Symptoms and signs (symptoms in brief) are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM). To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. The proposed method gets reliable gene rank list with AUC (area under curve) 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms.

BACKGROUND: Magnetic resonance imaging and echo color Doppler (ECD) scan techniques do not accurately assess the cerebral venous return. This generated considerable scientific controversy linked with the diagnosis of a vascular syndrome known as chronic cerebrospinal venous insufficiency (CCSVI) characterized by restricted venous outflow from the brain. The purpose of this study was to assess the cerebral venous return in relation to the change in position by means of a novel cervical plethysmography method. METHODS: This was a single-center, cross-sectional, blinded case-control study conducted at the Vascular Diseases Center, University of Ferrara, Italy. The study involved 40 healthy controls (HCs; 18 women and 22 men) with a mean age of 41.5 +/- 14.4 years, and 44 patients with multiple sclerosis (MS; 25 women and 19 men) with a mean age of 41.0 +/- 12.1 years. All participants were previously scanned using ECD sonography, and further subset in HC (CCSVI negative at ECD) and CCSVI groups. Subjects blindly underwent cervical plethysmography, tipping them from the upright (90 degrees ) to supine position (0 degrees ) in a chair. Once the blood volume stabilized, they were returned to the upright position, allowing blood to drain from the neck. We measured venous volume (VV), filling time (FT), filling gradient (FG) required to achieve 90% of VV, residual volume (RV), emptying time (ET), and emptying gradient (EG) required to achieve 90% of emptying volume (EV) where EV = VV - RV, also analyzing the considered parameters by receiver operating characteristic (ROC) curves and principal component mathematical analysis. RESULTS: The rate at which venous blood discharged in the vertical position (EG) was significantly faster in the controls (2.73 mL/second +/- 1.63) compared with the patients with CCSVI (1.73 mL/second +/- 0.94; P = .001). In addition, respectively, in controls and in patients with CCSVI, the following parameters were highly significantly different: FT 5.81 +/- 1.99 seconds vs 4.45 +/- 2.16 seconds (P = .003); FG 0.92 +/- 0.45 mL/second vs 1.50 +/- 0.85 mL/second (P < .001); RV 0.54 +/- 1.31 mL vs 1.37 +/- 1.34 mL (P = .005); ET 1.84 +/- 0.54 seconds vs 2.66 +/- 0.95 seconds (P < .001). Mathematical analysis demonstrated a higher variability of the dynamic process of cerebral venous return in CCSVI. Finally, ROC analysis demonstrated a good sensitivity of the proposed test with a percent concordant 83.8, discordant 16.0, tied 0.2 (C = 0.839). CONCLUSIONS: Cerebral venous return characteristics of the patients with CCSVI were markedly different from those of the controls. In addition, our results suggest that cervical plethysmography has great potential as an inexpensive screening device and as a postoperative monitoring tool.

PURPOSE: Epidemiologic research has shown that multifocal spectacle wearers (bifocal and progressive addition lenses [PALs]) are more than twice as likely to fall than are nonmultifocal spectacle wearers, with this risk further increasing when negotiating stairs. The present study investigated whether step and stair descent safety is improved by using single-vision distance lenses. METHODS: From a stationary standing position on top of a block, 20 long-term multifocal wearers stepped down (from different block heights) onto a lower level wearing bifocal, progressive addition, or single-vision distance lenses. RESULTS: Use of single-vision distance spectacles led to an increased single-limb support time, a reduced ankle and knee angle and vertical center-of-mass velocity at contact with the lower level, and a reduced ankle angular velocity and vertical center-of-mass velocity during initial landing (P < 0.03). These findings indicate that landing occurred in a more controlled manner when the subjects wore single-vision distance spectacles, rather than tending to "drop" onto the lower level as occurred when wearing bifocals or PALs. CONCLUSIONS: Use of single-vision distance spectacles led to improvements in landing control, consistent with individuals' being more certain regarding the precise height of the lower floor level. This enhanced control was attributed to having a view of the foot, step edge, and immediate floor area that was not blurred, magnified, or doubled and that did not suffer from image jump or peripheral distortions. These findings provide further evidence that use of single-vision distance lenses in everyday locomotion may be advantageous for elderly multifocal wearers who have a high risk of falling.

When descending stairs bodyweight becomes supported on a single limb while the forwards-reaching contralateral limb is lowered in order to make contact with the step below. This is associated with lowering of the centre of mass (CoM), which in order to occur in a controlled manner, requires increased ankle and knee joint torque production relative to that in overground walking. We have previously shown that when descending steps or stairs older people operate at a higher proportion of their maximum eccentric capacity and at, or in excess of the maximum passive reference joint range of motion. This suggests they have reduced and/or altered control over their CoM and we hypothesised that this would be associated with alterations in muscle activity patterns and in the CoM vertical acceleration and velocity profiles during both the lowering and landing phases of stair descent. 15 older (mean age 75 years) and 17 young (mean age 25 years) healthy adults descended a 4-step staircase, leading with the right limb on each stair, during which CoM dynamics and electromyographic activity patterns for key lower-limb muscles were assessed. Maximum voluntary eccentric torque generation ability at the knee and ankle was also assessed. Older participants compared to young participants increased muscle co-contraction relative duration at the knee and ankle of the trailing limb so that the limb was stiffened for longer during descent. As a result older participants contacted the step below with a reduced downwards CoM velocity when compared to young participants. Peak downwards and peak upwards CoM acceleration during the descent and landing phases respectively, were also reduced in older adults compared to those in young participants. In contrast, young participants descended quickly onto the step below but arrested their downward CoM velocity sooner following landing; a strategy that was associated with longer relative duration lead-limb plantar flexor activity, increased peak upwards CoM acceleration, and a reduced landing duration. These results suggest that a reduced ability to generate high eccentric torque at the ankle in the forward reaching limb is a major factor for older participants adopting a cautious movement control strategy when descending stairs. The implications of this CoM control strategy on the incidences of falling on stairs are discussed.

The purpose of this article is to investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA). This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (>/=50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis. At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group. PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.

PURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I-BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis-these results suggest that further investigation of I-BiT treatment is worthwhile.

PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled >/=2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.

OBJECTIVES: To compare the properties of solid dispersions of felodipine for oral bioavailability enhancement using two different polymers, polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), by hot-melt extrusion (HME) and spray drying. METHODS: Felodipine solid dispersions were prepared by HME and spray drying techniques. PVP and HPMCAS were used as polymer matrices at different drug : polymer ratios (1 : 1, 1 : 2 and 1 : 3). Detailed characterization was performed using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy and in-vitro dissolution testing. Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate. Stability of different solid dispersions was studied under accelerated conditions (40 degrees C/75% RH) over 8 weeks. KEY FINDINGS: Spray-dried formulations were found to release felodipine faster than melt extruded formulations for both polymer matrices. Solid dispersions containing HMPCAS exhibited higher drug release rates and better wettability than those produced with a PVP matrix. No significant differences in stability were observed except with HPMCAS at a 1 : 1 ratio, where crystallization was detected in spray-dried formulations. CONCLUSIONS: Solid dispersions of felodipine produced by spray drying exhibited more rapid drug release than corresponding melt extruded formulations, although in some cases improved stability was observed for melt extruded formulations.

To determine whether or not jugular venous reflux (JVR) is associated with structural brain parenchyma changes in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD). 16 AD patients (mean (SD): 81.9 (5.8) years), 33 MCI patients (mean (SD): 81.4 (6.1) years) and 18 healthy elderly controls (mean (SD): 81.5 (3.4) years) underwent duplex ultrasonography and magnetic resonance imaging scans to quantify structural brain parenchyma changes. Normalized whole brain (WB), gray matter (GM) and white matter (WM) volumes were collected, together with CSF volume. JVR was strongly associated with increased normalized WB (p = 0.014) and GM (p = 0.002) volumes across all three subject groups. There was a trend towards increased WB and GM volumes, which was accompanied by decreased CSF volume, in the JVR-positive subjects in both the MCI and AD groups. When the MCI and AD subjects were aggregated together significant increases were observed in both normalized WB (p = 0.009) and GM (p = 0.003) volumes for the JVR-positive group. No corresponding increases were observed for the JVR-positive subjects in the control group. Through receiver operating characteristic analysis of the brain volumetric data it was possible to discriminate between the JVR-positive and negative AD subjects with reasonable accuracy (sensitivity = 71.4%; specificity = 88.9%; p = 0.007). JVR is associated with intracranial structural changes in MCI and AD patients, which result in increased WB and GM volumes. The neuropathology of this unexpected and counterintuitive finding requires further investigation, but may suggest that JVR retrogradely transmits venous hypertension into the brain and leads to brain tissues swelling due to vasogenic edema.

In this paper we use multivariate statistical techniques to gain insights into how adaptive gait involving obstacle crossing is regulated in lower-limb amputees compared to able-bodied controls, with the aim of identifying underlying characteristics that differ between the two groups and consequently highlighting gait deficits in the amputees. Eight unilateral trans-tibial amputees and twelve able-bodied controls completed adaptive gait trials involving negotiating various height obstacles; with amputees leading with their prosthetic limb. Spatiotemporal variables that are regularly used to quantify how gait is adapted when crossing obstacles were determined and subsequently analysed using multivariate statistical techniques. There were fundamental differences in the adaptive gait between the two groups. Compared to controls, amputees had a reduced approach velocity, reduced foot placement distance before and after the obstacle and reduced foot clearance over it, and reduced lead-limb knee flexion during the step following crossing. Logistic regression analysis highlighted the variables that best distinguished between the gait of the two groups and multiple regression analysis (with approach velocity as a controlling factor) helped identify what gait adaptations were driving the differences seen in these variables. Getting closer to the obstacle before crossing it appeared to be a strategy to ensure the heel of the lead-limb foot passed over the obstacle prior to the foot being lowered to the ground. Despite adopting such a heel clearance strategy, the lead-foot was positioned closer to the obstacle following crossing, which was likely a result of a desire to attain a limb/foot angle and orientation at instant of landing that minimised loads on the residuum (as evidenced by the reduced lead-limb knee flexion during the step following crossing). These changes in foot placement meant the foot was in a different part of swing at point of crossing and this explains why foot clearance was considerably reduced in amputees. The results highlight that trans-tibial amputees use quite different gait adaptations to cross obstacles compared with controls (at least when leading with their prosthetic limb), indicating they are governed by different constraints; seemingly related to how they land on/load their prosthesis after crossing the obstacle.