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1.  Enzyme controlled glucose auto-delivery for high cell density cultivations in microplates and shake flasks 
Here we describe a novel cultivation method, called EnBase™, or enzyme-based-substrate-delivery, for the growth of microorganisms in millilitre and sub-millilitre scale which yields 5 to 20 times higher cell densities compared to standard methods. The novel method can be directly applied in microwell plates and shake flasks without any requirements for additional sensors or liquid supply systems. EnBase is therefore readily applicable for many high throughput applications, such as DNA production for genome sequencing, optimisation of protein expression, production of proteins for structural genomics, bioprocess development, and screening of enzyme and metagenomic libraries.
High cell densities with EnBase are obtained by applying the concept of glucose-limited fed-batch cultivation which is commonly used in industrial processes. The major difference of the novel method is that no external glucose feed is required, but glucose is released into the growth medium by enzymatic degradation of starch. To cope with the high levels of starch necessary for high cell density cultivation, starch is supplied to the growing culture suspension by continuous diffusion from a storage gel.
Our results show that the controlled enzyme-based supply of glucose allows a glucose-limited growth to high cell densities of OD600 = 20 to 30 (corresponding to 6 to 9 g l-1 cell dry weight) without the external feed of additional compounds in shake flasks and 96-well plates. The final cell density can be further increased by addition of extra nitrogen during the cultivation. Production of a heterologous triosphosphate isomerase in E. coli BL21(DE3) resulted in 10 times higher volumetric product yield and a higher ratio of soluble to insoluble product when compared to the conventional production method.
The novel EnBase method is robust and simple-to-apply for high cell density cultivation in shake flasks and microwell plates. The potential of the system is that the microbial growth rate and oxygen consumption can be simply controlled by the amount (and principally also by the activity) of the starch-degrading enzyme. This solves the problems of uncontrolled growth, oxygen limitation, and severe pH drop in shaken cultures. In parallel the method provides the basis for enhanced cell densities. The feasibility of the new method has been shown for 96-well plates and shake flasks and we believe that it can easily be adapted to different microwell and deepwell plate formats and shake flasks. Therefore EnBase will be a helpful tool especially in high throughput applications.
PMCID: PMC2588551  PMID: 19017379
2.  L-dopa-responsive movement disorder caused by Nocardia asteroides localized in the brains of mice. 
Infection and Immunity  1991;59(1):181-191.
Nocardia asteroides can cause infections in the brain of humans and a variety of animals. In mice, invasion of the central nervous system results in specific neurologic signs. Following intravenous injection of various doses of log-phase N. asteroides GUH-2 into female BALB/c mice, localization and growth of nocardial cells within the brains were determined, histopathological sections were prepared, and Nissl substance and tyrosine hydroxylase immunoreactivity were observed. Mice were monitored for the development of neurologic signs, and their responsiveness to L-dopa was determined. It was shown that nocardial cells became localized within specific regions of the brain and then underwent rapid growth followed by a delayed clearance, and there was no inflammatory response at the site of invasion for 24 h. Mice that received a subclinical dose of nocardiae developed specific neurologic signs that emerged following the elimination of nocardial cells from the brain. On the basis of the specific signs, mice could be divided into distinct groups. One group consisted of animals that had a form of hemiparesis that did not respond to L-dopa. They expressed a deviation of the head and a tendency to roll, and when suspended by the tail they would spin rapidly. The second group of mice developed a rhythmic, uncontrolled vertical shake of the head (four to five times per s) tremulous movement, stooped posture, restlessness, and no signs of hemiparesis. The head shakes were temporarily stopped by treatment with L-dopa. Mice that expressed head shakes had a loss of Nissl substance and tyrosine hydroxylase immunoreactivity in the neurons of the substantia nigra and ventral tegmental areas of the brain. Hyaline inclusion bodies that resembled Lewy bodies were found in the neurons of mice with head shake 1 month after infection. Therefore, mice infected with N. asteroides may serve as a model for studying parkinsonian signs and other degenerative diseases involving extrapyramidal and pyramidal systems.
PMCID: PMC257724  PMID: 1670928
3.  Factors Influencing the Production of H and M Antigens by Histoplasma capsulatum: Effect of Physical Factors and Composition of Medium1 
Applied Microbiology  1972;23(2):250-261.
Stagnant culture methods have permitted only limited physiological studies of the production of H and M antigens by Histoplasma capsulatum because, with such methods, antigen production is uncontrolled. In this investigation, a shake culture method was used to convert yeast-phase inoculum to mycelialphase growth at 25 C. Results strongly suggest that the release of H and M antigens relates to autolysis of the cells. Among the factors influencing production of H and M antigens under shaking conditions, choice of strain was the most important. Alterations of carbon or nitrogen source or variations in amino acid to carbohydrate ratios had limited influence on antigen production. With a strain that produced both H and M antigens, however, proportions of titers of M to H antigens could be made to vary considerably by changes in the medium, the pH, and the temperature. Results suggest that the source of M antigen during autolysis is enzymatic dissolution of the cell wall. The source of H antigen is more obscure. Production of both antigens may be differentially controlled under conditions of good reproducibility by a correct choice of strain and manipulation of culture medium.
PMCID: PMC380326  PMID: 4622822
4.  The Relationship between Reduplicated Babble Onset and Laterality Biases in Infant Rhythmic Arm Movements 
Brain and language  2006;101(3):198-207.
This study examined changes in rhythmic arm shaking and laterality biases in infants observed longitudinally at three points: just prior to, at, and just following reduplicated babble onset. Infants (ranging in age from 4 to 9 months at babble onset) were videotaped at home as they played with two visually identical audible and silent rattles presented at midline for 1.5 min each. Rate of rattle shaking increased sharply from the pre-babble to babble onset session; but there was no indication that this increase was specific to the right arm. This finding suggests that the link between babble onset and increased rhythmic arm activity may not be the product of language-specific mechanisms, but is rather part of a broader developmental process that is also perceptual and motor.
PMCID: PMC2034511  PMID: 17196644
5.  Management of patients with uncontrolled arterial hypertension – the role of electronic compliance monitoring, 24-h ambulatory blood pressure monitoring and Candesartan/HCT 
Incomplete drug regimen compliance (DRC) and white-coat hypertension are two of several possible causes of uncontrolled hypertension. Therefore the aim of the present study was to compare DRC in hypertensives treated with combination therapy whose blood pressures (BP) were controlled vers. uncontrolled after 4 weeks of self-monitored BP measurement. To observe the consequences in uncontrolled patients of switching one drug of the combination therapy to candesartan/HCTZ (16 mg/12.5 mg) with and without a compliance intervention program.
Self-and ambulatory-monitoring of BP were done with upper arm oscillometric devices. Patients' dosing histories were compiled electronically (MEMS(c), AARDEX). Patients with office blood pressure (OBP) >140/90 mmHg despite combination therapy were begun on MEMS monitoring and self BP measurement for 4 weeks of run-in. Of 62 such patients, 18 (29%) patients were normotensive according to self BP measurement and ambulatory BP measurement at 4 weeks (Group A); in the remaining 44 still uncontrolled patients, candesartan/HCTZ was substituted for one of the combination therapy drugs, with half these patients receiving passive compliance monitoring (B) and half a DRC intervention program (C). All groups were then followed for 8 weeks.
DRC before week 4 was significantly higher in A than in the uncontrolled patients (B&C). DRC was stable during run-in A, but declined in B and C. DRC after week 4 was not different in the three groups and stayed constant over time. DRC during weekends was lower than during weekdays in all groups.
In group A no significant change in blood pressure was observed with all three methods of BP measurements. In groups B and C significant reductions of systolic and diastolic BP were observed for ABPM and SBPM. After the change to candesartan/HCTZ in B&C ambulatory 24-h-BP (ABPM) was normalized in 39% of patients.
Normalization of BP was associated with superior drug regimen compliance in previously uncontrolled patients treated with a combination drug regimen. Switching still-uncontrolled patients to candesartan/HCTZ significantly improved BP control and stabilized a declining DRC.
PMCID: PMC1590051  PMID: 16942618
6.  Limb-shaking transient ischemic attacks: case report and review of literature 
BMC Neurology  2006;6:5.
Limb shaking Transient Ischemic Attack is a rare manifestation of carotid-occlusive disease. The symptoms usually point towards a seizure like activity and misdiagnosed as focal seizures. On careful history the rhythmic seizure like activity reveals no Jacksonian march mainly precipitated by maneuvers which lead to carotid compression. We here present a case of an elderly gentleman who was initially worked up as suffering from epileptic discharge and then later on found to have carotid occlusion.
Case presentation
Elderly gentleman presented with symptoms of rhythmic jerky movements of the left arm and both the lower limbs. Clinical suspicion of focal epilepsy was made and EEG, MRI-Brain with MRA were done. EEG and MRI-Brain revealed normal findings but the MRA revealed complete occlusion of right internal carotid artery. On a follow-up visit jerky movements of the left arm were precipitated by hyperextension and a tremor of 3–4 Hz was revealed. Based on this the diagnosis of low flow TIA was made the patient was treated conservatively with adjustment of his anti-hypertensive and anti-platelet medications.
Diagnosis of limb-shaking TIA is important and should be differentiated from other disorders presenting as tremors. Timely diagnosis is important as these patients are shown to benefit from reperfusion procedures either surgical or radiological reducing their risk of stroke.
PMCID: PMC1373644  PMID: 16438706
7.  The shaking limb--a lacunar syndrome. 
Postgraduate Medical Journal  1988;64(750):311-312.
A 76 year old man with shaking movements of the fingers, weakness of the arm and lacunar infarctions on computed tomographic scan is described. The shaking limb should be included in the group of lacunar syndromes.
PMCID: PMC2428488  PMID: 3186576
8.  Nurse-led Disease Management for Hypertension Control in a Diverse Urban Community: a Randomized Trial 
Treated but uncontrolled hypertension is highly prevalent in African American and Hispanic communities.
To test the effectiveness on blood pressure of home blood pressure monitors alone or in combination with follow-up by a nurse manager.
Randomized controlled effectiveness trial.
Four hundred and sixteen African American or Hispanic patients with a history of uncontrolled hypertension. Patients with blood pressure ≥150/95, or ≥140/85 for patients with diabetes or renal disease, at enrollment were recruited from one community clinic and four hospital outpatient clinics in East and Central Harlem, New York City.
Patients were randomized to receive usual care or a home blood pressure monitor plus one in-person counseling session and 9 months of telephone follow-up with a registered nurse. During the trial, the home monitor alone arm was added.
Change in systolic and diastolic blood pressure at 9 and 18 months.
Changes from baseline to 9 months in systolic blood pressure relative to usual care was −7.0 mm Hg (Confidence Interval [CI], -13.4 to −0.6) in the nurse management plus home blood pressure monitor arm, and +1.1 mm Hg (95% CI, -5.5 to 7.8) in the home blood pressure monitor only arm. No statistically significant differences in systolic blood pressure were observed among treatment arms at 18 months. No statistically significant improvements in diastolic blood pressure were found across treatment arms at 9 or 18 months. Changes in prescribing practices did not explain the decrease in blood pressure in the nurse management arm.
A nurse management intervention combining an in-person visit, periodic phone calls, and home blood pressure monitoring over 9 months was associated with a statistically significant reduction in systolic, but not diastolic, blood pressure compared to usual care in a high risk population. Home blood pressure monitoring alone was no more effective than usual care.
PMCID: PMC3358388  PMID: 22143452
hypertension; randomized trial; minority; nurse management; home blood pressure monitor
9.  Comparing Standard Care with a Physician and Pharmacist Team Approach for Uncontrolled Hypertension 
To assess the effect of a physician and pharmacist teamwork approach to uncontrolled hypertension in a medical resident teaching clinic, for patients who failed to meet the recommended goals of the fifth Joint National Commission on Detection, Evaluation and Treatment of High Blood Pressure.
Physician and pharmacist teamwork can improve the rate of meeting national blood pressure goals in patients with previously uncontrolled hypertension.
A single-blinded randomized controlled trial lasting 6 months.
A primary care outpatient teaching clinic.
A sample of 95 adult hypertensive patients who failed to meet national blood pressure goals based on three consecutive visits over a 6-month period.
Patients were randomly assigned to a control arm of standard medical care or to an intervention arm in which a physician and pharmacist worked together as a team.
At study completion, the percentage of patients achieving national goals due to intervention was more than double the percentage in the control arm (55% vs 20%, p < .001). Systolic blood pressure declined 23 mm Hg in the intervention arm versus 11 mm Hg in the control arm (p < .01). Diastolic blood pressure declined 14 and 3 mm Hg in the intervention and control arms, respectively (p < .001). The intervention worked equally as well in men and women and demonstrated noticeable promise in a minority of mixed-ancestry Hawaiians in whom hypertension is of special concern.
Patients who fail to achieve national blood pressure goals under standard outpatient medical care may benefit from a program that includes a physician and pharmacist teamwork approach.
PMCID: PMC1497023  PMID: 9824519
blood pressure; coronary heart disease; risk factor; pharmacist; ambulatory care
10.  In Vitro Study of Cerebrospinal Fluid Dynamics in a Shaken Basal Cistern after Experimental Subarachnoid Hemorrhage 
PLoS ONE  2012;7(8):e41677.
Cerebral arterial vasospasm leads to delayed cerebral ischemia and constitutes the major delayed complication following aneurysmal subarachnoid hemorrhage. Cerebral vasospasm can be reduced by increased blood clearance from the subarachnoid space. Clinical pilot studies allow the hypothesis that the clearance of subarachnoid blood is facilitated by means of head shaking. A major obstacle for meaningful clinical studies is the lack of data on appropriate parameters of head shaking. Our in vitro study aims to provide these essential parameters.
Methodology/Principal Findings
A model of the basal cerebral cistern was derived from human magnetic resonance imaging data. Subarachnoid hemorrhage was simulated by addition of dyed experimental blood to transparent experimental cerebrospinal fluid (CSF) filling the model of the basal cerebral cistern. Effects of various head positions and head motion settings (shaking angle amplitudes and shaking frequencies) on blood clearance were investigated using the quantitative dye washout method. Blood washout can be divided into two phases: Blood/CSF mixing and clearance. The major effect of shaking consists in better mixing of blood and CSF thereby increasing clearance rate. Without shaking, blood/CSF mixing and blood clearance in the basal cerebral cistern are hampered by differences in density and viscosity of blood and CSF. Blood clearance increases with decreased shaking frequency and with increased shaking angle amplitude. Head shaking facilitates clearance by varying the direction of gravitational force.
From this in vitro study can be inferred that patient or head shaking with large shaking angles at low frequency is a promising therapeutic strategy to increase blood clearance from the subarachnoid space.
PMCID: PMC3411603  PMID: 22870243
11.  Center for stroke disparities solutions community- based care transition interventions: study protocol of a randomized controlled trial 
Trials  2015;16:32.
Racial and ethnic disparities persist in stroke occurrence, recurrence, morbidity and mortality. Uncontrolled hypertension (HTN) is the most important modifiable risk factor for stroke risk. Home health care organizations care for many patients with uncontrolled HTN and history of stroke; however, recurrent stroke prevention has not been a home care priority. We are conducting a randomized controlled trial (RCT) to compare the effectiveness, relative to usual home care (UHC), of two Community Transitions Interventions (CTIs). The CTIs aim to reduce recurrent stroke risk among post-stroke patients via home-based transitional care focused on better HTN management.
This 3-arm trial will randomly assign 495 black and Hispanic post-stroke home care patients with uncontrolled systolic blood pressure (SBP) to one of three arms: UHC, UHC complemented by nurse practitioner-delivered transitional care (UHC + NP) or UHC complemented by an NP plus health coach (UHC + NP + HC). Both intervention arms emphasize: 1) linking patients to continuous, responsive preventive and primary care, 2) increasing patients’/caregivers’ ability to manage a culturally and individually tailored BP reduction plan, and 3) facilitating the patient’s reintegration into the community after home health care discharge. The primary hypothesis is that both NP-only and NP + HC transitional care will be more effective than UHC alone in achieving a SBP reduction. The primary outcome is change in SPB at 3 and 12 months. The study also will examine cost-effectiveness, quality of life and moderators (for example, race/ethnicity) and mediators (for example, changes in health behaviors) that may affect treatment outcomes. All outcome data are collected by staff blinded to group assignment.
This study targets care gaps affecting a particularly vulnerable black/Hispanic population characterized by persistent stroke disparities. It focuses on care transitions, a juncture when patients are particularly susceptible to adverse events. The CTI is innovative in adapting for stroke patients an established transitional care model shown to be effective for HF patients, pairing the professional NP with a HC, implementing a culturally tailored intervention, and placing primary emphasis on longer-term risk factor reduction and community reintegration rather than shorter-term transitional care outcomes.
Trial registration NCT01918891; Registered 5 August 2013.
PMCID: PMC4322449  PMID: 25622823
Care transitions; Home health; Stroke; Hypertension; Blood pressure; Health disparities; Trial design
12.  Therapeutic Devices for Epilepsy 
Annals of Neurology  2012;71(2):157-168.
Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation, which continues to develop new technology, is approved for use in the United States. Deep brain stimulation (DBS) of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to one or two seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS split on efficacy, and may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of “shake” detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of EEG is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience.
PMCID: PMC3296971  PMID: 22367987
epilepsy; seizures; devices; brain stimulation; drug perfusion; vagus nerve stimulation; optogenetics; brain cooling; seizure prediction
13.  A new wireless system for decentralised measurement of physiological parameters from shake flasks 
Shake flasks are widely used because of their low price and simple handling. Many researcher are, however, not aware of the physiological consequences of oxygen limitation and substrate overflow metabolism that occur in shake flasks. Availability of a wireless measuring system brings the possibilities for quality control and design of cultivation conditions.
Here we present a new wireless solution for the measurement of pH and oxygen from shake flasks with standard sensors, which allows data transmission over a distance of more than 100 metres in laboratory environments. This new system was applied to monitoring of cultivation conditions in shake flasks. The at-time monitoring of the growth conditions became possible by simple means. Here we demonstrate that with typical protocols E. coli shake flask cultures run into severe oxygen limitation and the medium is strongly acidified. Additionally the strength of the new system is demonstrated by continuous monitoring of the oxygen level in methanol-fed Pichia pastoris shake flask cultures, which allows the optimisation of substrate feeding for preventing starvation or methanol overfeed. 40 % higher cell density was obtained by preventing starvation phases which occur in standard shake flask protocols by adding methanol when the respiration activity decreased in the cultures.
The here introduced wireless system can read parallel sensor data over long distances from shake flasks that are under vigorous shaking in cultivation rooms or closed incubators. The presented technology allows centralised monitoring of decentralised targets. It is useful for the monitoring of pH and dissolved oxygen in shake flask cultures. It is not limited to standard sensors, but can be easily adopted to new types of sensors and measurement places (e.g., new sensor points in large-scale bioreactors).
PMCID: PMC1409794  PMID: 16504107
Neuroscience letters  2008;434(2):234-239.
Both an elaborate coordination of the hand grip force (G; normal component of force acting at the digits-object contact area) and load force (L; tangential component), and the role of cutaneous afferents in G-L coordination have been well documented in a variety of manipulation tasks. However, our recent studies revealed that G-L coordination deteriorates when L consecutively changes direction (bidirectional tasks; e.g., when vigorously shaking objects or using tools). The aim of the study was to distinguish between the possible role of the synergy of hand grip and arm muscles (exerting G and L, respectively) and the role of cutaneous afferent input in the observed phenomenon. Subjects (N=14) exerted sinusoidal L pattern in vertical direction against an externally fixed device in trials that gradually changed from uni- to fully bidirectional. In addition, a manipulation of an external arm support decoupled L measured by the device (and, therefore, recorded by the cutaneous receptors) from the action of arm muscles exerting L. The results revealed that switching from uni- to bidirectional tasks, no matter how low and brief L exertion was in the opposite direction, was associated with an abrupt decrease in G-L coordination. This coordination remained unaffected by the manipulation of external support. The first result corroborates our previous conclusion that the force coordination in uni- and bidirectional manipulation tasks could be based on partly different neural control mechanisms. However, the second finding suggests that the studied control mechanisms could depend more on the cutaneous afferent input, rather than on the synergy of the muscles exerting G and L.
PMCID: PMC2323603  PMID: 18313221
unidirectional; bidirectional; grip; load; force; neural control
The preceding experiments showed that partial or complete inactivation of serum by shaking brought about a marked decrease in the activity of homologous fibroblasts. Generally, serum was not completely inactivated by shaking. In only one instance was the hemo-lytic effect of chicken serum on sheep corpuscles entirely lost after the serum had been shaken for 8 hours. In all other cases, the normal hemolytic power of chicken and dog sera for sheep erythrocytes was merely decreased. The effect of shaking varied according to certain conditions of the serum. It may be compared to the inffuence of heat, which differs widely according to individual sera, even when they are obtained from animals which are apparently in identical condition. Shaken serum always inhibited the activity of homologous fibroblasts more than normal serum. When chicken serum was completely inactivated by shaking, its restraining action on chicken fibroblasts became also more marked. On the contrary, dog serum partly inactivated by shaking was much less toxic for chicken fibroblasts than normal serum. Thus, shaking brought about a change in the condition of serum, against which homologous and heterologous fibroblasts reacted in an opposite manner. At the same time, the normal lytic action of serum on foreign erythrocytes decreased. This last phenomenon is caused, as is well known, by the partial or complete destruction of alexin. The decrease of the restraining effect of shaken serum on foreign fibroblasts may be attributed to the same cause. The increase of the inhibiting action of shaken serum on homologous fibroblasts is due possibly to the disappearance of a substance favoring the activity of homologous cells. A similar hypothesis was advanced for explaining the increase of the growth-inhibiting action of serum under the influence of senescence and of heat. The restraining power of adult serum on cell multiplication may be due to the antagonistic action of growth-promoting and growth-inhibiting substances, the growth-promoting substance being as unstable as alexin and certain tissue juices which have the property of increasing the rate of cell proliferation. Alexin and growth-activating substances contained in embryonic and gland tissue juices have in common the property of being destroyed by heat and by shaking. Leucocytes added to serum under certain conditions increase its hemolytic power on foreign erythrocytes and decrease its inhibiting action on homologous fibroblasts. Variations in the alex-inic activity of serum under other influences are followed also by a change in its action on homologous cells. Long ago, Gengou found that serum from plasma is less bactericidal than serum from blood. We observed that the lytic effect on sheep erythrocytes of dog and chicken serum from blood was sometimes more marked than that of serum from plasma, but there was often no difference in the action of both sera. At the same time, the growth of homologous fibroblasts was always more extensive in the serum from blood. The opposite effect was observed when heterologous fibroblasts were used. The growth-inhibiting power of serum from blood was still less marked on leucocytes than on fibroblasts. But embryonic juice, which greatly enhances the rate of multiplication of homologous cells, did not increase the lytic action of serum on foreign erythrocytes. It may be concluded that, under the conditions of the experiments: 1. Chicken serum partly or completely inactivated by shaking becomes more inhibiting for chicken fibroblasts. 2. Dog serum partly inactivated by shaking becomes less inhibiting for chicken fibroblasts.
PMCID: PMC2128307  PMID: 19868682
16.  The organization of intralimb and interlimb synergies in response to different joint dynamics 
We sought to understand differences in joint coordination between the dominant and nondominant arms when performing repetitive tasks. The uncontrolled manifold approach was used to decompose the variability of joint motions into components that reflect the use of motor redundancy or movement error. First, we hypothesized that coordination of the dominant arm would demonstrate greater use of motor redundancy to compensate for interaction forces than would coordination of the nondominant arm. Secondly, we hypothesized that when interjoint dynamics were more complex, control of the interlimb relationship would remain stable despite differences in control of individual hand paths. Healthy adults performed bimanual tracing of two orientations of ellipses that resulted in different magnitudes of elbow interaction forces. For the dominant arm, joint variance leading to hand path error was the same for both ellipsis orientations, whereas joint variance reflecting the use of motor redundancy increased when interaction moment was highest. For the nondominant arm, more joint error variance was found when interaction moment was highest, whereas motor redundancy did not differ across orientations. There was no apparent difference in interjoint dynamics between the two arms. Thus, greater skill exhibited by the dominant arm may be related to its ability to utilize motor redundancy to compensate for the effect of interaction forces. However, despite the greater error associated with control of the nondominant hand, control of the interlimb relationship remained stable when the interaction moment increased. This suggests separate levels of control for inter- versus intra-limb coordination in this bimanual task.
PMCID: PMC3122082  PMID: 18982319
Dominance; Redundancy; Motor abundance; Bimanual coordination; Motor control
17.  Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts 
PLoS Medicine  2014;11(12):e1001764.
Martin Tammemägi and colleagues evaluate which risk groups of individuals, including nonsmokers and high-risk individuals from 65 to 80 years of age, should be screened for lung cancer using computed tomography.
Please see later in the article for the Editors' Summary
Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55–64 and ≥65–80 y.
Methods and Findings
Applying the PLCOm2012 model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCOm2012 risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCOm2012 risk ≥0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to −754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCOm2012 risk ≥0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%–83.0%] versus 71.2% [95% CI 67.6%–74.6%], p<0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%–66.7%] versus 62.7% [95% CI 62.2%–63.1%], p<0.001), and had higher PPV (4.2% [95% CI 3.9%–4.6%] versus 3.4% [95% CI 3.1%–3.7%], p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCOm2012 risk ≥0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCOm2012 risk ≥0.0151. None of 65,711 PLCO never-smokers had PLCOm2012 risk ≥0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥65–80 y than in those aged 55–64 y. This study omitted cost-effectiveness analysis.
The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCOm2012 risk ≥0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥65–80 y are a high-risk group who may benefit from screening.
Please see later in the article for the Editors' Summary
Editors' Summary
Lung cancer is the most commonly occurring cancer in the world and the most common cause of cancer-related deaths. Like all cancers, lung cancer occurs when cells acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The most common trigger for these genetic changes in lung cancer is exposure to cigarette smoke. Symptoms of lung cancer include a persistent cough and breathlessness. If lung cancer is diagnosed when it is confined to the lung (stage I), the tumor can often be removed surgically. Stage II tumors, which have spread into nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced lung cancers that have spread throughout the chest (stage III) or the body (stage IV), surgery is rarely helpful and these tumors are treated with chemotherapy and radiotherapy alone. Overall, because most lung cancers are not detected until they are advanced, less than 17% of people diagnosed with lung cancer survive for five years.
Why Was This Study Done?
Screening for lung cancer—looking for early disease in healthy people—could save lives. In the US National Lung Screening Trial (NLST), annual screening with computed tomography (CT) reduced lung cancer mortality by 20% among smokers at high risk of developing cancer compared with screening with a chest X-ray. But what criteria should be used to decide who is screened for lung cancer? The US Preventive Services Task Force (USPSTF), for example, recommends annual CT screening of people who are 55–80 years old, have smoked 30 or more pack-years (one pack-year is defined as a pack of cigarettes per day for one year), and—if they are former smokers—quit smoking less than 15 years ago. However, some experts think lung cancer risk prediction models—statistical models that estimate risk based on numerous personal characteristics—should be used to select people for screening. Here, the researchers evaluate PLCOm2012, a lung cancer risk prediction model based on the incidence of lung cancer among smokers enrolled in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Specifically, the researchers use NLST and PLCO screening trial data to identify a PLCOm2012 risk threshold for selecting people for screening and to compare the efficiency of the PLCOm2012 model and the USPSTF criteria for identifying “screenees.”
What Did the Researchers Do and Find?
By analyzing NLST data, the researchers calculated that at PLCOm2012 risk ≥0.0151, mortality (death) rates among NLST participants screened with CT were consistently below mortality rates among NLST participants screened with chest X-ray and that 255 people with a PLCOm2012 risk ≥0.0151 would need to be screened to prevent one lung cancer death. Next, they used data collected from smokers in the screened arm of the PLCO trial to compare the efficiency of the PLCOm2012 and USPSTF criteria for identifying screenees. They found that 8.8% fewer people had a PLCOm2012 risk ≥0.0151 than met USPSTF criteria for screening, but 12.4% more lung cancers were identified. Thus, using PLCOm2012 improved the sensitivity and specificity of the selection of individuals for lung cancer screening over using UPSTF criteria. Notably, 8.5% of PLCO former smokers with quit times of more than 15 years had PLCOm2012 risk ≥0.0151, none of the PLCO never-smokers had PLCOm2012 risk ≥0.0151, and the calculated risks and incidence of lung cancer were greater among PLCO smokers aged ≥65–80 years than among those aged 55–64 years.
What Do These Findings Mean?
Despite the absence of a cost-effectiveness analysis in this study, these findings suggest that the use of the PLCOm2012 risk ≥0.0151 threshold rather than USPSTF criteria for selecting individuals for lung cancer screening could improve screening efficiency. The findings have several other important implications. First, these findings suggest that screening may be justified in people who stopped smoking more than 15 years ago; USPSTF currently recommends that screening stop once an individual's quit time exceeds 15 years. Second, these findings do not support lung cancer screening among never-smokers. Finally, these findings suggest that smokers aged ≥65–80 years might benefit from screening, although the presence of additional illnesses and reduced life expectancy need to be considered before recommending the provision of routine lung cancer screening to this section of the population.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health-care professionals, including information on lung cancer screening (in English and Spanish)
Cancer Research UK also provides detailed information about lung cancer and about lung cancer screening
The UK National Health Service Choices website has a page on lung cancer that includes personal stories
MedlinePlus provides links to other sources of information about lung cancer (in English and Spanish)
Information about the USPSTF recommendations for lung cancer screening is available
PMCID: PMC4251899  PMID: 25460915
18.  Analysis of Accuracy in Pointing with Redundant Hand-held Tools: A Geometric Approach to the Uncontrolled Manifold Method 
PLoS Computational Biology  2013;9(4):e1002978.
This work introduces a coordinate-independent method to analyse movement variability of tasks performed with hand-held tools, such as a pen or a surgical scalpel. We extend the classical uncontrolled manifold (UCM) approach by exploiting the geometry of rigid body motions, used to describe tool configurations. In particular, we analyse variability during a static pointing task with a hand-held tool, where subjects are asked to keep the tool tip in steady contact with another object. In this case the tool is redundant with respect to the task, as subjects control position/orientation of the tool, i.e. 6 degrees-of-freedom (dof), to maintain the tool tip position (3dof) steady. To test the new method, subjects performed a pointing task with and without arm support. The additional dof introduced in the unsupported condition, injecting more variability into the system, represented a resource to minimise variability in the task space via coordinated motion. The results show that all of the seven subjects channeled more variability along directions not directly affecting the task (UCM), consistent with previous literature but now shown in a coordinate-independent way. Variability in the unsupported condition was only slightly larger at the endpoint but much larger in the UCM.
Author Summary
Daily motor tasks typically involve more degrees-of-freedom than strictly required. For instance, pressing a button in the elevator only requires positioning the fingertip at a three-dimensional location in space. However, to move the arm we need to control many more degrees-of-freedom (at least seven, only considering the shoulder, elbow and wrist) than required by the task, each with its own variability due to physiological factors such as tremor. Variability at proximal joints (e.g. shoulder or elbow) is expected to be amplified and projected at the distal end (fingertip). Remarkably, inter-joint coordination reduces the final variability at the fingertip position. Recent theories, such as the uncontrolled manifold (UCM), distinguished between inter-joint variability that would not affect the finger position and variability that would affect the final task. A major issue is that traditional UCM methods rely on the coordinate system chosen to analyse the arm motion. Therefore, we introduce a coordinate independent UCM method for tasks performed with handheld tools, e.g. surgery. This paper describes a new method and demonstrates that it enables an accurate analysis of static pointing. The results clearly show that the subjects can channel variability in dimensions that do not affect the task outcome.
PMCID: PMC3617015  PMID: 23592956
19.  Prevalence of Self-Reported Shaking and Smothering and Their Associations with Co-Sleeping among 4-Month-Old Infants in Japan 
Few studies have investigated the prevalence of shaking and smothering and whether they are associated with co-sleeping. In Japan, co-sleeping is common during infancy and early childhood. This study investigates the prevalence of shaking and smothering and their associations with co-sleeping among 4-month-old infants in Japan. A questionnaire was administered to mothers who participated in a 4-month health checkup program in Kamagaya City in Japan (n = 1307; valid response rate, 82%). The questionnaire investigated the frequency of self-reported shaking and smothering during the past one month, co-sleeping status, and living arrangements with grandparents, in addition to traditional risk factors such as stress due to crying. Associations between co-sleeping and self-reported shaking or smothering were analyzed using multiple logistic regression. The prevalence of self-reported shaking and smothering at least one time during the past one month was 3.4% (95% confidence interval (CI), 2.4%–4.3%) and 2.4% (95% CI, 1.5%–3.2%), respectively. Co-sleeping was marginally associated with the amount of crying and not associated with stress due to crying. Further, co-sleeping was not associated with either self-reported shaking or smothering, although stress due to crying showed strong association with shaking and smothering. Co-sleeping was not a risk factor for shaking and smothering.
PMCID: PMC4078590  PMID: 25003171
abusive head trauma; shaken baby syndrome; shaking; smothering; child abuse; co-sleeping; crying; Japan
20.  A teenager with uncontrolled hypertension: a case report 
BMC Research Notes  2012;5:659.
Takayasu Arteritis is a vasculitis occurring mostly in young females which may present in diverse ways. Here we report a teenager with Takayasu Arteritis who presented with uncontrolled hypertension. This case depicts an atypical presentation of this disease where the girl visited many physicians for controlling the level of hypertension and put a diagnostic dilemma about the underlying etiology of young hypertension.
Case presentation
A 13 year old girl presented with epistaxis, persistent headache and uncontrolled hypertension. Her clinical examination revealed normal radial, very feeble femoral and absent other lower limb pulses. There was a blood pressure discrepancy of 50/40 mm of Hg between two arms. There were bruits over multiple areas including the abdominal aorta. She had features of left ventricular hypertrophy. Her Arch aortogram showed hugely dilated arch of aorta which became abruptly normal just after origin of left subclavian artery. There was ostio-proximal stenosis of right bracheocephalic artery, left common carotid and left subclavian artery with post stenotic dilatation of all the vessels. Abdominal aortogram revealed critical stenosis of abdominal aorta above the origin of renal arteries with a pressure gradient of 80/11 mm of Hg.
Takayasu’s Arteritis should also be kept in mind while searching for the cause of uncontrolled hypertension in the young age group.
PMCID: PMC3599449  PMID: 23194278
Takayasu’s Arteritis (TA)
21.  Workspace location influences joint coordination during reaching in post-stroke hemiparesis 
The purpose of this study was to determine the influence of workspace location on joint coordination in persons with post-stroke hemiparesis when trunk motion was required to complete reaches beyond the arm’s functional reach length. Seven subjects with mild right hemiparesis following a stroke and seven age and gender matched control subjects participated. Joint motions and characteristics of hand and trunk movement were measured over multiple repetitions. The variance (across trials) of joint combinations was partitioned into two components at every point in the hand’s trajectory using the uncontrolled manifold approach; the first component is a measure of the extent to which equivalent joint combinations are used to control a given hand path, and reflects performance flexibility. The second component of joint variance reflects the use of non-equivalent joint combinations, which lead to hand path error. Compared to the control subjects, persons with hemiparesis demonstrated a significantly greater amount of non-equivalent joint variability related to control of the hand’s path and of the hand’s position relative to the trunk when reaching toward the hemiparetic side (ipsilaterally), but not when reaching to the less involved side. The relative timing of the hand and trunk was also altered when reaching ipsilaterally. The current findings support the idea that the previously proposed “arm compensatory synergy” may be deficient in subjects with hemiparesis. This deficiency may be due to one or a combination of factors: changes in central commands that are thought to set the gain of the arm compensatory synergy; a limited ability to combine shoulder abduction and elbow extension that limits the expression of an appropriately set arm compensatory synergy; or a reduction of the necessary degrees-of-freedom needed to adequately compensate for poor trunk control when reaching ipsilaterally.
PMCID: PMC1752211  PMID: 16328275
Stroke; Reaching; Synergy; Coordination
22.  Joint angle variability and co-variation in a reaching with a rod task 
The problem at the heart of motor control is how the myriad units of the neuromotor system are coordinated to perform goal-directed movements. Although for long these numerous degrees of freedom (DOFs) were considered redundant, recent views emphasize more that the DOFs should be considered abundant, allowing flexible performance. We studied how variability in arm joints was employed to stabilize the displaced end-effector in tool use to examine how the neuromotor system flexibly exploits DOFs in the upper extremity. Participants made pointing movements with the index finger and with the index finger extended by rods of 10, 20, and 30 cm. Using the uncontrolled manifold (UCM) method, the total joint angle variance was decomposed into two parts, the joint angle variance that did not affect the position of the end-effector (VUCM) and the variance that results in a deviation of the position of the end-effector from its mean (VORT). Analyses showed that some angles depended on length of the rod in use. For all rod lengths, VUCM was larger than VORT, and this did not differ over rod lengths, demonstrating that the arm was organized into a synergy. Finally, the variation in the joint angles in the arm as well as the degree of co-variation between these angles did not differ for the rod’s tip and the hand. We concluded that synergies are formed in the arm during reaching with an extended end-effector and those synergies stabilize different parts of the arm+rod system equally.
PMCID: PMC3018264  PMID: 21127846
Synergy; Uncontrolled manifold (UCM); Joint variability; Motor coordination; Tool use; Reaching
23.  Outcomes of a Weight Loss Intervention among Rural Breast Cancer Survivors 
Obese breast cancer survivors have increased risk of recurrence and death compared to their normal weight counterparts. Rural women have significantly higher obesity rates, thus weight control intervention may be a key strategy for prevention of breast cancer recurrence in this population. This one arm treatment study examined the impact of a group-based weight control intervention delivered through conference call technology to obese breast cancer survivors living in remote rural locations. The intervention included a reduced calorie diet incorporating prepackaged entrees and shakes, physical activity gradually increased to 225 min/week of moderate intensity exercise, and weekly group phone sessions. Outcomes included anthropomorphic, diet, physical activity, serum biomarker, and quality of life changes. Ninety-one percent of participants (31 of 34) attended > 75% of intervention sessions and completed post-treatment data collection visits. At 6 months, significant changes were observed for weight (-12.5 ± 5.8 kg, 13.9% of baseline weight), waist circumference (-9.4 ± 6.3 cm), daily energy intake (-349 ± 550 kcal/day), fruits and vegetables (+3.7 ± 4.3 servings/day), percent kcal from fat (-12.6 ± 8.6%), physical activity (+1235 ± 832 kcal/week; all p’s < .001), as well as significant reductions in fasting insulin (16.7% reduction, p = .006) and leptin (37.1% reduction, p < .001). Significant improvements were also seen for quality of life domains including mood, body image, and sexuality. In conclusion, the intervention produced > 10% weight loss as well as significant improvements across multiple endpoints. The group phone-based treatment delivery approach may help disseminate effective weight control intervention to hard-to-reach breast cancer survivors.
PMCID: PMC3314288  PMID: 22198470
breast cancer; survivors; rural; weight control; physical activity
24.  Laugh-induced seizure: a case report 
A laugh-induced seizure is an unrecognized condition and to the best of our knowledge no case has been reported in the medical literature until now. We present an interesting and extremely rare case in which laughing generated the seizure activity that was recorded and confirmed by video electroencephalography.
Case presentation
A 43-year-old obese Caucasian man with history of bipolar disorder and chronic headache presented with multiple episodes of seizures, all induced by laughter while watching comedy shows. Each episode lasted approximately five seconds. In each instance, he started laughing, then his arms started shaking and he felt like ‘his consciousness was being vacuumed away’. A physical examination revealed normal findings. He had been maintained on valproic acid for bipolar disorder and topiramate for his chronic headache, but this did not control his symptoms. His sleep-deprived electroencephalography and brain magnetic resonance imaging were normal except for an arachnoid cyst measuring 4.2 × 2.1cm in the anterior right middle cranial fossa. His video electroencephalography demonstrated laugh-induced seizure activities. He was then placed on carbamazepine. Following treatment, he had two episodes of mild staring but no frank seizures, and his seizures have remained well controlled on this regimen for more than a year.
Laugh-induced seizure is a most unusual clinical entity without any previous case report. Confirmatory diagnosis can be made by video electroencephalography recording of seizure activities provoked by laughing. As in gelastic seizure without hypothalamic hamartoma, our case responded well to polytherapy with topiramate and carbamazepine on top of laugh-provocation avoidance. Further study is required to establish the standard treatment of this condition.
PMCID: PMC3657544  PMID: 23668718
Laugh-induced seizure; Gelastic seizure; EEG; Cingulate gyrus; Topiramate; Carbamazepine
25.  View dependencies in the visual recognition of social interactions 
Recognizing social interactions, e.g., two people shaking hands, is important for obtaining information about other people and the surrounding social environment. Despite the visual complexity of social interactions, humans have often little difficulties to visually recognize social interactions. What is the visual representation of social interactions and the bodily visual cues that promote this remarkable human ability? Viewpoint dependent representations are considered to be at the heart of the visual recognition of many visual stimuli including objects (Bülthoff and Edelman, 1992), and biological motion patterns (Verfaillie, 1993). Here we addressed the question whether complex social actions acted out between pairs of people, e.g., hugging, are also represented in a similar manner. To this end, we created 3-D models from motion captured actions acted out by two people, e.g., hugging. These 3-D models allowed to present the same action from different viewpoints. Participants' task was to discriminate a target action from distractor actions using a one-interval-forced-choice (1IFC) task. We measured participants' recognition performance in terms of reaction times (RT) and d-prime (d'). For each tested action we found one view that led to superior recognition performance compared to other views. This finding demonstrates view-dependent effects of visual recognition, which are in line with the idea of a view-dependent representation of social interactions. Subsequently, we examined the degree to which velocities of joints are able to predict the recognition performance of social interactions in order to determine candidate visual cues underlying the recognition of social interactions. We found that the velocities of the arms, both feet, and hips correlated with recognition performance.
PMCID: PMC3800843  PMID: 24155731
visual recognition; view dependent; social interactions; visual cues; action observation

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