposed subjects. This 1997-to-2001 case-referent series was compared with 16 previous (1991-1996) case-referent patients. METHODS: New patients were bystanders of H2S exposure and none had been unconscious. In contrast, 13 members of the prior group were exposed at work and 7 had been unconscious. The three groups were compared on the basis of 8 physiologic and 12 psychological measurements. Observed measurements were compared with predicted ones after adjusting for age, sex, educational attainment (years), and other significant factors (observed/predicted x 100). RESULTS: The new group performed poorly compared with unexposed controls and were similar to the first group on balance, reaction time, color discrimination, visual performance, hearing, Culture Fair, digit symbol, vocabulary, verbal recall, peg placement, trail making A and B, and information. CONCLUSION: H2S impairments associated with H2S were similar in 19 workers (44% had been unconscious) and in 16 bystanders who had not been unconscious.
Adult↗
Nonsteroidal antiinflammatory agents in chemoprevention of colorectal cancer. At what cost?
The objective was to provide a comparison of the known toxicities of nonsteroidal antiinflammatory drugs (NSAIDS) and the likelihood of benefit from colorectal cancer (CRC) chemoprevention attributed to them. Chemoprevention trials require large numbers of subjects followed over many years and are therefore very expensive and difficult. Hence, it is important that agents tested in these trails have a realistic expectation of actual use in the population. Data sources were published literature on the toxicity and CRC chemopreventive activity of NSAIDS. Presently available NSAIDS, used at their usual therapeutic doses, have a serious toxicity rate that quickly exceeds any benefit from CRC prevention. In contrast, low-dose aspirin is worth evaluating, especially because of the potential for simultaneous cardiovascular risk reduction. Possibly, low doses of other NSAIDS may have benefit, but this remains unproven. Synthesis of other NSAIDS, with less toxicity, is another approach towards making the toxicity-benefit ratio more favorable for the use of these agents for CRC prevention.
Animals↗
Surgery for low-grade glioma: rationale for early intervention.
We feel that early surgical intervention is appropriate in the patient who presents with a clinical picture suggesting a low-grade glioma. Neuroimaging is not adequate to make an accurate diagnosis of the underlying pathology. Tumor tissue sampling allows a more specific diagnosis and testing for biologic factors such as the proliferative potential of the lesion. Surgical diagnosis allows a disease-specific therapy to be more appropriately prescribed to the patient, including the option for no further treatment, radiotherapy, and/or chemotherapy. There is compelling early data that suggest that the extent of surgery and the postoperative tumor volume will be predictive of outcome in at least some tumor types. We encourage participation of physician and patients in well-designed clinical trails that will ultimately answer the many questions that remain about these unique diseases.
Brain Neoplasms↗
Hydrogen sulfide and reduced-sulfur gases adversely affect neurophysiological functions.
Hydrogen sulfide (H2S) above 50 parts per million (ppm) causes unconsciousness and death. Lower doses of H2S and related gases have been regarded as innocuous, but the effects of prolonged exposure have not been studied. This study was designed to determine whether people exposed to sulfide gases as a result of working at or living downwind from the processing of "sour" crude oil demonstrate persistent neurobehavioral dysfunction. Thirteen former workers and 22 neighbors of a refinery complained of headaches, nausea, vomiting, depression, personality changes, nosebleeds, and breathing difficulties. Their neurobehavioral functions and a profile of mood states (POMS) were compared to 32 controls, matched for age and educational level. The exposed subjects' mean values were statistically significantly abnormal compared to controls for two-choice reaction time, balance (as speed of sway), color discrimination, digit symbol, trail-making A and B, and immediate recall of a story. Their POMS scores were much higher than those of controls. Visual recall was significantly impaired in neighbors, but not in exworkers. It was concluded that neurophysiological abnormalities were associated with exposure to reduced sulfur gases, including H2S from crude oil desulfurization.
Adult↗
Inhibition and shifting in children with learning deficits in arithmetic and reading.
The executive functions of inhibition and shifting were studied in arithmetic-disabled children, reading-disabled children, reading plus arithmetic-disabled children, and controls (N = 74). Measures involved the rapid naming of objects, digits, letters, or quantities with or without additional task requirements that reflected inhibition or shifting. Also, the Making Trails task, reflecting shifting, was administered. For tasks without executive demands, arithmetic-disabled children were slower in the naming of digits and quantities, whereas reading-disabled children were slower in the naming of digits and letters. For the executive tasks, arithmetic-disabled children as well as reading plus arithmetic-disabled children were impaired on the Making Trails task and on an object naming task that required both inhibition and shifting. Reading-disabled children exhibited no problems in executive functioning. Furthermore, it was shown that reading plus arithmetic-disabled children experienced the combination of problems that characterize children with a single learning deficit.
Child↗
Early lead exposure and neonatal jaundice: relation to neurobehavioral performance at 15 years of age.
A cohort of children who attended first grade in 1983 was identified in a Danish community with low-level lead pollution. Two groups with high and low postnatal lead exposure were generated on the basis of the dentin-lead concentration in shed deciduous incisors. At age 8 years, examination of 162 children matched according to gender and socioeconomic status had shown lead-related deficits in verbal intelligence and visuomotor coordination. Re-examination was now carried out in 141 children at age 15 years using the Wechsler Intelligence Scale for Children (WISC), Bender Visual Motor Gestalt, Trail Making, and Visual Gestalts. In general, no lead-related effects could be detected in the group. However, in children with a history of neonatal jaundice, increased lead exposure was associated with mild neurobehavioral deficits, as indicated by lower verbal IQ scores and decreased visuomotor coordination. This finding suggested that moderate neonatal hyperbilirubinemia may have precipitated an increased sensitivity to subsequent exposure to lead.
Adolescent↗
Lessons from Darwin: evolutionary biology's implications for Alzheimer's disease research and patient care.
What are the aims appropriate for a science of clinical pharmacology and clinical trials: to test drugs for efficacy and safety in the clinic, to establish the optimal effectiveness and safety of drugs in patient care or both? Current designs of clinical trials test drugs for efficacy and safety in clinical settings-they do not address the clinician's problems adequately. Clinical trials better address the effectiveness of drugs in patient care with analyses to determine drug effects for each individual in the trial. We use current standards and designs for clinical trails supplemented to control random error effects for the individuals in the trials. Test-retest standard error of measurement can control random error effects for individuals. This allows individual clinical courses to be plotted with known precision and certainty. For individuals in a clinical trial the clinical course of surrogate outcome variables can be associated with long-term health outcomes in followup to develop clinical decision rules. Clinical courses on surrogate outcome variables during patient care can be interpreted using these clinical decision rules. In this Age of the Internet, Computers and Handhelds, electronic records and interpretations of clinical examinations and tests can be a part of decision making for every patient. We conclude that practical methods are available for making clinical trials more informative for clinical practice. This modification replaces "unsystematic clinical judgments" with statistically characterized data and interpretations for individuals available as care is delivered in the doctor's office. An AD demonstration can be viewed at www.healthpragmatics.com.
Alzheimer Disease↗
Quantum dot-based cell motility assay.
Motility and migration are measurable characteristics of cells that are classically associated with the invasive potential of cancer cells, but in vitro assays of invasiveness have been less than perfect. We previously developed an assay to monitor cell motility and migration using water-soluble CdSe/ZnS nanocrystals; cells engulf the fluorescent nanocrystals as they crawl across them and leave behind a fluorescent-free trail. We show here that semiconductor nanocrystals can also be used as a sensitive two-dimensional in vitro invasion assay. We used this assay to compare the behavior of seven different adherent human cell lines, including breast epithelial MCF 10A, breast tumor MDA-MB-231, MDA-MB-435S, MCF 7, colon tumor SW480, lung tumor NCI H1299, and bone tumor Saos-2, and observed two distinct behaviors of cancer cells that can be used to further categorize these cells. Some cancer cell lines demonstrate fibroblastic behaviors and leave long fluorescent-free trails as they migrate across the dish, whereas other cancer cells leave clear zones of varying sizes around their periphery. This assay uses fluorescence detection, requires no processing, and can be used in live cell studies. These features contribute to the increased sensitivity of this assay and make it a powerful new tool for discriminating between non-invasive and invasive cancer cell lines.
Carcinogenicity Tests↗
Outcome variables for the study of periodontal regeneration.
The most reliable outcome variable for assessing periodontal regeneration is human histology; however, the morbidity associated with this technique makes it feasible only in isolated case studies designed to prove that a drug, device, or technique is capable of regenerating the lost periodontium including bone, cementum, and functionally oriented periodontal ligament. In the absence of this genuine variable, other "surrogate" variables must be used. Of these, measurement of new bone is the primary alternative. Direct bone measurements, including linear and volumetric assessment, are by far the best tools; however, the need for a second surgical procedure is a definite drawback of this technique. To overcome this problem, other outcomes have been employed: sounding bone measurements is a less invasive method, albeit it is also less accurate. Another tool that has been tested extensively is radiographic analysis. Conventional radiography is not useful in most regenerative trails where minimal or no crestal changes occur. The use of standardized radiographs and image processing techniques to measure alveolar bone changes has not significantly enhanced the applicability of this method. Digital subtraction radiography (DSR) offers some improvement over previous techniques; however, the correlation between the magnitude of clinical bone changes and changes in the digital image is yet to be substantiated. Other variables have been successfully used in regenerative studies. These include clinical attachment level changes, change in probing depth, and gingival recession. The information derived from these variables, especially attachment level changes, supplement and substantiate the direct bone measurements. Other variables that may be monitored are those associated with plaque formation, periodontal pathogens and gingival inflammation; while not direct measures of regeneration, these variables are likely to affect future prognosis and treatment stability. In summary, direct bone measurements are the most ideal surrogate outcome variable, although clinical attachment level measurements are commonly used in large-scale regenerative clinical trials. Clinical response may be assessed at different time intervals; however, the endpoint measurements for regenerative studies should be taken at least 12-months postoperatively.
Alveolar Bone Loss↗
Turning gap acceptance decision-making: the impact of driver distraction.
PROBLEM: A number of studies have found that use of in-car phones by drivers can interfere with the cognitive processing necessary for making appropriate and timely vehicle control decisions. However, the specific linkage between communication-based distraction and unsafe decision-making has not been sufficiently explored. METHOD: In a closed-course driving experiment, 39 subjects were exposed to approximately 100 gaps each in a circulating traffic stream of eight vehicles on an instrumented test track that was wet about half the time. The subjects were at the controls of an instrumented car, which was oriented in a typical left-turn configuration (traffic-crossing situation in North America) and with parking brake on and the transmission in neutral. The subjects were instructed to press on the accelerator pedal when they felt that a gap was safe to accept. Their performances were monitored and incentives were provided for balancing safe decision-making with expeditious completion of the task. For half of the gap exposures (randomly assigned), each subject was required to listen and respond to a complex verbal message. RESULTS: When not distracted, the subjects' gap acceptance judgment was found to be significantly influenced by their age, the gap size, the speed of the trailing vehicle, the level of "indecision," and the condition of the track surface. However, when distracted, the subjects did not factor pavement surface condition into the decision process. On wet pavement, the subjects were judged to have initiated twice the level of potential collisions when distracted by the messages that they did when not distracted. DISCUSSION: Listening/responding to verbal messages may reduce the capacity of drivers to process adequately all the important information necessary for safe decision-making. The effects of the messages in our study seemed to cause the subjects to misjudge gap size and speed information when operating under the additional disadvantage of adverse pavement condition. SUMMARY: Attention to complex messages while making decisions about turning through gaps in an on-coming vehicle stream was associated with significantly increased unsafe decision making by subjects in our experiment when the additional complexity of wet surface condition was introduced. IMPACT ON INDUSTRY: While the results reflected a somewhat artificial situation where the measure was signaled intention to act rather than the act itself, nevertheless, they do strongly suggest a scenario in which mental distraction could contribute to crash risk. With the rapid proliferation of telematics in the vehicle market, even with the laudable objectives represented by the Intelligent Transportation Systems initiative, there is a danger of the primary task of the driver being subordinated to a perceived need to enhance information flow to/from the external "world." Industry and governments need to work together to ensure that apparently desirable in-vehicle communication improvements do not compromise safety.
Accidents, Traffic↗