Fishing for function in noise.
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Animals↗
Biomedical subjects
J J Collins
Publications and source records attributed to J J Collins.
Symmetry in locomotor central pattern generators and animal gaits.
Animal locomotion is controlled, in part, by a central pattern generator (CPG), which is an intraspinal network of neurons capable of generating a rhythmic output. The spatio-temporal symmetries of the quadrupedal gaits walk, trot and pace lead to plausible assumptions about the symmetries of locomotor CPGs. These assumptions imply that the CPG of a quadruped should consist of eight nominally identical subcircuits, arranged in an essentially unique matter. Here we apply analogous arguments to myriapod CPGs. Analyses based on symmetry applied to these networks lead to testable predictions, including a distinction between primary and secondary gaits, the existence of a new primary gait called 'jump', and the occurrence of half-integer wave numbers in myriapod gaits. For bipeds, our analysis also predicts two gaits with the out-of-phase symmetry of the walk and two gaits with the in-phase symmetry of the hop. We present data that support each of these predictions. This work suggests that symmetry can be used to infer a plausible class of CPG network architectures from observed patterns of animal gaits.
Animals↗
Noise shaping in populations of coupled model neurons.
Biological information-processing systems, such as populations of sensory and motor neurons, may use correlations between the firings of individual elements to obtain lower noise levels and a systemwide performance improvement in the dynamic range or the signal-to-noise ratio. Here, we implement such correlations in networks of coupled integrate-and-fire neurons using inhibitory coupling and demonstrate that this can improve the system dynamic range and the signal-to-noise ratio in a population rate code. The improvement can surpass that expected for simple averaging of uncorrelated elements. A theory that predicts the resulting power spectrum is developed in terms of a stochastic point-process model in which the instantaneous population firing rate is modulated by the coupling between elements.
Mathematics↗
Risks of valve replacements in young women.
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Adult↗
The autonomous transactivation domain in helix H3 of the vitamin D receptor is required for transactivation and coactivator interaction.
A ligand-inducible transactivation function (AF-2) exists in the extreme carboxyl terminus of the vitamin D receptor (VDR) that is essential for 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-activated transcription and p160 coactivator interaction. Crystallographic data of related nuclear receptors suggest that binding of 1, 25-(OH)2D3 by VDR induces conformational changes in the ligand-binding domain (LBD), the most striking of which is a packing of the AF-2 helix onto the LBD adjacent to helices H3 and H4. In this study, a panel of VDR helix H3 mutants was generated, and residues in helix H3 that are important for ligand-activated transcription by the full-length VDR were identified. In particular, one mutant (VDR (Y236A)) exhibited normal ligand binding and heterodimerization with the retinoid X receptor (RXR) but was transcriptionally inactive. Yeast two-hybrid studies and in vitro protein interaction assays demonstrated that VDR (Y236A) was selectively impaired in interaction with AF-2-interacting coactivator proteins such as SRC-1 and GRIP-1. These data indicate an importance of helix H3 in the mechanism of VDR-mediated transcription, and they support the concept that helix H3 functions in concert with the AF-2 domain to form a transactivation surface for binding the p160 class of nuclear receptor coactivators.
Animals↗
Assessing muscle stiffness from quiet stance in Parkinson's disease.
In previous studies, we developed a postural stiffness measure that is extracted from foot center-of-pressure (COP) trajectories from quietly standing individuals and is based on an analytical mechanical model of posture control. Here we apply this measure to patients with Parkinson's disease (PD). We correlated the postural stiffness measure with different clinical rating scales, obtained from patients. Kendall's rank correlation was highly significant between the stiffness measure and rigidity, bradykinesia, posture impairment, gait, and leg agility, respectively, as rated by the Unified Parkinson's Disease Rating Scale. These results provide further evidence that a higher intrinsic muscle stiffness may contribute to the aforementioned clinically defined symptoms. From a clinical standpoint, this work indicates that the proposed postural stiffness measure may be useful as an assessment tool for the evaluation of PD patients subsequent to pharmacological and surgical treatment.
Disability Evaluation↗
The effects of stochastic galvanic vestibular stimulation on human postural sway.
Galvanic vestibular stimulation serves to modulate the continuous firing level of the peripheral vestibular afferents. It has been shown that the application of sinusoidally varying, bipolar galvanic currents to the vestibular system can lead to sinusoidally varying postural sway. Our objective was to test the hypothesis that stochastic galvanic vestibular stimulation can lead to coherent stochastic postural sway. Bipolar binaural stochastic galvanic vestibular stimulation was applied to nine healthy young subjects. Three different stochastic vestibular stimulation signals, each with a different frequency content (0-1 Hz, 1-2 Hz, and 0-2 Hz), were used. The stimulation level (range 0.4-1.5 mA, peak to peak) was determined on an individual basis. Twenty 60-s trials were conducted on each subject - 15 stimulation trials (5 trials with each stimulation signal) and 5 control (no stimulation) trials. During the trials, subjects stood in a relaxed, upright position with their head facing forward. Postural sway was evaluated by using a force platform to measure the displacements of the center of pressure (COP) under each subject's feet. Cross-spectral measures were used to quantify the relationship between the applied stimulus and the resulting COP time series. We found significant coherency between the stochastic vestibular stimulation signal and the resulting mediolateral COP time series in the majority of trials in 8 of the 9 subjects tested. The coherency results for each stimulation signal were reproducible from trial to trial, and the highest degree of coherency was found for the 1- to 2-Hz stochastic vestibular stimulation signal. In general, for the nine subjects tested, we did not find consistent significant coherency between the stochastic vestibular stimulation signals and the anteroposterior COP time series. This work demonstrates that, in subjects who are facing forward, bipolar binaural stochastic galvanic stimulation of the vestibular system leads to coherent stochastic mediolateral postural sway, but it does not lead to coherent stochastic anteroposterior postural sway. Our finding that the coherency was highest for the 1- to 2-Hz stochastic vestibular stimulation signal may be due to the intrinsic dynamics of the quasi-static postural control system. In particular, it may result from the effects of the vestibular stimulus simply being superimposed upon the quiet-standing COP displacements. By utilizing stochastic stimulation signals, we ensured that the subjects could not predict a change in the vestibular stimulus. Thus, our findings indicate that subjects can act as "responders" to galvanic vestibular stimulation.
Adolescent↗
Vagal afferents from the uterus and cervix provide direct connections to the brainstem.
Previous anatomical studies demonstrated vagal innervation to the ovary and distal colon and suggested the vagus nerve has uterine inputs. Recent behavioral and physiological evidence indicated that the vagus nerves conduct sensory information from the uterus to the brainstem. The present study was undertaken to identify vagal sensory connections to the uterus. Retrograde tracers, Fluorogold and pseudorabies virus were injected into the uterus and cervix. DiI, an anterograde tracer, was injected into the nodose ganglia. Neurectomies involving the pelvic, hypogastric, ovarian and abdominal vagus nerves were performed, and then uterine whole-mounts examined for sensory nerves containing calcitonin gene-related peptide. Nodose ganglia and caudal brainstem sections were examined for the presence of estrogen receptor-containing neurons in "vagal locales." Labeling of uterine-related neurons in the nodose ganglia (Fluorogold and pseudorabies virus) and in the brainstem nuclei (pseudorabies virus) was obtained. DiI-labeled nerve fibers occurred near uterine horn and uterine cervical blood vessels, in the myometrium, and in paracervical ganglia. Rats with vagal, pelvic, hypogastric and ovarian neurectomies exhibited a marked decrease in calcitonin gene-related peptide-immunoreactive nerves in the uterus relative to rats with pelvic, hypogastric, and ovarian neurectomies with intact vagus nerves. Neurons in the nodose ganglia and nucleus tractus solitarius were immunoreactive for estrogen receptors. These results demonstrated: (1) the vagus nerves serve as connections between the uterus and CNS, (2) the nodose ganglia contain uterine-related vagal afferent neuron cell bodies, and (3) neurons in vagal locales contain estrogen receptors.
Animals↗
Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates.
OBJECTIVES: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. METHODS: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. RESULTS: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 microg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. CONCLUSIONS: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol.
Administration, Cutaneous↗
Impact of body mass index and albumin on morbidity and mortality after cardiac surgery.
OBJECTIVE: Extremely thin and overly obese patients may not tolerate cardiac surgery as well as other patients. A retrospective study was conducted to determine whether the extremes of body mass index (weight/height(2) [kg/m(2)]) and/or cachexia increased the morbidity and mortality associated with cardiac operations. METHODS: Body mass index was used to objectively measure "thinness" (body mass index < 20) and "heaviness" (body mass index > 30); preoperative serum albumin was used to quantify nutritional status and underlying disease. Data were gathered between 1993 and 1997 from 5168 consecutive patients undergoing coronary artery bypass or valve operations, or both. RESULTS: No significant correlations were observed between body mass index and preoperative albumin levels. Low body mass index (<20) and low albumin level (<2.5 g/dL) were each independently associated with increased mortality after cardiopulmonary bypass (P </=.0005). Operative mortality was highest among those with both low body mass index and low albumin level. Multivariable logistic regression, adjusting for potentially confounding variables, demonstrated that an albumin level of less than 2.5 g/dL was independently associated with increased risk of reoperation for bleeding, postoperative renal failure, and prolonged ventilatory support, intensive care unit stay, and total length of stay. A body mass index of more than 30 was associated with increased sternal wound infection and saphenous vein harvest site infection. CONCLUSIONS: Hypoalbuminemia and low body mass index each independently predict increased morbidity and mortality after cardiac operations. Preoperative risk stratification with the use of body mass index and serum albumin may help to identify subgroups of patients at high risk for adverse outcomes after cardiac operations.
Aged↗
Effectiveness of short-course therapy (5 days) with grepafloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis.
Three hundred eighty-nine patients were enrolled in a double-masked, multicenter, randomized clinical trial comparing the clinical and bacteriologic efficacies and safety of a 5-day course (n = 195) versus a 10-day course (n = 194) of grepafloxacin 400 mg once daily in the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB). Patients in the 5-day treatment group received placebo on days 6 through 10. Bacteriologic assessments were based on cultures of sputum specimens obtained before and, when possible, during and after treatment. Organisms were isolated from the pretreatment sputum specimens of 332 of 388 (86%) patients, the primary pathogens being Haemophilus parainfluenzae, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus (29%, 19%, 4%, 5%, and 5% of isolates, respectively). Among isolates tested for beta-lactamase production, results were positive in 25% of H influenzae isolates and 90% of M catarrhalis isolates. Forty-two percent of S pneumoniae isolates demonstrated reduced susceptibility (intermediate or high-level resistance) to penicillin. A satisfactory clinical outcome (cure or improvement) was achieved in 83% (128 of 155) and 81% (122 of 150) of clinically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. Pathogens were eradicated or presumed eradicated in 77% (106 of 138) and 80% (98 of 123) of bacteriologically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. The 2 treatment groups were equivalent with respect to both clinical and bacteriologic efficacy, and no statistically significant differences in the incidence of drug-related adverse events were seen between the 2 groups. Substantial symptom relief was evident with both treatment regimens by the first during-treatment measurement, which occurred between days 3 through 5. These results indicate that treatment with 400 mg grepafloxacin once daily for 5 days is as well tolerated and effective as treatment for 10 days in patients with ABECB. The lower cost compared with a 10-day regimen and the increased likelihood that patients will complete the entire shorter, once-daily regimen make the 5-day grepafloxacin regimen a useful therapeutic option in the treatment of ABECB.
Acute Disease↗
A theory for controlling cell cycle dynamics using a reversibly binding inhibitor.
We demonstrate, by using mathematical modeling of cell division cycle (CDC) dynamics, a potential mechanism for precisely controlling the frequency of cell division and regulating the size of a dividing cell. Control of the cell cycle is achieved by artificially expressing a protein that reversibly binds and inactivates any one of the CDC proteins. In the simplest case, such as the checkpoint-free situation encountered in early amphibian embryos, the frequency of CDC oscillations can be increased or decreased by regulating the rate of synthesis, the binding rate, or the equilibrium constant of the binding protein. In a more complex model of cell division, where size-control checkpoints are included, we show that the same reversible binding reaction can alter the mean cell mass in a continuously dividing cell. Because this control scheme is general and requires only the expression of a single protein, it provides a practical means for tuning the characteristics of the cell cycle in vivo.
Animals↗
Mitral valve repair in cardiomyopathy.
BACKGROUND: Volume overload secondary to mitral regurgitation (MR) in cardiomyopathy is considered critical in the pathogenesis of subsequent ventricular dysfunction. Open mitral valve repair (OMVP) is hypothesized to improve symptomatology and ventricular function by reducing the volume overload of the left ventricle. METHODS AND RESULTS: All patients who underwent OMVP with a left ventricular ejection fraction (EF) of < 0.30 (n = 81) from 1984 through 1997 were reviewed (1 patient was lost to follow-up). Fifteen operations (18.5%) were repeat operations after previous coronary artery bypass graft surgery. Preoperative and postoperative EFs and NYHA class were compared. Survival probabilities were calculated, and multivariate analysis was performed. The average age of all patients was 67.1 years (range, 41 to 83 years). Mean follow-up was 1.7 years (range, 2 months to 8.5 years). The most common mitral repair was ring annuloplasty. Sixty-two patients (77%) had concomitant coronary artery bypass graft surgery. The surgery mortality rate was 11% (9 of 81); 6 of these 9 patients were > 70 years old. The overall Kaplan-Meier survival probability rate at 1, 2, 3, 4, and 5 years was 0.73, 0.68, 0.58, 0.50, and 0.38, respectively. EF improved significantly (0.24 to 0.32; P < 0.0001), as did the NYHA class (3.2 to 1.6; P < 0.0001), at follow-up. There was no difference in late survival between patients with an EF of < 0.20 (21 patients) and those with an EF between 0.20 and 0.30 (P = NS). Risk factors for death included heart failure and old age. CONCLUSIONS: OMVP for MR in the setting of ischemic cardiomyopathy and low EF appear to improve ventricular function, medium-term patient symptomatology, and survival.
Adult↗
It's a small world.
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Games, Experimental↗
Life-support system benefits from noise.
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Lung↗
Twenty-year follow-up of the Hancock modified orifice porcine aortic valve.
BACKGROUND: The entire experience with the Hancock modified orifice porcine bioprosthetic aortic valve from 1976 to 1996 at the Brigham and Women's Hospital has been reviewed. Eight hundred forty-three patients received this valve with a total follow-up of 61,114 months, and a mean follow-up of approximately 72.5 months. There were 490 men and 353 women, and the predominate lesion was aortic stenosis (636 of 843); 365 (43%) patients required a concomitant coronary artery bypass graft operation. METHODS: Patients were followed prospectively in the Brigham Cardiac Valve Data Registry, and the data were analyzed by the SAS statistical package, using actuarial survival curves and incidence per patient-year of morbidity and mortality. RESULTS: The overall operative mortality was 45 of 843 (5.3%) with 23 of 478 (4.8%) for isolated aortic valve replacement and 22 of 365 (6.0%) for aortic valve plus coronary artery bypass graft operation. The major morbidity of this valve was structural valve dysfunction, which was significantly related to the age of the patient in whom the valve was placed. Actuarial probability of freedom from structural valve degeneration at 5, 10, and 15 years overall was 99%+/-1%, 79%+/-3% and 57%+/-4%, at 15 years, respectively. In patients younger than 50 years, freedom from structural valve dysfunction was 16%+/-8%, whereas in the age group older than 70 years it was 87%+/-5% (p = 0.0005). Thromboembolism at 10 and 15 years was 81%+/-3% overall, 84%+/-2% in patients in normal sinus rhythm, and 57%+/-13% in patients with chronic atrial fibrillation. CONCLUSIONS: The Hancock modified orifice aortic valve, despite its more complicated fabrication, has been a reliable porcine bioprosthetic valve and can be used reliably in patients older than 70 years because of its low structural valve degeneration rate, and protection from stroke and anticoagulant hemorrhage in those patients in sinus rhythm.
Actuarial Analysis↗
Biomechanical gait alterations independent of speed in the healthy elderly: evidence for specific limiting impairments.
OBJECTIVES: It is not known whether changes in the biomechanics of elderly gait are related to aging per se, or to reduced walking speed in this population. The goals of the present study were to identify specific biomechanical changes, independent of speed, that might impair gait performance in healthy older people by identifying age-associated changes in the biomechanics of gait, and to determine which of these changes persist at increased walking speed. DESIGN: Stereophotogrammetric and force platform data were collected. Differences in peak joint motion (kinematic) and joint moment and power (kinetic) values between healthy young and elderly subjects at comfortable and increased walking speed were measured. SETTING: A gait laboratory. SUBJECTS: Thirty-one healthy elderly (age 65 to 84 years) and 31 healthy young adult subjects (age 18 to 36 years), all without known neurologic, musculoskeletal, cardiac, or pulmonary problems. MAIN OUTCOME MEASURES: All major peak kinematic and kinetic variables during the gait cycle. RESULTS: Several kinematic and kinetic differences between young and elderly adults were found that did not persist when walking speed was increased. Differences that persisted at both comfortable and fast walking speeds were reduced peak hip extension, increased anterior pelvic tilt, and reduced ankle plantarflexion and ankle power generation. CONCLUSION: Gait performance in the elderly may be limited by both subtle hip flexion contracture and ankle plantarflexor concentric weakness. Results of the current study should motivate future experimental trials of specific hip flexor stretching and ankle plantarflexor concentric strengthening exercises to preserve and potentially improve walking performance in the elderly.
Adolescent↗
Age-related changes in the initiation of gait: degradation of central mechanisms for momentum generation.
OBJECTIVE: To investigate cross-sectionally age-related changes in the expression and biomechanical efficiency of the gait-initiation motor program. DESIGN: Case-control study. PARTICIPANTS AND SETTING: Twenty healthy young research subjects and 20 healthy elderly subjects who volunteered from the community participated in this study at a university research laboratory. MAIN OUTCOME MEASURES: Participants performed gait-initiation trials at three speeds from a starting position on a force platform while ground reaction force data, 3-D motion analysis data, and electromyographic data were collected. Measures included: latency of tibialis anterior (TA) activation and soleus (SOL) and gastrocnemius (GA) inhibition, magnitude of center of pressure (COP) displacement, magnitude of momentum generated, and final walking velocity. RESULTS: The expression of the central motor program governing gait initiation, as evidenced by the invariant timing between TA activation and SOL/GA inhibition, was seen in both the young and elderly populations, but the frequency was diminished in the latter group. The momentum-generating capacity of the COP shift mechanism was present but significantly diminished in the elderly population. CONCLUSIONS: These findings suggest that the central nervous system uses stable, efficient mechanisms for dealing with the inherent instability of upright bipedalism and that the integrity of these mechanisms degrades with aging.
Adolescent↗