PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo.

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.

Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia.

Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two-joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis.

An artificial neural network approach to predicting arm movements from ECoG.

There are three specific aims. First, demonstrate the practicality of using an artificial neural network based approach to correlate these cortical signals with actual and imagined arm movements. Second, to identify areas of the cortical surface that provide the most useful command information. Third, quantify the information content and information transfer rate of the signals obtained from the subdural grids relative to a set of relevant arm movements. This work presents progress toward these aims.

Expression of the bilateral deficit during reflexively evoked contractions.

During maximal contractions, the sum of forces exerted by homonymous muscles unilaterally is typically larger than the sum of forces exerted by the same muscles bilaterally. This phenomenon is known as the bilateral deficit (BLD), and it is suggested that this deficit is due to neural inhibition. It remains unclear, however, whether such inhibition is mediated by supraspinal mechanisms or by reflex pathways at the level of spinal cord. To further study the origin of likely neural influences, we tested for the presence of BLD under the condition of reflexive force generation. Force output and integrated electromyogram (iEMG) (quadriceps femoris) were measured in 17 male participants after initiation of the myotatic patellar reflex under unilateral and bilateral conditions. A significant BLD of 9.26 +/- 1.19 (P = 0.004) and 16.76 +/- 4.69% (P = 0.001) was found for force and iEMG, respectively. However, because similar findings were not evident during maximal isometric knee extensions, it is difficult to predict the contribution of a spinal mechanism to the BLD under the condition of maximal voluntary activation.

Chronic stretching and running economy.

Research demonstrates an inverse relationship between the range of motion of selected joint movements (flexibility) and running economy. Since stretching exercises have been shown to increase joint range of motion, stretching exercises may be contraindicated for endurance running performance. Hence, this study investigated the influence of a 10-week program of stretching exercises on the oxygen costs of a 10 min sub-maximal (approx. 70% peak VO(2)) treadmill run. Thirty-two (16 female, 16 male) physically active, treadmill accommodated, college students participated in the study. All participants maintained their current activity level, with half the participants (8 female, 8 male) adding a 40 min, 3 days per week session of thigh and calf muscle stretching exercises. After 10 weeks, the stretching group (STR) exhibited a significant (P<0.05) increase (3.1+/-2.2 cm) in the sit-and-reach, while the non-stretching group (CON) experienced no significant (P>0.05) change (0.0+/-0.4 cm). However, neither the STR nor the CON exhibited a significant (P>0.05) change in the O(2) cost for the submaximal run. It is concluded, therefore, that a chronic stretching program does not necessarily negatively influence running economy.

SIDS, abnormal nighttime REM sleep and CNS immaturity.

SIDS (Sudden Infant Death Syndrome) is the major cause of death in young, apparently healthy, infants, yet its etiology and pathogenesis remain unknown. SIDS peaks at 2-4 months, is more prevalent in the winter months and typically occurs in the early morning hours when most babies are asleep, suggesting that sleep may be part of the pathophysiological mechanism of SIDS. The sleep patterns of infants at high risk for SIDS were analyzed to test the hypothesis that there are abnormalities specific to nighttime sleep which may be indicative of a central nervous system (CNS) deficit that contributes to a high frequency of SIDS during the night. Electrophysiological sleep variables were recorded at monthly intervals in 1-6 months-old infants during the peak age of SIDS. The risk group (R) was resuscitated from a potentially life-threatening Sudden A-Ventilatory Event (S.A.V.E.) and compared to a group of control infants (C) with no family history of SIDS. The data representing four equal time intervals from 11 p.m.-11 a.m. show an abrupt, statistically significant increase in REM sleep from 2-5 a.m. in R infants. In C infants, time spent in REM sleep after 2 a.m. becomes progressively shorter while NREM sleep is proportionately longer. From 11 p.m.-2 a.m., however, R and C infants do not differ either in the duration or in the percent of total sleep time (TST) of REM sleep. We hypothesize that these REM sleep abnormalities in vulnerable infants are indicative of a pervasive CNS immaturity. The higher prevalence of SIDS in the cold winter months and in the early morning hours, when darkness is prolonged, is discussed in relation to the possible involvement of the circadian rhythm of melatonin.

Nutritional status of urban homebound older adults.

The purposes of this study were to assess comprehensively the nutritional status of frail older adults living in an urban area and to identify factors associated with nutritional insufficiency. Subjects were 49 adults aged > or = 65 y followed by the Jefferson County Home Health Department. Twenty-nine percent of the women and 63% of the men had a body mass index (BMI; in kg/m2) < 24. Nineteen percent had serum albumin concentrations < 35 g/L (3.5 g/dL). More than one-half of the subjects reported symptoms of oral health problems. The key dependent variables were serum albumin concentration and BMI. In univariate analyses, a lower BMI correlated with oral symptoms, male sex, increased age, and less education. Lower serum albumin concentrations were associated with advanced age, increased dependence in Activities of Daily Living (ADL), oral symptoms, and presence of a caregiver. A stepwise multiple-regression model for BMI and serum albumin showed that predictors of low BMI were increased age, less education, difficulty in chewing, and absence of dentures. Variables in the model for lower serum albumin concentrations were sex, increased age, increased dependence in ADLs, and wearing of dentures. In a secondary analysis that controlled for age, education level, functional status, and sex, oral symptoms remained associated with lower BMI but not with lower serum albumin concentrations. This study found a high prevalence of undernutrition in urban homebound older adults and suggests that oral health disability may affect nutritional status in this population.

Relative contributions to the net joint moment for a planar multijoint throwing skill: early and late in practice.

The purpose of this investigation was to determine, for a planar, multijoint throwing skill, if the relative contributions of the components of the net joint moment (NJM) at the elbow and shoulder change after practice. Each participant (N = 7) performed 200 throwing trials equally distributed across 5 consecutive days. Each participant threw a 0.15-kg ball as far as possible using the nondominant arm while the motion of the throwing arm was restrained to a horizontal plans. From video data and body segment inertial estimations, NJMs and NJM components (i.e., generalized muscle moments and motion-dependent moments) were calculated for selected early and late practice trials. Performance (throwing distance) showed an expected improvement from early to late practice. The dynamics analysis indicated that participants increased average NJMs and NJM components at both joints. However, the relative contribution of NJM components, expressed as ratios of those components to the NJM at each joint, did not change after extended practice. Restraining the throwing arm to a horizontal plane may partly explain why no changes were found in the relative contributions of NJM components. The lack of change in moment ratios support a motor strategy of scaling joint moments for faster movements.

Quantitative electroencephalographic analyses in cocaine-preferring polysubstance abusers during abstinence.

Quantitative electroencephalographic (QEEG) analyses are presented for a group of 90 subjects recovering from polysubstance abuse (median = 90 days abstinent) who preferentially used cocaine. QEEGs showed significant decreases from normal in both absolute and relative delta power and decreased theta power in both absolute and relative power. Significantly increased relative but not absolute alpha and beta power was found. Asymmetry of frontal delta, theta, and alpha power differed from normal with right power greater than left. Globally, reduced interhemispheric coherence was found in delta and theta bands and frontally in the beta band. An atypical EEG pattern was observed in about half of the subjects. This was a paroxysmal-like EEG alpha pattern reminiscent of vertex waves typically associated with drowsiness but lacking the waxing and waning of alpha and the slow lateral eye drift associated with drowsiness.

Sex differences in the maturation of sleep/wake patterns in high risk for SIDS infants.

Male and female high risk for SIDS infants were compared with a group of rigorously matched controls in sleep/wake variables during the peak period for SIDS, i.e., 2-4 mos. Continuous 24-72 hr. in-hospital recordings yielded data based on 3,792 hrs. of electrophysiological activity. The data show that risk male infants fail to demonstrate an increase in wakefulness with age and reveal a lag in the maturation of REM sleep compared to controls and female risk infants during the critical age for SIDS. Significant sex differences within the first six months of life are of particular importance because of the consistently reported higher incidence of SIDS in males than females. An immature sleep/wake organization which occurs differentially in male high risk for SIDS infants suggests that a CNS functional disorder is present selectively in male infants as a precursor to SIDS. The greater susceptibility of male infants to SIDS emphasizes the importance of these data based on unique long-term recordings.

Corpus and cervix cancer: a nutritional comparison.

Nutritional parameters of patients with cervical cancer and endometrial cancer were prospectively evaluated. Analysis of anthropometric assessments that were abnormal in as many as 52% of patients indicated little difference between organ sites in mean values or percentage of patients with abnormal values. Biochemical parameters included serum albumin, total iron-binding capacity, copper, zinc, and creatinine height index. An abnormal value was present in as many as 60% of patients. Multiple abnormal values were more likely to be present in patients with endometrial cancer. Abnormal vitamin levels were more commonly present in patients with cervical cancer. When compared to control values, levels of plasma folate, beta carotene, and vitamin C were significantly lower in patients with cervical cancer. Patients with endometrial cancer had significantly lower levels of beta carotene and vitamin C. Analysis of surgical complications suggested a correlation with specific nutritional deficits.

Nutritional status of patients with untreated cervical cancer. I. Biochemical and immunologic assessment.

A prospective nutritional evaluation of 78 patients with untreated cervical cancer was undertaken. Stage-related abnormal anthropometric measurements were present in 60% of patients. Abnormal biochemical nutritional measurements were found in 67% of patients. Thirty percent of these patients were anergic to usual skin test antigens. The overall incidence of protein-calorie malnutrition was 12.5%; however, the risk was stage-related. Measured parameters were usually adversely affected following a surgical procedure. Although surgical complications were few, the implications of these findings as to the appropriate method and timing of nutritional assessment as well as the possible benefit from nutritional support in malnourished patients with cervical cancer are discussed.

Nutritional status of patients with untreated cervical cancer. II. Vitamin assessment.

Prospective vitamin assessment was undertaken in 78 patients with untreated cancer of the uterine cervix. At least one abnormal vitamin level was present in 67% of patients while individual levels were abnormal in as many as 38% of patients. Significantly lowered levels of plasma folate, vitamin A, and vitamin C were present. Although most of these vitamins did not correlate with other parameters of protein-calorie malnutrition, the possible preventative and treatment effects of these vitamins require additional investigation.

Respiratory and cardiac events observed and recorded during and following a "near miss" for Sudden Infant Death Syndrome episode.

Documented observations of a 5-week-old infant during a "near miss" for a Sudden Infant Death Syndrome (SIDS) episode by a physician were carried out during an in-hospital physiological recording of respiratory and cardiac activity. This "near miss" event occurred during quiet sleep and was characterized by a prolonged apneic attack with marked bradycardia, cyanosis and limpness which required immediate vigorous resuscitative efforts by a physician and trained nurse. Parental descriptions of similar events parallel these documented sudden unexpected changes in cardiorespiratory parameters. Objective polygraphic data were obtained immediately following the episode and at later ages during 24 and 48 hour continuous recordings of respiration, heart rate, sleep/wake and behavioral activity. The data show that numerous apneic episodes occurred following the "near miss" event, many accompanied by marked bradycardia. The moderately severe hypoxemia noted during these sleep-related apneas indicate that immediate intervention is required to prevent significant hypoxia and central depression in such infants.

Flicker: a "decay" effect after light deprivation.

The "decay" effect resulting from repetitive light stimulation at different flicker rates was investigated. Adult cats were visually deprived monocularly or binocularly for 1 or 2 weeks. The results showed a progressive decrease in the b-wave of the electroretinogram during the later flashes in a train. The data are presented as percent of the initial response to a flash. In the control eye the b-wave stabilized rapidly after the initial flash in a train of stimuli. Partial recovery occurred after 1 week of normal stimulation.

Sleep apnea studies in an infant with congenital primary hypoventilation ("Ondine's curse").

Recurrent apneic episodes were typically associated with sleep, not wakefulness, in an infant with congenital primary hypoventilation ("Ondine's Curse"). Quiet sleep (SLQ) was shown to constitute a higher risk condition than active sleep (SLA) at the ages she was recorded polygraphically (2-4 months old). This infant's respiratory disorder was complicated by recurrent pneumonia, seizures and deficient growth which resulted in death at the age of eight months. Necropsy revealed bronchopulmonary dysplastic fibrosis and cor pulmonale. Neuropathologic examination failed to reveal pathologic changes in the brainstem.

Tapetum disorganization in taurine-depleted cats.

A severe disorganization of the lattice arrangement of tapetal rods occurs in cats nutritionally deprived of taurine. This is the first reported example of a nutritionally related degeneration of tapetal cells. The tapetal cell degeneration, along with the previously noted photoreceptor degeneration in taurine-depleted cats, suggests that taurine plays a vital role in maintaining the structural integrity of some biological structures. The visual evoked potentials were severely reduced in taurine-depleted cats as were the electroretinogram responses, as previously noted, indicating that they are deficient in light processing. These results also emphasize the importance of dietary taurine for the maintenance of normal structure and function of the eye, at least in the cat.